Glaucoma neurodegeneration ameliorated by mitochondrial support

Vitamin B3 modulates mitochondrial vulnerability and prevents glaucomaGlaucoma is fundamentally a neurodegenerative disease, that becomes apparent with progressive loss of function of retinal ganglion cells (RGC). Elevated intraocular pressure (IOP) and increasing age are the major risk factors. A fascinating study, recently published in Science and reviewed in NEJM (New England Journal of Medicine), demonstrates that, like other neurodegenerative diseases, it may be ameliorated by support for aging neuronal mitochondrial function that renders the RGCs more tolerant of elevated IOP and other stressors.

Glaucoma susceptibility increases with age-related neurodegeneration

The authors state:

“Glaucoma is one of the most common neurodegenerative diseases worldwide, affecting over 70 million people. High intraocular pressure (IOP) and increasing age are important risk factors for glaucoma. However, specific mechanisms rendering retinal ganglion cells more vulnerable to damage with age are unknown. Here, we address how increasing age and high IOP interact to drive neurodegeneration using DBA/2J (D2) mice, a widely used model of chronic, age-related, inherited glaucoma.”

They determined age and IOP-dependent molecular changes within RGCs that precede the glaucomatous neurodegeneration in 9 month old (mo) D2 mice (termed early glaucoma – high IOP and molecular changes but lacking neurodegeneration; 4 month old D2 mice (precedes high IOP) and age, sex and strain matched D2-Gpnmb+ controls that do not develop high IOP or ocular disease. This yielded a high correlation of transcriptome changes with increasing glaucomatous disease:

“As disease progressed, there was an increase in transcript abundance that was most pronounced for mitochondrial reads. Emerging evidence suggests that imbalances in the relative proportions of mitochondrial proteins encoded by nuclear and mitochondrial genomes negatively impact mitochondrial function. In D2 Groups 2 to 4, differential expression of genes encoding mitochondrial proteins, and significant enrichment of differentially expressed (DE) genes in the mitochondrial dysfunction and oxidative phosphorylation pathways further point to mitochondrial abnormalities…Extending previous studies, our data demonstrate that mitochondrial perturbations are among the very first changes occurring within RGCs during glaucoma”

Retinal metabolites

The authors demonstrated that degradation of mitochondrial health reflecting reflected in deficiencies of retinal metabolites is a key factor in the progression to vision loss.

“Guided by the above data, we assessed metabolites in retinas with increasing age and disease. We detected early decreases in metabolites that are central to healthy mitochondrial metabolism and protection from oxidative stress (NAD+ and NADH [total NAD; NAD(t)], GSH and GSSG [total glutathione; glutathione(t)]).”

Importantly, this mitochondrial metabolic degradation occurs without increasing IOP, but renders the the RGCs more vulnerable to the stress of IOP when it occurs.

“These age-dependent decreases were not a response to IOP-insult(s) as they also occurred in control D2-Gpnmb+ retinas. These decreases are expected to sensitize retinal neurons to disease related stresses and mitochondrial dysfunction. Suggesting greater metabolic stress in RGCs than other retinal neurons, HIF-1α (a key metabolic regulator during perturbed redox states) is induced in the ganglion cell layer early in glaucoma.”

Progression to vision loss is multifactorial

Vision loss occurs as a result of causes that combine ocular stress, including increased IOP, acting on RGCs that have become sensitized to stress due to mitochondrial dysfunction.

“Our data suggest that RGCs go through a period of mitochondrial stress and metabolite depletion, potentially moving towards fatty acid metabolism. Fatty acid β-oxidation can increase generation of free radicals/reactive oxygen species (ROS). Both RNA-seq and γ-H2AX immunostaining support increased ROS and DNA damage within RGCs early in glaucoma. Providing a link between DNA damage, and increased metabolic stress, PARP activity (NAD consuming) is induced in RGCs with age.”

Supplementation protects against glaucoma

It stands to reason that supporting mitochondrial health may render the RGCs more resistant to damage that leads to vision loss; the author’s data show this to be correct.

“Our data support a model where age-dependent declines of NAD+ and glutathione in the retina render RGCs vulnerable to damage from elevated IOP. Thus, increasing NAD levels would be predicted to protect IOP-insulted eyes from glaucomatous changes, by decreasing the probability of metabolic/energetic failure and rendering the RGCs more resilient to IOP-induced stress. Oral supplementation of vitamin B3/nicotinamide (NAM; a precursor of NAD) has been successfully used to correct disturbances in NAD+metabolism in two mouse models of pre-eclampsia. Accordingly, we administered NAM to D2 mice, initially at the same dose (550 mg/kg/d, NAMLo). NAM administration in drinking water prevented the decline of NAD levels through to 12 mo (a standard end stage for assessing neurodegeneration in this glaucoma model).”

Vitamin B3/NAM supplementation protects against glaucoma development

Vitamin B3 protects against glaucoma development

It’s of major clinical significance that vitamin B3 protected without altering IOP.

Supporting our neuronal vulnerability hypothesis, NAMLo did not alter IOP, but protected from glaucoma. NAM was protective both prophylactically (starting at 6 mo, prior to IOP elevation in most eyes in our colony) and interventionally (starting at 9 mo, when the majority of eyes have had continuing IOP elevation). NAM significantly reduced the incidence of optic nerve degeneration, prevented RGC soma loss and retinal nerve fiber layer thinning, and protected visual function as assessed by PERG. NAM prevented RGC axonal loss, and these axons continued to support anterograde axonal. NAM administration was sufficient to inhibit the formation of dysfunctional mitochondria with abnormal cristae and also limited synapse loss that occurs in this model. Lipid droplet formation was also prevented in aged D2 retinas. NAM also decreased PARP activation, limited levels of DNA damage, and transcriptional induction of HIF-1α reflecting less perturbed cellular metabolism. NAM prevented even the earliest molecular signs of glaucoma in most treated eyes as assessed by RNA-seq and prevented the majority of age-related gene expression changes within RGCs. This highlights the unexpected potency of NAM in decreasing metabolic disruption and prevention of glaucoma.”

Even more was better; even demonstrating some reduction in IOP.

“Attempting to further decrease the probability of glaucoma, we administered a higher dose of NAM (2000mg/kg/d; NAMHi). NAMHi was extremely protective with 93% of treated eyes having no optic nerve damage. The degree of protection afforded by administering this single molecule is unprecedented and unanticipated. Although NAMLo demonstrates a clear neuroprotective effect (no effect on IOP), NAMHi lessens the degree of IOP elevation. This indicates that NAM can protect against age-related pathogenic processes in additional cell types to RGCs. Therefore vitamin B3/NAM, a single molecule that protects against both IOP elevation and neural vulnerability, has great potential for glaucoma treatment…”

Enzyme activity using vitamin B3 to produce NAD diminishes with stress and age

Alzheimer’s disease, not surprisingly, is also associated with degraded enzyme activity.

NMNAT2 is emerging as an important NAD producing enzyme in axons, protecting from axon degeneration (). Ongoing stress negatively impacts Nmnat2 expression in RGCs. This decline of NMNAT2 may induce vulnerability to axon degeneration in glaucomaNMNAT2 expression is decreased in brains with Alzheimer’s disease and is highly variable in aged postmortem human brains. Such variation in expression may contribute to individual differences in vulnerability to various neurodegenerations.”

Perspective

Nicking Glaucoma with Nicotinamide?Commentators writing in the New England Journal of Medicine further place the stunning value of these findings in context.

“Glaucomatous optic neuropathy is the most common form of neurodegeneration involving the central nervous system and the leading cause of irreversible vision loss worldwide. Although age is an important risk factor, early onset is not uncommon and may result in severe vision loss in younger persons, even when the rate of disease progression is slow.

The critical neurons that are damaged in glaucoma are the retinal ganglion cells, which reside in the inner retina and serve as neuronal intermediaries between the photosensitive outer retina and the brain. They transmit visual information to the visual cortex through synapses in the lateral geniculate nucleus. The site of injury in the glaucomatous human optic nerve is thought to be the lamina cribrosa, where the unmyelinated axons of the retinal ganglion cells exit the eye through collagenous pores in the sclera and are susceptible to perturbations in their microenvironment and microarchitecture. The progressive loss of neuronal elements leads to irreversible structural damage and functional loss.

For more than 150 years, the only proven treatment for glaucoma has been the reduction of intraocular pressure with either drugs or surgical approaches. As with the study of other multifactorial neurodegenerative conditions, the ultimate goal in glaucoma research is the identification of treatment interventions that directly target neuronal health and enhance neuronal survival. Unfortunately, several drugs designed to protect against glaucomatous neurodegeneration have failed in clinical trials.

The investigators proposed that the differences in gene expression and total NAD levels affect the function of the retinal ganglion cells partly by limiting the energy produced by — and thus available within — neurons. Although decreased NAD levels alone did not result in cell death, Williams et al. hypothesized that reduced levels do destabilize metabolism during periods of stress and that the age-dependent decline in NAD levels, when combined with stress from elevated intraocular pressure, has a negative effect on mitochondrial function. This compromise in function leads to increases in the metabolism of fatty acids and the generation of free radicals, and thus an impaired response to metabolic stress, which in turn leads to loss of retinal ganglion cells.

To test the “NAD-deficit” hypothesis, Williams et al. supplemented the mouse diet with nicotinamide (the amide of vitamin B3 and a precursor to NAD+) to enhance cellular energy production. At the lowest dose studied (equivalent to about 2.5 g per day for a person weighing 60 kg), the authors found that nicotinamide prevented the structural and functional loss of retinal ganglion cells despite the continued elevation of intraocular pressure. The dose-dependent protective effect was evident at different points in disease progression, and the authors did not observe adverse effects.”

Clinical Note

This wonderful study illustrates a vital clinical point: supporting mitochondrial function can protect from neuronal damage that occurs with stress and age, and rehabilitate to a very meaningful degrees damages neuronal function. And is resulted from supporting with only one cofactor, vitamin B3/NAM. Therefore, consider how much more effective we can be by targeting other mitochondrial cofactors found objectively to be suboptimal by organic acid testing, along with adding glutathione with shown to be deficient. Again, referring to one cofactor among the numerous ones that ensure mitochondrial integrity…

“Given these protections against severe acute insults, NAM could have broad implications for treating glaucoma and potentially other age-related neurodegenerative diseases.”

The authors conclude:

“In conclusion, we show that dietary supplementation with a single molecule (vitamin B3/nicotinamide), or Nmnat1 gene therapy, significantly reduces vulnerability to glaucoma by supporting mitochondrial health and metabolism. Combined with established medications that lower IOP, NAM treatment (and/or Nmnat1gene therapy) may be profoundly protective. By providing a new molecular and metabolic link between increased neuronal vulnerability with age and neurodegeneration these findings are of critical importance for glaucoma and possibly other age-related diseases.”

Readers may also be interested in Inflammation, mitochondrial dysfunction and neurodegeneration in major depression.

Mercury exposure at low levels induces autoimmunity

Environmental Health PerspectivesToxicity from high levels of mercury and other xenobiotics is less widespread a problem than autoimmunity induced by lower levels generally considered to be safe. The largest public health burden is not toxicity but loss of immune tolerance. A study recently published in the journal Environmental Health Perspectives illustrates this in the case of mercury exposure among females of reproductive age. The authors state:

“Autoimmunity, which can include autoantibody formation, represents a breakdown of tolerance against self-antigens. Self-reactive lymphocytes may occur in healthy individuals, and in the absence of related pathology, autoimmunity represents pre- or sub-clinical immune dysregulation. Thus, the term autoimmunity should be distinguished from autoimmune disease, as it does not denote clinical or symptomatic disease…autoantibodies may precede autoimmune diagnoses by several years, and nearly all autoimmune diseases are characterized by circulating autoantibodies. Antinuclear antibodies (ANAs) are highly sensitive for a variety of autoimmune conditions, including systemic lupus erythematosus (SLE), scleroderma, and Sjögren’s syndrome.”

Investigating the effect of low levels of mercury

Mercury is ubiquitous and a top priority pollutant with seafood consumption and dental amalgam as common sources of exposure with abundant data on concentrations exceeding what is considered safe by regulatory agencies.

“However, immune effects associated with low levels of exposure to each type of mercury in the general population are not well characterized…Utilizing NHANES data, we explored the associations between three types of biomarkers of mercury exposure and the presence, strength, and patterns of antinuclear antibodies in a representative sample of reproductive-age females from the US population.’

They used hair mercury for predominantly organic (methyl) mercury; total blood mercury, a combination of organic and inorganic mercury; and urinary mercury, mainly the inorganic/elemental form from the US National Health and Nutrition Examination Survey (NHANES) for 1932 adult females  ages 16-49 years correlating these with the level of antinuclear antibodies. Their data show a manifest correlation with subclinical autoimmunity:

“16% of females were ANA-positive; 96% of ANA-positives had a nuclear staining pattern of speckled. Mercury geometric means (standard deviations) were: 0.22 (0.03) ppm hair, 0.92 (0.05) µg/L blood, and 0.62 (0.04) µg/L urinary. Hair and blood, but not urinary, mercury were associated with ANA positivity (sample sizes 452, 1352, and 804, respectively), adjusting for confounders: hair odds ratio (OR)=4.10; blood OR=2.32 comparing highest versus lowest quantiles. Magnitudes of association were strongest for high-titer (≥1:1280) ANA: hair OR=11.41; blood OR=5.93.”

This reveals an association of organic mercury exposure (at levels not considered toxic) and antinuclear antibodies.

Pertinent for a wide variety of autoimmune disorders

The authors comment on their findings:

“In this population-based study, we found that mercury exposure is associated with increased risk of high-titer ANA positivity among reproductive-age females in the general US population. Specifically, this association appears to be driven by organic (methyl) mercury, the predominant species in hair and total blood. Notably, a dose-response relationship was observed for low methylmercury exposure levels (<0.37 ppm hair mercury; <1 μg/L total blood mercury), in the range generally considered safe for women of childbearing potential by regulatory agencies (Mergler et al. 2007). The predominant nuclear staining pattern of speckled found in our population is a marker of autoimmunity with a wide variety of clinical associations, including SLE, mixed connective tissue disease, Sjögren’s syndrome, and idiopathic inflammatory myopathies. The methylmercury association was robust across models, whereas other suspected risk factors in the multivariable models, including age and smoking, were not found to be associated with ANA risk.”

Regarding the gender of their study subjects…

“Our study focused on females, ages 16-49 years. It is well recognized that females have a higher risk of autoimmune diseases, and that risk among females may also correlate with reproductive stage. Moreover, estrogenic hormones may promote autoimmunity (Somers and Richardson 2014). Mercury metabolism may also contrast between sexes, and differences in mercury excretion and distribution have been observed between sexes in mouse models, as well as immunotoxic effects at lower internal doses in females.”

The role of oxidative stress

Oxidative stress can promote autoimmunity which the authors comment on in the case of mercury:

Oxidative stress has been shown to contribute to the induction of autoimmune phenotypes in animal models, such as through epigenetic mechanisms converting normal “helper” T cells to autoreactive lymphocytes sufficient to cause lupus in the absence of added antigen. Mercury induces oxidative stress through sulphydryl reactivity and depletion of cellular antioxidants. In human T cells treated with methylmercury, reductions in intracellular glutathione (GSH) concentration, glutathione S-transferase activity and mitochondrial transmembrane potential have been observed, followed by generation of reactive oxygen species; intracellular GSH depletion has further been linked to susceptibility of T cells to undergo methylmercury-induced apoptosis.”

Low levels of mercury considered safe can induce autoimmunity

Practitioners should recall that binding of mercury and native proteins creates a hapten that can induce loss of immune tolerance to the self-antigen in the bound complex. This can result as undifferentiated autoimmunity with an array of diverse symptoms years before evolving into a well-defined autoimmune disease due to extensive tissue damage already having occurred. The authors conclude on a note of vast importance to clinical practice:

Methylmercury, at low levels generally considered safe, was associated with subclinical autoimmunity among reproductive-age females. Autoantibodies may predate clinical disease by years, thus methylmercury exposure may be relevant to future autoimmune disease risk.”

Coffee is a liver elixir

Journal of Clinical GastroenterologyCoffee has been documented in a multitude of studies to have metabolic, cardiovascular and brain benefits, and it is especially salubrious for the liver. A paper just published in the Journal of Clinical Gastroenterology handily summarizes several of the virtues that coffee has for liver function:

“Coffee is one of the most widely used beverages in the world. It includes a wide array of components that can have potential implications for health. Several epidemiological studies associate coffee consumption with a reduced incidence of various chronic diseases such as diabetes, cardiovascular diseases, and neurodegenerative diseases. Over the past 20 years, an increasing number of epidemiological and experimental studies have demonstrated the positive effects of coffee on chronic liver diseases.”

Coffee improves liver enzymes, steatosis, fibrosis and cirrhosis

Considering that coffee is beneficial for glucose metabolism and insulin regulation it makes sense that it would protect against fatty liver by more than just an antioxidant effect:

“Coffee consumption has been inversely associated with the activity of liver enzymes in subjects at risk, including heavy drinkers. Coffee favours an improvement in hepatic steatosis and fibrosis, and a reduction in cirrhosis and the risk of hepatocellular carcinoma…Experimental studies show that coffee consumption reduces fat accumulation and collagen deposition in the liver…”

Coffee increases glutathione production and promotes detoxification

Glutathione is of premiere importance as an anti-inflammatory antioxidant necessary for immune tolerance of environmental toxins, and coffee…

…promotes antioxidant capacity through an increase in glutathione as well as modulation of the gene and protein expression of several inflammatory mediators. Animal and in vitro studies indicate that cafestol and kahweol, 2 diterpens, can operate by modulating multiple enzymes involved in the detoxification process of carcinogens causing hepatocellular carcinoma. It is unclear whether the benefits are significant enough to “treat” patients with chronic liver disease. While we await clarification, moderate daily unsweetened coffee use is a reasonable adjuvant to therapy for these patients.”

One caution

Sadly, some people who do not tolerate gluten also cross-react to coffee, at least until they have regained immune tolerance through treatment. This can be determined by the appropriate laboratory test.

Nigella sativa, a true ‘wonder medicine’?

Nigella sativa flower and seedsNigella sativa, also known as black cumin, produces seeds with a mind-boggling wealth of medicinal virtues. For colleagues and others who may not be familiar with the abundance of scientific evidence for the use of Nigella sativa seed extract in clinical practice, this selection of citations serves as an introduction to its wide range of indications.

An illustrious history

Asian Pacific Journal of Tropical MedicineTraditional uses of Nigella sativa are surveyed in a paper published in the Asian Pacific Journal of Tropical Medicine:

Nigella sativa (N. sativa) (Family Ranunculaceae) is a widely used medicinal plant throughout the world. It is very popular in various traditional systems of medicine like Unani and Tibb, Ayurveda and Siddha. Seeds and oil have a long history of folklore usage in various systems of medicines and food. The seeds of N. sativa have been widely used in the treatment of different diseases and ailments. In Islamic literature, it is considered as one of the greatest forms of healing medicine. It has been recommended for using on regular basis in Tibb-e-Nabwi (Prophetic Medicine). It has been widely used as antihypertensive, liver tonics, diuretics, digestive, anti-diarrheal, appetite stimulant, analgesics, anti-bacterial and in skin disorders. Extensive studies on N. sativa have been carried out by various researchers and a wide spectrum of its pharmacological actions have been explored which may include antidiabetic, anticancer, immunomodulator, analgesic, antimicrobial, anti-inflammatory, spasmolytic, bronchodilator, hepato-protective, renal protective, gastro-protective, antioxidant properties, etc. Due to its miraculous power of healing, N. sativa has got the place among the top ranked evidence based herbal medicines. This is also revealed that most of the therapeutic properties of this plant are due to the presence of thymoquinone which is major bioactive component of the essential oil. The present review is an effort to provide a detailed survey of the literature on scientific researches of pharmacognostical characteristics, chemical composition and pharmacological activities of the seeds of this plant.”

Critical Reviews in Food Science and NutritionA paper published in the journal Critical Reviews in Food Science and Nutrition also suggests Nigella sativa’s wide scope of use:

“…It possesses a nutritional dense profile as its fixed oil (lipid fraction), is rich in unsaturated fatty acids while essential oil contains thymoquinone and carvacrol as antioxidants. N. sativa seeds also contain proteins, alkaloids (nigellicines and nigelledine), and saponins (α-hederin) in substantial amounts. Recent pharmacological investigations suggested its potential role, especially for the amelioration of oxidative stress through free radical scavenging activity, the induction of apoptosis to cure various cancer lines, the reduction of blood glucose, and the prevention of complications from diabetes. It regulates hematological and serological aspects and can be effective in dyslipidemia and respiratory disorders. Moreover, its immunopotentiating and immunomodulating role brings balance in the immune system. Evidence is available supporting the utilization of Nigella sativa and its bioactive components in a daily diet for health improvement. This review is intended to focus on the composition of Nigella sativa and to elaborate its possible therapeutic roles as a functional food to prevent an array of maladies.”

Anti-inflammatory activity

Molecular Biology ReportsChronic inflammation is a hallmark of most chronic degenerative diseases. A study published in Molecular Biology Reports demonstrates that Nigella sativa reduces inflammation triggered by LPS (lipopolysaccharide), of particular relevance for autoimmunity.

“Inflammation has an important role in many diseases such as cystic fibrosis, allergies and cancer. The free radicals produced during inflammation, can induce gene mutations and posttranslational modifications of cancer related proteins. Nigella sativa L. (N. sativa) is herbaceous plant and commonly used as a natural food. It has many pharmacological effects including antibacterial, antifungal, antitumor, analgesic, antipyretic activity. The aim of this study was to investigate the anti-inflammatuar and anti-oxidant activity of N. sativa in acute inflammation. Thus we used the experimental lipopolysaccharides (LPS)-induced model. Intraperitoneal LPS 1 mg/kg was administered to groups. N. sativa (500 mg/kg) and essential oil (5 ml/kg) were given orally to treatment groups, after 24-h of intraperitoneal LPS-injection. To determine the lung inflammation, 18F-fluoro-deoxy-d-glucose (0.8 ml/kg) was administrated under the anesthesia before the 1 h of PET-scanning. After the FDG-PET, samples were collected. Lung and liver18F-FDG-uptake was calculated. Serum AST, ALT, LDH and hcCRP levels were determined and liver, lung and erythrocyte SOD, MDA and CAT levels were measured. Liver and lung NO and DNA fragmentation levels were determined. MDA levels were decreased in treated inflammation groups whereas increased in untreated inflammation group. SOD and CAT activities in untreated inflammation group were significantly lower. According to the control group, increased AST and ALT levels were found in untreated inflammation group. 18F-FDG uptake of inflammation groups were increased when compare the control group… We conclude that, in LPS-induced inflammation, N. sativa have therapeutic and anti-oxidant effects.”

Immunomodulatory effects of Nigella sativa

Chinese Journal of Integrative MedicineA fascinating study in the Chinese Journal of Integrative Medicine offers evidence that Nigella sativa, beyond having simply an anti-inflammatory effect, is an immunomodulator that may help to restore healthier immune regulation:

“Cells isolated from human PBMCs which were treated with methanolic extract of NS for 48 h into two separate environments (PHA and non-PHA stimulated). Flow cytometry (for T helper/inducer cells and natural killer cells) and real time-polymerase chain reaction (PCR) assays for a few selected proinflammatory gene expressions were performed. Extracts from NS had an immunostimulating effect on non-PHA-stimulated proliferation of human PBMCs. In contrast, immunosuppressive activity was observed on PHA-stimulated proliferation of human PBMCs.”

Antimicrobial activity

BioMed Research InternationalNigella sativa has also shown good effect in the treatment of infections. A study recently published in Biomed Research International validates its antibacterial and antifungal properties:

“…major components in black cumin essential oils which were thymoquinone (37.6%) followed by p-cymene (31.2%), α-thujene (5.6%), thymohydroquinone (3.4%), and longifolene (2.0%), whereas the oleoresins extracted in different solvents contain linoleic acid as a major component….The essential oil showed up to 90% zone inhibition against Fusarium moniliforme in inverted petri plate method. Using agar well diffusion method for evaluating antibacterial activity, the essential oil was found to be highly effective against Gram-positive bacteria.”

The authors summarize their findings by concluding:

“The results obtained in antimicrobial investigations of black cumin oil and oleoresins were in good agreement with the previous reported work…Seeds of black cumin seem to possess magical properties and have been worked out extensively. This study revealed that black cumin essential oil and its oleoresins constitute a good alternative source of essential fatty acids compared with common vegetable oil. The present results showed that essential oil and oleoresins of black cumin exhibited higher antioxidant activity than synthetic antioxidants. These findings could be used to prepare multipurpose products for pharmaceutical applications and its usage as dietary source of antioxidant should be considered largely for alleviating and ameliorating diseases.”

World Journal of GastroenterologyPotent antiviral effects of Nigella sativa are in evidence in a study published in the World Journal of Gastroenterology on hepatitis C:

“Thirty patients with hepatitis C virus (HCV) infection, who were not eligible for IFN/ribavirin therapy, were included in the present study…Various parameters, including clinical parameters, complete blood count, liver function, renal function, plasma glucose, total antioxidant capacity (TAC), and polymerase chain reaction, were all assessed at baseline and at the end of the study. Clinical assessment included: hepato and/or splenomegaly, jaundice, palmar erythema, flapping tremors, spider naevi, lower-limb edema, and ascites. N. sativa was administered for three successive months at a dose of (450 mg three times daily). Clinical response and incidence of adverse drug reactions were assessed initially, periodically, and at the end of the study.”

The improvements noted were outstanding:

“N. sativa administration significantly improved HCV viral load. After N. sativa administration, the following laboratory parameters improved: total protein, albumin, red blood cell count, and platelet count. Fasting blood glucose and postprandial blood glucose were significantly decreased in both diabetic and non-diabetic HCV patients. Patients with lower-limb edema decreased significantly from baseline compared with after treatment. Adverse drug reactions were unremarkable except for a few cases of epigastric pain and hypoglycemia that did not affect patient compliance.”

Clinicians involved in case management of HCV should note their conclusion:

N. sativa administration in patients with HCV was tolerable, safe, decreased viral load, and improved oxidative stress, clinical condition and glycemic control in diabetic patients.”

 Amelioration of metabolic disorders

Plant Foods for Human NutritionNigella sativa possesses remarkable properties that improve metabolic disorders ranging including insulin resistance and diabetes, obesity, and liver fibrosis. From a paper in Plant Foods for Human Nutrition:

“Obesity is closely associated with increased incidence of cardiovascular diseases, cancer, insulin resistance, and immune dysfunction, and thus obesity-mitigation strategies should take into account these secondary pathologies in addition to promoting weight loss. Recent studies indicate that black cumin (Nigella sativa) has cardio-protective, anti-cancer, anti-diabetic, antioxidant, and immune-modulatory properties.”

 Diabetes

Evidence-Based Complementary and Alternative MedicineEvidence for its benefit in diabetes is offered in a study published in Evidence-Based Complementary and Alternative Medicine:

“The main objective of this instant study was to explore the antidiabetic potential of Nigella sativa fixed oil (NSFO) and essential oil (NSEO). Three experimental groups of rats received diets during the entire study duration, that is, D1 (control), D2 (NSFO: 4.0%), and D3 (NSEO: 0.30%). Experimental diets (NSFO & NSEO) modulated the lipid profile, while decreasing the antioxidant damage. However, production of free radicals, that is, MDA, and conjugated dienes increased by 59.00 and 33.63%, respectively, in control. On the contrary, NSFO and NSEO reduced the MDA levels by 11.54 and 26.86% and the conjugated dienes levels by 32.53 and 38.39%, respectively. N. sativa oils improved the health and showed some promising anti-diabetic results.”

BMC Complementary & Alternative MedicineAnother study on Nigella sativa and diabetes was recently published in BMC Complementary and Alternative Medicine.

Nigella sativa fixed (NSFO) and essential (NSEO) oils have been used to treat diabetes mellitus and its complications. Present study was undertaken to explore and validate these folkloric uses…Sprague dawley rats having streptozotocin (STZ) induced diabetes mellitus were used to assess the role of NSFO and NSEO in the management of diabetes complications.”

Of note is its ability to increase levels of glutathione:

“The results indicated that STZ decreased the glutathione contents (25.72%), while NSFO and NSEO increased the trait significantly. Experimental diets increased the tocopherol contents and enhanced the expression of hepatic enzymes. Correlation matrix further indicated that antioxidant potential is positively associated responsible for the modulation of hepatic enzymes and the decrease of the nitric oxide production thus controlling the diabetes complications.”

Nigella sativa lowers cholesterol

Advanced Pharmaceutical BulletinCholesterol along with blood glucose was lowered in a study on Nigella sative for metabolic syndrome in menopausal women published in the Advanced Pharmaceutical Bulletin:

“Thirty subjects who were menopausal women within the age limit of 45-60 were participated in this study and randomly allotted into two experimental groups. The treatment group was orally administered with N. sativa seeds powder in the form of capsules at a dose of 1g per day after breakfast for period of two months and compared to control group given placebo…significant improvement was observed in total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and blood glucose…These results suggested that treatment with N. sativa exert a protective effect by improving lipid profile and blood glucose which are in higher risk to be elevated during menopausal period.”

Journal of Translational MedicineImprovements in hypercholesterolemia in menopause were also documented in a study recently published in the Journal of Translational Medicine:

“In this study, Nigella sativa was evaluated for its hypolipidemic effects among menopausal women. In a randomised trial, hyperlipidemic menopausal women were assigned to treatment (n = 19) or placebo groups (n = 18), and given N. sativa or placebo for two months after their informed consents were sought. At baseline, blood samples were taken and at one month intervals thereafter until one month after the end of the study…The results showed that N. sativa significantly improved lipid profiles of menopausal women (decreased total cholesterol, low density lipoprotein cholesterol and triglyceride, and increased high density lipoprotein cholesterol) more than the placebo treatment over 2 months of intervention.”

These benefits persisted for a month after treatment with Nigella sativa was discontinued:

One month after cessation of treatment, the lipid profiles in the N. sativa-treated group tended to change towards the pretreatment levels.”

The authors conclude:

“N. sativa is thought to have multiple mechanisms of action and is cost-effective. Therefore, it could be used by menopausal women to remedy hypercholesterolemia, with likely more benefits than with single pharmacological agents that may cause side effects. The use of N. sativa as an alternative therapy for hypercholesterolemia could have profound impact on the management of CVD among menopausal women especially in countries where it is readily available.”

International Journal of Preventive MedicineAnd a study in the International Journal of Preventive Medicine documented improvements in lipid metabolism and oxygen utilization:

“In this randomized, double-blind, controlled trial…20 sedentary overweight females were divided into two groups and assigned to N. sativa supplementation (N. sativa capsules) or a placebo for the 8 weeks, both groups participated in an aerobic training program (3 times/week)…. Blood lipids and VO2 max were determined at baseline and at the end of 8 weeks…N. sativa supplementation lowered total cholesterol (TC), triglyceride, low-density lipoprotein (LDL) and body mass index and increased high density lipoprotein (HDL) and VO2 max.”

It’s worth noting that the diet of the study subjects remained the same:

Since we asked all subjects not to change their usual daily diet, it seems that this changes may be due to the result of consuming black seeds and regular aerobic training.”

Interestingly in regard to lowering cholesterol:

“The hypotriglyceridemic effect of N. sativa is possibly due to its choleretic activity. The choleretic function of N. sativa is either by reducing the synthesis of cholesterol by hepatocytes or by decreasing its fractional reabsorption from the small intestine.”

Nigella sativa’s thymoquinone ameliorates liver fibrosis

International ImmunopharmacologyWith the proliferation of NAFLD and NASH medicines that sustainably alleviate hepatic fibrosis are in urgent need. A study published in International Immunopharmacology offers evidence that thymoquinone, a principal compound in Nigella sativa, has potent hepatic anti-fibrotic effects:

Thymoquinone (TQ) is the major active compound derived from the medicinal Nigella sativa. In the present study, we investigated the anti-fibrotic mechanism of TQ in lipopolysaccharide (LPS)-activated rat hepatic stellate cells line, T-HSC/Cl-6. T-HSC/Cl-6 cells were treated with TQ (3.125, 6.25 and 12.5 μM) prior to LPS (1 μg/ml). Our data demonstrated that TQ effectively decreased activated T-HSC/Cl-6 cell viability. TQ significantly attenuated the expression of CD14 and Toll-like receptor 4 (TLR4). TQ also significantly inhibited phosphatidylinositol 3-kinase (PI3K) and serine/threonine kinase-protein kinase B (Akt) phosphorylation. The expression of α-SMA and collagen-I were significantly decreased by TQ. Furthermore, TQ decreased X linked inhibitor of apoptosis (XIAP) and cellular FLIP (c-FLIPL) expression, which are related with the regulation of apoptosis. Furthermore, TQ significantly increased the survival against LPS challenge in d-galactosamine (d-GlaN)-sensitized mice, and decreased the levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), which were in line with in vitro results. Our data demonstrated that TQ attenuates liver fibrosis partially via blocking TLR4 expression and PI3K phosphorylation on the activated HSCs. Therefore, TQ may be a potential candidate for the therapy of hepatic fibrosis.

A follow-up study published recently in the same journal added more evidence to Nigella sativa’s benefits for hepatic fibrosis:Hepatic fibrosis attenuated by thymoquinone

“The current study was conducted to investigate the anti-fibrotic effect and its possible underlying mechanisms of thymoquinone (TQ) against hepatic fibrosis in vivo. TQ is the major active compound derived from the medicinal Nigella sativa. Liver fibrosis was induced in male Kunming mice by intraperitoneal injections of thioacetamide (TAA, 200 mg/kg). Mice were treated concurrently with TAA alone or TAA plus TQ (20 mg/kg or 40 mg/kg) given daily by oral gavage. Our data demonstrated that TQ treatment obviously reversed liver tissue damage compared with TAA alone group, characterized by less inflammatory infiltration and accumulation of extracellular matrix (ECM) proteins. TQ significantly attenuated TAA-induced liver fibrosis, accompanied by reduced protein and mRNA expression of α-smooth muscle actin (α-SMA), collagen-І and tissue inhibitor of metalloproteinase-1 (TIMP-1). TQ downregulated the expression of toll-like receptor 4 (TLR4) and remarkably decreased proinflammatory cytokine levels as well. TQ also significantly inhibited phosphatidylinositol 3-kinase (PI3K) phosphorylation. Furthermore, TQ enhanced the phosphorylation adenosine monophosphate-activated protein kinase (AMPK) and liver kinase B (LKB)-1. In conclusion, TQ may reduce ECM accumulation, and it may be at least regulated by phosphorylation of AMPK signaling pathways, suggesting that TQ may be a potential candidate for the therapy of hepatic fibrosis.

 Protection against diabetic kidney damage

Ultrastructural PathologyThymoquinone in Nigella sativa also reduced experimentally induced kidney damage in models of diabetes as reported in a study published in Ultrastructural Pathology:

“Diabetic rats exhibited morphological changes in both renal glomeruli and tubules with immunohistochemical expression of the mesenchymal markers Fsp1, desmin, and MMP-17 and disappearance of the epithelial marker ZO-1 largely in the glomeruli of diabetic kidneys. Treatment with TQ significantly attenuated renal morphological and immunohistochemical changes in STZ-induced diabetic ratsThymoquinone has protective effects on experimental diabetic nephropathy. Both mesenchymal and epithelial markers serve as excellent predictors of early kidney damage and indicators of TQ responsiveness in STZ-induced diabetic nephropathy.”

Hypertension and Oxidative Stress

Regarding the anti-hypertensive effects of Nigella sativa, from a paperEvidence-Based Complementary and Alternative Medicine in Evidence-Based Complementary & Alternative Medicine:

Excessive production of reactive oxygen species reduces nitric oxide bioavailability leading to an endothelial dysfunction and a subsequent increase in total peripheral resistance…Nigella sativa (NS) and its active constituents have been documented to exhibit antioxidant, hypotensive, calcium channel blockade and diuretic properties which may contribute to reduce blood pressure. This suggests a potential role of NS in the management of hypertension…”

Protection Against Heart Damage

Pakistan Journal of Pharmaceutical SciencesNot surprisingly, thymoquinone in Nigella sativa appears to exert protective effects against heart damage associated with coronary insufficiency and stress as documented by a study in the Pakistan Journal of Pharmaceutical Sciences. Here again the beneficial effects include support for glutathione:

“Myocardial injury constitutes a major cause of morbidity and mortality in humans. Present study aimed to investigate protective role of thymoquinone, which is an active principle of Nigella sativa (N. sativa) seed (Commonly called as black seed), in isoproterenol induced myocardial injury, a classical example of excess catecholamines related coronary insufficiency and stress cardiomyopathy. Thymoquinone, in olive oil, was administered orally (12.5, 25 and 50mg/kg) to three groups of Wistar albino rats for 7 days, while two control groups were given plain olive oil. Thereafter, thymoquinone receiving groups and one control group were injected, subcutaneously, with isoproterenol (125mg/kg) for 2 days. Myocardial injury was assessed by biochemical markers (plasma LDH, TBARS, GR & SOD and myocardial GSH/GSSG ratio) and cardiac histopathology. Plasma LDH, TBARS and GR increased in control groups receiving isoproterenol, while there was a dose related decrease in these markers in thymoquinone treated groups, down to levels in controls given olive oil only. Decrease in plasma SOD and myocardial GSH/GSSG ratio and histological changes produced with isoproternol were also reversed in thymoquinone treated rats. Results of our study revealed that thymoquinone protects the heart from injury induced by isoproterenol.”

Anti-cancer effects of Nigella sativa

Drug Discovery TodayThere is a wealth of evidence supporting the use Nigella sativa and its active compound thymoquinone as an adjunctive treatment in numerous malignancies as noted in a paper published earlier this year in Drug Discovery Today:

“Thymoquinone (TQ), the main active constituent of black seed essential oil, exhibits promising effects against inflammatory diseases and cancer. TQ, modulates signaling pathways that are key to cancer progression, and enhances the anticancer potential of clinical drugs while reducing their toxic side effects. Considering that TQ was isolated 50 years ago, this review focuses on TQ’s chemical and pharmacological properties and the latest advances in TQ analog design and nanoformulation. We discuss our current state of knowledge of TQ’s adjuvant potential and in vivo antitumor activity and highlight its ability to modulate the hallmarks of cancer.

  • This year marks 50 years since thymoquinone was isolated from black seed.
  • Thymoquinone has had a long history of battling cancer in vitro and in vivo.
  • Thymoquinone modulates nine of the ten hallmarks of cancer.”

American Journal of Chinese MedicineA paper in the American Journal of Chinese Medicine reviews Nigella sativa’s anticancer activities:

“…quite a few pharmacological effects of N. sativa seed, its oil, various extracts and active components have been identified to include immune stimulation, anti-inflammation, hypoglycemic, antihypertensive, antiasthmatic, antimicrobial, antiparasitic, antioxidant and anticancer effects…A literature search has revealed that a lot more studies have been recently carried out related to the anticancer activities of N. sativa and some of its active compounds, such as thymoquinone and alpha-hederin. Acute and chronic toxicity studies have recently confirmed the safety of N. sativa oil and its most abundant active component, thymoquinone, particularly when given orally. The present work is aimed at summarizing the extremely valuable work done by various investigators on the effects of N. sativa seed, its extracts and active principles against cancer. Those related to the underlying mechanism of action, derivatives of thymoquinone, nano thymoquinone and combinations of thymoquinone with the currently used cytotoxic drugs are of particular interest.”

Thymoquinone mechanisms of actionA paper in the African Journal of Traditional, Complementary and Alternative Medicines describes its activity against a number of malignancies and the molecular mechanisms involved:

“Nigella sativa has been used as traditional medicine for centuries. The crude oil and thymoquinone (TQ) extracted from its seeds and oil are effective against many diseases like cancer, cardiovascular complications, diabetes, asthma, kidney disease etc. It is effective against cancer in blood system, lung, kidney, liver, prostate, breast, cervix, skin with much safety. The molecular mechanisms behind its anticancer role is still not clearly understood, however, some studies showed that TQ has antioxidant role and improves body’s defense system, induces apoptosis and controls Akt pathway. Although the anti-cancer activity of N. sativa components was recognized thousands of years ago but proper scientific research with this important traditional medicine is a history of last 2∼3 decades…In this article, we have summarized the actions of TQ and crude oil of N. sativa against different cancers with their molecular mechanisms.”

Pharmacognosy ReviewsA review article in Pharmacognosy Review notes the anti-cancer potential implied by numerous investigations:

“Thymoquinone (TQ) is the bioactive phytochemical constituent of the seeds oil of Nigella sativa. In vitro and in vivo research has thoroughly investigated the anticancer effects of TQ against several cancer cell lines and animal models. As a result, a considerable amount of information has been generated from research thus providing a better understanding of the anti-proliferating activity of this compound. Therefore, it is appropriate that TQ should move from testing on the bench to clinical experiments. The purpose of this review is to highlight the potential of TQ as an anticancer agent and the chances of this compound in the clinical treatment of cancer, with special attention on breast cancer treatment.”

Evidence-Based Complementary and Alternative MedicineA paper in Evidence-Based Complementary and Alternative Medicine outlines mechanisms by which thymoquinone in Nigella sativa can act to prevent cancer:

Earlier studies have shown that N. sativa and its constituent thymoquinone (TQ) have important roles in the prevention and treatment of cancer by modulating cell signaling pathways. In this review, we summarize the role of N. sativa and its constituents TQ in the prevention of cancer through the activation or inactivation of molecular cell signaling pathways.”

Upregulation of tumor suppressor gene and inhibition of VEGF, Akt/PI3K pathways:

Upregulation of tumor suppresor geneThymoquinone role in prevention of cancer via modulation of phase I and phase II enzymes:

Thymoquinone's role in cancer prevention

Osteosarcoma, angiogenesis and NF-κB

Oncology ReportsEvidence for thymoquinone’s benefit in osteosarcoma through inhibition of tumor angiogenesis and tumor growth by suppressing NF-κB is offered by a study published in Oncology Reports:

“Recent studies reported that thymoquinone exhibited inhibitory effects on the cell proliferation of several cancer cell lines. This study was performed to investigate the antitumor and anti-angiogenic effects of thymoquinone on osteosarcoma in vitro and in vivo. Our results showed that thymoquinone induced a higher percentage of growth inhibition and apoptosis in the human osteosarcoma cell line SaOS-2 compared to that of control, and thymoquinone significantly blocked human umbilical vein endothelial cell (HUVEC) tube formation in a dose-dependent manner. To investigate the possible mechanisms involved in these events, we performed electrophoretic mobility shift assay (EMSA) and western blot analysis, and found that thymoquinone significantly downregulated NF-κB DNA-binding activity, XIAP, survivin and VEGF in SaOS-2 cells. Moreover, the expression of cleaved caspase-3 and Smac were upregulated in SaOS-2 cells after treatment with thymoquinone. In addition to these in vitro results, we also found that thymoquinone inhibits tumor angiogenesis and tumor growth through suppressing NF-κB and its regulated molecules. Collectively, our results demonstrate that thymoquinone effectively inhibits tumor growth and angiogenesis both in vitro and in vivo. Moreover, inhibition of NF-κB and downstream effector molecules is a possible underlying mechanism of the antitumor and anti-angiogenic activity of thymoquinone in osteosarcoma.”

Cytotoxic prooxidant effects of thymoquinone in copper rich malignant tissues

Cell Death & DiseaseUsing prostate cancer cells, a fascinating study published in Cell Death & Disease demonstrates that thymoquinone has a beneficial prooxidant cytoxic effect in copper-rich malignant tissue:

“Thymoquinone (TQ) is the major bioactive constituent of volatile oil of Nigella sativa and has been shown to exert various pharmacological properties, such as anti-inflammatory, cardiovascular, analgesic, anti-neoplastic, anticancer and chemopreventive…TQ is a known antioxidant at lower concentrations and most of the studies elucidating the mechanism have centered on the antioxidant property. However, recent publications have shown that TQ may act as a prooxidant at higher Nigella sativa flower 2concentrations. It is well known that plant-derived antioxidants can switch to prooxidants even at low concentrations in the presence of transition metal ions such as copper. It is well established that tissue, cellular and serum copper levels are considerably elevated in various malignancies. Copper is an important metal ion present in the chromatin and is closely associated with DNA bases, particularly guanine. Using human peripheral lymphocytes and comet assay, we first show that TQ is able to cause oxidative cellular DNA breakage. Such a DNA breakage can be inhibited by copper-chelating agents, neocuproine and bathocuproine, and scavengers of reactive oxygen species. Further, it is seen that TQ targets cellular copper in prostate cancer cell lines leading to a prooxidant cell death.”

Interestingly…

“We believe that such a prooxidant cytotoxic mechanism better explains the anticancer activity of plant-derived antioxidants.”

Inhibition of cell proliferation in liver cancer

Toxicology LettersMarked inhibition of tumor multiplicity in hepatocellular carcinoma was shown in a study published in Toxicology Letters:

“…agents that inhibit cell proliferation and restrain hepatic tumorigenesis through cell cycle regulation have a beneficial effect in the treatment of hepatocellular carcinogenesis. The present study was aimed to investigate the efficacy of thymoquinone (TQ), an active compound derived from the medicinal plant Nigella sativa, on N-nitrosodiethylamine (NDEA) [0.01% in drinking water for 16 weeks]-induced hepatocarcinogenesis in experimental rats. After experimental period, the hepatic nodules, liver injury markers and tumor markers levels were substantially increased in NDEA induced liver tumors in rats. However, TQ (20 mg/kg body weight) treatment greatly reduced liver injury markers and decreased tumor markers and prevented hepatic nodule formation and reduced tumor multiplicity in NDEA induced hepatic cancer bearing rats and this was evident from argyrophilic nucleolar organizer region (AgNORs) staining. Moreover…TQ significantly reduced the detrimental alterations by abrogating cell proliferation, which strongly induced G1/S arrest in cell cycle transition. In conclusion, our results suggest that TQ has a potent anti proliferative activity by regulating the G1/S phase cell cycle transition and exhibits a beneficial role in the treatment of HCC.”

Thymoquinone induces glioblastoma cell death

PLOS ONEA fascinating study in PLoS One demonstrates that thymoquinone is a rare agent that can inhibit autophagy (the cellular ‘housecleaning’ process by which degraded cellular components are removed) to promote malignant cell death in the brain cancer gliosblastoma:

“Glioblastoma is the most aggressive and common type of malignant brain tumor in humans, with a median survival of 15 months. There is a great need for more therapies for the treatment of glioblastoma…TQ has anti-oxidant, anti-inflammatory and anti-neoplastic actions with selective cytotoxicity for human cancer cells compared to normal cells. Here, we show that TQ selectively inhibits the clonogenicity of glioblastoma cells as compared to normal human astrocytes. Also, glioblastoma cell proliferation could be impaired by chloroquine, an autophagy inhibitor, suggesting that glioblastoma cells may be dependent on the autophagic pathway for survival…TQ also caused an accumulation of the LC3-associated protein p62, confirming the inhibition of autophagy. Furthermore, the levels of Beclin-1 protein expression were unchanged, indicating that TQ interferes with a later stage of autophagy. Finally, treatment with TQ induces lysosome membrane permeabilization…which mediates caspase-independent cell death… TQ induced apoptosis…”

Inhibition of autophagy by thymoquinoneThe authors note an important difference between the action of thymoquinone and other cytotoxic therapies:

Ionizing radiation and temozolomide have both been shown to increase a cytoprotective autophagy response in glioblastoma cells, leading to resistant tumors. In addition, many other chemotherapeutics, such as rapamycin, tamoxifen, and etoposide, induce a protective autophagic response in cancer cells. Therefore, inhibitors of autophagy, both alone and in combination with standard therapies, may provide a viable and promising new strategy in cancer treatment…To the best of our knowledge, this report represents the first finding of TQ as an autophagy inhibitor, and provides a platform for which to extend studies in the treatment of glioblastoma with TQ.”

The authors conclude:

“Inhibition of autophagy is an exciting and emerging strategy in cancer therapy. In this vein, our results describe a novel mechanism of action for TQ as an autophagy inhibitor selectively targeting glioblastoma cells.

Nigella sativa induces apoptosis in cervical cancer

Natural Product CommunicationsAccording to a study published in Natural Product Communications, Nigella sativa inhibits proliferation of cervical cancer cells by inducing apoptosis:

“Nigella sativa (NS) showed an 88.3% inhibition of proliferation of SiHa human cervical cancer cells at a concentration of 125 microL/mL methanolic extract at 24 h, and an IC50 value 93.2 microL/mL. NS exposure increased the expression of caspase-3, -8 and -9 several-fold. The analysis of apoptosis by Dead End terminal transferase-mediated dUTP-digoxigenin end labeling (TUNEL) assay was used to further confirm that NS induced apoptosis. Thus, NS was concluded to induce apoptosis in SiHa cell through both p53 and caspases activation. NS could potentially be an alternative source of medicine for cervical cancer therapy.”

Suppression of melanoma metastasis by inhibition of the NLRP3 inflammasome

Toxicology and Applied PharmacologyIn an exciting study published in Toxicology and Applied Pharmacology that has implications for a wide range of conditions, investigators report suppression of metastasis in melanoma inhibiting the proinflammatory activity of the NLRP3 inflammasome:

“The inflammasome is a multi-protein complex which when activated regulates caspase-1 activation and IL-1β and IL-18 secretion. The NLRP3 (NACHT, LRR, and pyrin domain-containing protein 3) inflammasome is constitutively assembled and activated in human melanoma cells. We have examined the inhibitory effect of thymoquinone (2-isopropyl-5-methylbenzo-1,4-quinone), a major ingredient of black seed obtained from the plant Nigella sativa on metastatic human (A375) and mouse (B16F10) melanoma cell lines. We have assessed whether thymoquinone inhibits metastasis of melanoma cells by targeting NLRP3 subunit of inflammasomes. Using an in vitro cell migration assay, we found that thymoquinone inhibited the migration of both human and mouse melanoma cells…The inhibition of migration of melanoma cells by thymoquinone was accompanied by a decrease in expression of NLRP3 inflammasome resulting in decrease in proteolytic cleavage of caspase-1. Inactivation of caspase-1 by thymoquinone resulted in inhibition of IL-1β and IL-18. Treatment of mouse melanoma cells with thymoquinone also inhibited NF-κB activity. Furthermore, inhibition of reactive oxygen species (ROS) by thymoquinone resulted in partial inactivation of NLRP3 inflammasome. Thus, thymoquinone exerts its inhibitory effect on migration of human and mouse melanoma cells by inhibition of NLRP3 inflammasome. Thus, our results indicate that thymoquinone can be a potential immunotherapeutic agent not only as an adjuvant therapy for melanoma, but also, in the control and prevention of metastatic melanoma.”

Readers will recall that activation of the inflammasome is a mechanism shared by many autoimmune and malignant disorders.

Nigella sativa attenuates iNOS pathway inflammation in liver cancer

Environmental Health and Preventive MedicineBecause iNOS activation of inflammation is a key process in a multitude of inflammatory disorders including a host of autoimmune diseases, a study published in Environmental Health and Preventative Medicine showing value in hepatocellular carcinoma is of is of particular importance:

“Nitric oxide (NO) and inducible nitric oxide synthase enzyme (iNOS) have been implicated in various tumors….Nigella sativa (NS) has been shown to have specific health benefits. The aim of this study was to investigate the in vivo modulation of the iNOS pathway by NS ethanolic extract (NSEE) and the implications of this effect as an antitumor therapeutic approach against diethylnitrosamine (DENA)-induced hepatocarcinogenesis…Serum AFP, NO, TNF-α, and IL-6 levels and iNOS enzyme activity were significantly increased in rats treated with DENA. Significant up-regulation of liver iNOS mRNA and protein expression was also observed. Subsequent treatment with NSEE significantly reversed these effects and improved the histopathological changes in malignant liver tissue which appeared after treatment with DENA, without any toxic effect when given alone.”

This data inspired the authors to conclude:

“These results provide evidence that attenuation of the iNOS pathway and suppression of the inflammatory response mediated by TNF-α, and IL-6 could be implicated in the antitumor effect of NSEE. As such, our findings hold great promise for the utilization of NS as an effective natural therapeutic agent in the treatment of hepatocarcinogenesis.”

Cytotoxic effect against lung cancer

Asian Pacific Journal of Cancer PreventionAuthors of a study just published in the Asian Pacific Journal of Cancer Prevention report that Nigella sativa seed extract significantly reduces the viability of lung cancer cells:

Nigella sativa (N sativa), commonly known as black seed, has been used in traditional medicine to treat many diseases. The antioxidant, anti-inflammatory, and antibacterial activities of N sativa extracts are well known. Therefore, the present study was designed to investigate the anticancer activity of seed extract (NSE) and seed oil (NSO) of N sativa against a human lung cancer cell line…The results showed NSE and NSO significantly reduce the cell viability and alter the cellular morphology of A-549 cells in a concentration dependent manner. The percent cell viability was recorded as 75%, 50%, and 26% at 0.25, 0.5, and 1 mg/ml of NSE by MTT assay and 73%, 48%, and 23% at 0.25, 0.5, and 1 mg/ml of NSE by NRU assay. Exposure to NSO concentrations of 0.1 mg/ml and above for 24 h was also found to be cytotoxic. The decrease in cell viability at 0.1, 0.25, 0.5, and 1 mg/ml of NSO was recorded to be 89%, 52%, 41%, and 13% by MTT assay and 85%, 52%, 38%, and 11% by NRU assay, respectively. A-549 cells exposed to 0.25, 0.5 and 1 mg/ml of NSE and NSO lost their typical morphology and appeared smaller in size. The data revealed that the treatment of seed extract (NSE) and seed oil (NSO) of Nigella sativa significantly reduce viability of human lung cancer cells.

Nigella sativa inhibits breast cancer

PLOS ONEEvidence is mounting for the use of Nigella sativa against breast cancer. Similar to the prooxidant effect described above, a study published in PLoS One describes how thymoquinone inhibits tumor growth and induces apoptosis in breast cancer cells through p38 phosphorylation and ROS production:

“Due to narrow therapeutic window of cancer therapeutic agents and the development of resistance against these agents, there is a need to discover novel agents to treat breast cancer. The antitumor activities of thymoquinone (TQ), a compound isolated from Nigella sativa oil, were investigated in breast carcinoma in vitro and in vivo. Cell responses after TQ treatment were assessed by using different assays including MTT assay, annexin V-propidium iodide staining, Mitosox staining and Western blot. The antitumor effect was studied by breast tumor xenograft mouse model, and the tumor tissues were examined by histology and immunohistochemistry. The level of anti-oxidant enzymes/molecules in mouse liver tissues was measured by commercial kits. Here, we show that TQ induced p38 phosphorylation and ROS production in breast cancer cells. These inductions were found to be responsible for TQ’s anti-proliferative and pro-apoptotic effects. Moreover, TQ-induced ROS production regulated p38 phosphorylation but not vice versa. TQ treatment was found to suppress the tumor growth and this effect was further enhanced by combination with doxorubicin. TQ also inhibited the protein expression of anti-apoptotic genes, such as XIAP, survivin, Bcl-xL and Bcl-2, in breast cancer cells and breast tumor xenograft. Reduced Ki67 and increased TUNEL staining were observed in TQ-treated tumors. TQ was also found to increase the level of catalase, superoxide dismutase and glutathione in mouse liver tissues.”

Again we see increases in the profoundly important glutatione under the influence of thymoquinone. Note also that the antitumor effect of the conventional chemotherapeutic agent was enhanced.

“In conclusion, our study provides evidence for the mechanism of action of TQ in suppressing human breast carcinoma in both in vitro and in vivo models. We demonstrated that the anti-proliferative and pro-apoptotic effects of TQ are mediated through its induction effect on p38 and ROS signaling. Our results also indicate the anti-tumor effects of TQ in breast tumor xenograft mice and its ability to potentiate the antitumor effect of doxorubicin. TQ serves as a promising anticancer agent and further studies may provide important leads for its clinical application.”

Journal of Medicinal FoodA study published in the Journal of Medicinal Food also reports proapoptotic and antimetastatic effects of Nigella sativa for breast cancer:

“This study investigated the apoptotic, antimetastatic, and anticancer activities of supercritical carbon dioxide (SC-CO2) extracts of the seeds of N. sativa Linn. against estrogen-dependent human breast cancer cells (MCF-7)….Of the 12 extracts, 1 extract (A3) that was prepared at 60°C and 2500 psi (~17.24 MPa) showed selective antiproliferative activity against MCF-7 cells with an IC50 of 53.34±2.15 μg/mL. Induction of apoptosis was confirmed by evaluating caspases activities and observing the cells under a scanning electron microscope. In vitro antimetastatic properties of A3 were investigated by colony formation, cell migration, and cell invasion assays. The elevated levels of caspases in A3 treated MCF-7 cells suggest that A3 is proapoptotic. Further nuclear condensation and fragmentation studies confirmed that A3 induces cytotoxicity through the apoptosis pathway. A3 also demonstrated remarkable inhibition in migration and invasion assays of MCF-7 cells at subcytotoxic concentrations. Thus, this study highlights the therapeutic potentials of SC-CO2 extract of N. sativa in targeting breast cancer.”

Pharmacognosy ResearchAnd authors of a study published in Pharmacognosy Research also report activity of thymoquinone against breast cancer:

“The study addressed the anti-cancer efficiency of long-term in vitro treatment with thymoquinone towards human breast cancer cell lines MCF-7...The 50% inhibitory concentration (IC50) value determined using the proliferation assay was 25 μM thymoquinone. Late apoptotic cell percentage increased rapidly when treatment duration was increased to 24 h with 25 and 100 μM thymoquinone. Further analysis using cell cycle assay showed thymoquinone inhibition of breast cancer cell proliferation at minimal dose 25 μM and led to S phase arrest significantly at 72 h treatment. It was also noted elevation sub-G1 peak following treatment with 25 μM thymoquinone for 12 h. Increase in thymoquinone to 50 μM caused G2 phase arrest at each time-point studied…In general thymoquinone showed sustained inhibition of breast cancer cell proliferation with long-term treatment. Specificity of phase arrest was determined by thymoquinone dose.”

Asian Pacific Journal of Cancer PreventionAntiproliferative effects against breast cancer cells were also shown in a study published in the Asian Pacific Journal of Cancer Prevention:

“Our data showed that Nigella sativa extracts significantly inhibited human breast cancer MDA-MB-231 cell proliferation at doses of 2.5-5 μg/mL. Apoptotic induction in MDA-MB-231 cells was observed in a dose-dependent manner after exposure to Nigella sativa extracts for 48 h. Real time PCR and flow cytometry analyses suggested that Nigella sativa extracts possess the ability to suppress the proliferation of human breast cancer cells through induction of apoptosis.”

Nigella sativa protects against liver damage caused by tamoxifen

Canadian Journal of Physiology and PharmacologyProtection against the harmful toxic effects of chemotherapy is a critical component of cancer case management. A welcome study published in the Canadian Journal of Physiology and Pharmacology shows that thymoquinone from Nigella sativa protects against the hepatotoxicity of tamoxifen:

“One of the major reasons for terminating a clinical trial is the liver toxicity induced by chemotherapy. Tamoxifen (TAM) is an anti-estrogen used in the treatment and prevention of hormone-dependent breast cancer. Tamoxifen therapy may cause hepatic injury. The seeds of Nigella sativa, which contain the active ingredient thymoquinone (TQ), have been used in folk medicine for diverse ailments. TQ is reported to possess anticancer and hepatoprotective effects. In this study, the protective effects of TQ against TAM-induced hepatotoxicity in female rats were evaluated. Four groups of rats were used: control; TAM; TQ; TAM+TQ. TAM (45 mg·(kg body mass)(-1)·day(-1), by intraperitoneal injection (i.p.), for 10 consecutive days) resulted in elevated serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase, total bilirubin, and gamma glutamyl transferase, as well as depletion of reduced glutathione in the liver and accumulation of lipid peroxides. Also, TAM treatment inhibited the hepatic activity of superoxide dismutase. Further, it raised the levels of tumor necrosis factor alpha in the liver and induced histopathological changes. Pretreatment with TQ (50 mg·(kg body mass)(-1)·day(-1); orally, for 20 consecutive days, starting 10 days before TAM injection) significantly prevented the elevation in serum activity of the assessed enzymes. TQ significantly inhibited TAM-induced hepatic GSH depletion and LPO accumulation. Consistently, TQ normalized the activity of SOD, inhibited the rise in TNF-α and ameliorated the histopathological changes. In conclusion, TQ protects against TAM-induced hepatotoxicity.”

Again we see beneficial effects on glutatione metabolism.

Protection against kidney toxicity of cisplatin

Iranian Journal of Kidney DiseasesWhile on the topic of protection unwanted against damage done by cytotoxic chemotherapy, we can appreciate a study published in the Iranian Journal of Kidney Diseases reporting evidence that Nigella sativa offers some protection against the nephrotoxic effects of cisplatin:

“Thirty rats were divided into 3 groups to receive distilled water (control group), cisplatin (3 mg/kg per body weight for 3 days), and cisplatin and alcoholic extract of NS (100 mg/kg per body weight). Biochemical and histopathologic parameters were compared between the three groups on days 14 and 42 of the study…Cisplatin-induced nephrotoxicity was confirmed in our study…Histology of the kidneys exposed to cisplatin showed significant kidney injury, but the rats treated with NS showed a relatively well-preserved architectureNigella sativa seeds had nonsignificant effects on biochemical parameters, although the histopathologic properties of the kidneys relatively recovered after NS use.”

Nigella sativa benefits for the brain, mood and cognition

Journal of EthnopharmacologyConsidering the immune-regulating and anti-inflammatory virtues of Nigella sativa it stands to reason that there would be benefits for the brain. A study published in the Journal of Ethnopharmacology reports that it helps stabilize mood, reduce anxiety and cognition in adolescent males.

“Previous studies conducted on animals linked consumption of Nigella sativa L. seeds (NS) to decreased anxiety and improved memory. The present study, which was carried out at a boarding school in Bangladesh, was designed to examine probable effect of NS on mood, anxiety and cognition in adolescent human males…Forty-eight healthy adolescent human males aged between 14 to 17 years were randomly recruited as volunteers and were randomly split into two groups: A (n=24) and B (n=24). The treatment procedure for group A and B were one capsule of 500 mg placebo and 500 mg NS respectively once daily for four weeks. All the volunteers were assessed for cognition with modified California verbal learning test-II (CVLT-II), mood with Bond–Lader scale and anxiety with State–Trait Anxiety Inventory (STAI) at the beginning and after four weeks of either NS or placebo ingestion…Over the 4 weeks study period, the use of NS as a nutritional supplement been observed to- stabilize mood, decrease anxiety and modulate cognition positively.”

Relieving neuroinflammation of depression

Journal of Pharmacy & BioAllied SciencesIt’s well known than neuroimmune inflammation plays a fundamental role in depression. Authors of a study published in the Journal of Pharmacy & BioAllied Sciences present welcome evidence that Nigella sativa and thymoquinone may relieve depression by reducing neuroinflammation:

Neuroimmune factors have been proposed as contributors to the pathogenesis of depression. Beside other therapeutic effects including neuroprotective, antioxidant, anticonvulsant and analgesic effects, Nigella sativa and its main ingredient, thymoquinone (TQ), have been shown to have anti-inflammatory effects. In the present study, the effects of Nigella sativa hydro-alcoholic extract and thymoquinone was investigated on lipopolysaccharide- induced depression like behavior in rats…The results of the present study showed that hydro-alcoholic extract of Nigella sativa can prevent LPS-induced depression like behavior in rats. These results support the traditional belief on the beneficial effects of Nigella sativa in the nervous system.”

Thymoquinone ameliorates lead-induced brain damage

Experimental and Toxicologic PathologyEnvironmental toxicity is a concern for brain health; an exciting study published Experimental and Toxicologic Pathology indicates that thymoquinone from Nigella sativa protects against brain damage from lead:

“The present study aims to investigate the protective effects of thymoquinone, the major active ingredient of Nigella sativa seeds, against lead-induced brain damage in Sprague-Dawley rats. In which, 40 rats were divided into four groups (10 rats each). The first group served as control. The second, third and fourth groups received lead acetate, lead acetate and thymoquinone, and thymoquinone only, respectively, for one month. Lead acetate was given in drinking water at a concentration of 0.5 g/l (500 ppm). Thymoquinone was given daily at a dose of 20 mg/kg b.w. in corn oil by gastric tube. Control and thymoquinone-treated rats showed normal brain histology. Treatment of rats with lead acetate was shown to produce degeneration of endothelial lining of brain blood vessels with peri-vascular cuffing of mononuclear cells consistent to lymphocytes, congestion of choroid plexus blood vessels, ischemic brain infarction, chromatolysis and neuronal degeneration, microglial reaction and neuronophagia, degeneration of hippocampal and cerebellar neurons, and axonal demyelination. On the other hand, co-administration of thymoquinone with lead acetate markedly decreased the incidence of lead acetate-induced pathological lesions.”

Protection against Parkinson’s disease α-synuclein-induced synapse damage

Neuroscience LettersAgents that offer protection against α-synuclein toxicity are welcome in the treatment of Parkinson’s disease and dementia. A study recently published in Neuroscience Letters presents evidence that thymoquinone from Nigella sativa has this property:

“The present study aimed to determine whether TQ protects against α-synuclein (αSN)-induced synaptic toxicity in rat hippocampal and human induced pluripotent stem cell (hiPSC)-derived neurons. Here, we report that αSN decreased the level of synaptophysin, a protein used as an indicator of synaptic density, in cultured hippocampal and hiPSC-derived neurons. However, simultaneous treatment with αSN and TQ protected neurons against αSN-induced synapse damage, as revealed by immunostaining. Moreover, administration of TQ efficiently induced protection in these cells against αSN-induced inhibition of synaptic vesicle recycling in hippocampal and hiPSC-derived neurons as well as against mutated P123H β-synuclein (βSN) in hippocampal neurons, as revealed by experiments using the fluorescent dye FM1-43. Using a multielectrode array, we further demonstrated that the treatment of hiPSC-derived neurons with αSN induced a reduction in spontaneous firing activity, and cotreatment with αSN and TQ partially reversed this loss. These results suggest that TQ protects cultured rat primary hippocampal and hiPSC-derived neurons against αSN-induced synaptic toxicity and could be a promising therapeutic agent for patients with Parkinson’s disease and dementia with Lewy bodies.

Thymoquinone prevents β-amyloid neurotoxicity of Alzheimer’s disease

Cellular and Molecular NeurobiologyOf great interest in the prevention of Alzheimer’s disease are agents that may protect agains β-amyloid neurotoxicity. Here too thymoquinone has effect as reported in a study published in Cellular and Molecular Neurobiology:

Thymoquinone (TQ), a bioactive constituent of Nigella sativa Linn (N. sativa) has demonstrated several neuropharmacological attributes. In the present study, the neuroprotective properties of TQ were investigated by studying its anti-apoptotic potential to diminish β-amyloid peptide 1-40 sequence (Aβ1-40)-induced neuronal cell death in primary cultured cerebellar granule neurons (CGNs)…Pretreatment of CGNs with TQ (0.1 and 1 μM) and subsequent exposure to 10 μM Aβ1-40 protected the CGNs against the neurotoxic effects of the latter. In addition, the CGNs were better preserved with intact cell bodies, extensive neurite networks, a loss of condensed chromatin and less free radical generation than those exposed to Aβ1-40 alone. TQ pretreatment inhibited Aβ1-40-induced apoptosis of CGNs via both extrinsic and intrinsic caspase pathways. Thus, the findings of this study suggest that TQ may prevent neurotoxicity and Aβ1-40-induced apoptosis. TQ is, therefore, worth studying further for its potential to reduce the risks of developing Alzheimer’s disease.”

 Nigella sativa protects and promotes healing from nerve trauma

Pathologie BiologieA study published Pathologie Biologie reports that Nigella sativa improves the neurodegeneration typical after nerve trauma:

“The aim of this study was designed to evaluate the possible protective effects of Nigella sativa (NS) on the neuronal injury in the sciatic nerve of rats. The rats were randomly allotted into one of the three experimental groups: A (control), B (only trauma) and C (trauma and treated with NS); each group contain 10 animals… To date, no histopathological changes of neurodegeneration in the sciatic nerve after trauma in rats by NS treatment have been reported. Results showed in the group B (only trauma), the neurons of sciatic nerve tissue became extensively dark and degenerated with picnotic nuclei. Treatment of NS markedly reduced degenerating neurons after trauma and the distorted nerve cells were mainly absent in the NS-treated rats. The morphology of neurons in groups treated with NS was well protected, but not as neurons of the control group. The number of neurons in sciatic nerve tissue of group B (only trauma) was significantly less than both control and treated with NS groups. The morphology of neurons revealed that the number of neurons were significantly less in group B compared to control and group C rats’ motor neurons anterior horn spinal cord tissue. We conclude that NS therapy causes morphologic improvement on neurodegeneration in sciatic nerve after trauma in rats.”

Nigella sativa for osteoporosis

Evidence-Based Complementary and Alternative MedicineConsidering that inflammation plays a key role in osteoporosis, it’s reasonable to investigate the use Nigella sativa as described in a paper in Evidence-Based Complementary and Alternative Medicine:

“Animal studies have shown that NS and TQ may be used for the treatment of diabetes-induced osteoporosis and for the promotion of fracture healing. The mechanism involved is unclear, but it was postulated that the antioxidative, and anti-inflammatory activities may play some roles in the treatment of osteoporosis as this bone disease has been linked to oxidative stress and inflammation. This paper highlights studies on the antiosteoporotic effects of NS and TQ, the mechanisms behind these effects and their safety profiles. NS and TQ were shown to inhibit inflammatory cytokines such as interleukin-1 and 6 and the transcription factor, nuclear factor κB. NS and TQ were found to be safe at the current dosage for supplementation in human with precautions in children and pregnant women. Both NS and TQ have shown potential as antiosteoporotic agent but more animal and clinical studies are required to further assess their antiosteoporotic efficacies.”

Inhibition of osteoporosis by Nigella sativa

BMC Complementary & Alternative MedicineIn an exciting study published in the BMC Complementary and Alternative Medicine, investigators report the reversal of osteoporosis in subjects whose ovaries had been removed:

“There is a direct relationship between the lack of estrogen after menopause and the development of osteoporosis…Nigella Sativa (NS) has been shown to have beneficial effects on bone and joint diseases. The present study was conducted to elucidate the protective effect of Nigella Sativa on osteoporosis produced by ovariectomy in rats…Female Wistar rats aged 12-14 months were divided into three groups: sham-operated control (SHAM), ovariectomized (OVX), and ovariectomized supplemented with nigella sativa (OVX-NS) orally for 12 weeks; 4 weeks before ovariectomy and 8 weeks after…OVX rats showed significant decrease in plasma Ca(+2), accompanied by a significant increase in plasma ALP, amino terminal collagen type 1 telopeptide, MDA, nitrates, TNF-α and IL-6. These changes were reversed by NS supplementation in OVX-NS group to be near SHAM levels. Histological examination of the tibias revealed discontinuous eroded bone trabeculae with widened bone marrow spaces in OVX rats accompanied by a significant decrease in both cortical and trabecular bone thickness compared to Sham rats. These parameters were markedly reversed in OVX-NS rats. Histological examination of the liver showed mononuclear cellular infiltration and congestion of blood vessels at the portal area in OVX rats which were not found in OVX-NS rats.”

Their data supported this exciting conclusion:

“It can be concluded that NS has shown potential as a safe and effective antiosteoporotic agent, which can be attributed to its high content of unsaturated fatty acids as well as its antioxidant and anti-inflammatory properties.”

Nigella sativa helps with psoriasis

Pharmacognosy MagazineConsidering its antiinflammatory and immunomodulating characteristics it seems a good bet that Nigella sativa would help with psoriasis as described in a study published in Pharmacognosy Magazine:

“The screening of antipsoriatic activity of 95% of ethanolic extract of Nigella sativa seeds by using mouse tail model for psoriasis and in vitro antipsoriatic activity was carried out by SRB Assay using HaCaT human keratinocyte cell lines….The ethanolic extract of Nigella sativa seeds extract produced a significant epidermal differentiation, from its degree of orthokeratosis (71.36±2.64) when compared to the negative control (17.30±4.09%)…The 95% ethanolic extract of Nigella sativa shown IC50 239 μg/ml, with good antiproliferant activity compared to Asiaticoside as positive control which showed potent activity with IC50 value of 20.13 μg/ml. From the present study it can be said that topical application of 95% ethanolic extract of Nigella sativa seeds has antipsoriatic activity and the external application is be beneficial in the management of psoriasis.”

Assists in treatment of vitiligo

Iranian Red Crescent Medical JournalNIgella sativa is an agent to consider in case management of any autoimmune disorder including vitiligo, for which it showed benefit in a study published in the Iranian Red Crescent Medical Journal:

Vitiligo is one of the autoimmune skin diseases that destroy the melanocytes of the skin…The aim of this study was to compare the effect of Nigella sativa and fish oil on vitiligo lesions of the patients referred to a dermatology clinic…After six months, a mean score of VASI decreased from 4.98 to 3.75 in patients applying topical Nigella sativa and from 4.98 to 4.62 in those using topical fish oil…In the current study, administration of Nigella sativa and fish oil significantly decreased skin lesions size, indicating an improvement in clinical condition…the depigmented areas were reduced over time and the skin color showed improvement. One reason for this positive response to treatment is the thymoquinone component of Nigella sativa…Thymoquinone can simulate the activity of acetylcholine, which causes the release of melanin and darkening of the skin through stimulation of cholinergic receptors. In addition, Nigella sativa oil administration was tolerable as well as safe and improved oxidative stress and clinical condition of patients…It was also shown that this type of treatment has no significant side effects and resulted in high patient satisfaction and acceptance.”

The authors state in conclusion:

“Nigella sativa oil and fish oil were effective in reduction the size of patient’s lesions; however, Nigella sativa was more effective in comparison to the fish oil. Therefore, using Nigella sativa with the major drugs in the treatment of vitiligo is recommended.”

Topical treatment of allergic rhinitis

Anti-Inflammatory & Anti-Allergy Agents in Medicinal ChemistryAllergic rhinitis as a chronic inflammatory disorder also responds to Nigella sativa applied topically as reported in Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry:

Allergic rhinitis (AR) is the most common manifestation of atopic reaction to inhaled allergens. It is a chronic inflammatory disease which may first appear at any age, but the onset is usually during childhood or adolescence…The individuals in the active group received N. sativa oil and the control group individuals received ordinary food oil in the form of nasal drops for 6 weeks…After the 6 weeks treatment course, 100% of the patients in the mild active group became symptoms free; while in moderate active group 68.7% became symptoms free and 25% were improved; while in severe active group 58.3% became symptoms free and 25% were improved. In addition, 92.1% of total patients in the active group demonstrated improvement in their symptoms or were symptoms free, while the corresponding value was 30.1% in the control group. At the end of 6 weeks of treatment with topical use, the improvement in tolerability of allergen exposure in active group became 55.2% which was significant as compared with control group which was accounted for 20% at the same time…Topical application of black seed oil was effective in the treatment of allergic rhinitis, with minimal side effects.”

Nigella sativa protects against radiation damage

Journal of Investigative SurgeryRadiation therapy can produce substantial ‘collateral damage’. Authors of a study just published in the Journal of Investigative Surgery demonstrate that Nigella sativa reduces oxidative stress in animals subjected to total head irradiation:

“Many cancer patients treated with radiotherapy suffer severe side effects during and after their treatment. The aim of this study was to investigate the effects of irradiation and the addition of Nigella sativa oil (NSO) on the oxidant/antioxidant system in the liver tissue of irradiated rats…The control group received neither NSO nor irradiation but received 1-ml saline orally. The irradiation group (IR) received total head 5 gray (Gy) of gamma irradiation as a single dose, plus 1-ml saline orally. The IR plus NSO group received both total head 5 Gy of gamma irradiation as a single dose and 1 g/kg/day NSO orally through an orogastric tube starting one hour before irradiation and continuing for 10 days…Conclusions: NSO reduces oxidative stress markers and has antioxidant effects, which also augments the antioxidant capacity in the liver tissue of rats.”

Cutaneous and Ocular ToxicologyNigella sativa was shown to reduce radiation-induced cataracts in a study published in Cutaneous and Ocular Toxicology:

“The aim of this study was to investigate the antioxidant and radioprotective effects of Nigella sativa oil (NSO) and thymoquinone (TQ) against ionizing radiation-induced cataracts in lens after total cranium irradiation (IR) of rats with a single dose of 5 gray (Gy)…At the end of the 10th d, cataract developed in 80% of the rats in IR group only. After IR, cataract rate dropped to 20% and 50% in groups which were treated with NSO and TQ, respectively, and was limited at grades 1 and 2. Nitric oxide synthase activity, nitric oxide and peroxynitrite levels in the radiotherapy group were higher than those of all other groups. Conclusions: The results implicate a major role for NSO and TQ in preventing cataractogenesis in ionizing radiation-induced cataracts in the lenses of rats, wherein NSO were found to be more potent.”

PhytomedicineAnd protection from radiation-induced damage to brain tissue was demonstrated in a study recently published in the journal Phytomedicine designed…

“To investigate Nigella sativa oil (NSO) and Thymoquinone (TQ) for their antioxidant effects on the brain tissue of rats exposed to ionizing radiation….Levels of NO· and ONOO(-), and enzyme activity of NOS in brain tissue of the rats treated with NSO or TQ were found to be lower than in received IR alone (p<0.002) Nigella sativa oil (NSO) and its active component, TQ, clearly protect brain tissue from radiation-induced nitrosative stress.

 Activity against Staphylococcal and fungal skin infections

Pakistan Journal of Biological SciencesNigella sativa is a benevolent agent in the treatment of skin infection and inflammation as documented by a study published in the Pakistan Journal of Biological Sciences:

“Nigella sativa has been used for a long time in Jordanian folk medicine to treat skin diseases like microbial infections and inflammation. Therefore, the present study was conducted to assess the healing efficacy of petroleum ether extract of Nigella sativa seeds (fixed oil) on staphylococcal-infected skin. Male BALB/c mice were infected with 100 microL of Staphylococcus aureus (ATCC 6538)… Application of treatments for each group (100 microL sterile saline, 100 microL chloramphenicol (10 microg/mouse) and Nigella sativa fixed oil at a dose of 50, 100 or 150 microL/mouse) was performed at the site of infection… At day 3 and 5 after infection, total White Blood Cells (WBCs) count; differential and absolute differential WBC counts and the number of viable bacteria present in the skin area were measured…Results indicated that fixed oil of Nigella sativa seeds enhance healing of staphylococcal-infected skin by reducing total and absolute differential WBC counts, local infection and inflammation, bacterial expansion and tissue impairment. These effects provide scientific basis for the use of Nigella sativa in traditional medicine to treat skin infections and inflammations.

Journal of EthnopharmacologyThe authors of a study published in the Journal of Ethnopharmacology report effectiveness against fungal skin infections (dermatophytes):

“The antifungal activity of ether extract of Nigella sativa seed and its active principle thymoquinone was tested against eight species of dermatophytes: four species of Trichophyton rubrum and one each of Trichophyton interdigitale, Trichophyton mentagrophytes, Epidermophyton floccosum and Microsporum canis. Agar diffusion method with serial dilutions of ether extract of Nigella sativa, thymoquinone and griseofulvin was employed…The minimum inhibitory concentration (MIC) was considered as the minimum concentration of the drug, which inhibited 80–100% of the fungal growth. The MICs of the ether extract of Nigella sativa and thymoquinone were between 10 and 40 and 0.125 and 0.25 mg/ml…These results denote the potentiality of Nigella sativa as a source for antidermatophyte drugs and support its use in folk medicine for the treatment of fungal skin infections.”

Case report of seroreversion in HIV

Afr J Tradit Complement Altern Med.A case report published in the African Journal of Traditional, Complementary, and Alternative Medicines presents unexpected results in the treatment of HIV:

“Nigella sativa had been documented to possess many therapeutic functions in medicine but the least expected is sero-reversion in HIV infection which is very rare despite extensive therapy with highly active anti-retroviral therapy (HAART). This case presentation is to highlight the complete recovery and sero-reversion of adult HIV patient after treatment with Nigella sativa concoction for the period of six months. The patient presented to the herbal therapist with history of chronic fever, diarrhoea, weight loss and multiple papular pruritic lesions of 3 months duration. Examination revealed moderate weight loss, and the laboratory tests of ELISA (Genscreen) and western blot (new blot 1 & 2) confirmed sero-positivity to HIV infection with pre-treatment viral (HIV-RNA) load and CD4 count of 27,000 copies/ml and CD4 count of 250 cells/ mm(3) respectively. The patient was commenced on Nigella sativa concoction 10 mls twice daily for 6 months. He was contacted daily to monitor side-effects and drug efficacy. Fever, diarrhoea and multiple pruritic lesions disappeared on 5th, 7th and 20th day respectively on Nigella sativa therapy. The CD4 count decreased to 160 cells/ mm3 despite significant reduction in viral load (≤1000 copies/ml) on 30th day on N. sativa. Repeated EIA and Western blot tests on 187th day on Nigella sativa therapy was sero-negative. The post therapy CD4 count was 650 cells/ mm(3) with undetectable viral (HIV-RNA) load. Several repeats of the HIV tests remained sero-negative, aviraemia and normal CD4 count since 24 months without herbal therapy. This case report reflects the fact that there are possible therapeutic agents in Nigella sativa that may effectively control HIV infection.

Improvement in semen quality

PhytomedicineAnother study published in Phytomedicine presents evidence from a double-blind, placebo-controlled that Nigella sativa improves abnormal semen quality in infertility:

“Since Nigella sativa L. seed (N. sativa) has many uses including infertility in traditional medicine, the effects of Nigella sativa L. seed oil on abnormal semen quality in infertile men with abnormal semen quality are of interest. This study was conducted on Iranian infertile men with inclusion criteria of abnormal sperm morphology less than 30% or sperm counts below 20×10(6)/ml or type A and B motility less than 25% and 50% respectively. The patients in N. sativa oil group (n=34) received 2.5mlN. sativa oil and placebo group (n=34) received 2.5ml liquid paraffin two times a day orally for 2 months. At baseline and after 2 months, the sperm count, motility and morphology and semen volume, pH and round cells as primary outcomes were determined in both groups. Results showed that sperm count, motility and morphology and semen volume, pH and round cells were improved significantly in N. sativa oil treated group compared with placebo group after 2 months. It is concluded that daily intake of 5ml N. sativa oil for two months improves abnormal semen quality in infertile men without any adverse effects.”

Is Nigella sativa safe?

Advanced Pharmaceutical BulletinA study investigating the potential for liver toxicity was reported last year in the journal Advanced Pharmaceutical Bulletin:

“The aim of this study was to determine the toxic effect of Nigella sativa powder on the liver function which was evaluated by measuring liver enzymes and through histopathological examination of liver tissue…Twenty four male Sprague Dawley rats were allotted randomly to four groups including: control (taking normal diet); low dose (supplemented with 0.01 g/kg/day Nigella sativa); normal dose (supplemented with 0.1 g/kg/day Nigella sativa) and high dose (supplemented with 1 g/kg/day Nigella sativa)…To assess liver toxicity, liver enzymes measurement and histological study were done at the end of supplementation…The study showed that supplementation of Nigella sativa up to the dose of 1 g/kg supplemented for a period of 28 days resulted no changes in liver enzymes level and did not cause any toxicity effect on the liver function

The authors stated this conclusion regarding human consumption of Nigella sativa:

“With the evidence of normal ALT and AST level in blood and normal liver tissue in histology examination for all treatment groups, it is suggested that there are no toxic effect on liver function of Nigella sativa at different doses for 4 weeks period. As a conclusion, popular consumption of Nigella sativa powder by human did not cause any toxicity effect on the liver function and safe to be consumed for many purposes.”

 Protection against alcohol-induced liver injury

Chinese Journal of Natural MedicinesNot only is Nigella sativa safe for the liver, but a study published in the Chinese Journal of Natural Medicines provides data showing that it protects the liver against oxidative damage caused by alcohol:

Nigella sativa L. (Ranunculaceae) is considered as a therapeutic plant-based medicine for liver damage. In this study, the aim was to study the effect of Nigella sativa oil (NSO) pretreatment on ethanol-induced hepatotoxicity in rats…Rats were given Nigella sativa oil at doses of 2.5 and 5.0 mL·kg(-1), orally for 3 weeks, followed by oral ethanol (EtOH) administration (5 g·kg(-1)) every 12 h three times (binge model).”

Amazingly…

Binge ethanol application caused significant increases in plasma transaminase activities and hepatic triglyceride and malondialdehyde (MDA) levels. It decreased hepatic glutathione (GSH) levels, but did not change vitamins E and vitamin C levels and antioxidant enzyme activities. NSO (5.0 mL·kg(-1)) pretreatment significantly decreased plasma transaminase activities, hepatic MDA, and triglyceride levels together with amelioration in hepatic histopathological findings.”

Based on these findings the authors conclude:

“NSO pretreatment may be effective in protecting oxidative stress-induced hepatotoxicity after ethanol administration.”

Practical use of Nigella sativa

Nigella sativa seeds 3The foregoing sampling of studies from the scientific literature on Nigella sativa should not be construed as an endorsement for its use in any specific case or condition. It is a presentation of the extraordinary scope of action and clinical potential of an agent that I am finding valuable in practice. Colleagues who are interested in knowing the particular Nigella sativa whole seed extract that I am using are welcome to contact me. For the general reader, I caution against taking anything (especially something found on the internet) without having first discussed it with your knowledgeable health care practitioner who has the background and depth to advise on how this may fit into your treatment or health maintenance plan.

Antioxidants in excess can increase inflammation and blunt benefits of exercise

PLOS ONEAntioxidants, even glutathione, taken in excess can increase rather than ameliorate harmful inflammation as attested by two revealing papers recently published in PLOS (Public Library of Science). In a fascinating study on experimental colitis, the authors demonstrate that certain levels of ROS (reactive oxygen species, well known to be damaging at higher levels) are critically necessary to regulate the Treg (regulatory T cell) function that controls autoimmune inflammation. Moreover, of premiere clinical importance is their observation that higher levels of glutathione that excessively dampened ROS blocked Treg function and thus worsened the inflammation of inflammatory bowel disease (IBD). Antioxidants, of course, are employed to keep the lid on ROS. And with good reason:

Reactive oxygen species (ROS) are highly reactive and interact with many bio-molecules. At high concentrations, they are likely to destroy biological structures, promoting cellular damage and tissue destruction. Traditionally, ROS have been implicated in ageing and the progression of inflammatory and autoimmune diseases, including inflammatory bowel diseases (IBD).

However…

Meanwhile, many recent observations are opposing the traditional concept on ROS, suggesting the protective role of ROS in immune-mediated inflammatory diseases.”

The authors relate the fascinating background to this study on ROS, antioxidants and autoimmune inflammation:

“Mice with lower level of ROS than WT mice due to defects in ROS-producing enzyme system, such as Ncf1−/− or Nox2−/−, are more susceptible to autoimmune diseases, such as arthritis and encephalomyelitis. Humans with lower levels ROS than normal persons, such as chronic granulomatous disease (CGD) patients and carriers, are also more susceptible to autoimmune diseases. By contrast, mice with higher level ROS than WT mice due to the defect in a ROS metabolizing enzyme, glutathione peroxidase-1 (GPx-1), are resistant to immune-mediated inflammatory diseases, such as allergen-induced airway inflammation and high fat diet-induced atherosclerosis. In particular, mice with higher level of ROS due to defect of a non-enzymatic cellular anti-oxidant, peroxiredoxin (Prx) II, are resistant to dextran sodium sulfate (DSS)-induced colitis.”

In other words, more enzyme activity producing antioxidants such as glutathione and peroxiredoxin increased susceptibility to autoimmune inflammatory disorders. Moreover…

“These clinical or experimental observations implicated the immunoregulatory role of ROS, and adoptive-transfer of CD4+ cells from rats with lower ROS level induced arthritis in rats with normal ROS level, demonstrating the key role of CD4+ cells in the hyperinflammatory response in lowered levels of ROS. On the other hand, oxidative stress induces T cell hyporesponsiveness in several human pathologies (e.g. cancer, rheumatoid arthritis, AIDS and leprosy). Accordingly, ROS level is supposed to be closely associated with T cell responsiveness. In particular, regulatory T cell (Treg) function seems to be closely linked to ROS level. Tregs isolated from mice with lower level of ROS, such as Ncf1−/− mice, were hypofunctional than WT Tregs. Tregs were also hypofunctional in vitro at lowered levels of ROS by adding antioxidants or NADPH oxidase inhibitors. Differentiation of inducible Treg (iTreg) seems also linked to the level of ROS. Induction of FoxP3+ iTreg was attenuated, whereas that of Th17 cells was enhanced in lowered levels of ROS due to Nox2 deficiency or addition of apocynin. By contrast, induction of FoxP3+ Treg was enhanced in elevated levels of ROS due to PrxII deficiency.”

Thus, whereas excessive oxidative stress (ROS) with insufficient antioxidants can contribute to T cell hypoactivity in some pathologies including cancer and AIDS, levels of regulatory T cell (FoxP3+ iTreg) that rein in autoimmune Th17 inflammation are suppressed in the presence to ROS levels that are too low.

Colitis inflammation attenuated in KO mice, aggravated by NACSo the authors set out to investigate the suppressive function of Tregs isolated from mice with elevated levels of ROS due to defects in the enzymes that make the antioxidatns glutathione (GPx1) and catalase. Their results illuminated the aspects of ROS and antioxidants that are critical to case management of inflammatory disorders:

“In the present study, we demonstrated for the first time that Tregs were hyperfunctional in elevated level of ROS by using GPx1−/− × Cat−/− Tregs. As it has been already reported that Tregs were hypofunctional in lowered levels of ROS, it could be argued that Treg function is closely linked to ROS level. Actually in the present study, IP injection of NAC [N-acetylcysteine] into GPx1−/− × Cat−/− mice reduced the suppressive function of Tregs to the level comparable to WT Tregs. Administration of NAC also has made GPx1−/− × Cat−/− mice, which are naturally resistant, susceptible to DSS-induced colitis, suggesting the critical role of ROS in the prevention of DSS-induced colitis. The importance of Tregs in the maintenance of intestinal immune balance has been already shown in many other studies. Consequently, ROS level might be critical in the maintenance of intestinal immune homeostasis, providing an insight for the immunomodulation by ROS.”

In other words, elevated ROS increase the antiinflammatory activity of Treg cells, while administration of NAC (which increases glutathione production) suppressed Tregs by reducing ROS, resulting in increased intestinal inflammation.

Clinical note: Excessive suppression of ROS by overenthusiastic application of antioxidants can disturb immune homeostasis resulting in increased autoimmune inflammation.

The authors also shed light on the association of ROS and inflammation with tryptophan metabolism:

At molecular level, the expression of an immunoregulatory enzyme, IDO, is also associated with ROS level. IDO catabolizes the essential amino acid tryptophan into the stable metabolite, kynurenine. Consequently, IDO depletes tryptophan from the environment, thus starving effector cells. It was also found that tryptophan depletion resulted in inhibition of Th17 cell differentiation and expansion of Foxp3+ Tregs….Thus, IDO expression might be induced as a consequence of the inflammatory reaction, contributing to the feedback regulation…Elevated levels of ROS not only contribute to the induction but also enhance the enzyme activity of IDO, as superoxide radical acts as a cofactor of IDO. Therefore, high expression and strong activity of IDO from the beginning in GPx1−/− × Cat−/− mice might contribute to the preparation of immunosuppressive environment preventing inflammatory tissue damage during treatment with DSS.”

Clinical note: antioxidant and ROS status can be investigated with a urinary organic acid analysis that includes p-Hydroxyphenyllactate, 8-Hydroxy-2′-deoxyguanosine, kynurenate and quinolinate; and a blood assay for oxidative stress that includes cysteine, cystine, glutathione, glutathione peroxidase, lipid peroxides, sulfate, superoxide dismutase (SOD), and total antioxidant capacity (TAC).

The authors summarize implications for modulation of ROS by antioxidants:

“Actually in the present study, the frequency of FoxP3+ cells was significantly increased in parallel with significantly attenuated inflammatory reaction in the lesions of DSS-induced colitis in mice with elevated level of ROS due to defects in GPx1 and Cat. By contrast, IP injection of NAC significantly reduced the frequency of FoxP3+ cells and aggravated inflammatory reaction in the lesions of DSS-induced colitis… we demonstrated an experimental colitis was attenuated in elevated level of ROS. Enhancement of Treg function and IDO expression, investigated in the present study, might be involved in the underlying mechanism…Taken together, the results of the present study suggest the potential therapeutic strategy for IBD through immunomodulation by ROS.”

ROS and Psoriasis

The same team of scientists a study also in PLOS One similarly investigating the role of ROS and by implication the use of antioxidants in regard to psoriatic dermatitis:

Psoriasis is a chronic inflammatory skin disease resulting from immune dysregulation. Regulatory T cells (Tregs) are important in the prevention of psoriasis. Traditionally, reactive oxygen species (ROS) are known to be implicated in the progression of inflammatory diseases, including psoriasis, but many recent studies suggested the protective role of ROS in immune-mediated diseases. In particular, severe cases of psoriasis vulgaris have been reported to be successfully treated by hyperbaric oxygen therapy (HBOT), which raises tissue level of ROS. Also it was reported that Treg function was closely associated with ROS level. However, it has been only investigated in lowered levels of ROS so far.”

The authors state:

Psoriasis is known to develop as a result of immune dysregulation, in particular hyperfunction of T helper 17 (Th17) cells. In steady state, immune homeostasis is maintained by regulatory T cells (Tregs) that suppress immune effectors including Th17 cells. It was also reported that psoriasis is associated with impaired suppressive function of Tregs. Therefore, in order to restore the dysregulated immune status in psoriasis, it is necessary to suppress immune effectors including Th17 cells and/or to enhance Tregs.”

Consonant with their study on colitis:

“Traditionally, reactive oxygen species (ROS) are known to be implicated in the progression of many inflammatory diseases. As ROS are highly reactive and interact with many bio-molecules, they are likely to destroy biological structures, promoting cellular damage and tissue destruction. In contrast, many recent evidences are accumulating on the protective role of ROS in immune-mediated diseases. Autoimmune arthritis was aggravated in rodents with lower levels of ROS than wildtype (WT) mice due to defects in ROS-producing enzyme system, such as mutation in the neutrophil cytosolic factor (Ncf)-1 or NADPH oxidase (NOX)2. In human, too, many autoimmune diseases develop more frequently in chronic granulomatous disease (CGD) patients with lower level of ROS than normal persons due to defect in ROS-producing NOX. To the contrary, experimentally induced asthmatic inflammation was attenuated in mice with higher level of ROS than WT mice due to the defect of a ROS metabolizing enzyme, glutathione peroxidase-1 (GPx-1). Atherosclerotic lesions induced by high-fat diet were also decreased in GPx-1−/− mice. In addition, experimental colitis was attenuated in mice with a higher level of ROS due to defect in a non-enzymatic anti-oxidant, peroxiredoxin II.”

So they set out to…

“…clarify the relationship between ROS level and Treg function, as well as their role in the pathogenesis of psoriasis, we investigated imiquimod-induced psoriatic dermatitis (PD) in association with Treg function both in elevated and lowered levels of ROS by using knockout mice, such as glutathione peroxidase-1−/− and neutrophil cytosolic factor-1−/− mice, as well as by using HBOT or chemicals, such as 2,3-dimethoxy-1,4-naphthoquinone and N-acetylcysteine.

Reactive Oxygen Species Prevent Imiquimod-Induced Psoriatic Dermatitis through Enhancing Regulatory T Cell FunctionHere too they found that moderately high levels of ROS were protective against autoimmune inflammation PD (psoriatic dermatitis):

The results consistently showed Tregs were hyperfunctional in elevated levels of ROS, whereas hypofunctional in lowered levels of ROS. In addition, imiquimod-induced PD was attenuated in elevated levels of ROS, whereas aggravated in lowered levels of ROS. For the molecular mechanism that may link ROS level and Treg function, we investigated the expression of an immunoregulatory enzyme, indoleamine 2,3-dioxygenase (IDO) which is induced by ROS, in PD lesions. Taken together, it was implied that appropriately elevated levels of ROS might prevent psoriasis through enhancing IDO expression and Treg function.”

Reflecting on the clinical significance of these results and the crucial difference between moderately high levels of ROS which are protective versus higher levels that are damaging:

“In the present study, we demonstrated that imiquimod-induced PD was attenuated in elevated levels of ROS, whereas aggravated in lowered levels of ROS. This observation provides experimental evidence supporting the immunoregulatory role of ROS, that is contradictory to the traditional concept. Traditionally, ROS is implicated in the progression of inflammatory diseases by promoting cellular damage and tissue destruction as well as ageing. At the moment, it is necessary to establish a new conceptual framework where the recent observations and the traditional concept can be compromised…Taken together, we can imagine a threshold level of ROS that divides the moderately high tolerable range and the intolerably higher levels. In the higher levels such as GPx-1−/−×GPx-2−/− mice, inflammatory reactions are augmented due to the direct tissue damage by ROS. Many evident previous observations that contribute to establish the traditional concept of ROS, such as vascular reperfusion injury and other in vitro observations, might fall in this range of intolerably higher levels of ROS. In contrast, as demonstrated previously by others and by us in the present study, inflammatory diseases are attenuated in the moderately high tolerably ranges such as in GPx-1−/− or PrxII−/− mice. Thus, we suppose some kinds of anti-inflammatory mechanisms are operating in the moderately high tolerable range of ROS. As ROS can induce direct tissue damages at high levels, it would be natural to develop defensive or compensatory mechanisms counteracting the destructive effects of ROS in the body.”

Clinical note: Here is where the rubber meets the road in clinical case management of autoimmune diseases in respect to ROS versus excessive use of antioxidants:

“In this aspect, enhancement of Treg function depending on ROS level is quite pertinent to counteract the destructive damages induced by ROS, as Tregs suppress every arm of immune response, including Th1, Th2, Th17, B, NK cells and DCsTregs play a critical role in the prevention of autoimmune diseases, and functional impairment of Tregs is important in the pathogenesis of psoriasis. Therefore, restoration or strengthening of impaired Treg function would be a desirable therapeutic strategy for psoriasis. The results of the present study suggested appropriately elevated levels of ROS could enhance Treg function, and thus might attenuate psoriasis.”

In particular for clinicians involved in case management of autoimmune disorders, from a personal communication with one of the lead authors Ju-young Seoh, MD, Ph,D.:

“Your understanding, “too much as well as too little antioxidant activity can be harmful, and too aggressive use of antioxidant agent, such as vitamin C, could impair Treg activity and accelerate autoimmune inflammatory activity.” is exact our message.”

 

Clinical Chimica ActaThe authors of a paper just published in Clinica Chimica Acta also note the distinction between low and high levels of ROS and the role of antioxidants:

“Oxidative stress plays a pivotal role in the development of human diseases. Reactive oxygen species (ROS) that includes hydrogen peroxide, hyphochlorus acid, superoxide anion, singlet oxygen, lipid peroxides, hypochlorite and hydroxyl radical are involved in growth, differentiation, progression and death of the cell. They can react with membrane lipids, nucleic acids, proteins, enzymes and other small molecules. Low concentrations of ROS has an indispensable role in intracellular signalling and defence against pathogens, while, higher amounts of ROS play a role in number of human diseases, including arthritis, cancer, diabetes, atherosclerosis, ischemia, failures in immunity and endocrine functions. Antioxidants presumably act as safeguard against the accumulation of ROS and their elimination from the system.”

Antioxidants and Exercise

Journal of the International Society of Sports NutritionIt’s edifying in this context to consider the effects of antioxidants on desirable physiological adaptations to the stress of exercise. In a study recently published in the Journal of the International Society of Sports Nutrition the investigators documented that while antioxidants increased the strength of muscle contraction acutely, there was also a suppression of the desirable growth hormone (GH) response to exercise (which increases muscle mass).

Antioxidant supplementation is known to increase human endogenous antioxidant (AOX) capacity providing a means of blunting exercise induced reactive oxygen species (ROS). The purpose of this study was to compare the effects of a single acute dose of an AOX (vs blinded placebo) on muscle contractile performance and hormonal responses to a single bout of lower limb ‘hypertrophic’ resistance training (RT).”

Their data should be considered in the context of antioxidant supplementation and exercise:

“It was found that in comparison to a placebo mixture, subjects were able to perform 3.75% more work (W), and generate greater mean concentric power and velocity throughout the HTS after consuming the AOX mixture…however circulating GH levels was significantly reduced in the AOX trial compared to the placebo trial…This would suggest that the GH results from this study indicate they may be undesirable in regards to promoting muscular hypertrophy. It is therefore of interest for future studies to examine whether this decreased circulating GH would affect muscular hypertrophy after a prolonged period of use or whether it acutely affects IGF-1 levels. Moreover, recent research suggests excessive AOX supplementation may hinder important physiological training adaptations. This has prompted the suggestion that optimal oxidant content for maximal force production exists within the muscle…GH secretion is involved in MH and strength development and its attenuation may negatively impact training adaptations…These recent findings and the GH results in this study, highlight the need to further our understanding of the effect of AOX supplementation on training adaptations.”

 

Sports MedicineThese results further validate the findings documented in paper published a couple of years earlier in the journal Sports Medicine:

“High levels of reactive oxygen species (ROS) produced in skeletal muscle during exercise have been associated with muscle damage and impaired muscle function. Supporting endogenous defence systems with additional oral doses of antioxidants has received much attention as a noninvasive strategy to prevent or reduce oxidative stress, decrease muscle damage and improve exercise performance…The consistent finding is that antioxidant supplementation attenuates exercise-induced oxidative stress. However, any physiological implications of this have yet to be consistently demonstrated, with most studies reporting no effects on exercise- induced muscle damage and performance. Moreover, a growing body of evidence indicates detrimental effects of antioxidant supplementation on the health and performance benefits of exercise training. Indeed, although ROS are associated with harmful biological events, they are also essential to the development and optimal function of every cell. The aim of this review is to present and discuss 23 studies that have shown that antioxidant supplementation interferes with exercise training-induced adaptations.”

Here again we see that antioxidants have both positive and negative effects:

“The main findings of these studies are that, in certain situations, loading the cell with high doses of antioxidants leads to a blunting of the positive effects of exercise training and interferes with important ROS-mediated physiological processes, such as vasodilation and insulin signalling. More research is needed to produce evidence-based guidelines regarding the use of antioxidant supplementation during exercise training.”

 

Bottom line: The use of antioxidants must be calibrated with careful consideration of the balance between protective and suppressive effects according to the needs of the individual patient by observing appropriate lab values for ROS and oxidative damage, outcomes for regulation of inflammation, and the patient’s subjective impression of energy versus fatigue.

Thyroid in heart, metabolism, brain, kidney; vital importance of T3

The American Journal of MedicineNote: Scroll to the bottom of this post for an ‘executive summary.’

Thyroid disorders have widespread impact and although subclinical hypothyroidism and low triiodothyronine (T3) syndrome are common they are frequently overlooked in practice.

Thyroid function is very important for cardiovascular health. The authors of freshly published paper in The American Journal of Medicine remind readers:

Thyroid hormones modulate every component of the cardiovascular system necessary for normal cardiovascular development and function. When cardiovascular disease is present, thyroid function tests are characteristically indicated to determine if overt thyroid disorders or even subclinical dysfunction exists.”

The authors apparently rely on TSH as do many others, but in my opinion and as subsequent papers illustrate, this can result in many missed diagnoses…

“As hypothyroidism, hypertension and cardiovascular disease all increase with advancing age monitoring of TSH, the most sensitive test for hypothyroidism, is important in this expanding segment of our population. A better understanding of the impact of thyroid hormonal status on cardiovascular physiology will enable health care providers to make decisions regarding thyroid hormone evaluation and therapy in concert with evaluating and treating hypertension and cardiovascular disease.”

This includes the…

“…potential role of overt and subclinical hypothyroidism and hyperthyroidism in a variety of cardiovascular diseases.”

 

The Annals Of Thoracic SurgeryMore inspiration to  not overlook the widespread occurrence and clinical importance of low T3 (triiodothyronine, the ‘active’ thyroid hormone) is offered in a study just published in The Annals of Thoracic Surgery differentiates low triiodothyronine syndrome from gross hypothyroid in the context of coronary artery disease.

“There is strong clinical and experimental evidence that altered thyroid homeostasis negatively affects survival in cardiac patients, but a negative effect of the low triiodothyronine (T3) syndrome on the outcome of coronary artery bypass grafting (CABG) has not been demonstrated. This study was designed to evaluate the prognostic significance of low T3 syndrome in patients undergoing CABG.”

The authors evaluated 806 consecutive CABG patients for any effect of baseline free T3 (fT3) concentration and of preoperative low T3 syndrome (fT3 <2.23 pmol/L) on the risk of low cardiac output (CO) and death, finding a significant association:

“There were 19 (2.3%) deaths, and 64 (7.8%) patients experienced major complications. After univariate analysis, fT3, low T3, New York Heart Association class greater than II, low left ventricular ejection fraction (LVEF), and emergency were associated with low CO and hospital death…At multivariate analysis, only fT3, low T3, emergency, and LVEF were associated with low CO, and fT3 and LVEF were the only independent predictors of death.”

They summarize these striking results in their conclusion:

“Our study demonstrates that low T3 is a strong predictor of death and low CO in CABG patients. For this reason, the thyroid profile should be evaluated before CABG, and patients with low T3 should be considered at higher risk and treated accordingly.”

 

Acta CardiologicaIn this vein a very interesting paper was published in the journal Acta Cardiologica (Official Journal of the Belgian Society of Cardiology) that identifies low free (bioactive) T3 as a contributor to the development of cardiac dysfunction. The authors outline their intent:

“A low T3 syndrome was described in patients with heart failure (HF), and it appears to be associated with adverse outcome, representing an independent predictor of mortality. However, it is not known if low T3 levels contribute to the pathophysiology of HF. On the other hand, it has been seen that an elevation of brain natriuretic peptides (BNP and NT-proBNP) may represent a warning signal for future cardiovascular disease and may be an early marker of diastolic dysfunction. Therefore we tested the hypothesis that low levels of free-triiodothyronine (FT3) are sufficient to determine an increased concentration of the amino-terminal fragment of pro-brain natriuretic peptide (NT-proBNP), as the result of an initial and asymptomatic cardiac impairment.”

They evaluated thyroid function and measured NT-proBNP in 52 consecutive non-cardiac patients. Dividing them into a low T3 group (19 patients) and a normal T3 group (33 patients) they found…

“The median NT-proBNP concentration of patients with low T3 syndrome was significantly higher than in those with normal FT3 (370 vs. 120 pg/ml). There is a strong and inverse correlation between FT3 and Log NT-proBNP (R = -0.47); this relation persists in a multivariable regression analysis, after adjustment for other potentially confounding variables.”

The authors articulate the clinical significance in their conclusion:

“In absence of overt cardiovascular disease, patients with low T3 syndrome present an increased concentration of NT-proBNP. These data suggest that low FT3 levels may be a contributing factor for the development of cardiac dysfunction.”

 

European Journal of Clinical InvestigationThe same syndrome of subclinical low thyroid manifesting as low T3 applies to stroke as well according to a study published in the European Journal of Clinical Investigation. The authors state:

Low triiodothyronine (T3) has been associated with increased short-term mortality in intensive care unit patients and long-term mortality in patients with heart disease. The objective of this study was to investigate possible associations of thyroid hormone status with clinical outcome in patients admitted for acute stroke.”

Considering T3 values ≤ 78 ng dL (1·2 nmol L as ‘low T3’ and T4 values ≤ 4·66 µg dL (60 nmol L) were as ‘low T4′, they examined data for 737 consecutive patients with acute first ever stroke within 24 hours of onset. They measured total T3, thyroxin (T4) and thyroid-stimulating hormone (TSH) levels and evaluated the basic clinical characteristics, stroke risk factors, and brain imaging. Low thyroid (T3) turned out to be a significant predictor:

“Four hundred and seventeen (56%) patients had T3 values ≤ 78 ng dL−1 and 320 had normal T3 values. The 1-year mortality was 27·34% for low T3 and 19·37% for normal T3 cases. A smaller percentage of patients with low T3 values were independent at 1 year compared to those with normal T3 values [54·2% vs. 68·7%, odds ratio (OR) = 0·53]. Cox regression analysis revealed that increased age, haemorrhagic stroke, low Scandinavian Stroke Scale score, increased glucose and low T3 values (hazards ratio 0·69) were significant predictors of 1-year mortality.”

Clinicians should bear in mind the authors’ conclusion about low T3 thyroid syndrome and stroke:

“A high proportion of patients with acute stroke were found soon after the event with low T3 values. The low-T3 syndrome is an independent predictor of early and late survival in patients with acute stroke, and predicts handicap at 1 year.”

 

Saudi Medical JournalA valuable paper published in the Saudi Medical Journal offers evidence that low T3 is the strongest correlate of suboptimal thyroid function with metabolic syndrome and insulin resistance. The authors determined to…

“…determine the association between thyroid hormones, insulin resistance, and metabolic syndrome in euthyroid women.”

They examine forty-five women free of past medical conditions by estimating body fat and measuring fasting blood for total triiodothyronine (T3), total thyroxine (T4), thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), lipids, insulin, and glucose. T3 turned out to be a much more significant indicator than T4:

“The mean age of the participants was 32.6 +/= 9.6 years with a body mass index (BMI) of 29.9 +/= 3.8 kg/m2. Evidence of homeostasis model assessment index for insulin resistance (HOMA-IR) more than 3 was seen in 34 (75%) and metabolic syndrome in 29 (64%) participants. Total T3 showed a positive correlation with triglycerides, low density lipoprotein- cholesterol (LDL-C), total cholesterol, insulin, HOMA-IR and negatively with body fat. Thyroid-stimulating hormone correlated positively with BMI, insulin, HOMA-IR, LDL-C and negatively with HDL-cholesterol (p<0.05). Free triiodothyronine correlated positively with waist circumference and T4 did not correlate with metabolic syndrome parameters.”

The authors conclude:

“Our preliminary data show an association between thyroid hormones and some components specific of the metabolic syndrome in euthyroid women. Total triiodothyronine and TSH correlated more with variables of metabolic syndrome than FT3 and T4.”

 

Endocrine JournalLow-grade systemic inflammation is a common denominator of aging and almost every chronic disease. It is, of course, a key factor in both type 2 diabetes and thyroid disorders. A study published recently in the Endocrine Journal (Japan Endocrine Society) demonstrates the association of type 2 diabetes with low T3 in the context of low-grade systemic inflammation:

“Previous reports highlight the role of systemic inflammation in the genesis of non-thyroidal illness syndrome and type 2 diabetes mellitus (T2DM). Our objective was to assess whether body mass index and the low-grade systemic inflammation would be associated with changes in thyroid hormone metabolism in patients with type 2 diabetes.”

They examined data for 104 subjects, half with type 2 diabetes and half comprised a control group who were paired by age, gender and body mass index. They measured total (T) and free (F) thyroxine (T4) and triiodothyronine (T3), reverse T3 (rT3), the ratios FT3/rT3, FT3/FT4 and FT4/rT3, and obtained additional data on diabetes duration and complications, body mass index, waist circumference, hypertension, HbA1c, and high sensitivity C-reactive protein. T3 stands out here as well:

“Patients with DM presented lower levels of TT4, TT3 and FT3 and higher of FT4, waist circumference and C-reactive protein. Body mass index was inversely correlated with FT4 and TT3. C-reactive protein was positively correlated with rT3 and inversely with FT4/rT3 and FT3/rT3. Body mass index was an independent predictor for FT4 and TT3 levels. Inflammation predicted the FT4/rT3 ratio. C-reactive protein and body mass index were independent predictors for rT3.”

Clinical note: this implies that thyroid assessment is incomplete if it doesn’t include at least free and total T3 and T4 (along with TSH). The authors conclude with a statement of great significance because it is so common to encounter in clinical practice:

“In conclusion, type 2 diabetes was associated with a low T3 state. Body mass index and the low-grade systemic inflammation are related to the non-thyroidal illness syndrome in these patients, possibly by altering the activity of peripheral deiodinases.”

I find low-grade systemic inflammation impairment of the activity of deiodinase enzymes to convert T4 into the metabolically active T3 regularly in my patient population.

 

Journal of Clinical Endocrinology & MetabolismMore complete assessment of seemingly euthyroid (‘normal’ thyroid) patients is often dismissed with the  test data limited meagerly to TSH and total T4 levels, a practical flaw that likely fails to uncover many diagnoses. In a study published in the Journal of Clinical Endocrinology & Metabolism, the authors demonstrate that ‘low normal’ free T4 correlated significantly with metabolic syndrome and cardiovascular risk factors. The authors state:

“Thyroid disease and the metabolic syndrome are both associated with cardiovascular disease…The aim of this study was to explore the hypothesis that thyroid function, in euthyroid subjects, is associated with components of the metabolic syndrome, including serum lipid concentrations and insulin resistance.”

They assessed data for 2703 euthyroid adult subjects that included homeostasis model assessment for insulin resistance (HOMA-IR and usual criteria for metabolic syndrome:

“After adjustment for age and sex, free T4 (FT4) was significantly associated with total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides. Both FT4 and TSH were significantly associated with HOMA-IR. Median HOMA-IR increased from 1.42 in the highest tertile of FT4 to 1.66 in the lowest tertile of FT4. FT4 was significantly related to four of five components of the metabolic syndrome (abdominal obesity, triglycerides, high-density lipoprotein cholesterol, and blood pressure), independent of insulin resistance.”

Clinical note: so-called euthyroid = ‘normal’ thyroid or ‘subclinical hypothyroid’ must not be overlooked in case management of metabolic syndrome and cardiovascular risk. The authors conclude by asserting:

“We have demonstrated an association between FT4 levels within the normal reference range and lipids, in accordance with the earlier observed association between (sub)clinical hypothyroidism and hyperlipidemia. Moreover, low normal FT4 levels were significantly associated with increased insulin resistance. These findings are consistent with an increased cardiovascular risk in subjects with low normal thyroid function.”

 

Metabolic Syndrome and Related DisordersMore on T3 and metabolic syndrome was presented in a study published in the journal Metabolic Syndrome and Related Disorders (yes, there is a journal by that title) in which the authors examined date for 211 patients with a mean age of about 40 years who had a body mass index (BMI) >30 kg/m(2) without any other hormonal disorder related to obesity. Measurements included fasting blood glucose (FBG), insulin, insulin resistance (HOMA-IR),total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), thyroid-stimulating hormone (TSH), total triiodothyronine (TT3), total thyroxine (TT4), free T3 (FT3), and free T4 (FT4). They used TSH cutoff value of 2.5 mU/L. Sure enough T3 stood out:

Metabolic syndrome positive patients had significantly higher FBG, triglycerides, FT4, systolic (SBP) and diastolic blood pressure (DBP), and statistically lower HDL-C and FT3/FT4 ratio than metabolic syndrome negative patients. TSH decreased with age and was not related with any metabolic syndrome parameters. The FT3/FT4 ratio negatively correlated with FBG, triglycerides, SBP, and DBP; TT3 positively correlated with HOMA-IR, FBG, and waist circumference.”

In other words, as free T3 went down in relation to free T4 fasting blood glucose, triglycerides, and both systolic and diastolic blood pressure went up. And as total T3 went down insulin resistance, fasting blood glucose and waist circumference went up. The authors conclude:

“”Metabolic syndrome parameters (except HDL) correlated with TT3, FT4, and the FT3/FT4 ratio. FT4 levels were associated with obesity and metabolic syndrome independently of insulin resistance, whereas TT3 levels were associated with both insulin resistance and metabolic syndrome. This relationship can be explained by compensatory effects of TT3, and probably FT4, on energy expenditure and thermogenesis in obese people.”

 

Journal of Clinical InvestigationAt the crux of the matter is the manner in which low grade chronic inflammation impairs conversion of the relatively inactive T4 thyroid hormone to the active T3. The authors of a very valuable paper published in The Journal of Clinical Investigation shed light on an important mechanism by describing the role of the pro-inflammatory cytokine IL-6.

Nonthyroidal illness syndrome (NTIS) is a state of low serum 3,5,3′ triiodothyronine (T₃) that occurs in chronically ill patients; the degree of reduction in T₃ is associated with overall prognosis and survival. Iodthyronine deiodinases are enzymes that catalyze iodine removal from thyroid hormones; type I and II deiodinase (D1 and D2, respectively) convert the prohormone thyroxine T₄ to active T₃, whereas the type III enzyme (D3) inactivates T₄ and T₃. Increased production of cytokines, including IL-6, is a hallmark of the acute phase of NTIS.”

They investigated this by measuring the effect of IL-6 the different types deiodinase activities in human cell lines. (Recall that deiodinase enzyme activity is required to convert T4 to T3.) Their results reveal not only the role of pro-inflammatory IL-6, but implicate glutathione (GSH) as a likely key factor:

Active T₃ generation by D1 and D2 in intact cells was suppressed by IL-6, despite an increase in sonicate deiodinases (and mRNAs). N-acetyl-cysteine (NAC), an antioxidant that restores intracellular glutathione (GSH) concentrations, prevented the IL-6-induced inhibitory effect on D1- and D2-mediated T₃ production, which suggests that IL-6 might function by depleting an intracellular thiol cofactor, perhaps GSH. In contrast, IL-6 stimulated endogenous D3-mediated inactivation of T₃.”

The authors’ conclusion contains comments of great clinical significance:

“In conclusion, our findings demonstrated that pathophysiologically relevant concentrations of IL-6 reduce D1 and D2 function and increase that of D3, providing a single mechanistic explanation for the decreased serum T3 and increased rT3 observed in the acute phase of NTIS. The decrease in D1 will both reduce plasma T3 production and impair rT3 deiodination, while the decrease in D2 will supplement this by impairing intracellular T4-to-T3 conversion. On the other hand, the increased D3 protein, which has its function preserved by its more ready access to GSH (or other extracellular reducing agents), will further decrease plasma T3 and increase the production of rT3 from T4. The general increase in the cellular deiodinase proteins is caused by a combination of IL-6–induced ROS (also found with H2O2) and specific activation of JAK/STAT pathways by this cytokine.”

In a larger context…

“Although other factors in sick patients may also contribute to NTIS, these observations and unifying hypothesis represent a major step forward in unraveling this longstanding enigma, leading to what we believe to be a previously unrecognized combinatorial pathway that may be viewed largely as a general response to oxidative stress. Our results therefore suggest that rather than a protective or a maladaptive process, the changes in plasma T4, T3, and rT3 are a consequence of cellular stress. Whether antioxidants, such as NAC, could be beneficial as an adjuvant therapy together with other therapeutic measures in critically ill patients remains to be evaluated.”

 

Nephrology Dialysis TransplantationFurther insight into the nature of the low T3 in thyroid dysregulation associated with chronic disease is offered in a study published in the journal Nephrology Dialysis Transplantation on chronic kidney diseae (CKD) and low T3. These authors observe:

“The evaluation of thyroid function in systemic illness remains complex because the changes occur at all levels of the hypothalamic-pituitary-thyroid axis. During illness, a decrease in triiodothyronine (T3) and pulsatile thyroid-stimulating hormone (TSH) release and increases in reverse T3 occur. This constellation of findings is termed the low T3 syndrome, the euthyroid sick syndrome or non-thyroid illness. Low T3 syndrome is the most common manifestation in non-thyroid illness and this phenomenon has been believed to be due to inhibition of 5′-deiodinase, which is a catalyzing enzyme for production of T3 from circulating T4. To date, a variety of alterations in thyroid hormone levels and metabolism have been reported in patients with chronic renal failure and low T3 has been consistently found to be the most common disturbance.”

Of widespread importance:

“Several lines of evidence suggested that low T3 was an independent predictor of survival in various illness states. Furthermore, the recent data proposed that biomarkers of inflammation were associated with low T3 levels in haemodialysis and peritoneal dialysis patients and thyroid dysfunction might be implicated in the pathogenetic pathway which link microinflammation to survival in dialysis patients.”

They determined to see if low T3 correlated to chronic kidney disease prior to the stage of dialysis:

“However, there are no data about the prevalence of low T3 in persons with chronic kidney disease (CKD) who do not require maintenance dialysis. We hypothesized that the prevalence of low T3 would be increased according to the increase of a CKD stage. This study was performed to explore the prevalence in each stage of CKD and relationship with eGFR.”

Their data on 2284 subjects with normal serum TSH and not taking thyroid hormones confirmed their hypothesis, leading to the conclusion:

“This study showed that low T3 syndrome was highly prevalent in CKD and was a remarkable finding in early CKD. Furthermore, serum T3 levels were associated with severity of CKD even in the normal TSH level.”

 

Iranian Journal of Kidney DiseasesAlong these lines a study showing that low T3 in various conditions including CKD is linked to systemic low grade inflammation reflected in altered cytokines was published in the Iranian Journal of Kidney Diseases. The authors evaluated the interleukins (IL) IL-6 and IL-10 and euthyroid sick syndrome (ESS) in patients with nonthyroidal illnesses (NTI) including chronic kidney disease (CKD), congestive heart failure (CHF), or acute myocardial infarction (MI) while measuring serum levels of IL-6 and IL-10, thyroid stimulating hormone (TSH), total T4, and T3:

“In the 60 patients with NTI, we detected a significantly lower T3 and T4 levels compared to controls, while TSH level was within the reference range. Also, IL-6 level was substantially higher than that in controls and correlated with T3 and T4. Similarly was IL-10 level that correlated with T3, but not with T4. The ILs correlated positively with each other. Only IL-6 was a predictor of low T3. The proportion of patients with subnormal T3, T4, and TSH levels was highest in those with MI along with greatest IL-6 and IL-10 levels compared to patients with CHF and CKD. Patients with CKD showed the least disturbance in IL-6 and IL-10 despite the lower levels of T3, T4, and TSH in a higher proportion of them compared to patients with CHF.”

Their discussion of these results contains some key points for clinicians:

“In the current study, we observed a considerably lower serum T3 and total T4 concentrations, signifying thyroid dysfunction, in patients with variable NTIs, while serum TSH showed a mean value that was not significantly different from that in the healthy controls…In this study, we detected a substantially high level of the pro-inflammatory cytokine, IL-6, in patients with NTI, supporting its possible role as an endocrine cytokine with a regulatory effect on many endocrine systems including the thyroid gland.”

Here is something readers who test cytokines may have seen too that illustrates a fundamental principal in case management and disease progression: suppression of receptors due to chronically high levels of signaling agents (in this case anti-inflammatory IL-10):

We also detected a considerably high level of the anti-inflammatory cytokine, IL-10 in the patients with NTI.Therefore, within the cytokine network, activation of pro-inflammatory mediators such as IL-6 is followed by increased production of endogenous inhibitory molecules including the antagonistic cytokine IL-10 in an attempt to suppress release of pro-inflammatory cytokines. This dimorphic response may be related to macrophages resistance to the suppressive effect of IL-10 as a result of down-regulation of the expression of soluble IL-10 receptors. The high IL-10 levels was hoped for to minimize the deleterious effect of the raised IL-6. Taniguchi and colleagues highlighted this potential protective effect of IL-10 in their 25 patients with systemic inflammatory states…In this study, the suppressed thyroid hormones were inversely associated with serum IL-6 elevations.”

There was a particularly strong association with heart attacks (MI), consonant with the degree of thyroid dysfunction tracking the severity of non-thyroidal illness:

“We observed a highest level of IL-6 along with lowest measurements of both serum T3 and serum T4 in the patients with MI, while the least changes were noticed in patients with chronic illness exemplified by CHF. This is in accordance with the hypothesis that the magnitude of thyroid hormones’ alteration parallels the severity of the associated NTI.”

 

Clinical note: It is very important for practitioners to bear in mind that thyroid effect, in addition to thyroid hormone production and conversion, encompasses thyroid hormone transporters and receptors. The felt metabolic and brain effects of thyroid activation depends on all of these. Failing to take them into consideration is a common reason why ‘subclinical hypothyroidism’, NTIS (nonthyroidal illness syndrome) or ESS (euthyroid sick syndrome) is often overlooked.

Journal of Molecular EndocrinologyA paper published in the Journal of Molecular Endocrinology sheds light on the role of MCT8, MCT10, organic anion transporting polypeptides (OATP) transporters:

“Thyroid hormone is a pleiotropic hormone with widespread biological actions. The follicular cells of the thyroid gland produce predominantly thyroxine (T4), but it is mainly 3,3′,5-tri-iodothyronine (T3) that binds to the nuclear thyroid hormone receptor. The biological activity of T3 is therefore largely determined by the intracellular T3 concentration which is dependent on a) the circulating T3 concentration; b) the transport of thyroid hormone across the cell membrane; and c) the presence of iodothyronine deiodinases, which activate or inactivate thyroid hormone. To date, three deiodinases have been characterized as homologous selenoproteins. Both D1 and D2 converts T4 to T3, whereas D3 catalyzes the degradation of T4 to reverse T3 (rT3) and of T3 to 3,3′-T2.”

The enzymes that convert T4 to T3 have their active portions inside the cell, and transporters are required to get T4 through the cell membrane into the cytoplasm where the action happens:

“The deiodinases are membrane proteins with their active sites located in the cytoplasm. Therefore, transport across the cell membrane is essential for thyroid hormone action and metabolism. Based on the lipophilic structure of thyroid hormones, it is long thought that thyroid hormone enters the cell through passive diffusion. However, it has become increasingly clear that there are specific thyroid hormone transporters, and that the activity of these transporters in part determines the intracellular thyroid hormone concentration.”

Thyroid hormone transporters MCT8 and MCT10Transporters MCT8, MCT10 and OATP have been the most studied:

“To date, several transporters with high affinity for thyroid hormone, but with different tissue distributions and ligand affinities have been identified. This review will focus on the molecular aspects of the monocarboxylate transporter 8 (MCT8) and MCT10, and several members of the organic anion transporting polypeptide (OATP) family…both MCT8 and MCT10 increase the intracellular availability of iodothyronines, as evidenced by the marked increase in their intracellular deiodination by co-transfected deiodinases. However, both MCT8 and MCT10 facilitate not only the cellular uptake but also the efflux of iodothyronines.”

In other words, they get necessary thyroid stuff both into and out of the cell. These transporters are subject to genetic variation of course, and some mutations in the MCT8 gene can cause severe psychomotor retardation:

Mutations in the MCT8 gene cause a syndrome of severe psychomotor retardation and high serum T3 levels in affected male patients, known as the Allan–Herndon–Dudley syndrome. The neurological deficits are probably explained by an impeded uptake of T3 in MCT8-expressing central neurons and, hence, an impaired brain development. This has been reviewed in detail elsewhere. Since mutations in the MCT8 gene have such profound effects, the question arises whether small changes in the MCT8 gene may affect transport activity as well.”

Such as depression, etc. The implication is that much milder disruption of MCT8 transporter function can significantly diminish metabolism in the brain that impairs cognition and mood. The authors conclude their lengthy paper detailing the action of other transports with comments of great clinical significance:

“…it has become clear that thyroid hormone requires active transport across cell membrane to carry out its biological functions…It is surprising that few studies have been published investigating the association of polymorphisms in these transporters with serum thyroid parameters or thyroid hormone-related endpoints, especially since polymorphism studies have yielded new insights into the role of thyroid hormone in several processes in the human body. For instance, a genome-wide linkage scan identified the type 2 deiodinase as a susceptibility locus for osteoarthritis. In addition, genetic variation seems to play a role in psychological well-being…”

 

Thyroid ResearchThe authors of a paper published in the journal Thyroid Research chime in with an expansion of these observations:

Thyroid hormones are of crucial importance for the functioning of nearly every organ. Remarkably, disturbances of thyroid hormone synthesis and function are among the most common endocrine disorders affecting approximately one third of the working German population. Over the last ten years our understanding of biosynthesis and functioning of these hormones has increased tremendously. This includes the identification of proteins involved in thyroid hormone biosynthesis like Thox2 and Dehal where mutations in these genes are responsible for certain degrees of hypothyroidism. One of the most important findings was the identification of a specific transporter for triiodothyronine (T3), the monocarboxylate transporter 8 (MCT8) responsible for directed transport of T3 into target cells and for export of thyroid hormones out of thyroid epithelial cells.”

They remind of the role of thyroid dysregulation in depression and dementia:

“Disturbed TH action is linked with major health problems especially in critical life phases such as development, disease or ageing. Thus, lack of TH action in the adult brain causes impaired neuro-cognitive function and psychiatric states such as severe depression and dementia. Not only hypothyroidism but also hyperthyroidism affects the CNS and frequently results in agitation, increased irritability and dysregulation of body temperature.”

Cardiovascular disease can also have a thyroid component:

“There is ample epidemiological evidence that both, hyper- and hypothyroidism confer an increased risk for cardiovascular morbidity(e.g. arrhythmia, heart failure and stroke) and mortality.”

Interestingly in regard to obesity:

“Besides the classic hormones T4 and T3 new data demonstrate that the rare thyroid hormone metabolite 3,5-T2 is effective in the prevention of high fat diet-induced adiposity and prevents hepatic steatosis, however, without exerting the severe side effects on the cardiac system that have been observed with T3-based treatments. The vital importance of thyroid hormones for regulation of thermogenesis and for maintenance of the homeostasis of the mitochondrial energy metabolism has long been established. However, the functional interactions between the activities of uncoupling proteins (UCP) which are triggered by T3 and catecholamines affecting brown adipose tissue (BAT) as well as skeletal muscle of the adult, provide new possibilities for therapeutic intervention in obesity that have only recently become apparent.”

Old and new concepts of thyroid hormone actionThey summarize a ‘bird’s-eye’ view of hormone physiology:

“Thus in the present concept of thyroid hormone action, the cellular thyroid hormone status is defined by thyroid hormone transporters, thyroid hormone membrane receptors, thyroid hormone molecules and TAM mediated actions.

There is no question that aging increases the tendency to subclinical hypothyroid conditions:

“Epidemiology has shown unequivocally that with age the ratio of subclinical to clinically manifest thyroid disorders increases, thus thyroid disorders are a disease of the ageing population. In light of the demographic changes of our societies, improvements of human health care systems should not be limited to better management of only cardiovascular disorders, cancer, and neurodegenerative diseases. We believe that modern and future-oriented health politics and policy making institutions need to take an endocrine organ into account that has been known for decades, but is still not fully “revealed”, the thyroid gland.”

 

Journal of EndocrinologyAppreciation of the weighty influence of the MCT8 transporter is enhanced by recognition of its role in the global neurological impairment of intrauterine growth restriction (IUGR) as described in a study published in the Journal of Endocrinology:

Intrauterine growth restriction (IUGR) describes the failure of a fetus to attain its genetically determined growth potential, with the most common underlying etiology being uteroplacental failure associated with abnormal placental development. IUGR is often characterized by continued head and brain growth at the expense of other less vital organs resulting in an elevated brain:liver weight ratio postnatally. IUGR complicates 5–10% of pregnancies and is associated with increased perinatal mortality. Survivors demonstrate an increased prevalence of cognitive impairment compared with babies born appropriately grown for gestational age.”

They measured changes in cortical MCT8 expression with IUGR by immunohistochemistry performed on brain sections obtained from appropriately grown for gestational age (AGA) human fetuses and MCT8 immunostaining in the occipital cortex of stillborn IUGR human fetuses which was compared with that in the occipital cortex of gestationally matched AGA fetuses:

“When complicated by IUGR, fetuses showed a significant fivefold reduction in the percentage area of cortical plate immunostained for MCT8 compared with AGA fetuses… Cortical MCT8 expression was negatively correlated with the severity of IUGR indicated by the brain:liver weight ratios at post-mortem. Our results support the hypothesis that a reduction in MCT8 expression in the IUGR fetal brain could further compromise TH-dependent brain development…This study is the first to demonstrate significantly reduced cortical MCT8 expression within the developing CNS of human fetuses stillborn with severe IUGR. Our results suggest that altered TH transporter activity in cerebral neurons could be a contributory factor to the pathophysiology of neurodevelopmental impairment associated with IUGR.”

 

Molecular and Cellular EndocrinologyAs described in an earlier post (Depression, aging and brain inflammation: indications for sustainable treatment) there is evidence that the global driving factor of biological aging is inflammation in the hypothalamus, practitioners doing case management of thyroid conditions should know the importance of thyroid hormone feedback in the hypothalamus and pituitary as described in a paper published in Molecular and Cellular Endocrinology:

“A major change in thyroid setpoint regulation occurs in various clinical conditions such as critical illness and psychiatric disorders. As a first step towards identifying determinants of these setpoint changes, we have studied the distribution and expression of thyroid hormone receptor (TR) isoforms, type 2 and type 3 deiodinase (D2 and D3), and the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) in the human hypothalamus and anterior pituitary.”

Their examination of these agents through immunoreactivity and immunostaining revealed important activity of hypothalamic glial cells:

“These findings suggest that the prohormone thyroxine (T4) is taken up in hypothalamic glial cells that convert T4 into the biologically active triiodothyronine (T3) via the enzyme D2, and that T3 is subsequently transported to TRH producing neurons in the PVN. In these neurons, T3 may either bind to TRs or be metabolized into inactive iodothyronines by D3. By inference, local changes in thyroid hormone metabolism resulting from altered hypothalamic deiodinase or MCT8 expression may underlie the decrease in TRH mRNA reported earlier in the PVN of patients with critical illness and depression.”

The pituitary, of course, also comes into play:

“In the anterior pituitary, D2 and MCT8 immunoreactivity occurred exclusively in folliculostellate (FS) cells. Both TR and D3 immunoreactivity was observed in gonadotropes and to a lesser extent in thyrotropes and other hormone producing cell types.”

The authors summarize their results:

“Based upon these neuroanatomical findings, we propose a novel model for central thyroid hormone feedback in humans, with a pivotal role for hypothalamic glial cells and pituitary FS cells in processing and activation of T4. Production and action of T3 appear to occur in separate cell types of the human hypothalamus and anterior pituitary.”

 

Pediatric Endocrinology ReviewsHormone receptors are a critical link in the signaling chain for thyroid as for other hormones and neurotransmitters. Receptor function can be impaired by elevated hormone levels, genetic mutation and chronic inflammation. A paper published in Pediatric Endocrinology Reviews serves as a reminder to consider thyroid hormone receptor function in case management:

The important physiological actions of the thyroid hormones are mediated by binding to nuclear thyroid hormone receptors (TRs), encoded by two genes TRalpha and TRbeta. These receptors act as hormone-dependent transcription factors by binding to DNA motifs located in the regulatory regions of target genes…”

Receptor resistance to thyroid hormones can cause a hypothyroid state in the presence of normal TSH and thyroid hormone levels:

“TRbeta gene mutations cause resistance to thyroid hormones (RTH), characterized by inappropriately high thyroid-stimulating hormone (TSH) levels due to lack of feedback inhibition of thyroid hormones on the hypothalamus and pituitary gland, and to reduced sensitivity of other TRbeta target tissues to thyroid hormones. Very recently, patients heterozygous for TRalpha mutations have been identified. These patients exhibit clinical symptoms of hypothyroidism in TRalpha target tissues such as intestine or heart and near normal circulating TSH and thyroid hormone levels.”

 

Nephrology Dialysis TransplantationChronic low-grade inflammation, also termed micro-inflammation, is an almost universal ‘fact of life’ in chronic disorders and aging. Its link to peripheral thyroid resistance and low T3 is seen in high magnification in Nephrology Dialysis Transplantation in which the authors observe its role in continuous ambulatory peritoneal dialysis (CAPD) patients with end-stage renal disease (ESRD):

Low T3 is a frequent alteration in patients with ESRD. This derangement has been recently linked to inflammation in haemodialysis patients. Whether this association holds true in peritoneal dialysis patients has not been studied…We investigated the relationship between low-grade inflammation [IL-6, C-reactive protein (CRP) and serum albumin levels] and free tri-iodothyronine (fT3) in a cohort of 41 CAPD patients without heart failure and inter-current illnesses.”

 

They found multiple correlations, including low free T3 as a predictor of mortality:

“CAPD patients had lower fT3 levels than healthy subjects of similar age. Free T3 levels were directly related to those of serum albumin and inversely to IL-6 and CRP. Age, haemoglobin levels and diastolic blood pressure were also related to fT3. In multiple regression models adjusting for all variables related to fT3, CRP and albumin were retained as independent correlates of fT3…Plasma fT3 levels were lower in patients who died compared with survivors. In Cox analyses, fT3 was a significant predictor of mortality independent of the main traditional as well as non-traditional risk factors.”

 

The association of micro-inflammation and low free T3 noted by the authors likely applies to numerous other conditions:

“The relationship between fT3, CRP and serum albumin suggests that inflammation–malnutrition might be involved in the low T3 syndrome in CAPD patients. Thyroid dysfunction might be implicated in the pathogenic pathway which links micro-inflammation to survival in PD patients.”

 

Journal of Endocrinological InvestigationClinicians should also keep in mind that low T3 can be the only thyroid abnormality contributing to psychiatric depression. A paper published in the Journal of Endocrinological Investigation focuses on the link between low T3 syndrome and depression.

“In euthyroid sick syndrome [non-thyroidal illness (NTI)], a number of investigators have described TSH and serum thyroid hormone abnormalities, low T3, low T3 and T4, increased T4, low TSH, etc. Those cases of NTI where there is only T3 decrease [and normal serum T4, free T4 (FT4), and TSH levels] are specifically referred to as low T3 syndrome. However, the information in regard to low T3 syndrome in psychiatric subjects who are clinically euthyroid and do not have any other systemic illness is scanty. In our facility, since thyroid function is routinely assessed in psychiatric patients at admission, this provided the opportunity to study low T3 syndrome in a large group of psychiatric patients.”

The authors found low T3 syndrome in a substantial percentage of depressed patients:

Out of 250 subjects with major psychiatric depression, 6.4% exhibited low T3 syndrome (mean serum T3 concentration 0.94 nmol/l vs normal mean serum concentration of 1.77 nmol/l). The low T3 levels could not be ascribed to malnutrition or any other illness and the metabolic parameters were all normal…The depression might constitute an illness having the same relation to low T3 as found in the low T3 syndrome previously described in euthyroid sick subjects. The present findings, besides describing low T3 syndrome in psychiatric patients without systemic illnesses, suggest the possibility of subgrouping in clinical psychiatric depression which may have a broader clinical significance.”

 

Minerva EndocrinologicaA point of premiere clinical importance is that supplemental T3 can be the treatment of choice in depression with hypothyroid as asserted by the authors of an excellent paper published in Minerva Endocrinologica:

Hypothyroidism has been linked to depression as there is irrefutable evidence that it triggers affective disease and psychic disorders. Depressive patients have a higher frequency of hypothyroidism and patients with hypothyroidism have a higher occurrence of depressive syndrome. Hypothyroidism exhibits considerable alterations in blood flow and glucose metabolism in the brain. Furthermore, patients with major depression may have structural abnormalities of the hippocampus that can affect memory performance. Thyroid peroxidase antibodies have, moreover, been positively associated with trait markers of depression.”

Remember that more than 90% of hypothyroid in developed countries is autoimmune thyroiditis (Hashimoto’s disease) with the presence of thyroid peroxidase antibodies, a frequent finding on laboratory tests that can be very significant even at ‘predictive’ (low) levels. Furthermore…

Depressive symptomatology is variable and is influenced by susceptibility and the degree, though not always, of thyroid failure. In addition, glucose homeostasis and rapid weight loss have been associated to thyroid hormones and increased depressive symptoms. Thyroxine treatment in patients older than 65 years does not improve cognition. In contrast, T3 administration is the therapy of choice in patients with resistance to antidepressive drugs, and especially to SSIR. Genetic variants of thyroid hormone transporters or of deiodinases I and II may predispose to depression and, therefore, a personalized approach should be implemented.”

 

BMC CancerAlso of great interest is the finding that treatment of subclinical hypothyroid/non-thyroidal illness syndrome (NTIS) with T3 can improve the response to chemotherapy in breast cancer as reported in a study published in BMC Cancer:

Thyroid hormones have been shown to regulate breast cancer cells growth, the absence or reduction of thyroid hormones in cells could provoke a proliferation arrest in G0-G1 or weak mitochondrial activity, which makes cells insensitive to therapies for cancers through transforming into low metabolism status. This biological phenomenon may help explain why treatment efficacy and prognosis vary among breast cancer patients having hypothyroid, hyperthyroid and normal function. Nevertheless, the abnormal thyroid function in breast cancer patients has been considered being mainly caused by thyroid diseases, few studied influence of chemotherapy on thyroid function and whether its alteration during chemotherapy can influence the response to chemotherapy is still unclear. So, we aimed to find the alterations of thyroid function and non-thyroidal illness syndrome (NTIS) prevalence during chemotherapy in breast cancer patients, and investigate the influence of thyroid hormones on chemotherapeutic efficacy.”

The authors examined thyroid hormone levels and NTIS prevalence at initial diagnosis of breast cancer and during chemotherapy in 685 patients (369 with breast cancer, 316 with breast benign lesions). They also measured the influence of thyroid hormones on chemotherapeutic efficacy by the chemosensitization test and compared chemotherapeutic efficacy between breast cancer cells with chemotherapeutics plus triiodothyronine (T3) versus chemotherapeutics only. A distinct benefit from treatment by T3 emerged from their data:

“In breast cancer, NTIS prevalence at the initial diagnosis was higher and increased during chemotherapy, but declined before the next chemotherapeutic course. Thyroid hormones decreased significantly during chemotherapy. T3 can enhance the chemosensitivity of MCF-7 to 5-Fu and taxol, with progression from G0-G1 phase to S phase. The similar chemosensitization role of T3 were found in MDA-MB-231. We compared chemotherapeutic efficacy among groups with different usage modes of T3, finding pretreatment with lower dose of T3, using higher dose of T3 together with 5-Fu or during chemotherapy with 5-Fu were all available to achieve chemosensitization, but pretreatment with lower dose of T3 until the end of chemotherapy may be a safer and more efficient therapy.”

Their conclusions are highly important for breast cancer management:

“Taken together, thyroid hormones decreasing during chemotherapy was found in lots of breast cancer patients. On the other hand, thyroid hormones can enhance the chemotherapeutic efficacy through gathering tumor cells in actively proliferating stage, which may provide a new adjuvant therapy for breast cancer in future, especially for those have hypothyroidism during chemotherapy.”

 

Clinical Endocrinology & MetabolismThyroid function tests may be often oversimplified to the detriment of the patient. As studies shown above and many more have shown, low T3 can be a complicating factor in a wide range of disorders. Dysregulation of thyroid function has multiple forms and causes. In a paper entitled Pitfalls in the measurement and interpretation of thyroid function tests published in Clinical Endocrinology & Metabolism the authors review conditions in which measuring TSH alone can be be particularly misleading:

When measuring TSH alone may misleadAnd they offer a diagram of different patterns of thyroid function tests and their causes:

Microsoft PowerPoint - ybeem_930_Koulouri et al - FIGURES - FINA

 

Nature Reviews EndocrinologyFinally, a paper recently published in Nature Reviews Endocrinology articulates an eloquent case for adding T3 to T4 and the need to recognize the patients who may need it:

Impaired psychological well-being, depression or anxiety are observed in 5–10% of hypothyroid patients receiving levothyroxine, despite normal TSH levels. Such complaints might hypothetically be related to increased free T4 and decreased free T3 serum concentrations, which result in the abnormally low free T4:free T3 ratios observed in 30% of patients on levothyroxine.”

Furthermore…

“Evidence is mounting that levothyroxine monotherapy cannot assure a euthyroid state in all tissues simultaneously, and that normal serum TSH levels in patients receiving levothyroxine reflect pituitary euthyroidism alone.”

No wonder then that more are resorting to the combination of T4 (levothyroxine) and T3 (liothyronine):

Levothyroxine plus liothyronine combination therapy is gaining in popularity; although the evidence suggests it is generally not superior to levothyroxine monotherapy, in some of the 14 published trials this combination was definitely preferred by patients and associated with improved metabolic profiles. Disappointing results with combination therapy could be related to use of inappropriate levothyroxine and liothyronine doses, resulting in abnormal serum free T4:free T3 ratios. Alternatively, its potential benefit might be confined to patients with specific genetic polymorphisms in thyroid hormone transporters and deiodinases that affect the intracellular levels of T3 available for binding to T3 receptors. Levothyroxine monotherapy remains the standard treatment for hypothyroidism. However, in selected patients, new guidelines suggest that experimental combination therapy might be considered.”

 

‘Executive Summary’

This post is merely a ‘sampling’ of the vast subject of thyroid hormone regulation and case management. Forthcoming posts will examine other aspects. Here are key points contained in this limited presentation:

  • Thyroid activity is vitally important for all systems throughout the body. Thyroid dysfunction can play a role in common cardiovascular, metabolic, renal and brain disorders.
  • Low T3 syndrome, also known as subclinical hypothyroidism, ‘euthyroid sick syndrome’ and ‘non-thyroidal illness syndrome’ occurs frequently and contributes to morbidity and mortality in numerous ways, adding to the burden of cardiovascular disease, metabolic syndrome (insulin resistance), type 2 diabetes, kidney disease, overweight, depression and dementia.
  • Low T3 is often overlooked due to insufficient testing in clinical practice when TSH and T4 are appear normal.
  • Chronic low grade inflammation is ubiquitous contributing cause to low T3.
  • Disturbances of enzymes that convert T4 to T3, transporters that usher thyroid agents into and out of cells, and peripheral receptor resistance are common and also contribute to Impaired thyroid function.
  • T3 can enhance to response to chemotherapy in the treatment of breast cancer.
  • Treatment of a hypothyroid component in depression can require T3.

High homocysteine is a risk factor for colorectal cancer

Am Journal Clin NutritionColorectal cancer can be added to the list of conditions for which high levels of homocysteine are a risk factor according to a study recently published in The American Journal of Clinical Nutrition. Perhaps more important than the association of high homocysteine with low levels of vitamins B12, B6 or folate is the fact that homocysteine is a biomarker for inflammation. The authors state:

Inflammation underlies the etiology of colorectal cancer (CRC). Hyperhomocysteinemia is associated with inflammation and may be a risk marker for CRC. Cysteine is a metabolic product of homocysteine and a precursor of the antioxidant glutathione. It is unknown whether cysteine is associated with CRC.”

The authors went about investigating the link between homocysteine and colorectal cancer in postmenopausal women examining data from the Women’s Health Initiative. They compared homocysteine and cysteine levels between 988 women with colorectal cancer and the same number matched for age, ethnicity and hysterectomy status. Their data showed a clear association:

Multivariate-adjusted ORs for CRC [colorectal cancer] were 1.46 for the highest quartile of homocysteine (>9.85 μmol/L) compared with the lowest quartile (≤6.74 μmol/L) and 0.57 for the highest quartile of cysteine (>309 μmol/L) compared with the lowest quartile (≤260 μmol/L). The association with homocysteine was significant for proximal colon tumors but not for distal or rectal tumors, whereas the association with cysteine was significant for rectal tumors, borderline for proximal tumors, and not significant for distal tumors. The associations with both homocysteine and cysteine were significant for localized tumors but not for metastases.”

In other words, proximal colon tumors were significantly less with the lowest homocysteine level. Practitioners take note: higher levels of cysteine, a precursor for both the noxious irritant homocysteine and the profoundly important glutathione, was associated with less rectal and proximal tumors. We should be attentive to functional levels of homocysteine (I always screen homocysteine and note when it is above 6 μmol/L) and support the conversion of cysteine to glutathione as opposed to allowing it to be hijacked down the homocysteine pathway. The authors conclude:

High plasma homocysteine is associated with increased risk of CRC [colorectal cancer], whereas high cysteine is associated with decreased risk.”

Schizophrenia, brain inflammation and depression

Schizophrenia shares underlying causal mechanisms with depression that are important for case management and treatment. A paper just published in the journal Progress in Neuro-Psychopharmacology and Biological Psychiatry highlights key features of the inflammatory process in schizophrenia that clinicians should be aware of. The authors state:

Schizophrenia and depression are two common and debilitating psychiatric conditions. Up to 61% of schizophrenic patients have comorbid clinical depression, often undiagnosed. Both share significant overlaps in underlying biological processes, which are relevant to the course and treatment of both conditions.”

All of these processes in both schizophrenia and depression are linked in some way to inflammation:

“Shared processes include changes in cell‐mediated immune and inflammatory pathways, e.g. increased levels of pro-inflammatory cytokines and a Th1 response; activation of oxidative and nitrosative stress (O&NS) pathways, e.g. increased lipid peroxidation, damage to proteins and DNA; decreased antioxidant levels, e.g. lowered coenzyme Q10, vitamin E, glutathione and melatonin levels; autoimmune responses; and activation of the tryptophan catabolite (TRYCAT) pathway through induction of indoleamine-2,3-dioxygenase. Both show cognitive and neurostructural evidence of a neuroprogressive process.”

The authors assert that patients with schizophrenia are immunologically predisposed to depression:

“Here we review the interlinked nature of these biological processes, suggesting that schizophrenia is immunologically primed for an increased expression of depression. Such a conceptualization explains, and incorporates, many of the current perspectives on the nature of schizophrenia and depression, and has implications for the nature of classification and treatment of both disorders.”

As readers here likely know, latent autoimmune phenomena are often triggered by infection. The authors discuss how this comes into play in promoting and differentiating schizophrenia and depression in regard to maternal infections.

“An early developmental etiology to schizophrenia, driven by maternal infection, with subsequent impact on offspring immuno-inflammatory responses, creates alterations in the immune pathways, which although priming for depression, also differentiates the two disorders.”

For concerned clinicians this offers a rich assortment of pathways that can be investigated with appropriate tests as candidates for interventional support.

Relevant to this topic is a presentation on psychiatric conditions as immune disorders entitled Redefining Psychiatric and Neurologic Co-morbidities as Systemic Dysfunction delivered at the Autoimmunity Congress Asia in Singapore last September by Dr Roswitha Goetze-Pelka of the Ev. Krankenhaus Bethanien in Greifswald, Germany:

Oral magnesium helps asthma in children—reduces inflammation, supports glutathione

Asthma is a disease of chronic inflammation and magnesium is known to have anti-inflammatory effects. A rigorous trial published in the European Journal of Clinical Nutrition offers evidence that oral magnesium helps relieve asthma in children. The authors set out to…

“…investigate the long-term effect of oral magnesium supplementation on clinical symptoms, bronchial reactivity, lung function and allergen-induced skin responses in children and adolescents with moderate persistent asthma.”

They staged a double-blind randomized parallel placebo-controlled study randomizing 37 patients aged 7–19 years into two groups. One got 300 mg/day of magnesium and the rest placebo over 2 months. The primary outcome was bronchial reactivity which was evaluated by a methacholine challenge test (PC20). The data showed a significant benefit from magnesium:

“After a follow-up of 2 months, the methacholine PC20 for testing bronchial reactivity has augmented significantly in the magnesium group only. The skin responses to recognized antigens have also decreased in patients treated with magnesium. The forced vital capacity (FVC), the forced expiratory volume at first second (FEV1), the forced expiratory flow at 25–75 and the FEV1/FVC ratio were similar in both groups. The magnesium group presented fewer asthma exacerbations and used less salbutamol compared to the placebo group.”

The magnesium clearly produced a welcome anti-inflammatory effect. The authors conclude:

Oral magnesium supplementation helped to reduce bronchial reactivity to methacholine, to diminish their allergen-induced skin responses and to provide better symptom control in pediatric patients with moderate persistent asthma treated with inhaled fluticasone.”

It’s very interesting that magnesium reduced inflammation in both the lung mucosa and skin. Besides the antiinflammatory effect of increasing parasympathetic tone (see posts on heart rate variability and others on magnesium and calcium), a striking paper published in the journal Inflammation Research shows that magnesium also supports the glutathione redox system, an extremely important factor in autoimmunity and allergy. The authors conducted their randomized, double-blind, placebo-controlled study to…

“…investigate the effects of 12-week oral magnesium (Mg) supplementation on the RBC redox system in stable, persistent, moderately asthmatic children.”

They examined oxidized glutathione (GSSG) and reduced (GSH) glutathione, oxyhaemoglobin, methaemoglobin (metHb), hemichrome and bilirubin levels before and after treatment with magnesium and GSH stability in 40 kids aged 4-16 (24 boys, 16 girls). There was a clear benefit from the magnesium:

“The GSH concentration was significantly higher in the Mg-treated than in the placebo-treated patients after the treatment period. There was a positive correlation between the decreased plasma metHb and hemichrome levels and the decreased plasma haemoglobin concentrations in the Mg-treated patients at the end of the study.”

Clinicians who case manage autoimmunity please note: impairment of the glutathione redox system is a major contributor to the loss of self-tolerance. Evidence that magnesium, a benign and inexpensive agent, can significantly help to improve glutathione activity is valuable. The authors conclude:

Mg in the given doses exerts antioxidant activity and influences the glutathione redox system.”