CLINICAL STUDIES ON THE FOLLOWING INGREDIENTS:
Turmeric Root Extract
Efficacy and mechanism of action of turmeric supplements in the treatment of experimental arthritis
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).
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 particular gene expression, and verification of the physiologic effects of alterations in gene expression.
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.
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.
Funk, Janet L., et al. “Efficacy and mechanism of action of turmeric supplements in the treatment of experimental arthritis.” Arthritis & Rheumatism: Official Journal of the American College of Rheumatology 54.11 (2006): 3452-3464.
A commercialized dietary supplement alleviates joint pain in community adults: a double-blind, placebo-controlled community trial
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.
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).
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
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.
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.
Anti-Arthritic Effects and Toxicity of the Essential Oils of Turmeric (Curcuma longa L.)
Turmeric (Curcuma longa L., Zingiberaceae) rhizomes contain two classes of secondary metabolites, curcuminoids, and the less well-studied essential oils. Having previously identified potent anti-arthritic effects of the curcuminoids in turmeric extracts in an animal model of rheumatoid arthritis (RA), studies were undertaken to determine whether the turmeric essential oils (TEO) were also joint protective using the same experimental model. Crude or refined TEO extracts dramatically inhibited joint swelling (90−100% inhibition) in female rats with the streptococcal cell wall (SCW)-induced arthritis when extracts were administered via intraperitoneal injection to maximize uniform delivery. However, this anti-arthritic effect was accompanied by significant morbidity and mortality. Oral administration of a 20-fold higher dose TEO was nontoxic, but only mildly joint-protective (20% inhibition). These results do not support the isolated use of TEO for arthritis treatment but, instead, identify potential safety concerns invertebrates exposed to TEO.
Funk, Janet L., et al. “Anti-arthritic effects and toxicity of the essential oils of turmeric (Curcuma longa L.).” Journal of agricultural and food chemistry 58.2 (2009): 842-849.
Antioxidants and antiinflammatory dietary supplements for osteoarthritis and rheumatoid arthritis.
Abstract: OBJECTIVE: To review efficacy studies of antioxidant and anti-inflammatory dietary supplements used to manage osteoarthritis (OA) and rheumatoid arthritis (RA) and make conclusions about their place in therapy. Glucosamine, chondroitin, and methylsulfonylmethane were excluded. DATA SOURCES: A literature search was conducted using MEDLINE (1996 through January 2009), EMBASE, Cochrane Library, Natural Medicines Comprehensive Database, and Natural Standard, with a bibliographic review of relevant articles. Cited studies from before our search range were included if they represented the only published human data available. Search words included “antioxidant,” “anti-inflammatory,” “cat’s claw,” “ginger,” “fish oil,” “omega-3,” “turmeric,” “vitamin E,” “vitamin C,” “Baikal skullcap,” “barberry,” “Chinese goldthread,” “green tea,” “Indian holy basil,” “hu Zhang,” “oregano,” and “rosemary.” STUDY SELECTION AND DATA EXTRACTION: Efficacy studies published in English were included provided they evaluated the dietary supplements in patients with OA or RA. DATA SYNTHESIS: Our search strategy yielded 16 clinical studies (11 randomized, placebo-controlled clinical trials, three crossover trials, one case-controlled study, and one open-label study) in addition to one meta-analysis and one review article. CONCLUSIONS: Three studies support cat’s claw alone or in combination for OA, and two studies support omega-3 fatty acids for the treatment of RA. We cannot recommend the use of vitamin E alone; vitamins A, C, and E in combination; ginger; turmeric; or Zyflamend (New Chapter, Brattleboro, Vermont) for the treatment of OA or RA or omega-3 fatty acids for OA. Whether any of these supplements can be effectively and safely recommended to reduce nonsteroidal anti-inflammatory drug or steroid usage is unclear and requires more high-quality research.
Rosenbaum, Cathy Creger, et al. “Antioxidants and antiinflammatory dietary supplements for osteoarthritis and rheumatoid arthritis.” Alternative Therapies in Health & Medicine 16.2 (2010).
Intra‐articular resveratrol injection prevents osteoarthritis progression in a mouse model by activating SIRT1 and thereby silencing HIF‐2α
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.
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
Nuclear factor kappa B (NF-κB), is a pivotal transcription factor involved in the activation of the TNF-α and IL-1β genes. Activation of NF-κB in synovial cells is a feature seen in arthritis patients. Resveratrol, a polyphenolic, a natural phytoalexin found with particularly high levels in grape skin and red wine is a potent and specific inhibitor of TNF-α and IL-1β induced NF-κB activation. We aimed to determine the in vivo effects of intra-articular injections of resveratrol on cartilage and synovium in an experimental rabbit inflammatory arthritis model.
Materials and methods:
Arthritis was induced by intra-articular injection of three times of 50 μg lipopolysaccharide (LPS) at day 0, 4 and 8 at 4-day intervals into the knee joints of rabbits. To the test group, 10 μMol/kg resveratrol in the DMSO was injected in the knees at day 0 and then it was continued once daily for 2 weeks. To the control group at the same time and amount of DMSO was injected the knees of rabbits. All rabbits were killed 1 week after the last injection and cartilage tissue and synovium was evaluated with semiquantitative scoring histologically.
According to the control group in the resveratrol group, significantly decreased cartilage destruction was determined by H&E staining (p = 0.04). Loss of matrix proteoglycan content in the cartilage was much lower, as determined by safranin O staining (p = 0.03). We also observed marked synovial inflammation after intra-articular injection to control knees, but not in the resveratrol-treated group knees (p = 0.01).
This study suggests that intra-articular injection of resveratrol may protect cartilage against the development of experimentally induced IA.
Elmali, N., et al. “Effects of resveratrol in inflammatory arthritis.” Inflammation 30.1-2 (2007): 1-6.
A randomized, controlled trial of the effects of resveratrol administration in performance horses with lameness localized to the distal tarsal joints
CONCLUSIONS AND CLINICAL RELEVANCE Results 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.
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.
Chondroprotective effects and mechanisms of resveratrol in advanced glycation end products-stimulated chondrocytes
Accumulation of advanced glycation end products (AGEs) in joints contributes to the pathogenesis of cartilage damage in osteoarthritis (OA). We aim to explore the potential chondroprotective effects of resveratrol on AGEs-stimulated porcine chondrocytes and cartilage explants.
Chondrocytes were isolated from pig joints. Activation of the IκB kinase (IKK)-IκBα-nuclear factor-kappaB (NF-κB) and c-Jun N-terminal kinase (JNK)/extracellular signal-regulated kinase (ERK)-activator protein-1 (AP-1) pathways were assessed by electrophoretic mobility shift assay (EMSA), Western blot and transfection assay. The levels of inducible nitric oxide synthase (iNOS)-NO and cyclooxygenase-2 (COX-2)-prostaglandin E2 (PGE2) were measured by Western blot, Griess reaction or ELISA. The expression and enzyme activity of matrix metalloproteinase-13 (MMP-13) were determined by real-time RT/PCR and gelatin zymography, respectively.
We show that AGEs-induced expression of iNOS and COX-2 and production of NO and PGE2 were suppressed by resveratrol. Such effects of resveratrol were likely mediated through inhibiting IKK-IκBα-NF-κB and JNK/ERK-AP-1 signaling pathways induced by AGEs. By targeting these critical signaling pathways, resveratrol decreased AGEs-stimulated expression and activity of MMP-13 and prevented AGEs-mediated destruction of collagen II. Histochemistry analysis further confirms that resveratrol could prevent AGEs-induced degradation of proteoglycan and aggrecan in cartilage explants.
The present study reveals not only the effects and mechanisms regarding how resveratrol may protect cartilage from AGEs-mediated damage but also the potential therapeutic benefit of resveratrol in the treatment of OA.
Liu, Feng-Cheng, et al. “Chondroprotective effects and mechanisms of resveratrol in advanced glycation end products-stimulated chondrocytes.” Arthritis research & therapy 12.5 (2010): R167.
Boswellia serrata extract attenuates inflammatory mediators and oxidative stress in collagen-induced arthritis
Rheumatoid arthritis (RA) is a chronic inflammatory disease which leads to the destruction of joints. Current treatment modalities for RA either produce symptomatic relief (NSAIDs) or modify the disease process (DMARDs). Though effective, their use is also limited by their side effects. As a result, the interest in alternative, well-tolerated anti-inflammatory remedies has re-emerged. Our aim was to evaluate the antioxidant and antiarthritic activity of Boswellia serrata gum resin extract (BSE) in collagen-induced arthritis. Arthritis was induced in male Wistar rats by collagen-induced arthritis (CIA) method. BSE was administered at doses of 100 and 200 mg/kg body weight once daily for 21 days. The effects of treatment in the rats were assessed by biochemical (articular elastase, MPO, LPO, GSH, catalase, SOD and NO), inflammatory mediators (IL-1β, IL-6, TNF-α, IL-10, IFN-γ, and PGE2), and histological studies in joints. BSE was effective in bringing significant changes on all the parameters (articular elastase, MPO, LPO, GSH, catalase, SOD and NO) studied. Oral administration of BSE resulted in significantly reduced levels of inflammatory mediators (IL-1β, IL-6, TNF-α, IFN-γ, and PGE2), and increased level of IL-10. The protective effects of BSE against RA were also evident from the decrease in arthritis scoring and bone histology. The abilities to inhibit proinflammatory cytokines and modulation of antioxidant status suggest that the protective effect of Boswellia serrata extract on arthritis in rats might be mediated via the modulation of the immune system.
Reference: Sadiq Umar et.al., Boswellia serrata extract attenuates inflammatory mediators and oxidative stress in collagen-induced arthritis. Phytomedicine. May 15,2014: V21, Issue 6; P847-856. doi:10.1016/j.phymed.2014.02.001
Efficacy and tolerability of Boswellia serrata extract in the treatment of osteoarthritis of knee – A randomized double-blind placebo-controlled trial
Osteoarthritis is a common, chronic, progressive, skeletal, degenerative disorder, which commonly affects the knee joint. Boswellia serrata tree is commonly found in India. The therapeutic value of its gum (Guggulu) has been known. It posses good anti-inflammatory, anti-arthritic and analgesic activity.
A randomized double-blind placebo-controlled crossover study was conducted to assess the efficacy, safety, and tolerability of Boswellia serrata Extract (BSE) in 30 patients of osteoarthritis of the knee, 15 each receiving active drug or placebo for eight weeks. After the first intervention, washout was given and then the groups were crossed over to receive the opposite intervention for eight weeks. All patients receiving drug treatment reported a decrease in knee pain, increased knee flexion and increased walking distance. The frequency of swelling in the knee joint was decreased. Radiologically there was no change. The observed differences between drug-treated and placebo being statistically significant, are clinically relevant. BSE was well tolerated by the subjects except for minor gastrointestinal ADRs. BSE is recommended in the patients of osteoarthritis of the knee with possible therapeutic use in other arthritis.
Reference: N. Kimmatkara, V. Thawanib, L. Hingoranic, R. Khiyanid. Efficacy and tolerability of Boswellia serrata extract in the treatment of osteoarthritis of knee – A randomized double-blind placebo-controlled trial. Phytomedicine. 2003: V10, Issue 1; P3-7. doi:10.1078/094471103321648593
Effects of gum resin of Boswellia serrata in patients with chronic colitis.
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
Pharmacology of an extract of salai guggal ex-Boswellia Serrata, a new non-steroidal anti-inflammatory agent
Pharmacological evaluation of alcoholic extract of salai guggal (AESG) has been carried out in experimental animals. AESG displayed marked anti-inflammatory activity in carrageenan-induced oedema in rats and mice and dextran oedema in rats. It was equally effective in adrenalectomized rats. In formaldehyde and adjuvant arthritis, AESG produced prominent anti-arthritic activity but no significant effect was observed in cotton pellet-induced granuloma test. It inhibited inflammation-induced an increase in serum transaminase levels and leucocyte counts but lacked any analgesic or antipyretic effects. The gestation period or parturition time in pregnant rats or onset time of castor oil-induced diarrhea was unaffected by AESG and no significant effect was seen on cardiovascular, respiratory and central nervous system functions. No ulcerogenic effects were found in the rat stomach. The oral and intraperitoneal LD50 was greater than 2 g/Kg in mice and rats.
Reference: G. B. Singh, C. K. Atal. Pharmacology of an extract of salai guggal ex-Boswellia Serrata, a new non-steroidal anti-inflammatory agent. Agents and Actions. June 1986: V18, Issue3; PP407-412. DOI 10.1007/BF01965005
Boswellia Serrata, A Potential Antiinflammatory Agent: An Overview
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 the Middle East. Oleo-gum-resin is tapped from the incision made on the trunk of the tree and is then stored in a 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 flavor, color, 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.
Reference:M. Z. Siddiqui. Boswellia Serrata, A Potential Antiinflammatory Agent: An Overview. Indian J Pharm Sci. May-Jun 2011: V73, Issue 3; P255-261. doi: 10.4103/0250-474X.93507
Effect of Boswellia serrata on intestinal motility in rodents: inhibition of diarrhea without constipation
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.
3-acetyl-11-keto-β-boswellic acid, one of the main active ingredients of B. serrata, inhibited acetylcholine-induced contractions.
BSE inhibited upper gastrointestinal transit in croton oil-treated mice as well as castor oil-induced diarrhea. However, BSE did not affect intestinal motility in control mice, both in the small and in the large intestine.
It is concluded that BSE directly inhibits intestinal motility with a mechanism involving L-type Ca2+ channels. BSE prevents diarrhea and normalizes intestinal motility in pathophysiological states without slowing the rate of transit in control animals. These results could explain, at least in part, the clinical efficacy of this Ayurvedic remedy in reducing diarrhea in patients with inflammatory bowel disease.
Reference: Francesca Borrelli et. al.Effect of Boswellia serrata on intestinal motility in rodents: inhibition of diarrhea without constipation. British Journal of Pharmacology. June 2006: V148, Issue 4; P553-560. DOI: 10.1038/sj.bjp.0706740
Type 2 Collagen
Osteopontin deficiency protects joints against destruction in anti-type II collagen antibody-induced arthritis in mice
Rheumatoid arthritis is one of the most critical diseases that impair the quality of life of patients, but its pathogenesis has not yet been fully understood. Osteopontin (OPN) is an extracellular matrix protein containing Arg-Gly-Asp (RGD) sequence, which interacts with αvβ3 integrins, promotes cell attachment, and cell migration and is expressed in both synovial cells and chondrocytes in rheumatoid arthritis; however, its functional relationship to arthritis has not been known. Therefore, we investigated the roles of OPN in the pathogenesis of the inflammatory process in a rheumatoid arthritis model induced by a mixture of anti-type II collagen mAbs and lipopolysaccharide (mAbs/LPS). mAbs/LPS injection induced OPN expression in synovia as well as cartilage, and this expression was associated with joint swelling, destruction of the surface structures of the joint based on scanning electron microscopy, and loss of toluidine blue-positive proteoglycan content in the articular cartilage in wild-type mice. In contrast, OPN deficiency prevented the mice from such surface destruction, loss of proteoglycan in the articular joint cartilage, and swelling of the joints even when the mice were subjected to mAbs/LPS injection. Furthermore, mAbs/LPS injection in wild-type mice enhanced the levels of CD31-positive vessels in synovia and terminal deoxynucleotidyltransferase-mediated UTP end labeling-positive chondrocytes in the articular cartilage, whereas such angiogenesis, as well as chondrocyte apoptosis, was suppressed significantly in OPN-deficient mice. These results indicated that OPN plays a critical role in the destruction of joint cartilage in the rheumatoid arthritis model in mice via the promotion of angiogenesis and induction of chondrocyte apoptosis.
Yumoto, Kenji, et al. “Osteopontin deficiency protects joints against destruction in anti-type II collagen antibody-induced arthritis in mice.” Proceedings of the National Academy of Sciences 99.7 (2002): 4556-4561.
Effects of oral administration of type II collagen on rheumatoid arthritis
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.
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
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.
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.
Mimicked cartilage scaffolds of silk fibroin/hyaluronic acid with stem cells for osteoarthritis surgery: Morphological, mechanical, and physical clues
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.
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
Immunization against heterologous type II collagen induces arthritis in mice
The induction of polyarthritis in rats by intradermal immunization with homologous or heterologous type II collagen in complete or incomplete Freund’s adjuvant was reported recently by Trentham et al.1. We have now produced a similar disease in certain strains of mice.
Courtenay, J. S., et al. “Immunisation against heterologous type II collagen induces arthritis in mice.” Nature 283.5748 (1980): 666.
Omega – 3
A meta-analysis of the analgesic effects of omega-3 polyunsaturated fatty acid supplementation for inflammatory joint pain
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 NSAID consumption (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.
Goldberg, Robert J., and Joel Katz. “A meta-analysis of the analgesic effects of omega-3 polyunsaturated fatty acid supplementation for inflammatory joint pain.” Pain 129.1-2 (2007): 210-223.
The Long-term effect of omega‐3 fatty acid supplementation in active rheumatoid arthritis
Objective. To study the long‐term effects of supplementation with omega‐3 fatty acids (ω3) in patients with active rheumatoid arthritis. Methods. Ninety patients were enrolled in a 12‐month, double‐blind, randomized study comparing daily supplementations with either 2.6 gm of ω3, or 1.3 gm of ω3 + 3 gm of olive oil, or 6 gm of olive oil. Results. Significant improvement in the patient’s global evaluation and in the physician’s assessment of pain was observed only in those taking 2.6 gm/day of ω3. The proportions of patients who improved and of those who were able to reduce their concomitant antirheumatic medications were significantly greater with 2.6 gm/day of ω3. Conclusion. Daily supplementation with 2.6 gm of ω3 results in significant clinical benefit and may reduce the need for concomitant antirheumatic medication.
Geusens, Piet, et al. “Long‐term effect of omega‐3 fatty acid supplementation in active rheumatoid arthritis.” Arthritis & Rheumatism: Official Journal of the American College of Rheumatology 37.6 (1994): 824-829.
Omega-3 Polyunsaturated Fatty Acids and the Treatment of Rheumatoid Arthritis: A Meta-analysis
Background and Aims
We undertook this study to assess the effects of omega-3 polyunsaturated fatty acids (PUFAs) (administered at ≥2.7 g/day) for a minimum duration of 3 months on clinical outcomes in patients with rheumatoid arthritis (RA).
The authors surveyed randomized controlled trials (RCTs) that examined the effects of omega-3 PUFAs on clinical outcomes in RA patients using Medline and the Cochrane Controlled Trials Register and by performing manual searches. A meta-analysis of RCTs was performed using fixed and random effects models. Outcomes are presented as standardized mean differences (SMD).
Ten RCTs involving 183 RA patients and 187 placebo-treated RA controls were included in this meta-analysis. The analysis showed that omega-3 PUFAs clearly reduced nonsteroidal anti-inflammatory drug (NSAID) consumption (SMD −0.518, 95% CI −0.915 to −0.121, p = 0.011) without between-study heterogeneity (I2 = 0%). Tender joint count (SMD −0.214, 95% CI−0.489–0.062, p = 0.128), swollen joint count (SMD −0.170, 95% CI−0.454–0.114, p = 0.241), morning stiffness (SMD −0.224, 95% CI−0.955–0.212, p = 0.221), and physical function (SMD 0.264, 95% CI−0.232–0.724, p = 0.314) showed a trend to improve more in patients treated with omega-3 PUFAs than in placebo-treated controls, but they did not reach statistical significance.
This meta-analysis suggests that the use of omega-3 PUFAs at dosages >2.7 g/day for >3 months reduces NSAID consumption by RA patients. Further studies are needed to explore the clinical and NSAID-sparing effects of omega-3 PUFAs in RA.
Lee, Young-Ho, Sang-Cheol Bae, and Gwan-Gyu Song. “Omega-3 polyunsaturated fatty acids and the treatment of rheumatoid arthritis: a meta-analysis.” Archives of medical research 43.5 (2012): 356-362.
Omega-3 Fatty Acids in Inflammation and Autoimmune Diseases
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 erythematosus 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.
Simopoulos, Artemis P. “Omega-3 fatty acids in inflammation and autoimmune diseases.” Journal of the American College of Nutrition 21.6 (2002): 495-505.
Dietary supplement for nutritionally promoting healthy joint function
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 a herbal blend.
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
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.
Javaid, Nadia. “BioPerine, Absorption & Bioavailability.”
Cody Bramlett’s Turmeric with BioPerine
A Comprehensive Review of Turmeric with BioPerine Supplement
There are many brands making different types of supplements on the market, all with certain health benefits. But have you ever thought of decreasing the number of supplements that you take, while still experiencing almost the same, and maybe even better health outcomes?
One particular formula that’s changing the supplement industry is Turmeric with BioPerine, a bright orange powder that is sourced from the root rhizome of a plant in the ginger family. Scientists and researchers have backed the Turmeric with BioPerine because of its superior health benefits and you too can tap its health properties by having it in supplement form.
Bramlett, Cody. “Cody Bramlett’s Turmeric with BioPerine.” (2019).