There has been a lot of interesting science, some of it reported here, documenting the benefits of resveratrol for factors contributing to inflammation, insulin resistance, obesity, diabetes and longevity. A paper just published in the American Journal of Clinical Nutrition offers evidence that the valuable phenolic compound quercitin may be even more effective than resveratrol for reducing the inflammation associated with insulin resistance and diabetes. The authors state:

“Quercetin and trans-resveratrol (trans-RSV) are plant polyphenols reported to reduce inflammation or insulin resistance associated with obesity. Recently, we showed that grape powder extract, which contains quercetin and trans-RSV, attenuates markers of inflammation in human adipocytes and macrophages and insulin resistance in human adipocytes…The aim of this study was to examine the extent to which quercetin and trans-RSV prevented inflammation or insulin resistance in primary cultures of human adipocytes [fat cells] treated with tumor necrosis factor-{alpha} (TNF-{alpha})—an inflammatory cytokine elevated in the plasma and adipose tissue of obese, diabetic individuals.”

They stimulated fat cells with TNF-{alpha} to promote inflammation after pretreatment with quercetin and trans-RSV, then measured gene and protein markers of inflammation and insulin resistance. What did the data show?

Quercetin, and to a lesser extent trans-RSV, attenuated the TNF-{alpha}–induced expression of inflammatory genes such as interleukin (IL)-6, IL-1β, IL-8, and monocyte chemoattractant protein-1 (MCP-1) and the secretion of IL-6, IL-8, and MCP-1… Quercetin, but not trans-RSV, decreased TNF-{alpha}–induced nuclear factor-{kappa}B transcriptional activity. Quercetin and trans-RSV attenuated the TNF-{alpha}–mediated suppression of peroxisome proliferator–activated receptor {gamma} (PPAR{gamma}) and PPAR{gamma} target genes and of PPAR{gamma} protein concentrations and transcriptional activity….”

Quercitin is known to be helpful for gut inflammation associated with food allergies, and I have found it to be a surprisingly helpful palliative for airborne allergies. In light of this the authors’ conclusion is not a surprise:

“These data suggest that quercetin is equally or more effective than trans-RSV in attenuating TNF-–mediated inflammation and insulin resistance in primary human adipocytes.”

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We’re always on the lookout for physiological agents that have the potential to calm the activity of pro-inflammatory cytokines when they are elevated in autoimmune disease. An exciting finding was reported in a paper just published in the European Journal of Clinical Nutrition:

“The purpose of this study was to investigate whether vitamin B6 supplementation had a beneficial effect on inflammatory and immune responses in patients with rheumatoid arthritis (RA).”

The control group of patients was given 5 mg/day of folic acid only while the study group was given 100 mg/day of vitamin B6 in addition for 12 weeks. Indicators of inflammation (C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and lymphocyte subsets were measured on day 1 (week 0) and after 12 weeks (week 12) of the intervention.

At the end of twelves the data painted this picture:

“In the group receiving vitamin B6, plasma IL-6 and TNF-α levels significantly decreased at week 12. Plasma IL-6 level remained significantly inversely related to plasma PLP (pyridoxal 5′-phosphate, B6) after adjusting for confounders.”

The bottom line conclusion is worth bearing in mind when evaluating any autoimmune disorder because underlying causal factors are similar regardless of the specific tissue under attack:

“A large dose of vitamin B6 supplementation (100 mg/day) suppressed pro-inflammatory cytokines (that is, IL-6 and TNF-α) in patients with RA.”

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This interesting paper recently published in the Journal of Clinical Endocrinology & Metabolism describes one of the reasons why support when undergoing a surgical procedure is so important (and links to the risks for delirium and accelerated dementia after surgery in the elderly). The authors set out to investigate the…

“…mechanisms behind postoperative insulin resistance and impaired glucose utilization…”

They shrewdly analyzed the expression of 21 target genes in abdominal adipose (fat) tissue from samples taken at the beginning and end of patients undergoing abdominal surgery. What did the data show?

“After surgery, both sc [subcutaneous] and omental adipose tissue mRNA levels of genes involved in the IL6 and nicotinamide phosphoribosyltransferase pathways were increased, whereas mRNA levels of insulin receptor substrate 1 and adiponectin were reduced. TNF pathway genes were differently regulated between sc and omental adipose tissue, and glucose transporter 4 mRNA levels were decreased only in omental adipose tissue.”

In other words, surgery elicits a shift in genetic expression that favors insulin resistance and inflammation. The authors conclude:

“The transcriptional output of pivotal inflammatory and insulin signaling pathway genes is altered after surgery…This could be of importance for the metabolic aberrations associated to postsurgical complications…”

This helps to understand why patients who are lucky enough to receive adjunctive support for the insulin and inflammatory signaling pathways and receptors recover faster and with less complications.

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An interesting study just published in the journal Cell demonstrates one mechanism by which immunological dysfunction causes obsessive-compulsive disorder (OCD). The authors show that microglia (the immune cells in the brain) when abnormal can cause compulsive behaviors in mice that correspond to OCD in humans:

“Mouse Hoxb8 mutants (with faulty microglia) show unexpected behavior manifested by compulsive grooming and hair removal, similar to behavior in humans with the obsessive-compulsive disorder spectrum disorder trichotillomania.”

They then showed that transplanting normal microglia eliminated their pathological OCD behavior.

“Immunological dysfunctions have been associated with neuropsychiatric disorders…In this mouse, a distinct compulsive behavioral disorder is associated with mutant microglia.”

The author of a report on this study published in Science Now comments:

“Previous studies have implied a link between the immune system and obsessive-compulsive disorder and other neuropsychiatric conditions, Capecchi says. “Here, we say there is a direct connection.”…The results raise the possibility of treating obsessive-compulsive disorder by targeting the immune system rather than the brain.”

What other evidence might there be that OCD in humans is an autoimmune disease? A paper published a year and a half ago in Neuroscience Letters shows how an immune cytokine abnormality also contributes to OCD. The authors begin by observing:

“Several lines of evidence support an immunologic involvement in obsessive-compulsive disorder (OCD): the increased prevalence of OCD in patients with rheumatic fever (RF), and the aggregation of obsessive-compulsive spectrum disorders among relatives of RF probands [affected persons studied in a genetic investigation]. Tumor necrosis factor alpha is a proinflammatory cytokine involved in RF and other autoimmune diseases…the goal of the present study was to investigate a possible association between polymorphisms within the promoter region of TNFA and OCD.”

They studied two polymorphisms of the genes for TNF-alpha and found that:

“Significant associations were observed between both polymorphisms and OCD.”

The theme is carried forward in a paper more recently published in the journal Neuropsychopharmacology that reports the presence of anti-brain autoantibodies that derange excitatory neurotransmitters with OCD. The authors begin by observing:

“…serum autoantibodies directed against basal ganglia (BG) implicate autoimmunity in the pathogenesis of obsessive–compulsive disorder (OCD),…We examined this by investigating the presence of autoantibodies directed against the BG or thalamus in the serum as well as CSF of 23 OCD patients compared with 23 matched psychiatrically normal controls.”

They also measured several neurotransmitters including the most abundant excitatory neurotransmitter glutamate. What did their data show?

“There was evidence of significantly more binding of CSF autoantibodies to homogenate of BG as well as to homogenate of thalamus among OCD patients compared with controls. …CSF glutamate and glycine levels were also significantly higher in OCD patients compared with controls…”

Thus their conclusion:

“The results of our study implicate autoimmune mechanisms in the pathogenesis of OCD and also provide preliminary evidence that autoantibodies against BG and thalamus may cause OCD by modulating excitatory neurotransmission.”

This post would not be complete without including the recognized association of OCD with Tourette’s disorder (TD). The authors of this clinically useful study published not long ago in the journal Progress in Neuro-Psychopharmacology and Biological Psychiatry linked TD and OCD in their investigation of the cytokines promoting the autoimmune attack on brain tissue:

“This study examined the potential role of cytokines, modulators of the immune system. We hypothesized that children with TD would have increased levels of tumor necrosis factor (TNF)-α, interleukin (IL)-12, IL-1β and IL-6, and decreased IL-2. We also explored whether comorbid [happening together] obsessive compulsive disorder (OCD) had an effect on the cytokine profile of TD patients.”

They found that both TD and OCD had abnormal elevations of cytokines associated with their immune dysfunction, only those who had OCD comorbid with TD had significantly elevated IL-12.

“Findings suggest a role for IL-12 and IL-2 in TD, and that the TD+OCD subgroup may involve different neuroimmunological functions than the TD−OCD subgroup.”

Their conclusion confirms both the autoimmune etiology and that each patient must be precisely evaluated and treated as in individual for their autoimmune disorder.

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Is there any evidence that chiropractic adjustments help chronic headache? A study just published in The Spine Journal begins with the observation:

“Systematic reviews of randomized controlled trials suggest that spinal manipulative therapy (SMT) is efficacious for care of cervicogenic headache (CGH). The effect of SMT dose on outcomes has not been studied.”

Eighty patients with chronic cervicogenic (originating in the neck) headache were randomised for treatment with either spinal manipulation or massage therapy and their outcomes analyzed. What did the data show?

“There was an advantage for SMT over the control…For the higher dose patients, the advantage was greater. Patients receiving SMT were also more likely to achieve a 50% improvement in pain scale…Secondary outcomes showed similar trends favoring SMT. For SMT patients, the mean number of CGH was reduced by half.”

The conclusion:

“Clinically important differences between SMT and a control intervention were observed favoring SMT.”

In light of the importance of the role of cytokines such as TNF-α (tumor necrosis factor-alpha) in chronic inflammation, a case review recently published in the Journal of Manipulative and Physiological Therapeutics that documents a marked improvement associated with recovery from cervicogenic headache has a result of SMT:

“Two patients with whiplash injury and disk herniation developed CHA (cervical headache) associated with very high TNF-α levels. After manipulative therapy, these patients became symptom-free, and their TNF-α levels decreased substantially.”

The study size is only two patients, but it’s consistent with the findings of another study published in the same journal that show the connection between recovery from headache by manual therapy and improvements in Heart Rate Variability (analysis of changes in the intervals between heartbeats that reveals autonomic nervous system function) and mood:

“The purpose of this study was to investigate the immediate effects of head-neck massage on heart rate variability (HRV), mood states, and pressure pain thresholds (PPTs) in patients with chronic tension-type headache (CTTH).”

Heart Rate Variability is a powerful indicator of the functional state of the part of the nervous system that automatically “runs” the internal organs and functions. Most chronic conditions are characterized by excessive activity of the sympathetic nervous system (SNS) and deficient parasympathetic nervous system (PSNS) resources and less overall variability (more rigidity). The author’s data led to this conclusion:

“The application of a single session of manual therapy program produces an immediate increase of index HRV and a decrease in tension, anger status, and perceived pain in patients with CTTH.”

This is impressive, and duplicates my own clinical experience with treatment and HRV analysis. These findings help establish the scientific basis for why people feel so much better after their treatments.

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Not to oversimplify since depression can have multiple contributing causes, but there have been many studies published about brain inflammation as an important component of major and minor depression. An illuminating paper published in the latest volume of the journal Biological Psychiatry undertakes an extensive analysis of accumulated scientific evidence. The authors begin by noting:

“Major depression occurs in 4.4% to 20% of the general population. Studies suggest that major depression is accompanied by immune dysregulation and activation of the inflammatory response system (IRS). Our objective was to quantitatively summarize the data on concentrations of specific cytokines in patients diagnosed with a major depressive episode and controls.”

Cytokines are, among other things, signalling molecules that regulate immune system function. This has great practical significance because there is an evidence-based approach in functional medicine to analyzing and treating cytokine imbalances. The authors evaluated 24 studies that included eight different cytokines. Here’s what their data showed:

“This meta-analysis reports significantly higher concentrations of the proinflammatory cytokines TNF-α and IL-6 in depressed subjects compared with control subjects…this meta-analytic result strengthens evidence that depression is accompanied by activation of the IRS.”

You may enjoy the interesting comment on this study just published in Journal Watch.

Although this is a valuable study it’s important to keep a broad perspective. Here’s another paper published not long ago in the journal Pharmacopsychiatry, one among many others on cytokines and depression. It documents cases of brain inflammation with a different cytokine pattern. This paper is also interesting for the therapeutic comparison of Prozac and electroacupuncture:

“An increase in inflammatory response and an imbalance between T-helper (Th) 1 and 2 functions have been implicated in major depression. The aims of the present study were to 1) study the relationship between pro- and anti-inflammatory cytokines and between Th1 and Th2 produced cytokines in depressed patients and 2) evaluate and compare the effect of treatments with electroacupuncture (EA) and fluoxetine on these cytokines.”

Th1 and Th2 are the two primary poles of immune system function, cell-mediated and humoral (antibody). Imbalances result in immune dysregulation. Fluoxetine is Prozac. (The inclusion of electroacupuncture might tip you off that this study was done in Germany.) Their data tells a fascinating story:

“Increased proinflammatory cytokine interleukin (IL)-1β and decreased anti-inflammatory cytokine IL-10 were found in the depressed patients. By contrast, Th1 produced proinflammatory cytokines, tumor necrosis factor (TNF)-α and interferon (IFN)-γ were decreased, and Th2 produced cytokine IL-4 was significantly increased in depressed patients…Both acupuncture and fluoxetine treatments, but not the placebo, reduced IL-1β concentrations in responders. However, only acupuncture attenuated TNF-α concentration and INF-γ/IL-4 ratio towards the control level.”

How interesting that what we call a peripheral sensory nervous system modality (stimulation of the brain through the peripheral sensory nerves, in this case with electroacupuncture) reduced inflammation and TNF-α. This corresponds exactly with my clinical experience employing these modalities for a range of conditions including autoimmune disorders, and explains part of why patients feel so much better after a treatment. Their conclusion is worth noting:

“These results suggest that an imbalance between the pro- and anti-inflammatory cytokines (IL-1 and IL-10), and between Th1 and Th2 cytokines (INF-γ or TNF-α and IL-4) occurred in untreated depressed patients. Both EA and fluoxetine had an anti-inflammatory effect by reducing IL-1β. EA treatment also restored the balance between Th1 and Th2 systems by increasing TNF-α and decreasing IL-4.”

Thus depression involves inflammation, but the cytokine expression can vary.

This topic is multifaceted and a proper synopsis of the functional approach to depression is too long for this forum, but here’s one more paper to keep the horizon open. This study published not long ago in the Journal of Psychiatric Practice investigates the role of low testosterone in depression.

“Studies suggest that testosterone (TT) replacement may have an antidepressant effect in depressed patients…The objective of this study was to explore the effect of TT administration on depression using both a systematic review of the literature and a meta-analysis.”

What did the data show?

“Meta-analysis of the data from these seven studies showed a significant positive effect of TT therapy on…depressed patients when compared with placebo. Subgroup analysis also showed a significant response in the subpopulations with hypogonadism…”

This certainly confirms expectations considering the population of testosterone receptors in the brain and their density in the frontal lobe. Hypogonadism means that the testicles are producing too little testosterone in response to stimulation by luteinizing hormone (LH). This validates my common sense practice of always including biologically active free fraction testosterone and LH in workups for male depression. Note: testosterone replacement, especially by a transdermal route (gel, patch, cream) can give a good initial result but end up back-firing. This is a topic for another post. For now just remember there is a better way.

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This interesting paper published in the Journal of Physiology & Biochemistry describes how caffeine significantly reduced levels of TNF-alpha, a major pro-inflammatory cytokine (signalling molecule). Individuals with sympathetic nervous system (“fight or flight”) hyperarousal have reason to avoid or minimize caffeine, but this and other studies that will be posted here show evidence for benefit under the right circumstances. From the paper: “Adipose tissue secretions play an important role in the development of obesity-related pathologies such as diabetes…Thus, caffeine, by decreasing TNFalpha expression, could improve adipose tissue inflammation during obesity.”

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