Prediabetes, chronic inflammation and hemoglobin A1c

PrediabetesPrediabetes, blood glucose is slightly higher than normal but not enough to qualify for diabetes, is associated with an increased systemic burden of inflammation and elevated risk for cardiovascular, cancer, dementia and other diseases. The first study described in this post, published in the European Journal of Nutrition, highlights the link between prediabetes, chronic inflammation and mortality from a range of diseases tied to HgbA1c (hemoglobin A1c, glycosylated hemoglobin), the key biomarker for glucose regulation. The authors state:

Chronic inflammation is associated with increased risk of cancer, cardiovascular disease (CVD), and diabetes. The role of pro-inflammatory diet in the risk of cancer mortality and CVD mortality in prediabetics is unclear. We examined the relationship between diet-associated inflammation, as measured by dietary inflammatory index (DII) score, and mortality, with special focus on prediabetics.”

Pro-inflammatory diet plus prediabetes (increased HgbA1c)

Of great significance is the effect they reveal when a pro-inflammatory diet, measured by the dietary inflammatory index (DII) score, is consumed when there is elevated HgbA1c. They categorized 13,280 subjects between the ages 20 of and 90 years according to whether or not they were prediabetic, which they defined as a HgbA1c percentage of 5.7–6.4. Their data highlighted this connection between all-cause mortality, a pro-inflammatory diet and prediabetes:

“The prevalence of prediabetes was 20.19 %. After controlling for age, sex, race, HgbA1c, current smoking, physical activity, BMI, and systolic blood pressure, DII scores in tertile III (vs tertile I) was significantly associated with mortality from all causes (HR 1.39, 95 % CI 1.13, 1.72), CVD (HR 1.44, 95 % CI 1.02, 2.04), all cancers (HR 2.02, 95 % CI 1.27, 3.21), and digestive-tract cancer (HR 2.89, 95 % CI 1.08, 7.71). Findings for lung cancer (HR 2.01, 95 % CI 0.93, 4.34) suggested a likely effect.”

The authors conclude:

“A pro-inflammatory diet, as indicated by higher DII scores, is associated with an increased risk of all-cause, CVD, all-cancer, and digestive-tract cancer mortality among prediabetic subjects.”

 Prediabetes and cardiovascular risk

Research published in The BMJ (British Medical Journal) focusses on the substantial impact of prediabetes on the risk of heart attack and ischemic stroke. The authors set out to…

“…evaluate associations between different definitions of prediabetes and the risk of cardiovascular disease and all cause mortality…”

…by analyzing 53 prospective cohort studies with 1,611,339 individuals that passed the screening tests for validity. In this study they applied several definitions of prediabetes:

“Prediabetes was defined as impaired fasting glucose according to the criteria of the American Diabetes Association (IFG-ADA; fasting glucose 5.6-6.9 mmol/L = 101-124 mg/dL), the WHO expert group (IFG-WHO; fasting glucose 6.1-6.9 mmol/L = 110-124 mg/dL), impaired glucose tolerance (2 hour plasma glucose concentration 7.8-11.0 mmol/L = 141-198 mg/dL during an oral glucose tolerance test), or raised haemoglobin A1c (HbA1c) of 39-47 mmol/mol [5.7-6.4%] according to ADA criteria or 42-47 mmol/mol [6.0-6.4%] according to the National Institute for Health and Care Excellence (NICE) guideline.”

Their data show that prediabetes with a ‘mildly’ elevated HgbA1c was clearly associated with increased cardiovascular risk:

“Compared with normoglycaemia, prediabetes (impaired glucose tolerance or impaired fasting glucose according to IFG-ADA or IFG-WHO criteria) was associated with an increased risk of composite cardiovascular disease (relative risk 1.13, 1.26, and 1.30 for IFG-ADA, IFG-WHO, and impaired glucose tolerance, respectively), coronary heart disease (1.10, 1.18, and 1.20, respectively), stroke (1.06, 1.17, and 1.20, respectively), and all cause mortality (1.13, 1.13 and 1.32, respectively). Increases in HBA1c to 39-47 mmol/mol [5.7-6.4%] or 42-47 mmol/mol [6.0-6.4%] were both associated with an increased risk of composite cardiovascular disease (1.21 and 1.25, respectively) and coronary heart disease (1.15 and 1.28, respectively), but not with an increased risk of stroke and all cause mortality.”

Interestingly, risk of stroke does not emerge from these data, suggesting other factors promoting vascular inflammation. The authors conclude:

“…we found that prediabetes defined as impaired fasting glucose or impaired glucose tolerance is associated with an increased risk of composite cardiovascular events, coronary heart disease, stroke, and all cause mortality. There was an increased risk in people with fasting plasma glucose as low as 5.6 mmol/L [100 mg/dL]. Additionally, the risk of composite cardiovascular events and coronary heart disease increased in people with raised HbA1c. These results support the lower cut-off point for impaired fasting glucose according to ADA criteria as well as the incorporation of HbA1c in defining prediabetes.”

HgbA1c and risk of all-cause and cause-specific mortality without diabetes

Similar results were obtained in a study published in Scientific Reports. Here the authors concluded:

“We found evidence of a non-linear association between HbA1c and mortality from all causes, CVD and cancer in this meta-analysis. The dose-response curves were relatively flat for HbA1c less than around 5.7%, and rose steeply thereafter. This fact reveals a clear threshold effect for the association of HbA1clevels with mortality. In addition, from the perspective of mortality benefit and health care burden, it suggests that the most appropriate HbA1c level of initiating intervention is approximately 5.7%…higher HbA1c level is associated with increased mortality from all causes, CVD, and cancer among subjects without known diabetes. However, this association is influenced by those with undiagnosed diabetes or prediabetes .Because of limited studies, the results in relation to cancer mortality should be treated with caution, and more studies are therefore warranted to investigate whether higher HbA1c level is associated with increased cancer mortality.”

 

Calcium supplementation may increase risk for dementia

NeurologyCalcium supplementation continues to come under scrutiny as evidence accumulates that it can increase the risk of inflammatory disorders, most notably cerebrovascular disease, likely by opposing the anti-inflammatory effects of magnesium. A study just published in the journal Neurology offers evidence that supplementation can increase the risk for dementia in women with cardiovascular disease. The authors set out to…

“…determine whether calcium supplementation is associated with the development of dementia in women after a 5-year follow-up.”

700 dementia-free women aged 70–92 years were examined at baseline and at follow-up 5 years later with comprehensive neuropsychiatric and physical examinations. 447 underwent CT scans at baseline. Dementia was diagnosed according to DSM-III-R criteria, and this was correlated with information on the use and dosage of calcium supplements.

Calcium supplementation dramatically increased the risk for dementia

Neurology 2The risk more was increased almost 7 times for the subset of women with a history of stroke, and tripled for those with white matter lesions, in comparison to similar subjects who did not supplement:

Women treated with calcium supplements (n = 98) were at a higher risk of developing dementia (odds ratio [OR] 2.10) and the subtype stroke-related dementia (vascular dementia and mixed dementia) (OR 4.40) than women not given supplementation (n = 602)….supplementation was associated with the development of dementia in groups with a history of stroke (OR 6.77) or presence of white matter lesions (OR 2.99), but not in groups without these conditions.”

Correspondence with previous studies

This was a relatively small study, but the findings correspond to earlier evidence that supplementation can increase the burden of systemic inflammation (some have been written about here). It opposes the absorption and action of magnesium, a likely mechanism accounting for these observations. Recall that osteoporosis is not a calcium deficiency disorder, rather a failure to maintain the protein matrix of bone to which the minerals attach. Though it was only subjects with a history of cerebrovascular disease or white matter lesions for whom the risk of dementia was markedly increased, clinicians should consider very carefully before recommending supplementation. The authors conclude:

Calcium supplementation may increase the risk of developing dementia in elderly women with cerebrovascular disease.”

Alzheimer’s disease and blood-brain barrier leakage

RadiologyAlzheimer’s disease is not a unitary condition but variable in causation at the individual level like all complex chronic disorders. Neuroinflammation, metabolic damage, vascular compromise, accumulation of noxious debris (amyloid β and tau), impairments in brain CSF and lymphatic drainage and other causes can all variously contribute to Alzheimer’s and other dementias. Now original research recently published in the journal Radiology demonstrates that leakiness of the blood-brain barrier (BBB) can permit an environment hostile to neuronal health that contributes to cognitive decline, Alzheimer’s and other dementias. The authors state:

“Evidence is increasing that impairment of the cerebral microvasculature is a contributing factor in the pathophysiology of Alzheimer disease (AD). However, the exact pathway remains unclear. Results of histologic evaluation and albumin sampling studies show that an increased permeability of the blood-brain barrier (BBB) is likely a key mechanism.”

An intact blood-brain barrier is essential for brain health

The BBB is a collection of cells and other structures in the cerebrovascular wall that when healthy permits only privileged access into the brain from the extra-cerebral blood compartment.

“It regulates the delivery of important nutrients to the brain through active and passive transport mechanisms and prevents neurotoxins from entering the brain. It also has a clearance function, meaning that it removes surplus substances from the brain. A well-functioning BBB is essential to keeping the brain tissue in a healthy condition. Results of previous studies suggest that deterioration of the BBB can cause an ill-conditioned environment for neuronal cells and other pathologic changes such as small-vessel abnormality, protein deposits, inflammation, and neuronal cell death. These changes eventually may lead to cognitive decline and dementia.”

Early Alzheimer’s shows abnormal BBB permeability

Blood-brain barrier degradation has earlier been demonstrated in advanced Alzheimer’s disease. Here the authors examined whether or not BBB leakage contributes to the early stages of disease.

“To investigate whether BBB leakage contributes to the early pathophysiology of AD, we hypothesized that patients with early forms of AD already show increased BBB permeability in comparison with age-matched control subjects. For this pilot study, we used a dedicated dynamic contrast-enhanced MR imaging acquisition protocol with dual-time resolution that separates the filling of the blood vessels from the leakage. We also investigated differences in local blood plasma volume fraction, and the relationship between BBB permeability and global cognition.”

The analyzed data for patients diagnosed with mild cognitive impairment (MCI) due to AD or patients or patients with early AD (a continuum of cognitive decline who had been referred by general practitioners because of memory concerns, in comparison with healthy controls. Individuals with dementia of vascular origin were excluded, as were those with major cardiovascular and neuropsychiatric disorders, Parkinson’s, MS, trauma, major structural abnormalities of the brain, and alcohol or drug abuse. They indeed demonstrated a marked distinction between their study subjects and controls:

“The BBB leakage rate was significantly higher in patients compared with that in control subjects in the total GM (grey matter) and cortex but not in the WM, normal-appearing WM, deep GM, or WM hyperintensities…When adjustments were made for all covariates, the patients exhibited a significantly higher leakage volume in the WM and GM and also in the normal-appearing WM, deep GM, cortex, but not in WM hyperintensities…The median blood plasma volume was significantly lower in the patients than in the control subjects in all tissue classes.”

BBB leakage rate shown in early Alzheimer's

BBB leakage rate shown on the right, with some periventricular hot spots

BBB leakage in early Alzheimer’s is widespread

The leakage is not due to vascular abnormalities, and leakage volume was even more striking than rate:

The results of this study showed increased BBB leakage in patients with early AD. The leakage was globally distributed throughout the cerebrum and was associated with declined global cognitive performance. By using dynamic contrast-enhanced MR imaging with dual-time resolution, we found an increased BBB leakage rate in the GM of patients with early AD. By also showing very subtle BBB impairment in the WM, leakage volume proved to be even more sensitive to the differences in BBB leakage than was the leakage rate. Not only did this show that the differences between patients with early AD and healthy control subjects were in the extent of the BBB leakage rather than the rate (ie, strength), but it also showed that the leakage was widespread rather than localized to a single tissue class such as WM hyperintensities, normal-appearing WM, or cortex. In addition, the BBB impairment did not fully originate from vascular abnormality, because adding diabetes and other noncerebral vascular diseases to the analysis model did not change the results. This suggested that the BBB impairment stemmed from the AD abnormality instead of from vascular comorbidities.”

Breakdown in tight junctions like the intestinal barrier

The intestinal barrier, critical for healthy immune system regulation, loses integrity with a breakdown of the tight cellular junctions. So too with the blood-brain barrier.

“The leakage observed in this study can be explained as a breakdown of the BBB tight junctions. It has been shown in rodents that tight junction damage allows gadolinium leakage through the BBB. The regions with high BBB leakage were diffusely distributed throughout the brain, showing that BBB tight junctions were globally impaired. This could have allowed the passage of small and lipophilic molecules that could not cross a healthy BBB. The loss of tight junctions also changes cell polarity, which influences the expression of transporter complexes and thus indirectly affects active transport across the BBB. Therefore, both passive and active transport mechanisms may be impaired in patients with early AD, possibly disturbing homeostasis.”

Toxic accumulations in the brain and cognitive impairment

The authors have demonstrated that BBB leakage tracks cognitive impairment in early Alzheimer’s:

“We found that cognitive decline was associated with stronger BBB leakage, and both the patients with MCI and those with early AD showed increased BBB leakage. These observations suggest that BBB impairment may be a contributing factor in the early pathophysiology of AD. A possible mechanism is that loss of tight junctions impairs the filter function of the BBB, leading to a toxic accumulation of substances in the brain. This, combined with the altered active transport systems, might add up to a substantial effect on neuronal function that eventually leads to dementia.”

BBB and amyloid β

Clearance of amyloid β is also impaired:

“…amyloid β is actively transported across the BBB, whereas gadolinium leaks passively through the tight junctions. Previous work with positron emission tomographic data has shown that clearance of amyloid β is also impaired in patients with AD. An impaired clearance of amyloid β would mean that the BBB is impaired in different ways, contributing to the pathologic cascade leading to AD.”

Most importantly…

“Therefore, BBB leakage may help to provide a biomarker for early diagnosis, or at least a marker indicating vulnerability for the development of dementia. Successful prediction of dementia eventually might lead to optimized treatment, delay, or even prevention of the disease.”

Clinical note

Early diagnosis is key here, and for those of us without dynamic gadolinium contrast-enhanced MR imaging at hand I highly recommend the Blood Brain Barrier Permeability™ screen from Cyrex Labs (Array 20) which offers the clinician the ability to detect early changes in BBB permeability. Clinicians experienced in rehabilitation of the gut barrier will be familiar with resources to evaluate and remediate inflammation and other insults to the blood-brain barrier.

The authors conclude:

“…in this pilot study, MR imaging was used to show global, diffusely distributed BBB leakage in patients with early AD, which suggests that a compromised BBB is part of the early pathology of AD and might be part of a cascade of pathologic events that eventually lead to cognitive decline.”

  • “Patients with early Alzheimer disease have significantly more tissue characterized by blood-brain barrier leakage than do healthy control subjects, both in the normal-appearing white matter and in the gray matter.
  • Blood-brain barrier leakage in the gray matter correlates with lower scores on the Mini-Mental State Examination.”

Depression, inflammation and light therapy

JAMA PsychiatryDepression has much more going on under the surface than neurotransmitter deficiencies. A constellation of papers published recently illustrate the fascinating links between depression, inflammation and exposure to light (not just during the winter). The implies an exciting potential for relief from depression by combining management of chronic inflammation with bright light and chronotherapy to correct circadian dysregulation.

Depression and inflammation

Brain inflammation is recognized as a core contributing cause in numerous neuropsychiatric disorders (search ‘neuroinflammation‘ in this blog). A study just published in JAMA Psychiatry illustrates the association between depression and a variety of symptoms arising from systemic inflammation. The authors used C-reactive protein (CRP) as an inflammatory biomarker:

Elevated levels of inflammatory markers, such as C-reactive protein, are well-documented in people with depression. Raison and Miller suggested that this association may, in fact, be symptom-specific. Higher levels of inflammation are particularly likely to underlie depression symptoms that characterize sickness behavior, including fatigue, reduced appetite, withdrawal, and inhibited motivation…Here, we tested the hypothesis that the association between C-reactive protein and depression is symptom-specific.”

They examined the relationship between CRP and depression for specific symptoms using data on about 15,000 men and women in three US National Health and Nutrition Surveys. Inflammation was associated with cognitive and emotional symptoms including anhedonia, depressed mood, feelings of low self-worth, poor concentration, and thoughts of suicide though they were not independent of the other depression symptoms. Three symptoms particularly stood out:

Inflammation was associated with a range of depression symptoms, particularly with tiredness, lack of energy, sleep problems, and changes in appetite.”

Medscape Medical News quotes comments by Golam Khandaker, MBBS, MPhil, MRCPsych, PhD, clinical lecturer, Department of Psychiatry, University of Cambridge, United Kingdom (not an author of the study):

“While the association between inflammatory markers such as CRP and depression is well known, studies such as this looking at particular symptoms provide important clues for mechanism of illness pathogenesis…This work points to a potentially important role for inflammation in the pathogenesis of the so-called somatic symptoms of depression, such as sleep problems, anergia, and loss of appetite, which are, of course, an integral part of the syndrome of depression.”

The author of this coverage in also notes:

“As previously reported by Medscape Medical News, a recent meta-analysis of 14 relevant randomized, placebo-controlled studies found that nonsteroidal anti-inflammatory drugs (NSAIDs) may help ease depressive symptoms…Results showed that the adjunctive use of NSAIDs was associated with improved antidepressant treatment response without an increased risk for adverse effects.”

Of course safer antiinflammatory agents are readily available.

Circadian misalignment increases inflammation

Brain, Behavior, and ImmunityChronic inflammation can be caused by a disrupted circadian rhythm. In a study published in Brain, Behavior, and Immunity the authors investigated the effects of chronic circadian misalignment on cortisol levels and TNF-α, CRP and IL-10.

“How chronic circadian misalignment influences cortisol and inflammatory proteins, however, is largely unknown and this was the focus of the current study. Specifically, we examined the influence of weeks of chronic circadian misalignment on cortisol, stress ratings, and pro- and anti-inflammatory proteins in humans.”

After 3 weeks of maintaining regular sleep–wake schedules at home and six laboratory baseline days and nights, then a 40 hour constant routine (CR, total sleep deprivation) their subjects endured a 25-day laboratory entrainment protocol with eight of them selected for circadian disruption. Their data showed a shift in inflammatory biomarkers in the subjects induced for circadian misalignment:

Circadian misalignment significantly increased plasma tumor necrosis factor-alpha (TNF-α), interleukin 10 (IL-10) and C-reactive protein (CRP). Little change was observed for the TNF-α/IL-10 ratio during circadian misalignment, whereas the TNF-α/IL-10 ratio and CRP levels decreased in the synchronized control group across weeks of circadian entrainment.”

In other words, as the normally circadian synchronized subjects adapted to the lab conditions their TNF-α/IL-10 (pro/anti-inflammatory) ratio decreased, which was not the case in those subject to circadian misalignment. Interestingly, they also found a difference in cortisol levels between acute sleep deprivation which is used as a therapeutic intervention and chronic circadian misalignment:

“Acute total sleep deprivation significantly increased cortisol levels, whereas chronic circadian misalignment significantly reduced cortisol levels.”

Bottom line here is that circadian misalignment promotes a proinflammatory state.

Bright Light Therapy—Not Just For Seasonal Affective Disorder

Harvard Review of PsychiatryCommenting on the scope of bright light therapy in a paper published recently in the Harvard Review of Psychiatry entitled The Psychiatry of Light, the authors state:

“Bright light therapy and the broader realm of chronotherapy remain underappreciated and underutilized, despite their empirical support. Efficacy extends beyond seasonal affective disorder and includes nonseasonal depression and sleep disorders, with emerging evidence for a role in treating attention-deficit/hyperactivity disorder, delirium, and dementia. A practical overview is offered, including key aspects of underlying biology, indications for treatment, parameters of treatment, adverse effects, and transformation of our relationship to light and darkness in contemporary life.”

JAMA PsychiatryMore evidence supporting the use of this “underappreciated and underutilized” therapy was just added in a study published in JAMA Psychiatry in which bright light therapy outperformed fluoxetine (Prozac®) in the treatment of nonseasonal major depressive disorder (MDD). The authors set out to:

…determine the efficacy of light treatment, in monotherapy and in combination with fluoxetine hydrochloride, compared with a sham-placebo condition in adults with nonseasonal MDD.

In an eight week randomized, double-blind, placebo- and sham-controlled trial in adults with MDD of at least moderate severity were assigned to one of four interventions: (1) light monotherapy (active 10 000-lux fluorescent white light box for 30 minutes per day in the early morning plus placebo pill); (2) antidepressant monotherapy (inactive negative ion generator for 30 minutes per day plus fluoxetine 20 mg/day); (3) combination light and antidepressant; or (4) total placebo (inactive negative ion generator plus a placebo pill). The efficacy of bright light therapy shone clearly in this trial:

A total of 122 patients were randomized (light monotherapy, 32; fluoxetine monotherapy, 31; combination therapy, 29; placebo, 30). The mean (SD) changes in MADRS score for the light, fluoxetine, combination, and placebo groups were 13.4 (7.5), 8.8 (9.9), 16.9 (9.2), and 6.5 (9.6), respectively. The combination and light monotherapy were significantly superior to placebo in the MADRS change score, but fluoxetine monotherapy was not superior to placebo. For the respective placebo, fluoxetine, light, and combination groups at the end point, response was achieved by 10 (33.3%), 9 (29.0%), 16 (50.0%), and 22 (75.9%) and remission was achieved by 9 (30.0%), 6 (19.4%), 14 (43.8%), and 17 (58.6%).”

In other words, bright light therapy by itself was very effective. It was slightly more effective when combined with fluoxetine, but the fluoxetine (Prozac®) by itself did no better than placebo. The authors state in their conclusion:

Bright light treatment, both as monotherapy and in combination with fluoxetine, was efficacious and well tolerated in the treatment of adults with nonseasonal MDD.”

Medscape Medical News quotes comments on the study by Michael Terman, PhD, professor of psychiatry, Columbia University, and director of the Comprehensive Chronotherapy Group, New York City:

“The major surprise was the failure of a standard therapeutic dose of fluoxetine to beat the placebo rate, while light therapy showed a large effect size within 4 weeks…If light had proved ineffective or only weakly effective in comparison with fluoxetine, it would have consigned light therapy to the dustbin, but the dramatic, opposite result turns the tables on the choice of somatic treatment for major depression ― 10,000 lux light therapy upon awakening or, by implication, a walk outdoors if the sun is up ― now can be recommended to patients with recurrent depression, many of whom will respond without recourse to drugs.”

Medscape Medical News also quotes the original study in regard to circadian phase-shifting:

“Nonseasonal major depressive disorder may also be associated with disturbances in circadian rhythms,” they write. “And bright light has predictable circadian phase-shifting effectiveness in humans.”

Circadian rhythms and inflammation in rheumatoid arthritis

Nature Reviews RheumatologyClosing the biological circle connecting depression, inflammation, bright light therapy and circadian rhythm it’s edifying to consider a paper published in Nature Reviews Rheumatology in which the authors discuss inflammation, depression and chronobiology in the context of rheumatoid arthritis:

“Circadian rhythms are of crucial importance for cellular and physiological functions of the brain and body. Chronobiology has a prominent role in rheumatoid arthritis (RA), with major symptoms such as joint pain and stiffness being most pronounced in the morning, possibly mediated by circadian rhythms of cytokine and hormone levels. Chronobiological principles imply that tailoring the timing of treatments to the circadian rhythm of individual patients (chronotherapy) could optimize results. Trials of NSAID or methotrexate chronotherapy for patients with RA suggest such an approach can improve outcomes and reduce adverse effects. The most compelling evidence for RA chronotherapy, however, is that coordinating the timing of glucocorticoid therapy to coincide with the nocturnal increase in blood IL-6 levels results in reduced morning stiffness and pain compared with the same glucocorticoid dose taken in the morning.”

Effect of RA Chronotherapy on associated depressionThis suggests significant potential for the treatment of depression:

Aside from optimizing relief of the core symptoms of RA, chronotherapy might also relieve important comorbid conditions such as depression and sleep disturbances. Surprisingly, chronobiology is not mentioned in official guidelines for conducting RA drug registration trials. Given the imperative to achieve the best value with approved drugs and health budgets, the time is ripe to translate the ‘circadian concept’ in rheumatology from bench to bedside.”

Chronotherapy with bright light beats exercise for depression

Acta Psychiatrica ScandinavicaExercise has been well-established as a remedy for depression, yet in a fascinating study recently published in Acta Psychiatrica Scandinavica chronotherapeutics with bright light therapy was significantly more effective. To investigate the long-term antidepressant effect of a chronotherapy they randomized 75 patients with major depression to fixed duloxetine and either a chronotherapeutic intervention (wake group) with three initial wake therapies, daily bright light therapy, and sleep time stabilization for 29 weeks. Chronotherapy was the clear winner for remission of major depression:

Patients in the wake group had a statistically significant higher remission rate of 61.9% vs. 37.9% in the exercise group at week 29. This indicated continued improvement compared with the 9 weeks of treatment response (44.8% vs. 23.4%) with maintenance of the large difference between groups. HAM-D17 endpoint scores were statistically lower in the wake group.”

Clinical note: All of the above argues in favor of a trial of chronotherapy with bright light plus exercise (free of fluoxetine or duloxetine) in case management of depression.

The authors of the this study conclude:

In this clinical study patients continued to improve in the follow-up phase and obtained very high remission rates. This is the first study to show adjunct short-term wake therapy and long-term bright light therapy as an effective and feasible method to attain and maintain remission.”

Bottom Line

  • Bright light therapy can be effective for major depression even when nonseasonal.
  • Brain inflammation is a core contributing biological cause of neuropsychiatric disorders including depression.
  • Correcting a misaligned circadian rhythm using early waking with bright light to phase shift is also anti-inflammatory.
  • These effective interventions combined can be enhanced by further optimizing brain metabolism and circulation based on appropriate tests.

Saliva cortisol associated with brain volume, cognitive function

NeurologyCortisol is closely linked to brain health through both its effects on the brain and its circadian regulation by the hippocampus, also the brain center for short-term memory. A study recently published in the journal Neurology shows that measurements of salivary cortisol can be an indicator for cognitive impairment and loss of brain volume.

“We investigated the associations of morning and evening salivary cortisol levels with regional brain volumes and cognitive functioning in community-dwelling older persons without dementia. “

The authors collected data for 4,244 subjects without dementia between 71 and 81 years of age who had a brain MRI  and assessment of cognitive function. To measure cortisol saliva was collected at home 45 minutes after awakening and again at night. These were used to observe the relationship among cortisol levels, brain volumes, and cognitive functioning.

Higher evening cortisol linked with cognitive impairment and loss of brain volume

Clinicians should recall that healthy adrenal regulation by the hippocampus displays a cortisol rhythm characterized by the highest level in the morning with a downward slope ending in the lowest level at night.

Higher evening cortisol was associated with smaller total brain volume (highest vs lowest tertile −16.0 mL; 95% confidence interval −19.7 to −12.2 mL, adjusted for age, sex, education, intracranial volume, smoking, steroid use, white matter lesions, and brain infarcts on MRI). The smaller volumes were observed in all brain regions, but were significantly smaller in gray matter than in white matter regions. Poorer cognitive functioning across all domains was also associated with higher evening cortisol. Higher levels of morning cortisol were associated with slightly greater normal white matter volume and better processing speed and executive functioning, but not with gray matter volume or with memory performance.”

Note also the positive indication of higher morning cortisol in reference to the cortisol circadian rhythm.

Clinical Note

The salivary cortisol circadian rhythm is easily measured in practice and a sensitive indicator for fundamental functions that must be well managed including inflammation,  glucose regulation, stress and brain function.

The authors conclude:

“In older persons, evening and morning cortisol levels may be differentially associated with tissue volume in gray and white matter structures and cognitive function. Understanding these differential associations may aid in developing strategies to reduce the effects of hypothalamic-pituitary-adrenal axis dysfunction on late-life cognitive impairment.”

Migraine, depression, Alzheimer’s and lipid metabolism

NeurologyMigraine, with its variety of symptoms associated with aberrant neuronal activation, is linked to abnormal metabolism of a class of bioactive lipids in an important study just published in the journal Neurology. Sphingolipids are involved in a variety of functions in mammalian systems including cell membrane formation, signaling, apoptosis, energy balance and inflammation. The authors set out to assess the levels of sphingolipids in circulation in women migraneurs between migraine attacks compared to control subjects. Their data show that altered sphingolipid metabolism clearly distinguished those with episodic migraine (EM) from controls:

Total ceramide (EM 6,502.9 ng/mL vs controls 10,518.5 ng/mL) and dihydroceramide (EM 39.3 ng/mL vs controls 63.1 ng/mL) levels were decreased in those with EM as compared with controls. Using multivariate logistic regression, each SD increase in total ceramide (odds ratio [OR] 0.07) and total dihydroceramide (OR 0.05) levels was associated with more than 92% reduced odds of migraine. Although crude sphingomyelin levels were not different in EM compared with controls, after adjustments, every SD increase in the sphingomyelin species C18:0 (OR 4.28) and C18:1 (OR 2.93) was associated with an increased odds of migraine. Recursive portioning models correctly classified 14 of 14 randomly selected participants as EM or control.”

Brain-liver axis and migraine

SphingolipidsThese interesting results shed light on a topic that deserves more attention: the role of the brain-liver axis in neuroinflammatory, neurodegenerative and neuropsychiatric disorders including migraine. This may be extended to include metabolism of lipids and other bioactive agents on a cellular level. The authors conclude in regard to sphingolipid metabolism and migraine:

“These results suggest that sphingolipid metabolism is altered in women with EM and that serum sphingolipid panels may have potential to differentiate EM presence or absence…This study provides Class III evidence that serum sphingolipid panels accurately distinguish women with migraine from women without migraine.”

Clinical note: for practitioners using medicines from the TCM (traditional Chinese medicine) and Ayurvedic systems the ‘brain-liver axis’ encompasses not just the visceral entity but consonant functions distributed throughout the organism.

Dementia, multiple sclerosis, obesity, and pain

Beyond migraine, a commentary on the study in Medscape Medical News states:

“The authors, led by B. Lee Peterlin, DO, from Johns Hopkins University School of Medicine, Baltimore, Maryland, note that neurologic disorders that are the result of severe deficiencies in enzymes that regulate sphingolipid metabolism have long been described (eg, Gaucher disease), and recent studies have suggested that even subtle changes of sphingolipid balance may be involved in dementia, multiple sclerosis, obesity, and pain…Now they also are reporting a study showing changes in sphingolipid levels in patients with migraine, implicating in particular two sphingolipid subtypes: ceramide and sphingomyelin…“Taken together, our findings suggest it is possible that migraine is a neurologic disorder of ‘minor’ sphingolipid dysmetabolism,” they conclude.”

Depression and anxiety

BBA - Molecular and Cell Biology of LipidsAlso in addition to migraine, a fascinating paper recently published in Biochimica et Biophysica Acta (BBA) – Molecular and Cell Biology of Lipids reviews the function of neuronal membrane lipids including sphingolipids as a barrier and signaling medium in the brain and their role in depression and anxiety.

“Brain lipids determine the localization and function of proteins in the cell membrane and in doing so regulate synaptic throughput in neurons. Lipids may also leave the membrane as transmitters and relay signals from the membrane to intracellular compartments or to other cells. Here we review how membrane lipids, which play roles in the membrane’s function as a barrier and a signaling medium for classical transmitter signaling, contribute to depression and anxiety disorders and how this role may provide targets for lipid-based treatment approaches. Preclinical findings have suggested a crucial role for the membrane-forming n-3 polyunsaturated fatty acids, glycerolipids, glycerophospholipids, and sphingolipids in the induction of depression- and anxiety-related behaviors.”

This opens the door to a class of treatment options…

“These polyunsaturated fatty acids also offer new treatment options such as targeted dietary supplementation or pharmacological interference with lipid-regulating enzymes. While clinical trials support this view, effective lipid-based therapies may need more individualized approaches. Altogether, accumulating evidence suggests a crucial role for membrane lipids in the pathogenesis of depression and anxiety disorders; these lipids could be exploited for improved prevention and treatment.”

Alzheimer’s disease

Journal of Alzheimer's DiseaseA review in the Journal of Alzheimer’s Disease discusses the metabolism and the presence in biofluids of sphingolipids and other lipids in Alzheimer’s disease (AD):

“With the difficulties of studying the brain directly, it is hoped that identifying the effect of AD on the metabolite composition of biofluids will provide insights into underlying mechanisms of pathology…Sphingolipid, antioxidant, and glutamate metabolism were found to be strongly associated with AD and were selected for detailed investigation of their role in pathogenesis. In plasma, two ceramides increased and eight sphingomyelins decreased with AD, with total ceramides shown to increase in both serum and cerebrospinal fluid. In general antioxidants were shown to be depleted, with oxidative stress markers elevated in a range of biofluids in patients suggesting AD produces a pro-oxidative environment. Shifts in glutamate and glutamine and elevation of 4-hydroxy-2-nonenal suggests peroxidation of the astrocyte lipid bilayer resulting in reduced glutamate clearance from the synaptic cleft, suggesting a excitotoxicity component to AD pathology; however, due to inconsistencies in literature reports, reliable interpretation is difficult.”

In addition to defective clearance of amyloid beta, tau proteins and glutamate, altered sphingolipid metabolism emerges as a significant factor.

“The present review has shown that metabolite shifts in biofluids can provide valuable insights into potential pathological mechanisms in the brain, with sphingolipid, antioxidant, and glutamate metabolism being implicated in AD pathology.”

Sphingolipids in food

Journal of NutritionSphingolipids are in a variety of foods and, though not known to be an ‘essential’ nutrient, have functional effects as discussed in a paper published in the The Journal of Nutrition. The authors state:

“There is no known nutritional requirement for sphingolipids; nonetheless, they are hydrolyzed throughout the gastrointestinal tract to the same categories of metabolites (ceramides and sphingoid bases) that are used by cells to regulate growth, differentiation, apoptosis and other cellular functions…both complex sphingolipids and their digestion products (ceramides and sphingosines) are highly bioactive compounds that have profound effects on cell regulation. This article reviews the structures of sphingolipids, their occurrence in food, digestion and metabolism, biochemical functions and apparent roles in both the etiology and prevention of disease.”

Sphingolipids and cell regulationIn regard to their functional role:

“Studies with experimental animals have shown that feeding sphingolipids inhibits colon carcinogenesis, reduces serum LDL cholesterol and elevates HDL, suggesting that sphingolipids represent a “functional” constituent of food. Sphingolipid metabolism can also be modified by constituents of the diet, such as cholesterol, fatty acids and mycotoxins (fumonisins), with consequences for cell regulation and disease. Additional associations among diet, sphingolipids and health are certain to emerge as more is learned about these compounds. “

The authors offer a table showing sphingolipid levels in various foods.

Blood pressure forced too low and cognitive impairment

JAMA Internal MedicineBlood pressure treatment should relieve hypertension without attempting to achieve ‘perfect’ levels which can harm by impairing brain perfusion resulting in cognitive impairment. A study just published JAMA Internal Medicine adds to the body of evidence indicating that blood pressure management in the elderly must allow adequate pressure to maintain circulation to the periphery (which includes the brain). The authors set out to…

“…assess whether office blood pressure, ambulatory blood pressure monitoring, or the use of antihypertensive drugs (AHDs) predict the progression of cognitive decline in patients with overt dementia and mild cognitive impairment (MCI).”

Daytime systolic blood pressure equal or less than 128 mm Hg

They analyzed data for 172 patients whose average age was 79 with a Mini-Mental State Examination (MMSE) mean score of 22.1, among whom 68% had dementia, 32% had mild cognitive impairment (MCI), and 69.8% were being treated with anti-hypertensive drugs (AHDs). Over-medicating for blood pressure was associated with cognitive impairment:

Patients in the lowest tertile of daytime systolic blood pressure (SBP) (≤128 mm Hg) showed a greater MMSE score change compared with patients in the intermediate tertile (129-144 mm Hg) and patients in the highest tertile (≥145 mm Hg). The association was significant in the dementia and MCI subgroups only among patients treated with AHDs. In a multivariable model that included age, baseline MMSE score, and vascular comorbidity score, the interaction term between low daytime SBP tertile and AHD treatment was independently associated with a greater cognitive decline in both subgroups. The association between office SBP and MMSE score change was weaker. Other ambulatory blood pressure monitoring variables were not associated with MMSE score change.”

Lower is not always better

The authors of a commentary in the same issue of JAMA Internal Medicine write:

“We think it is time to move from the concept of ‘the lower the better’ to the concept of ‘hemodynamic optimization‘ to decelerate the pace of cognitive decline by a proper management of blood pressure.”

Evidence-based guideline from the Eighth Joint National Committee (JNC 8) 2014

Recommendations from these guidelines as listed in Medscape include:

  • In patients aged 60 years or older, start treatment for SBP >150 mm Hg or DBP >90 mm Hg and treat to under those thresholds.
  • In patients aged 18-60 years, treatment initiation and goals should be 140/90 mm Hg.
  • The same goals apply to patients with diabetes or CKD.
  • In nonblack patients, initial treatment can be a thiazide-type diuretic, calcium channel blocker (CCB), angiotensin-converting-enzyme (ACE) inhibitor, or angiotensin receptor blocker (ARB).
  • For black patients, initial therapy should be a thiazide-type diuretic or CCB.
  • In patients aged 18 years or older with CKD, initial or add-on therapy should be an ACE inhibitor or ARB, regardless of race or diabetes status.

The authors of the study on blood pressure treatment and cognitive impairment conclude:

Low daytime SBP was independently associated with a greater progression of cognitive decline in older patients with dementia and MCI among those treated with AHDs. Excessive SBP lowering may be harmful for older patients with cognitive impairment. Ambulatory blood pressure monitoring can be useful to help avoid high blood pressure overtreatment in this population.

Benzodiazepines associated with increased Alzheimer’s risk

BMJBenzodiazepines are well known to be deleterious to brain health with more than very short-term use. Research just published in BMJ (British Medical Journal) presents evidence that use of benzodiazepines longer than three months to treat anxiety or insomnia is associated with a substantial increase in the risk of Alzheimer’s disease.The authors note urgent public health concerns regarding dementia:

Rising tide of dementia

Dementia is currently the main cause of dependency in older people and a major public health concern affecting about 36 million people worldwide. Because of population growth and demographic ageing, this number is expected to double every 20 years and to reach 115 million in 2050, resulting in tragic human consequences and social costs. As there are no effective treatments, the search for putative modifying factors remains a priority. Several studies have shown that benzodiazepine use could be one of these. This class of drugs is mainly used to treat anxiety or insomnia. Prevalence of use among elderly patients is consistently high in developed countries and ranges from 7% to 43%. International guidelines recommend short term use, mainly because of withdrawal symptoms that make discontinuation problematic. Although the long term effectiveness of benzodiazepines remains unproved for insomnia and questionable for anxiety, their use is predominantly chronic in older people.”

Benzodiazepines and dementia

“While the acute deleterious effects of benzodiazepines on memory and cognition are well documented, the possibility of an increased risk of dementia is still a matter of debate.”

So they investigated the relation between the risk of Alzheimer’s disease with exposure to benzodiazepines that started at least five years before, in 1796 subjects who ended up developing Alzheimer’s who were matched with 7184 controls and found:

Benzodiazepine ever use was associated with an increased risk of Alzheimer’s disease (adjusted odds ratio 1.51). No association was found for a cumulative dose <91 prescribed daily doses. The strength of association increased with exposure density 1.32 for 91-180 prescribed daily doses and 1.84 for >180 prescribed daily doses and with the drug half life (1.43) for short acting drugs and 1.70 for long acting ones.”

Benzodiazepines duration and discontinuation

MedscapeA comment in Medscape Family Medicine states:

“The investigators note that although these medications are important treatment options, clinicians should “comply with good practice guidelines” and prescribe benzodiazepines for as short a time as possible. In addition, use should not exceed 3 months.”

Note: Benzodiazepines in long term use should never be discontinued abruptly and without the guidance of a clinician due to the likelihood of serious adverse withdrawal effects.

The authors conclude:

Benzodiazepine use is associated with an increased risk of Alzheimer’s disease. The stronger association observed for long term exposures reinforces the suspicion of a possible direct association, even if benzodiazepine use might also be an early marker of a condition associated with an increased risk of dementia. Unwarranted long term use of these drugs should be considered as a public health concern.”

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.

Insulin resistance damages brain white matter even with normal glucose

Neurology 82 (18)Insulin resistance (IR) exposes the brain along with the rest of the body to elevated insulin levels produced to overcome receptor resistance. Following earlier studies noted here including Dementia risk increased by higher blood sugar before diabetes, a new study just published in the journal Neurology offers yet more evidence that the higher levels of insulin damage brain white matter well before glucose and HgbA1c levels become elevated.

To investigate the relationship between insulin resistance and brain white matter (WM, myelinated axonal tissue) damage the authors correlated diffusion tensor imaging of the brains of 127 subjects age 41–86 years with insulin resistance as determined by the homeostasis model assessment of IR (HOMA-IR). There was indeed a significant association:

“Participants were divided into 2 groups based on HOMA-IR values: “high HOMA-IR” (≥2.5, n = 27) and “low HOMA-IR” (<2.5, n = 100)…The high HOMA-IR group demonstrated decreased axial diffusivity broadly throughout the cerebral WM in areas such as the corpus callosum, corona radiata, cerebral peduncle, posterior thalamic radiation, and right superior longitudinal fasciculus, and WM underlying the frontal, parietal, and temporal lobes, as well as decreased fractional anisotropy in the body and genu of corpus callosum and parts of the superior and anterior corona radiata, compared with the low HOMA-IR group, independent of age, WM signal abnormality volume, and antihypertensive medication status. These regions additionally demonstrated linear associations between diffusion measures and HOMA-IR across all subjects, with higher HOMA-IR values being correlated with lower axial diffusivity.”

In other words, regardless of age, higher insulin resistance predicted more abnormalities in the brain white matter. The authors conclude:

“In generally healthy adults, greater IR is associated with alterations in WM tissue integrity. These cross-sectional findings suggest that IR contributes to WM microstructural alterations in middle-aged and older adults. “

Clinical note: It is imperative for practitioners to assess for insulin resistance well before HgbA1c and glucose become elevated.