Motion Bliss

SCIENTIFIC RESEARCH ON THE FOLLOWING INGREDIENTS:

Omega 3

The Effect of Omega-3 Fatty Acids in Patients With Active Rheumatoid Arthritis Receiving DMARDs Therapy: Double-Blind Randomized Controlled Trial ¹

Background: Rheumatoid arthritis is a symmetric peripheral polyarthritis of unknown etiology that, untreated or if unresponsive the therapy, typically leads to deformity and destruction of joints due to erosion of cartilage and bone. Omega-3 fatty acids have been shown to reduce morning stiffness, the number of tender joints and swollen joints in patients with rheumatoid arthritis. This study is designed for evaluation of omega-3 effects on disease activity and remission of rheumatoid arthritis in DMARDs treated patients and on weight changes and reduction of analgesic drugs consumption versus placebo.

Methods: Sixty patients with active rheumatoid arthritis (49 female and 11 male) underwent rheumatologist examination and disease activity score were calculated. Then patients were enrolled in this 12 week, double blind, randomized, placebo- controlled study. The patients in both groups continued their pre study standard treatment. The patients were visited every 4 weeks, 4 times and data were recorded.

Results: Significant improvement in the patient’s global evaluation and in the physician’s assessment of disease was observed in those taking omega-3. The proportions of patients who improved and of those who were able to reduce their concomitant analgesic medication were significantly greater with omega-3 consumption. There were no weight changes.

Conclusion: Daily supplementation with omega-3 results has significant clinical benefit and may reduce the need for concomitant analgesic consumption without weight changes.

Source: Elham Rajaei, Karim Mowla, Ali Ghorbani, Sara Bahadoram, Mohammad Bahadoram, Mehrdad Dargahi-Malamir. “The Effect of Omega-3 Fatty Acids in Patients With Active Rheumatoid Arthritis Receiving DMARDs Therapy: Double-Blind Randomized Controlled Trial” Global Journal of Health Science (2016): 8(7): 18–25.

¹ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4965662/

Omega-3 Fatty Acids in Rheumatic Diseases - A Critical Review ²

Abstract

Many clinical trials of omega-3 fatty acids, supplied as fish oil supplements, have been carried out in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), lupus nephritis, and osteoarthritis (OA) over the past 3 decades. This review attempts to summarize the highlights of these studies to evaluate the clinical efficacy for omega-3 fatty acids to be added alongside existing treatment regimens. A total of 20 clinical trials have been carried out in RA, of which 16 exhibited significant improvements in multiple disease clinical outcomes. Nine clinical trials have been completed in SLE and lupus nephritis, of which 6 exhibited significant improvements in 1 or more clinical outcomes. A total of 4 clinical trials have been conducted in OA, of which 3 exhibited significant improvements in at least 1 clinical parameter. Multiple mechanisms for the clinical effects of omega-3 fatty acids have been implicated, including the modulation of eicosanoid synthesis toward a more anti-inflammatory profile and suppressed production of proinflammatory cytokines. Overall, fish oil supplements appear to be a safe and effective agent that could be added to the current treatment regimens in RA. Longer-term trials with larger patient cohort sizes are warranted to establish any long-term benefits of fish oil supplements in SLE, lupus nephritis, and OA.

Source: Umair Akbar, BS, Melissa Yang, BS, Divya Kurian, BS, Chandra Mohan, MD, PhD. “Omega-3 Fatty Acids in Rheumatic Diseases - A Critical Review” Journal of Clinical Rheumatology (2017): Volume 23, Issue 6, 330-339.

² https://journals.lww.com/jclinrheum/fulltext/2017/09000/omega_3_fatty_acids_in_rheumatic_diseases__a.6.aspx

Omega-3 Fatty Acids in Inflammation and Autoimmune Diseases

Abstract

Among the fatty acids, it is the omega-3 polyunsaturated fatty acids (PUFA) which possess the most potent immunomodulatory activities, and among the omega-3 PUFA, those from fish oil—eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)—are more biologically potent than α-linolenic acid (ALA). Some of the effects of omega-3 PUFA are brought about by modulation of the amount and types of eicosanoids made, and other effects are elicited by eicosanoid-independent mechanisms, including actions upon intracellular signaling pathways, transcription factor activity and gene expression. Animal experiments and clinical intervention studies indicate that omega-3 fatty acids have anti-inflammatory properties and, therefore, might be useful in the management of inflammatory and autoimmune diseases. Coronary heart disease, major depression, aging and cancer are characterized by an increased level of interleukin 1 (IL-1), a proinflammatory cytokine. Similarly, arthritis, Crohn’s disease, ulcerative colitis and lupus erythematosis are autoimmune diseases characterized by a high level of IL-1 and the proinflammatory leukotriene LTB4 produced by omega-6 fatty acids. There have been a number of clinical trials assessing the benefits of dietary supplementation with fish oils in several inflammatory and autoimmune diseases in humans, including rheumatoid arthritis, Crohn’s disease, ulcerative colitis, psoriasis, lupus erythematosus, multiple sclerosis and migraine headaches. Many of the placebo-controlled trials of fish oil in chronic inflammatory diseases reveal significant benefit, including decreased disease activity and a lowered use of anti-inflammatory drugs. 

Source: Simopoulos, Artemis P. "Omega-3 fatty acids in inflammation and autoimmune diseases." Journal of the American College of nutrition 21.6 (2002): 495-505. 

A meta-analysis of the analgesic effects of omega-3 polyunsaturated fatty acid supplementation for inflammatory joint pain ³

Abstract

Between 40% and 60% of Americans use complementary and alternative medicine to manage medical conditions, prevent disease, and promote health and well-being. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) have been used to treat joint pain associated with several inflammatory conditions. We conducted a meta-analysis of 17 randomized, controlled trials assessing the pain relieving effects of ω-3 PUFAs in patients with rheumatoid arthritis or joint pain secondary to inflammatory bowel disease and dysmenorrhea. Meta-analysis was conducted with Cochrane Review Manager 4.2.8. for six separate outcomes using standardized mean differences (SMDs) as a measure of effect size: (1) patient assessed pain, (2) physician assessed pain, (3) duration of morning stiffness, (4) number of painful and/or tender joints, (5) Ritchie articular index, and (6) nonselective nonsteroidal anti-inflammatory drug consumption. Supplementation with ω-3 PUFAs for 3–4 months reduces patient reported joint pain intensity (SMD: −0.26; 95% CI: −0.49 to −0.03, p = 0.03), minutes of morning stiffness (SMD: −0.43; 95% CI: −0.72 to −0.15, p = 0.003), number of painful and/or tender joints (SMD: −0.29; 95% CI: −0.48 to −0.10, p = 0.003), and NSAIDconsumption (SMD: −0.40; 95% CI: −0.72 to  − 0.08, p = 0.01). Significant effects were not detected for physician assessed pain (SMD: −0.14; 95% CI: −0.49 to 0.22, p = 0.45) or Ritchie articular index (SMD: 0.15; 95% CI:  − 0.19 to 0.49, p = 0.40) at 3–4 months. The results suggest that ω-3 PUFAs are an attractive adjunctive treatment for joint pain associated with rheumatoid arthritis, inflammatory bowel disease, and dysmenorrhea.

Source: Robert  J. Goldberg, Joel Katz “A meta-analysis of the analgesic effects of omega-3 polyunsaturated fatty acid supplementation for inflammatory joint pain” Pain (2007): Volume 129, Issues 1–2, 210-223.

³ https://www.sciencedirect.com/science/article/abs/pii/S0304395907000413

EPA (Eicosapentaenoic Acid) and DHA (Docosahexaenoic Acid) Eicosapentaenoic Acid Suppresses the Proliferation of Synoviocytes from Rheumatoid Arthritis ⁴

Abstract

Eicosapentaenoic acid (EPA) is essential for normal cell growth, and may play an important role in inflammatory and autoimmune disorders including rheumatoid arthritis. We investigate that EPA could suppress the proliferation of fibroblast like synoviocytes in vitro. We treated synoviocytes with 1 to 50 µM EPA and measured cell viabilities by the modified MTT assay. We sorted the number of them in sub G1 stage by fluorescence-activated cell sorting caliber. And we stained them by light green or Hoechst 33258, and investigate microscopic appearance. The cell viabilities were decreased at 30 µM, 40 µM, and 50 µM of EPA comparing to 0 µM of EPA. The half maximal concentration of synoviocytes inhibition was approximately 25 µM. At day 1 and day 3, cell number was also decreased at 50 µM EPA comparing to control. FACS caliber indicated the number of synoviocytes in sub G1 stage did not increase in each concentration of EPA. Hoechst staining indicated normal chromatin pattern and no change in a nuclear morphology both in EPA treated synoviocytes and in untreated synoviocytes. These findings suggest that EPA could suppress the proliferation of synoviocytes in vivo dose dependently and time dependently, however, the mechanism is not due to apoptosis.

Source: Masahide Hamaguchi, Yutaka Kawahito, Atsushi Omoto, Yasunori Tsubouchi, Masataka Kohno, Takahiro Seno, Masatoshi Kadoya, Aihiro Yamamoto, Hidetaka Ishino, Masahide Matsuyama, Rikio Yoshimura, Toshikazu Yoshikawa. “Eicosapentaenoic Acid Suppresses the Proliferation of Synoviocytes from Rheumatoid Arthritis” Journal of Clinical Biochemistry and Nutrition (2008) Sep; 43(2): 126–128.

⁴ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2533717/

Tissue inhibitor of metalloproteinases (TIMP, aka EPA): Structure, control of expression and biological functions

Abstract

The TIMPs play an important role in regulating the activity of the secreted metalloproteinases (collagenases, stromelysins, gelatinases). Two different TIMPs have been well characterized, each capable of inhibiting all tested eukaryotic metalloproteinases but showing specific binding to a particular gelatinase at a site distinct from the active site. They influence the activation of the prometalloproteinase and act to modulate proteolysis of extracellular matrix, notably during tissue remodeling and inflammatory processes. On certain cell types, they can exhibit growth factor-like activity, and they can inhibit the tumorigenic and metastatic phenotype of cancer cells.

Source: David T.Denhardt,  Bo Feng, Dylan R.Edwards, Enzo T.Cocuzzi, Uriel M.Malyankar. “Tissue inhibitor of metalloproteinases (TIMP, aka EPA): Structure, control of expression and biological functions” Pharmacology & Therapeutics (1993) Volume 59, Issue 3, 329-341.

Eicosapentaenoic acid and docosapentaenoic acid monoglycerides are more potent than docosahexaenoic acid monoglyceride to resolve inflammation in a rheumatoid arthritis model ⁵

Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease of the joints and bones. Omega-3 (ω3) fatty acid supplementation has been associated with a decreased production of inflammatory cytokines and eicosanoids involved in RA pathogenesis. The aim of this study was to determine the therapeutic potential of ω3 monoglyceride (MAG-ω3) compounds in an in vivo rat model of RA induced by Complete Freund’s Adjuvant (CFA).

Method: CFA rats were untreated or treated per os with three specific compounds, namely, MAG-docosahexaenoic acid (MAG-DHA), MAG-eicosapentaenoic acid (MAG-EPA) and MAG-docosapentaenoic acid (MAG-DPA). Morphological and histological analyses, as well as pro-inflammatory marker levels were determined following MAG-ω3 treatments.

Results: Morphological and histological analyses revealed that MAG-EPA and MAG-DPA exhibited strong activity in reducing the progression and severity of arthritic disease in CFA rats. Following MAG-EPA and MAG-DPA treatments, plasma levels of the pro-inflammatory cytokines; interleukin 17A (IL-17A), IL-1β, IL-6 and tumor necrosis factor α (TNFα) were markedly lower when compared to CFA-untreated rats. Results also revealed a decreased activation of p38 mitogen-activated protein kinases (p38 MAPK) and nuclear factor-kappa B (NFκB) pathways correlated with a reduced expression of TNFα, cyclooxygenase-2 (COX-2), matrix metalloproteinase-2 (MMP-2) and MMP-9 in paw homogenates derived from MAG-EPA and MAG-DPA-treated rats. Of interest, the combined treatment of MAG-EPA and vitamin E displayed an antagonistic effect on anti-inflammatory properties of MAG-EPA in CFA rats.

Conclusion: Altogether, the present data suggest that MAG-EPA, without vitamin E, represents a new potential therapeutic strategy for resolving inflammation in arthritis.

Source: Caroline Morin, Pierre U. Blier, Samuel Fortin. “Eicosapentaenoic acid and docosapentaenoic acid monoglycerides are more potent than docosahexaenoic acid monoglyceride to resolve inflammation in a rheumatoid arthritis model” Arthritis Research & Therapy (2015): 17: 142. 

⁵ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624173/

The effects of intraarticular administration of hyaluronan in a model of early osteoarthritis in sheep II. Cartilage composition and proteoglycan metabolism ⁶

A model of early osteoarthritis (OA) induced in ovine joints by medial meniscectomy was used to study the effects of two hyaluronan (HA) preparations (AHA and DHA) on cartilage composition and proteoglycan (PG) metabolism. DHA was an HA preparation with an average molecular weight (MW) of ∼2.0 × 106 d, and AHA had an MW of ∼8.0 × 105 d. Both preparations were administered intraarticularly once a week for 5 weeks starting 16 weeks after meniscectomy, and animals (n = 5) were killed 5 weeks after the last injection. Meniscectomized, saline-injected (n = 5) and nonoperated (n = 5) animals were used for controls. At necropsy, 3-mm-diameter full-depth cartilage plugs were sampled under sterile conditions from specific locations on the medial and lateral femoral condyles, tibial plateaus, patella, and trochlear groove. The cartilage plugs were cultured in Hams-F12 medium supplemented with 10% fetal calf serum for 24 hours, then for a further 48 hours in the presence of H235SO4 to determine the biosynthesis of PGs. The percentage of 35S-PGs and sulfated glycosami-noglycans released into the media was also ascertained. The cartilage adjacent to the plugs was analyzed for collagen and proteoglycan content and differential extractability with guanidine hydrochloride (GuHCl) solutions. The extractability of PGs with 0.4 mol/L GuHCI (nondissociative conditions) was lower from the medial femoral cartilages of the DH A-treated group than from the corresponding saline-treated group. In contrast, the release of 35S-PGs from the tibial cartilages of the DHA-treated animals was higher than in the saline-treated group. The biosynthesis of 35S-PGs, determined in vitro, for cartilage derived from the medial compartment was generally lower than for the lateral regions of the meniscectomized joints. The biosynthetic activity was further reduced in joints injected with the two HA preparations, but DHA reduced 35SO4 incorporation into PGs more than AHA. It was concluded that reduced biosynthesis of 35S-PGs and secretion into media was a consequence of increased loading of joints in the HA-treated animals rather than a direct effect of these preparations on chondrocyte metabolism.

Source: Peter Ghosh, Richard Read, Yukiko Numata, Suzanne Smith, Sarah Armstrong, Diana Wilson. “The effects of intraarticular administration of hyaluronan in a model of early osteoarthritis in sheep II. Cartilage composition and proteoglycan metabolism” Seminars in Arthritis and Rheumatism (1993) Volume 22, Issue 6, Supplement 1, 31-42.

⁶ https://www.sciencedirect.com/science/article/abs/pii/S0049017210800174

Leptin alone and in combination with interleukin-1-beta induced cartilage degradation potentially inhibited by EPA and DHA ⁷

Osteoarthritis (OA) is the most common form of arthritis. Obesity has been believed to be an important risk factor for OA development and the progression of not only load-bearing joints, but low-load-bearing joints as well. Increased leptin has been the focus of a link between obesity and OA. In this study, the effects of pathological (100ng/ml) or supra-pathological (10μg/ml) concentrations of leptin alone or in combination with IL1β on cartilage metabolisms were studied in porcine cartilage explant. The involved mechanisms were examined in human articular chondrocytes (HACs). Moreover, the protective effect of omega-3 polyunsaturated acids, eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) was also investigated. Leptin (10μg/ml) alone or in combination with IL1β could induce cartilage destruction, although lower concentrations had no effect. Leptin activated NFκB, ERK, JNK and p38 in HACs, which led to the induction of MMP3, MMP13 and ADAMTS4 secretions. The combined effect could further induce those enzymes through the additive effect on activation of NFκB and JNK. Interestingly, both EPA and DHA could inhibit cartilage damage induced by leptin plus IL1β by reducing the activation of NFκB and JNK, which led to the decrease of ADAMTS4 secretion. Altogether, only a supra-pathological concentration of leptin alone or in combination with IL1β could induce cartilage destruction, whereas a pathological one could not. This effect could be inhibited by EPA and DHA. To gain greater understanding of the link between leptin and OA, the effect of different levels of leptin on several states of OA cartilage requires further investigation.

Source: Thanyaluck Phitak, Kanchanit Boonmaleerat, Peraphan Pothacharoen, Dumnoensun Pruksakorn, Prachya Kongtawelert. "Leptin alone and in combination with interleukin-1-beta induced cartilage degradation potentially inhibited by EPA and DHA" Connective Tissue Research (2017): 316-331.

⁷ https://www.tandfonline.com/doi/abs/10.1080/03008207.2017.1385605

Eicosapentaenoic acid (EPA) production from microorganisms: a review

Abstract

Eicosapentaenoic acid EPA has been shown to be of major importance in the prevention and treatment of a range of human diseases and disorders. At present fish oil is the only source of EPA that is considered unattractive because it contains substantial amounts of undesirable fatty acids and cholesterol. Consequently, alternative sources of EPA are being sought, especially from algae and from fungi of the order Mucorales. This review presents information about EPA producing microorganisms, data on the production and recovery aspects along with the potential of microorganisms as commercial sources of EPA.

Source: Bajpai, Pratima, and Pramod K. Bajpai. "Eicosapentaenoic acid (EPA) production from microorganisms: a review." Journal of biotechnology 30.2 (1993): 161-183.

Effects of Eicosapentaenoic Acid Versus Docosahexaenoic Acid on Serum Lipids: A Systematic Review and Meta-Analysis

Abstract

Omega-3 fatty acid supplements containing both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been shown to reduce triglycerides but also increase low-density lipoprotein (LDL). Whether EPA or DHA given as monotherapy has differential effects on serum lipoproteins has not been systematically evaluated. We performed a meta-analysis of randomized placebo-controlled trials of monotherapy with EPA (n = 10), DHA (n = 17), or EPA versus DHA (n = 6). Compared with placebo, DHA raised LDL 7.23 mg/dL (95% CI, 3.98–10.5) whereas EPA non-significantly reduced LDL. In direct comparison studies, DHA raised LDL 4.63 mg/dL (95% CI, 2.15–7.10) more than EPA. Both EPA and DHA reduced triglycerides, with a greater reduction by DHA in direct comparison studies. DHA also raised high-density lipoprotein (4.49 mg/dL; 95% CI, 3.50–5.48) compared with placebo, whereas EPA did not. Although EPA and DHA both reduce triglycerides, they have divergent effects on LDL and high-density lipoprotein. Further research is needed to elucidate the mechanisms and significance of these differences.

Source: Wei, Melissa Y., and Terry A. Jacobson. "Effects of eicosapentaenoic acid versus docosahexaenoic acid on serum lipids: a systematic review and meta-analysis." Current atherosclerosis reports 13.6 (2011): 474-483.

Heterotrophic production of eicosapentaenoic acid by microalgae

Abstract

Eicosapentaenoic acid (EPA) is an ω-3 polyunsaturated fatty acid that plays an important role in the regulation of biological functions and prevention and treatment of a number of human diseases such as heart and inflammatory diseases. As fish oil fails to meet the increasing demand for purified EPA, alternative sources are being sought. Microalgae contain large quantities of high-quality EPA and they are considered a potential source of this important fatty acid. Some microalgae can be grown heterotrophically on cheap organic substrates without light. This mode of cultivation can be well controlled and provides the possibility to maximize EPA production on a large scale. Numerous strategies have been investigated for commercial production of EPA by microalgae. These include screening of high EPA-yielding microalgal strains, improvement of strains by genetic manipulation, optimization of culture conditions, and development of efficient cultivation systems. This paper reviews recent advances in heterotrophic production of EPA by microalgae with an emphasis on the use of diatoms as producing organisms.

Source: Wen, Zhi-You, and Feng Chen. "Heterotrophic production of eicosapentaenoic acid by microalgae." Biotechnology advances 21.4 (2003): 273-294.

Production of eicosapentaenoic acid from marine bacteria

Abstract

A marine bacterium, judged as a new species close to Shewanella putrefaciens, was isolated from the intestinal contents of the Pacific mackerel. The isolated strain SCRC‐2378 produced eicosapentaenoic acid (EPA) as the sole polyunsaturated fatty acid, which amounted to 24–40% of the total fatty acid in the cell, which corresponded to 2% of dry cell weight. Under the optimal growth conditions (pH 7.0, 20°C, and grown aerobically for 12–18 h), the yield of SCRC‐2738 reached 15 g of dry cells/L or 2×1010 viable cells/mL. EPA existed as phospholipid and was found in the sn‐2 position of phosphatidylethanolamine and phosphatidylglycerol. The 38 kbp (1,000 base pairs) genome DNA fragment was cloned from SCRC‐2738 and expressed in Escherichia coli, which resulted in the production of EPA. The nucleotide sequence of the 38 kbp DNA fragment was determined. The DNA fragment contains eight open reading frames, and three of them posses homology with enzymes involved in fatty acid synthesis. Thus, it may be possible that these EPA biosynthesis genes are applied for EPA production in yeasts or higher plants, and offer a new method for EPA synthesis as new foods containing EPA.

Source: Yazawa, Kazunaga. "Production of eicosapentaenoic acid from marine bacteria." Lipids 31.1Part2 (1996): S297-S300.

A novel omega3-fatty acid desaturase involved in the biosynthesis of eicosapentaenoic acid

Abstract

Long-chain n−3 PUFAs (polyunsaturated fatty acids) such as EPA (eicosapentaenoic acid; 20:5n−3) have important therapeutic and nutritional benefits in humans. In plants, cyanobacteria and nematodes, ω3-desaturases catalyse the formation of these n−3 fatty acids from n−6 fatty acid precursors. Here we describe the isolation and characterization of a gene (sdd17) derived from an EPA-rich fungus, Saprolegnia diclina, that encodes a novel ω3-desaturase. This gene was isolated by PCR amplification of an S. diclina cDNA library using oligonucleotide primers corresponding to conserved regions of known ω3-desaturases. Expression of this gene in Saccharomyces cerevisiae, in the presence of various fatty acid substrates, revealed that the recombinant protein could exclusively desaturate 20-carbon n−6 fatty acid substrates with a distinct preference for ARA (arachidonic acid; 20:4n−6), converting it into EPA. This activity differs from that of the known ω3-desaturases from any organism. Plant and cyanobacterial ω3-desaturases exclusively desaturate 18-carbon n−6 PUFAs, and a Caenorhabditis elegans ω3-desaturase preferentially desaturated 18-carbon PUFAs over 20-carbon substrates, and could not convert ARA into EPA when expressed in yeast. The sdd17-encoded desaturase was also functional in transgenic somatic soya bean embryos, resulting in the production of EPA from exogenously supplied ARA, thus demonstrating its potential for use in the production of EPA in transgenic oilseed crops.

Source: Pereira, Suzette L., et al. "A novel omega3-fatty acid desaturase involved in the biosynthesis of eicosapentaenoic acid." Biochemical Journal 378.2 (2004): 665-671.

Health Benefits of Docosahexaenoic Acid(DHA)

Abstract

Docosahexaenoic acid (DHA) is essential for the growth and functional development of the brain in infants. DHA is also required for maintenance of normal brain function in adults. The inclusion of plentiful DHA in the diet improves learning ability, whereas deficiencies of DHA are associated with deficits in learning. DHA is taken up by the brain in preference to other fatty acids. The turnover of DHA in the brain is very fast, more so than is generally realized. The visual acuity of healthy, full-term, formula-fed infants is increased when their formula includes DHA. During the last 50 years, many infants have been fed formula diets lacking DHA and other omega-3 fatty acids. DHA deficiencies are associated with foetal alcohol syndrome, attention deficit hyperactivity disorder, cystic fibrosis, phenylketonuria, unipolar depression, aggressive hostility, and adrenoleukodystrophy. Decreases in DHA in the brain are associated with cognitive decline during aging and with onset of sporadic Alzheimer disease. The leading cause of death in western nations is cardiovascular disease. Epidemiological studies have shown a strong correlation between fish consumption and reduction in sudden death from myocardial infarction. The reduction is approximately 50% with 200 mg day−1of DHA from fish. DHA is the active component in fish. Not only does fish oil reduce triglycerides in the blood and decrease thrombosis, but it also prevents cardiac arrhythmias. The association of DHA deficiency with depression is the reason for the robust positive correlation between depression and myocardial infarction. Patients with cardiovascular disease or Type II diabetes are often advised to adopt a low-fat diet with a high proportion of carbohydrate. A study with women shows that this type of diet increases plasma triglycerides and the severity of Type II diabetes and coronary heart disease. DHA is present in fatty fish (salmon, tuna, mackerel) and mother's milk. DHA is present at low levels in meat and eggs, but is not usually present in infant formulas. EPA, another long-chain n-3 fatty acid, is also present in fatty fish. The shorter chain n-3 fatty acid, α-linolenic acid, is not converted very well to DHA in man. These long chain n-3 fatty acids (also known as omega-3 fatty acids) are now becoming available in some foods, especially infant formula and eggs in Europe and Japan. Fish oil decreases the proliferation of tumour cells, whereas arachidonic acid, a long chain n-6 fatty acid, increases their proliferation. These opposite effects are also seen with inflammation, particularly with rheumatoid arthritis, and with asthma. DHA has a positive effect on diseases such as hypertension, arthritis, atherosclerosis, depression, adult-onset diabetes mellitus, myocardial infarction, thrombosis, and some cancers.

Source: Horrocks, Lloyd A., and Young K. Yeo. "Health benefits of docosahexaenoic acid (DHA)." Pharmacological research 40.3 (1999): 211-225.

Effect of maternal docosahexaenoic acid (DHA) supplementation on breast milk composition

Abstract

OBJECTIVE: To assess the effect of varying maternal intake of docosahexaenoic acid (DHA, 22 : 6n-3), in the absence of other dietary polyunsaturated, on breast milk fatty acids. DESIGN AND INTERVENTION: Lactating mothers were randomised on day 5 postpartum to groups consuming equal numbers of capsules but containing either placebo or an oil containing DHA (43%) as its only polyunsaturated to receive 0, 0.2, 0.4, 0.9, 1.3 g DHA/day. Breast milk fatty acids as well as maternal plasma and erythrocyte phospholipids were assessed at 12 weeks post partum by capillary gas chromatography. RESULTS: Breast milk DHA levels ranged from 0.2 to 1.7% of total fatty acids and increased in a dose dependent manner (r2 = 0.89, P <0.01). Maternal plasma (r2 = 0.71, P <0.01) and erythrocyte (r2 = 0.77, P <0.01) phospholipid DHA levels increased and were also strongly associated with dietary dose of DHA. Increasing maternal dietary doses of DHA did not affect breast milk arachidonic acid (AA, 20 : 4n-6) levels or antioxidant status as measured by plasma vitamin A or E levels. CONCLUSIONS: Our results have demonstrated that DHA in the diet has a strong, specific and dose-dependent effect on breast milk DHA.

Source: Makrides, Maria, M. A. Neumann, and Robert A. Gibson. "Effect of maternal docosahexaenoic acid (DHA) supplementation on breast milk composition." European journal of clinical nutrition 50.6 (1996): 352-357.

Docosahexaenoic acid (DHA) and the developing central nervous system (CNS) – Implications for dietary recommendations

Abstract

The accretion of docosahexaenoic acid (DHA) in membranes of the central nervous system is required for the optimum development of retina and brain functions. DHA status is determined by the dietary intake of n-3 polyunsaturated fatty acids (PUFA), both the metabolic precursor α-linolenic acid (α-LNA) and DHA. Clinical studies have shown that feeding term or premature infants with formula low in total n-3 PUFA may alter the maturation of visual acuity. Moreover, feeding infants over the first 6 months of life with formula containing adequate α-LNA, but no DHA, did not sustain the same cerebral accretion of DHA as that of breast-fed infants. Whether lower DHA accretion in the brain of formula-fed term infants impairs neurophysiological performances is not clearly established. Contradictory data have been published, possibly owing to confounding factors such as maternal intakes and/or genetic variations in PUFA metabolism. Nevertheless, a large corpus of data is in favor of the recommendation of regular dietary intakes of DHA (during at least the first 6 mon of life) and suggest that DHA should be added in formulas at the level generally found in human milk (0.2–0.3 wt% of total fatty acids). The maternal intake of n-3 PUFA during pregnancy and lactation is also crucial, since the n-3 PUFA are provided during perinatal development through placental transfer and maternal milk, which determines the DHA status of the newborn and consequently impacts on postnatal development of brain and visual functions. Whether more clinical studies are needed to control and improve the impact of DHA maternal intakes on the progeny’s neurodevelopment, several commissions recommended by precaution that DHA average intake for pregnant and lactating women should be of 200–300 mg/day.

Source: Guesnet, Philippe, and Jean-Marc Alessandri. "Docosahexaenoic acid (DHA) and the developing central nervous system (CNS)–implications for dietary recommendations." Biochimie 93.1 (2011): 7-12.

Docosahexaenoic Acid (DHA): An Ancient Nutrient for the Modern Human Brain

Abstract

Modern humans have evolved with a staple source of preformed docosahexaenoic acid (DHA) in the diet. An important turning point in human evolution was the discovery of high-quality, easily digested nutrients from coastal seafood and inland freshwater sources. Multi-generational exploitation of seafood by shore-based dwellers coincided with the rapid expansion of grey matter in the cerebral cortex, which characterizes the modern human brain. The DHA molecule has unique structural properties that appear to provide optimal conditions for a wide range of cell membrane functions. This has particular implications for grey matter, which is membrane-rich tissue. An important metabolic role for DHA has recently been identified as the precursor for resolvins and protectins. The rudimentary source of DHA is marine algae; therefore it is found concentrated in fish and marine oils. Unlike the photosynthetic cells in algae and higher plants, mammalian cells lack the specific enzymes required for the de novo synthesis of alpha-linolenic acid (ALA), the precursor for all omega-3 fatty acid synthesis. Endogenous synthesis of DHA from ALA in humans is much lower and more limited than previously assumed. The excessive consumption of omega-6 fatty acids in the modern Western diet further displaces DHA from membrane phospholipids. An emerging body of research is exploring a unique role for DHA in neurodevelopment and the prevention of neuropsychiatric and neurodegenerative disorders. DHA is increasingly being added back into the food supply as fish oil or algal oil supplementation.

Source: Bradbury, Joanne. "Docosahexaenoic acid (DHA): an ancient nutrient for the modern human brain." Nutrients 3.5 (2011): 529-554.

Fish, docosahexaenoic acid and Alzheimer’s disease

Abstract

Cognitive decline in the elderly, particularly Alzheimer’s disease (AD), is a major socio-economic and healthcare concern. We review here the literature on one specific aspect of diet affecting AD, that of the ω3 fatty acids, particularly the brain’s principle ω3 fatty acid – docosahexaenoic acid (DHA). DHA has deservedly received wide attention as a nutrient supporting both optimal brain development and for cardiovascular health. Our aim here is to critically assess the quality of the present literature as well as the potential of ω3 fatty acids to treat or delay the onset of AD. We start with a brief description of cognitive decline in the elderly, followed by an overview of well recognized biological functions of DHA. We then turn to epidemiological studies, which are largely supportive of protective effects of fish and DHA against risk of AD. However, biological studies, including blood and brain DHA analyses need careful interpretation and further investigation, without which the success of clinical trials with DHA may continue to struggle. We draw attention to some of the methodological issues that need resolution as well as an emerging mechanism that may explain how DHA could be linked to protecting brain function in the elderly.

Source: Cunnane, Stephen C., et al. "Fish, docosahexaenoic acid and Alzheimer’s disease." Progress in lipid research 48.5 (2009): 239-256.

Turmeric Root Extract

Efficacy of Turmeric Extracts and Curcumin for Alleviating the Symptoms of Joint Arthritis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials ⁸

Although turmeric and its curcumin-enriched extracts have been used for treating arthritis, no systematic review and meta-analysis of randomized clinical trials (RCTs) have been conducted to evaluate the strength of the research. We systemically evaluated all RCTs of turmeric extracts and curcumin for treating arthritis symptoms to elucidate the efficacy of curcuma for alleviating the symptoms of arthritis. Literature searches were conducted using 12 electronic databases, including PubMed, Embase, Cochrane Library, Korean databases, Chinese medical databases, and Indian scientific database. Search terms used were “turmeric,” “curcuma,” “curcumin,” “arthritis,” and “osteoarthritis.” A pain visual analogue score (PVAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) were used for the major outcomes of arthritis. Initial searches yielded 29 articles, of which 8 met specific selection criteria. Three among the included RCTs reported reduction of PVAS (mean difference: −2.04 [−2.85, −1.24]) with turmeric/curcumin in comparison with placebo (P<0xE2><0x80><0x89> .00001), whereas meta-analysis of four studies showed a decrease of WOMAC with turmeric/curcumin treatment (mean difference: −15.36 [−26.9, −3.77]; P = .009). Furthermore, there was no significant mean difference in PVAS between turmeric/curcumin and pain medicine in meta-analysis of five studies. Eight RCTs included in the review exhibited low to moderate risk of bias. There was no publication bias in the meta-analysis. In conclusion, these RCTs provide scientific evidence that supports the efficacy of turmeric extract (about 1000 mg/day of curcumin) in the treatment of arthritis. However, the total number of RCTs included in the analysis, the total sample size, and the methodological quality of the primary studies were not sufficient to draw definitive conclusions. Thus, more rigorous and larger studies are needed to confirm the therapeutic efficacy of turmeric for arthritis.

Source: James W. Daily, Mini Yang, Sunmin Park. “Efficacy of Turmeric Extracts and Curcumin for Alleviating the Symptoms of Joint Arthritis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials” Journal of Medicinal Food (2016): 19(8): 717–729.

⁸ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5003001/

Efficacy and mechanism of action of turmeric supplements in the treatment of experimental arthritis ⁹

Abstract

Objective: Scientific evidence is lacking for the antiarthritic efficacy of turmeric dietary supplements that are being promoted for arthritis treatment. Therefore, we undertook studies to determine the antiarthritic efficacy and mechanism of action of a well‐characterized turmeric extract using an animal model of rheumatoid arthritis (RA).

Methods: The composition of commercial turmeric dietary supplements was determined by high‐performance liquid chromatography. A curcuminoid‐containing turmeric extract similar in composition to these supplements was isolated and administered intraperitoneally to female Lewis rats prior to or after the onset of streptococcal cell wall–induced arthritis. Efficacy in preventing joint swelling and destruction was determined clinically, histologically, and by measurement of bone mineral density. Mechanism of action was elucidated by analysis of turmeric's effect on articular transcription factor activation, microarray analysis of articular gene expression, and verification of the physiologic effects of alterations in gene expression.

Results: A turmeric fraction depleted of essential oils profoundly inhibited joint inflammation and periarticular joint destruction in a dose‐dependent manner. In vivo treatment prevented local activation of NF‐κB and the subsequent expression of NF‐κB–regulated genes mediating joint inflammation and destruction, including chemokines, cyclooxygenase 2, and RANKL. Consistent with these findings, inflammatory cell influx, joint levels of prostaglandin E2, and periarticular osteoclast formation were inhibited by turmeric extract treatment.

Conclusion: These translational studies demonstrate in vivo efficacy and identify a mechanism of action for a well‐characterized turmeric extract that supports further clinical evaluation of turmeric dietary supplements in the treatment of RA.

Source: Janet L. Funk, Jennifer B. Frye, Janice N. Oyarzo, Nesrin Kuscuoglu. “Efficacy and mechanism of action of turmeric supplements in the treatment of experimental arthritis” Arthritis and Rheumatology (2006).

⁹ https://pubmed.ncbi.nlm.nih.gov/17075840/

Efficacy of Turmeric Extracts and Curcumin for Alleviating the Symptoms of Joint Arthritis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials ¹⁰

Abstract

Although turmeric and its curcumin-enriched extracts have been used for treating arthritis, no systematic review and meta-analysis of randomized clinical trials (RCTs) have been conducted to evaluate the strength of the research. We systemically evaluated all RCTs of turmeric extracts and curcumin for treating arthritis symptoms to elucidate the efficacy of curcuma for alleviating the symptoms of arthritis. Literature searches were conducted using 12 electronic databases, including PubMed, Embase, Cochrane Library, Korean databases, Chinese medical databases, and Indian scientific database. Search terms used were “turmeric,” “curcuma,” “curcumin,” “arthritis,” and “osteoarthritis.” A pain visual analogue score (PVAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) were used for the major outcomes of arthritis. Initial searches yielded 29 articles, of which 8 met specific selection criteria. Three among the included RCTs reported reduction of PVAS (mean difference: −2.04 [−2.85, −1.124]) with turmeric/curcumin in comparison with placebo (P<0xE2><0x80><0x89> .00001), whereas meta-analysis of four studies showed a decrease of WOMAC with turmeric/curcumin treatment (mean difference: −15.36 [−26.9, −3.77]; P = .009). Furthermore, there was no significant mean difference in PVAS between turmeric/curcumin and pain medicine in meta-analysis of five studies. Eight RCTs included in the review exhibited low to moderate risk of bias. There was no publication bias in the meta-analysis. In conclusion, these RCTs provide scientific evidence that supports the efficacy of turmeric extract (about 1000 mg/day of curcumin) in the treatment of arthritis. However, the total number of RCTs included in the analysis, the total sample size, and the methodological quality of the primary studies were not sufficient to draw definitive conclusions. Thus, more rigorous and larger studies are needed to confirm the therapeutic efficacy of turmeric for arthritis.

Source: James W. Daily, Mini Yang, Sunmin Park. “Efficacy of Turmeric Extracts and Curcumin for Alleviating the Symptoms of Joint Arthritis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials” Journal of Medicinal Food (2016) Vol. 19, No. 8.

¹⁰ https://www.liebertpub.com/doi/full/10.1089/jmf.2016.3705

A commercialized dietary supplement alleviates joint pain in community adults: a double-blind, placebo-controlled community trial

Abstract

Background: The purpose of this study was to assess the effect of 8-weeks ingestion of a commercialized joint pain dietary supplement (InstaflexTM Joint Support, Direct Digital, Charlotte, NC) compared to placebo on joint pain, stiffness, and function in adults with self-reported joint pain. InstaflexTM is a joint pain supplement containing glucosamine sulfate, methylsulfonylmethane (MSM), white willow bark extract (15% salicin), ginger root concentrate, Boswellia Serrata extract (65% boswellic acid), turmeric root extract, cayenne, and hyaluronic acid.

Methods: Subjects included 100 men and women, ages 50-75 years, with a history (>3 months) of joint pain, and were randomized to Instaflex™ or placebo (3 colored gel capsules per day for 8 weeks, double-blind administration). Subjects agreed to avoid the use of non-steroidal anti-inflammatory drugs (NSAID) and all other medications and supplements targeted for joint pain. Primary outcome measures were obtained pre- and post-study and included joint pain severity, stiffness, and function (Western Ontario and McMaster Universities [WOMAC]), and secondary outcome measures included health-related quality of life (Short Form 36 or SF-36), systemic inflammation (serum C-reactive protein and 9 plasma cytokines), and physical function (6-minute walk test). Joint pain symptom severity was assessed bi-weekly using a 12-point Likert visual scale (12-VS).

Results: Joint pain severity was significantly reduced in Instaflex™ compared to placebo (8-week WOMAC, ↓37% versus ↓16%, respectively, interaction effect P = 0.025), with group differences using the 12-VS emerging by week 4 of the study (interaction effect, P = 0.0125). Improvements in the ability to perform daily activities and stiffness scores in Instaflex™ compared to placebo were most evident for the 74% of subjects reporting knee pain (8-week WOMAC function score, ↓39% versus ↓14%, respectively, interaction effect P = 0.027; stiffness score, ↓30% versus ↓12%, respectively, interaction effect P = 0.081). Patterns of change in SF-36, systemic inflammation biomarkers, and the 6-minute walk test did not differ significantly between groups during the 8-week study

Conclusions: Results from this randomized, double-blind, placebo-controlled community trial support the use of the Instaflex™ dietary supplement in alleviating joint pain severity in middle-aged and older adults, with mitigation of difficulty performing daily activities most apparent in subjects with knee pain.

Source: Nieman, David C., et al. “A commercialized dietary supplement alleviates joint pain in community adults: a double-blind, placebo-controlled community trial.” Nutrition journal 12.1 (2013): 154.

Resveratrol

Resveratrol, Potential Therapeutic Interest in Joint Disorders: A Critical Narrative Review ¹¹

Abstract

Trans-resveratrol (t-Res) is a natural compound of a family of hydroxystilbenes found in a variety of spermatophyte plants. Because of its effects on lipids and arachidonic acid metabolisms, and its antioxidant activity, t-Res is considered as the major cardioprotective component of red wine, leading to the "French Paradox" health concept. In the past decade, research on the effects of resveratrol on human health has developed considerably in diverse fields such as cancer, neurodegenerative and cardiovascular diseases, and metabolic disorders. In the field of rheumatic disorders, in vitro evidence suggest anti-inflammatory, anti-catabolic, anti-apoptotic and anti-oxidative properties of t-Res in various articular cell types, including chondrocytes and synoviocytes, along with immunomodulation properties on T and B lymphocytes. In preclinical models of osteoarthritis and rheumatoid arthritis, resveratrol has shown joint protective effects, mainly mediated by decreased production of pro-inflammatory and pro-degradative soluble factors, and modulation of cellular and humoral responses. Herein, we comprehensively reviewed evidence supporting a potential therapeutic interest of t-Res in treating symptoms related to rheumatic disorders.

Source: Christelle Nguyen, Jean-François Savouret, Magdalena Widerak, Marie-Thérèse Corvol, and François Rannou. "Resveratrol, Potential Therapeutic Interest in Joint Disorders: A Critical Narrative Review" Nutrients (2017): 9(1): 45.

¹¹ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5295089/

Intra‐articular resveratrol injection prevents osteoarthritis progression in a mouse model by activating SIRT1 and thereby silencing HIF‐2α

Abstract

We investigated the feasibility of the intra‐articular injection of resveratrol for preventing the progression of existing cartilage degeneration in a mouse model of osteoarthritis (OA). The effects of resveratrol on the expression of silent information regulator 2 types 1 (SIRT1), hypoxia‐inducible factor‐2α (HIF‐2α) and catabolic factors in OA cartilage was explored. OA was induced in the mouse knee via destabilization of the medial meniscus (DMM). Resveratrol was injected weekly into the operated knee beginning 4 weeks after surgery. The OA phenotype was evaluated via histological and immunohistochemical analyses at 8 weeks after DMM. Western blot analysis was performed to identify whether resveratrol modulated the interleukin (IL)‐1β‐induced expression of HIF‐2α in human chondrocytes. Histologically, resveratrol treatment preserved the structural homeostasis of the articular cartilage and the subchondral bone. Following resveratrol injection, the expression of collagen type II was retained, but the expression of inducible nitric oxide synthase and matrix metalloproteinase‐13 was reduced in OA cartilage. Moreover, the administration of resveratrol significantly induced the activation of SIRT1 and the inhibition of HIF‐2α expression in mouse OA cartilage and in IL-1β‐treated human chondrocytes. These findings indicate that the intra‐articular injection of resveratrol significantly prevents the destruction of OA cartilage by activating SIRT1 and thereby suppressing the expression of HIF‐2α and catabolic factors. © 2015 Orthopaedic Research Society.

Source: Li, Wuyin, et al. "Intra‐articular resveratrol injection prevents osteoarthritis progression in a mouse model by activating SIRT1 and thereby silencing HIF‐2α." Journal of Orthopaedic Research 33.7 (2015): 1061-1070.

Effects of Resveratrol in Inflammatory Arthritis

A randomized, controlled trial of the effects of resveratrol administration in performance horses with lameness localized to the distal tarsal joints

Abstract

Suggested that in performance horses with lameness localized to the distal tarsal joints, injection of triamcinolone in the centrodistal and tarsometatarsal joints of both hind limbs followed by oral supplementation with resveratrol for 4 months resulted in reduced lameness, compared with triamcinolone injection and supplementation with placebo.

Source: Watts, Ashlee E., et al. "A randomized, controlled trial of the effects of resveratrol administration in performance horses with lameness localized to the distal tarsal joints." Journal of the American Veterinary Medical Association 249.6 (2016): 650-659.

Boswellia Serrata ¹²

A commercialized dietary supplement alleviates joint pain in community adults: a double-blind, placebo-controlled community trial

Abstract

Background: The purpose of this study was to assess the effect of 8-weeks ingestion of a commercialized joint pain dietary supplement (InstaflexTM Joint Support, Direct Digital, Charlotte, NC) compared to placebo on joint pain, stiffness, and function in adults with self-reported joint pain. InstaflexTM is a joint pain supplement containing glucosamine sulfate, methylsulfonylmethane (MSM), white willow bark extract (15% salicin), ginger root concentrate, Boswellia Serrata extract (65% boswellic acid), turmeric root extract, cayenne, and hyaluronic acid.

Methods: Subjects included 100 men and women, ages 50-75 years, with a history (>3 months) of joint pain, and were randomized to Instaflex™ or placebo (3 colored gel capsules per day for 8 weeks, double-blind administration). Subjects agreed to avoid the use of non-steroidal anti-inflammatory drugs (NSAID) and all other medications and supplements targeted for joint pain. Primary outcome measures were obtained pre- and post-study and included joint pain severity, stiffness, and function (Western Ontario and McMaster Universities [WOMAC]), and secondary outcome measures included health-related quality of life (Short Form 36 or SF-36), systemic inflammation (serum C-reactive protein and 9 plasma cytokines), and physical function (6-minute walk test). Joint pain symptom severity was assessed bi-weekly using a 12-point Likert visual scale (12-VS).

Results: Joint pain severity was significantly reduced in Instaflex™ compared to placebo (8-week WOMAC, ↓37% versus ↓16%, respectively, interaction effect P = 0.025), with group differences using the 12-VS emerging by week 4 of the study (interaction effect, P = 0.0125). Improvements in the ability to perform daily activities and stiffness scores in Instaflex™ compared to placebo were most evident for the 74% of subjects reporting knee pain (8-week WOMAC function score, ↓39% versus ↓14%, respectively, interaction effect P = 0.027; stiffness score, ↓30% versus ↓12%, respectively, interaction effect P = 0.081). Patterns of change in SF-36, systemic inflammation biomarkers, and the 6-minute walk test did not differ significantly between groups during the 8-week study

Conclusions: Results from this randomized, double-blind, placebo-controlled community trial support the use of the Instaflex™ dietary supplement in alleviating joint pain severity in middle-aged and older adults, with mitigation of difficulty performing daily activities most apparent in subjects with knee pain.

Source: Nieman, David C., et al. "A commercialized dietary supplement alleviates joint pain in community adults: a double-blind, placebo-controlled community trial." Nutrition journal 12.1 (2013): 154.

¹² https://nutritionj.biomedcentral.com/articles/10.1186/1475-2891-12-154

Boswellia Serrata, A Potential Anti-inflammatory Agent: An Overview ¹³

Abstract

The resin of Boswellia species has been used as incense in religious and cultural ceremonies and in medicines since time immemorial. Boswellia serrata (Salai/Salai guggul), is a moderate to large sized branching tree of family Burseraceae (Genus Boswellia), grows in dry mountainous regions of India, Northern Africa and Middle East. Oleo gum-resin is tapped from the incision made on the trunk of the tree and is then stored in specially made bamboo basket for removal of oil content and getting the resin solidified. After processing, the gum-resin is then graded according to its flavour, colour, shape and size. In India, the States of Andhra Pradesh, Gujarat, Madhya Pradesh, Jharkhand and Chhattisgarh are the main source of Boswellia serrata. Regionally, it is also known by different names. The oleo gum-resins contain 30-60% resin, 5-10% essential oils, which are soluble in the organic solvents, and the rest is made up of polysaccharides. Gum-resin extracts of Boswellia serrata have been traditionally used in folk medicine for centuries to treat various chronic inflammatory diseases. The resinous part of Boswellia serrata possesses monoterpenes, diterpenes, triterpenes, tetracyclic triterpenic acids and four major pentacyclic triterpenic acids i.e. β-boswellic acid, acetyl-β-boswellic acid, 11-keto-β-boswellic acid and acetyl-11-keto-β-boswellic acid, responsible for inhibition of pro-inflammatory enzymes. Out of these four boswellic acids, acetyl-11-keto-β-boswellic acid is the most potent inhibitor of 5-lipoxygenase, an enzyme responsible for inflammation.

Source: M. Z. Siddiqui. "Boswellia Serrata, A Potential Antiinflammatory Agent: An Overview" Indian Journal of Pharmaceutical Sciences (2011): 73(3): 255-261.

¹³ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3309643/

Effects of gum resin of Boswellia serrata in patients with chronic colitis

Abstract

Patients studied here suffered from chronic colitis characterized by vague lower abdominal pain, bleeding per rectum with diarrhea and palpable tender descending and sigmoid colon. The inflammatory process in colitis is associated with increased formation of leukotrienes causing chemotaxis, chemokinesis, synthesis of superoxide radicals and release of lysosomal enzymes by phagocytes. The key enzyme for leukotriene biosynthesis is 5-lipoxygenase. Boswellic acids were found to be non-redox, non-competitive specific inhibitors of the enzyme 5-lipoxygenase. We studied the gum resin of Boswellia serrata for the treatment of this disease. Thirty patients, 17 males and 13 females in the age range of 18 to 48 years with chronic colitis were included in this study. Twenty patients were given a preparation of the gum resin of Boswellia serrata (900 mg daily divided in three doses for 6 weeks) and ten patients were given sulfasalazine (3 gm daily divided in three doses for 6 weeks) and served as controls. Out of 20 patients treated with Boswellia gum resin 18 patients showed an improvement in one or more of the parameters: including stool properties, histopathology as well as scanning electron microscopy, besides hemoglobin, serum iron, calcium, phosphorus, proteins, total leukocytes, and eosinophils. In the control group, 6 out of 10 patients showed similar results with the same parameters. Out of 20 patients treated with Boswellia gum resin, 14 went into remission while in case of sulfasalazine remission rate was 4 out of 10. In conclusion, this study shows that a gum resin preparation from Boswellia serrata could be effective in the treatment of chronic colitis with minimal side effects.

Reference: Gupta I et. al.Effects of gum resin of Boswellia serrata in patients with chronic colitis.Planta Medica. 2001: V67, Issue 5; P391-395. DOI: 10.1055/s-2001-15802

Effect of Boswellia serrata on intestinal motility in rodents: inhibition of diarrhea without constipation

Abstract

Clinical studies suggest that the Ayurvedic plant Boswellia serrata may be effective in reducing diarrhea in patients with inflammatory bowel disease. In the present study, we evaluated the effect of a Boswellia serrata gum resin extract (BSE) on intestinal motility and diarrhea in rodents. BSE depressed electrically-, acetylcholine-, and barium chloride-induced contractions in the isolated guinea-pig ileum, being more potent in inhibiting the contractions induced by acetylcholine and barium chloride. The inhibitory effect of BSE on acetylcholine-induced contractions was reduced by the L-type Ca2+ channel blockers verapamil and nifedipine, but not by the sarcoplasmic reticulum Ca2+-ATPase inhibitor cyclopiazonic acid, by the phosphodiesterase type IV inhibitor rolipram or by the lipoxygenase inhibitor zileuton.

Type II Collagen

Effects of Native Type II Collagen Treatment on Knee Osteoarthritis: A Randomized Controlled Trial ¹⁴

Abstract

Objective: The aim of this randomized controlled study was to evaluate the efficacy of oral native type II collagen treatment on the symptoms and biological markers of cartilage degradation, when given concomitantly with acetaminophen in patients with knee osteoarthritis.

Materials and Methods: Thirty-nine patients diagnosed with knee osteoarthritis were included and randomly distributed into two groups: one treated with 1500 mg/day of acetaminophen (group AC; n=19) and the other treated with 1500 mg/day of acetaminophen plus 10 mg/day of native type II collagen (group AC+CII; n=20) for 3 months. Visual Analogue Scale (VAS) at rest and during walking, Western Ontario McMaster (WOMAC) pain, WOMAC function, and Short Form-36 (SF-36) scores, were recorded. Coll2-1, Coll2-1NO2 and Fibulin-3 levels were quantified in urine as biomarkers of disease progression. ClinicalTrials.gov: NCT02237989.

Results: After 3 months of treatment, significant improvements compared to baseline were reported in joint pain (VAS walking), function (WOMAC) and quality of life (SF-36) in the AC+CII group, while only improvements in some subscales of the SF-36 survey and VAS walking were detected in the AC group. Comparisons between the groups revealed a significant difference in VAS walking score in favour of the AC+CII group as compared to AC group. Biochemical markers of cartilage degradation in urine did not significantly improve in any of the groups.

Conclusion: All in all, these results suggest that native type II collagen treatment combined with acetaminophen is superior to only acetaminophen for symptomatic treatment of patients with knee osteoarthritis.

Source: Fulya Bakilan, Onur Armagan, Merih Ozgen, Funda Tascioglu, Ozge Bolluk, and Ozkan Alatas. "Effects of Native Type II Collagen Treatment on Knee Osteoarthritis: A Randomized Controlled Trial" The Eurasian Journal of Medicine (2016): 48(2): 95-101.

¹⁴ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970562/

Effects of oral administration of type II collagen on rheumatoid arthritis

Abstract

Rheumatoid arthritis is an inflammatory synovial disease thought to involve T cells reacting to an antigen within the joint. Type II collagen is the major protein in articular cartilage and is a potential autoantigen in this disease. Oral tolerization to autoantigens suppresses animal models of T cell-mediated autoimmune disease, including two models of rheumatoid arthritis. In this randomized, double-blind trial involving 60 patients with severe, active rheumatoid arthritis, a decrease in the number of swollen joints and tender joints occurred in subjects fed chicken type II collagen for 3 months but not in those that received a placebo. Four patients in the collagen group had complete remission of the disease. No side effects were evident. These data demonstrate the clinical efficacy of an oral tolerization approach for rheumatoid arthritis.

Source: Trentham, David E., et al. "Effects of oral administration of type II collagen on rheumatoid arthritis." Science 261.5129 (1993): 1727-1730.

Collagen gene expression during the development of avian synovial joints: Transient expression of types II and XI collagen genes in the joint capsule

Abstract

The developmental sequence of the embryonic joint has been well studied morphologically. There are, however, no definitive studies of cell function during joint development. In order to begin to understand the differentiation events that contribute to the joint formation, we examined the expression of collagen mRNAs encoding types I, IIA, IIB, and XI. In situ hybridization was performed on chicken embryo hind limb buds and digits from day 7 to day 18 (Hamburger and Hamilton stage 31-44). In the day 7 (stage 31) limb bud, there was a condensation of mesenchyme forming the primitive tarsal and metatarsal bones that showed abundant expression of type IIA procollagen message, but no type IIB or type α1(XI) message. By day 8 (stage 33), co-expression of types IIA, and type XI procollagen mRNAs was observed in the condensations, with an expression of IIB restricted to early chondrocytes with a metachromatically staining matrix. At this stage, DNA fragmentation characteristic of apoptosis was observed in cells near the midline of the Interzone region between the developing anlagen, and in areas between and around the individual digits of the paddle. The presumptive apoptotic cells were more numerous at day 9 (stage 35), and were not found in the developing joint at subsequent time points, including the initiation of spatial cavitation of the joint. From days 11-18, type IIA procollagen mRNA was expressed in flattened cells at the surface of the anlagen, and in the perichondrium and in the developing joint capsule; type IIB mRNA message was found only in chondrocytes. Type XI mRNA was expressed by all type II-expressing cells. Alpha 1(I) mRNA was expressed early by cells of the Interzone and capsule, but as cavitation progressed, the type I expressing cells of the Interzone merged with the superficial layer of the articular surface. Thus, at the time of joint cavitation, there was a distinct pattern of expression of procollagen messages at the articular surface, with type I being outermost, followed by morphologically similar cells expressing type IIA, then chondrocytes expressing type IIB. The progenitor cells expressing type IIA message define a new population of cells. These cell populations contribute to the molecular heterogeneity of the articular cartilage, and these same populations likely exist in the developing joints of other species. The transient transcription of type II and type XI collagen genes, characteristic of chondrocytes, by cells in the joint capsule demonstrates that these cells may have chondrogenic potential.

Source: Nalin, Andrew M., Theodore K. Greenlee Jr, and Linda J. Sandell. "Collagen gene expression during development of avian synovial joints: transient expression of types II and XI collagen genes in the joint capsule." Developmental dynamics 203.3 (1995): 352-362.

Hyaluronic Acid

Oral hyaluronan relieves knee pain: a review ¹⁵

Hyaluronan (HA) is a component that is particularly abundant in the synovial fluid. Randomized, double-blinded, placebo-controlled trials carried out between 2008 and 2015 have proven the effectiveness of HA for the treatment of symptoms associated with synovitis, and particularly, knee pain, relief of synovial effusion or inflammation, and improvement of muscular knee strength. The mechanism by which HA exerts its effects in the living body, specifically receptor binding in the intestinal epithelia, has gradually been clarified. This review examines the effects of HA upon knee pain as assessed in clinical trials, as well as the mechanism of these effects and the safety of HA.

Source: Mariko Oe, Toshiyuki Tashiro, Hideto Yoshida, Hiroshi Nishiyama, Yasunobu Masuda, Koh Maruyama, Takashi Koikeda, Reiko Maruya, Naoshi Fukui.  Nutrition Journal (2016): 15: 11.

¹⁵ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4729158/

Effects of the molecular weight of hyaluronic acid and its action mechanisms on experimental joint pain in rats ¹⁶

Abstract

OBJECTIVES: It has been shown previously that hyaluronic acid (HA) has an analgesic action on bradykinin induced pain in the knee joints of rats. This study further clarifies the effects of the molecular weight of HA and its mechanism of action in the same model using HA of molecular weight 800 to 2.3 x 10(6) daltons and a bradykinin antagonist. METHODS: Bradykinin and the test HA preparations were given to rats by intra-articular injection, and the severity of pain was evaluated by a change in the walking behaviour. RESULTS: HA with a molecular weight greater than 40 kilodaltons produces analgesic effects with a simultaneous or earlier injection. The ID50 values of HA with molecular weight 40, 310, 860, and 2300 kilodaltons were greater than 2.5, 0.6, 0.07, and 0.06 mg/joint respectively. The duration of the analgesic effect of 860 and 2300 kilodalton HA was 72 hours at 10 mg/ml, whereas that of 310 kilodalton HA was short, being undetectable after 24 hours. The analgesic action of HA of 860 kilodaltons was not changed by pretreatment with four saccharide HA and inhibited by pretreatment with HA larger than six to eight saccharides, capable of binding to HA receptors. Further, HA did not interfere with the analgesic action of the bradykinin antagonist, indicating that HA does not directly bind with bradykinin receptors. CONCLUSIONS: HA with a molecular weight of greater than 40 kilodaltons produced an analgesic effect, and HA of 860 and 2300 kilodaltons produced high and long-lasting analgesia. These effects of HA appear to be caused by the interaction between HA and HA receptors.

Source: S. Gotoh, J. Onaya, M. Abe, K. Miyazaki, A. Hamai, K. Horie, K. Tokuyasu. "Effects of the molecular weight of hyaluronic acid and its action mechanisms on experimental joint pain in rats" Annals of the Rheumatic Diseases (1993): 52:817-822.

¹⁶ https://ard.bmj.com/content/52/11/817

Mimicked cartilage scaffolds of silk fibroin/hyaluronic acid with stem cells for osteoarthritis surgery: Morphological, mechanical, and physical clues

Abstract

Osteoarthritis is a critical disease that comes from the degeneration of cartilage tissue. In severe cases, surgery is generally required. Tissue engineering using scaffolds with stem cell transplantation is an attractive approach and a challenge for orthopedic surgery. For sample preparation, silk fibroin (SF)/hyaluronic acid (HA) scaffolds in different ratios of SF/HA (w/w) (i.e., 100:0, 90:10, 80:20, and 70:30) were formed by freeze-drying. The morphological, mechanical, and physical clues were considered in this research. The morphological structure of the scaffolds was observed by a scanning electron microscope. The mechanical and physical properties of the scaffolds were analyzed by compressive and swelling ratio testing, respectively. For the cell experiments, scaffolds were seeded and cultured with human umbilical cord-derived mesenchymal stem cells (HUMSCs). The cultured scaffolds were tested for cell viability, histochemistry, immunohistochemistry, and gene expression. The SF with HA scaffolds showed regular porous structures. Those scaffolds had a soft and elastic characteristic with a high swelling ratio and water uptake. The SF/HA scaffolds showed a spheroid structure of the cells in the porous structure particularly in the SF80 and SF70 scaffolds. Cells could express Col2a, Agg, and Sox9 which are markers for chondrogenesis. It could be deduced that SF/HA scaffolds showed significant clues for suitability in cartilage tissue engineering and in surgery for osteoarthritis.

Source: Jirayut Jaipaew et. al., Mimicked cartilage scaffolds of silk fibroin/hyaluronic acid with stem cells for osteoarthritis surgery: Morphological, mechanical, and physical clues. Materials Science and Engineering: C. July 1, 2016: V64, P173-182. doi:10.1016/j.msec.2016.03.063

Bioperine

Anti-inflammatory and antiarthritic effects of piperine in human interleukin 1β-stimulated fibroblast-like synoviocytes and in rat arthritis models ¹⁷

Abstract

Introduction: The objective of this study was to determine the anti-inflammatory, nociceptive, and antiarthritic effects of piperine, the active phenolic component in black pepper extract.

Methods: The in vitro anti-inflammatory activity of piperine was tested on interleukin 1β (IL1β)-stimulated fibroblast-like synoviocytes derived form patients with rheumatoid arthritis. The levels of IL6, matrix metalloproteinase (MMPs), cyclo-oxygenase 2 (COX-2), and prostaglandin E2 (PGE2) were investigated by ELISA and RT-PCR analysis. The analgesic and antiarthritic activities of piperine were investigated on rat models of carrageenan-induced acute paw pain and arthritis. The former were evaluated with a paw pressure test, and the latter by measuring the squeaking score, paw volume, and weight distribution ratio. Piperine was administrated orally to rats at 20 and 100 mg/kg/day for 8 days.

Results: Piperine inhibited the expression of IL6 and MMP13 and reduced the production of PGE2 in a dose dependant manner at concentrations of 10 to 100 μg/ml. In particular, the production of PGE2 was significantly inhibited even at 10 μg/ml of piperine. Piperine inhibited the migration of activator protein 1 (AP-1), but not nuclear factor (NF)κB, into the nucleus in IL1β-treated synoviocytes. In rats, piperine significantly reduced nociceptive and arthritic symptoms at days 8 and 4, respectively. Histological staining showed that piperine significantly reduced the inflammatory area in the ankle joints.

Conclusions: These results suggest that piperine has anti-inflammatory, antinociceptive, and antiarthritic effects in an arthritis animal model. Thus, piperine should be further studied with regard to use either as a pharmaceutical or as a dietary supplement for the treatment of arthritis.

Source: Jun Soo Bang, Da Hee Oh, Hyun Mi Choi, Bong-Jun Sur, Sung-Jig Lim, Jung Yeon Kim, Hyung-In Yang, Myung Chul Yoo, Dae-Hyun Hahm, and Kyoung Soo Kim. "Anti-inflammatory and antiarthritic effects of piperine in human interleukin 1β-stimulated fibroblast-like synoviocytes and in rat arthritis models" Arthritis Research and Therapy (2009):  11(2): R49.

¹⁷ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2688199/

Dietary supplement for nutritionally promoting healthy joint function

Abstract

A dietary supplement for nutritionally promoting healthy joint function in human subjects is disclosed. The supplement includes as a major ingredient a protein derived from the enzymatic hydrolysis of collagen in combination with lesser proportions of glucosamine sulfate, ginkgo biloba, borage oil powder, turmeric, Boswellia Serrata, ashwagandha, piper nigrum extract, and an herbal blend.

Source: Hastings, Carl W., David J. Barnes, and Christine A. Daley. "Dietary supplement for nutritionally promoting healthy joint function." U.S. Patent No. 6,224,871. 1 May 2001.

Bioperine, Absorption & Bioavailability

Abstract

BioPerine® has been found to enhance the gastrointestinal absorption of nutrients by at least 30% in a double-blind and in vivo studies. BioPerine® has been clinically tested with several nutrient groups, including fat-soluble vitamins (ß-carotene), water-soluble vitamins (vitamin B6, vitamin C), curcumin, coenzyme Q10. It was shown to significantly enhance the bioavailability of these supplemented nutrients through increased gastrointestinal absorption. Studied nutrients were measured by amounts present in the blood when administered with BioPerine® as compared to the control group receiving the above nutrients alone.

Source: Javaid, Nadia. "BioPerine, Absorption & Bioavailability."

Recent Developments in Delivery, Bioavailability, Absorption and Metabolism of Curcumin: the Golden Pigment from Golden Spice

Curcumin (diferuloylmethane) is a yellow pigment present in the spice turmeric (Curcuma longa) that has been associated with antioxidant, anti-inflammatory, anticancer, antiviral, and antibacterial activities as indicated by over 6,000 citations. In addition, over one hundred clinical studies have been carried out with curcumin. One of the major problems with curcumin is perceived to be the bioavailability. How curcumin should be delivered in vivo, how bioavailable is it, how well curcumin is absorbed and how it is metabolized, is the focus of this review. Various formulations of curcumin that are currently available are also discussed.

Piperine Besides these natural compounds have been also used to increase the bioavailability of curcumin. One of them is piperine, a major component of black pepper, known as inhibitor of hepatic and intestinal glucuronidation and is also shown to increase the bioavailability of curcumin. This effect of piperine on the pharmacokinetics of curcumin has been shown to be much greater in humans than in rats. In humans, curcumin bioavailability was increased by 2,000% at 45 minutes after co-administering curcumin orally with piperine, whereas in rats, it has been found that concomitant administration of piperine 20 mg/kg with curcumin 2 g/kg increased the serum concentration of curcumin by 154% for a short period of 1-2 hours post drug. The study shows that in the dosages used, piperine enhances the serum concentration, extent of absorption and bioavailability of curcumin in both rats and humans with no adverse effects [95]. Another study also showed that piperine (20 mg/kg orally) when administered with curcumin (2 g/kg orally) enhances the bioavailability of the latter up to 20-fold more in epileptic rats [111]. Enhanced bioavailability of curcumin was also evidenced by other researcher when curcumin was administered orally concomitant with piperine. Intestinal absorption of curcumin was also found relatively higher when administered concomitantly with piperine, and it stayed significantly longer in the body tissues [112]. In view of these findings, curcumin-piperine (Cu-Pi) nanoparticles has been prepared by various methods [113]. The bioavailability, cellular uptake and biological effects of this nanoparticles are being tested.

Source: Sahdeo Prasad, PhD, Amit K. Tyagi, PhD, and  Bharat B. Aggarwal, PhD. "Recent Developments in Delivery, Bioavailability, Absorption and Metabolism of Curcumin: the Golden Pigment from Golden Spice" Cancer Research and Treatment (2014): 46(1): 2-18.

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