Dr. Ron’s Research Review – July 21, 2010

This week’s research review contains articles on several topics:

Forms of vitamin B3: NAD (Sauve 2008) and Nicotinamide (Maiese, Chong et al. 2009)

Mild adrenocortical deficiency - patients with rheumatoid arthritis improved with small, physiologic dosages of cortisol (Jefferies 1994)

I’ve also included two articles on autoimmune diseases:

Low serum levels of sex steroids are associated with disease characteristics in primary Sjogren's syndrome; supplementation with dehydroepiandrosterone restores the concentrations (Forsblad-d'Elia, Carlsten et al. 2009)

Reversing bacteria-induced vitamin D receptor dysfunction is key to autoimmune disease (Waterhouse, Perez et al. 2009)

Of Interest:

Naturopathy and the primary care practice (Fleming and Gutknecht 2010)

Bioidentical Hormone Replacement Therapy (BHRT): Common Issues and Solutions, Townsend Letter January 2010 Link

Dr. Ron


Articles

The vitamin nicotinamide: translating nutrition into clinical care

            (Maiese, Chong et al. 2009) Download

Nicotinamide, the amide form of vitamin B(3) (niacin), is changed to its mononucleotide compound with the enzyme nicotinic acide/nicotinamide adenylyltransferase, and participates in the cellular energy metabolism that directly impacts normal physiology. However, nicotinamide also influences oxidative stress and modulates multiple pathways tied to both cellular survival and death. During disorders that include immune system dysfunction, diabetes, and aging-related diseases, nicotinamide is a robust cytoprotectant that blocks cellular inflammatory cell activation, early apoptotic phosphatidylserine exposure, and late nuclear DNA degradation. Nicotinamide relies upon unique cellular pathways that involve forkhead transcription factors, sirtuins, protein kinase B (Akt), Bad, caspases, and poly (ADP-ribose) polymerase that may offer a fine line with determining cellular longevity, cell survival, and unwanted cancer progression. If one is cognizant of the these considerations, it becomes evident that nicotinamide holds great potential for multiple disease entities, but the development of new therapeutic strategies rests heavily upon the elucidation of the novel cellular pathways that nicotinamide closely governs.

NAD+ and vitamin B3: from metabolism to therapies

            (Sauve 2008) Download

The role of NAD(+) metabolism in health and disease is of increased interest as the use of niacin (nicotinic acid) has emerged as a major therapy for treatment of hyperlipidemias and with the recognition that nicotinamide can protect tissues and NAD(+) metabolism in a variety of disease states, including ischemia/reperfusion. In addition, a growing body of evidence supports the view that NAD(+) metabolism regulates important biological effects, including lifespan. NAD(+) exerts potent effects through the poly(ADP-ribose) polymerases, mono-ADP-ribosyltransferases, and the recently characterized sirtuin enzymes. These enzymes catalyze protein modifications, such as ADP-ribosylation and deacetylation, leading to changes in protein function. These enzymes regulate apoptosis, DNA repair, stress resistance, metabolism, and endocrine signaling, suggesting that these enzymes and/or NAD(+) metabolism could be targeted for therapeutic benefit. This review considers current knowledge of NAD(+) metabolism in humans and microbes, including new insights into mechanisms that regulate NAD(+) biosynthetic pathways, current use of nicotinamide and nicotinic acid as pharmacological agents, and opportunities for drug design that are directed at modulation of NAD(+) biosynthesis for treatment of human disorders and infections.

Mild adrenocortical deficiency, chronic allergies, autoimmune disorders and the chronic fatigue syndrome: a continuation of the cortisone story

            (Jefferies 1994) Download

The possibility that patients with disorders that improve with administration of large, pharmacologic dosages of glucocorticoids, such as chronic allergies and autoimmune disorders, might have mild deficiency of cortisol production or utilization has received little attention. Yet evidence that patients with rheumatoid arthritis improved with small, physiologic dosages of cortisol or cortisone acetate was reported over 25 years ago, and that patients with chronic allergic disorders or unexplained chronic fatigue also improved with administration of such small dosages was reported over 15 years ago, suggesting that these disorders might be associated with mild adrenocortical deficiency. The apparent reasons for the failure of these reports to be confirmed or mentioned in medical textbooks and the facts needed to restore perspective are reviewed, and the need for further studies of the possible relationship of a mild deficiency of the production or utilization of cortisol and possibly other normal adrenocortical hormones to the development of these disorders is discussed.

Low serum levels of sex steroids are associated with disease characteristics in primary Sjogren's syndrome; supplementation with dehydroepiandrosterone restores the concentrations

            (Forsblad-d'Elia, Carlsten et al. 2009) Download

CONTEXT: Serum levels of the sex steroid prohormones dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S) decline upon aging and are reduced in primary Sjogren's syndrome. OBJECTIVE: Our aim was to investigate: 1) effects of 50 mg oral DHEA/day on changes in serum levels of DHEA and 12 of its metabolites; 2) relationships between steroid levels and disease characteristics; and 3) whether these parameters were influenced by DHEA. DESIGN: Twenty-three postmenopausal women with primary Sjogren's syndrome and subnormal levels of DHEA-S were included in a randomized, 9-month, controlled, double blind crossover study. Liquid chromatography/mass spectrometry (MS)/MS and gas chromatography/MS were used to measure the sex steroids. Anti-SS-A/Ro and/or anti-SS-B/La, salivary gland focus score, salivary flow rates, dry mouth and eye symptoms, and routine laboratory tests were assessed. RESULTS: Baseline erythrocyte sedimentation rate was inversely correlated with testosterone (Testo), dihydrotestosterone, and DHEA-S (rs = -0.42, -0.45, and -0.58, respectively). Dry mouth symptoms correlated with low Testo and androstenedione, whereas dry eyes correlated with low estrogens, most strongly estrone (rs = -0.63). Presence of anti-SS-A and/or anti-SS-B was independently associated with low estradiol (area under the receiver operating characteristic curve, 0.82). All metabolites increased during DHEA but not during placebo. The relative increases were less for estrogens and Testo compared to dihydrotestosterone and glucuronidated androgen metabolites. Dry mouth symptoms decreased during DHEA therapy. CONCLUSIONS: Disease manifestations in primary Sjogren's syndrome were associated with low sex hormone levels, dry mouth symptoms with low androgens, and dry eyes with low estrogens. Exogenous DHEA was preferentially transformed into androgens rather than into estrogens.

Reversing bacteria-induced vitamin D receptor dysfunction is key to autoimmune disease

(Waterhouse, Perez et al. 2009) Download

Vitamin D research is discussed in light of the hypothesis that the lower average levels of vitamin D frequently observed in autoimmune disease are not a sign of deficiency. Instead, it is proposed that the lower levels result from chronic infection with intracellular bacteria that dysregulate vitamin D metabolism by causing vitamin D receptor (VDR) dysfunction within phagocytes. The VDR dysfunction causes a decline in innate immune function that causes susceptibility to additional infections that contribute to disease progression. Evidence has been accumulating that indicates that a number of autoimmune diseases can be reversed by gradually restoring VDR function with the VDR agonist olmesartan and subinhibitory dosages of certain bacteriostatic antibiotics. Diseases showing favorable responses to treatment so far include systemic lupus erythematosis, rheumatoid arthritis, scleroderma, sarcoidosis, Sjogren's syndrome, autoimmune thyroid disease, psoriasis, ankylosing spondylitis, Reiter's syndrome, type I and II diabetes mellitus, and uveitis. Disease reversal using this approach requires limitation of vitamin D in order to avoid contributing to dysfunction of nuclear receptors and subsequent negative consequences for immune and endocrine function. Immunopathological reactions accompanying bacterial cell death require a gradual elimination of pathogens over several years. Practical and theoretical implications are discussed, along with the compatibility of this model with current research.

Naturopathy and the primary care practice

            (Fleming and Gutknecht 2010) Download

Naturopathy is a distinct type of primary care medicine that blends age-old healing traditions with scientific advances and current research. Naturopathy is guided by a unique set of principles that recognize the body's innate healing capacity, emphasize disease prevention, and encourage individual responsibility to obtain optimal health. Naturopathic treatment modalities include diet and clinical nutrition, behavioral change, hydrotherapy, homeopathy, botanical medicine, physical medicine, pharmaceuticals, and minor surgery. Naturopathic physicians (NDs) are trained as primary care physicians in 4-year, accredited doctoral-level naturopathic medical schools. At present, there are 15 US states, 2 US territories, and several provinces in Canada, Australia, and New Zealand that recognize licensure for NDs.


References

Fleming, S. A. and N. C. Gutknecht (2010). "Naturopathy and the primary care practice." Prim Care 37(1): 119-36.

Forsblad-d'Elia, H., H. Carlsten, et al. (2009). "Low serum levels of sex steroids are associated with disease characteristics in primary Sjogren's syndrome; supplementation with dehydroepiandrosterone restores the concentrations." J Clin Endocrinol Metab 94(6): 2044-51.

Jefferies, W. M. (1994). "Mild adrenocortical deficiency, chronic allergies, autoimmune disorders and the chronic fatigue syndrome: a continuation of the cortisone story." Med Hypotheses 42(3): 183-9.

Maiese, K., Z. Z. Chong, et al. (2009). "The vitamin nicotinamide: translating nutrition into clinical care." Molecules 14(9): 3446-85.

Sauve, A. A. (2008). "NAD+ and vitamin B3: from metabolism to therapies." J Pharmacol Exp Ther 324(3): 883-93.

Waterhouse, J. C., T. H. Perez, et al. (2009). "Reversing bacteria-induced vitamin D receptor dysfunction is key to autoimmune disease." Ann N Y Acad Sci 1173: 757-65.