Effect of downregulation of serum MMP-3 levels by traditional Chinese medicine ingredients combined with methotrexate on the progression of bone injury in patients with rheumatoid arthritis: A protocol for a systematic review and meta-analysis.

BACKGROUND: A large number of clinical studies have confirmed that after treatment with traditional Chinese medicine components such as sinomenine (SIN), the matrix -metalloproteinase3 (MMP-3) level of patients with rheumatoid arthritis (RA) shows a significant decrease, whereas MMP-3 can be involved in degrading bone matrix in humans, so in the progression of bone and joint injury in patients with RA, serum MMP-3 can be used as an important biochemical marker. The traditional Chinese medicine components commonly used in clinical practice include total glucosides of paeony (TGP), SIN, and tripterygium glycosides, which have the characteristics of disease-modifyinganti-rheumatic drugs and non-steroidal anti-inflammatory drugs, while they can reduce the toxic side effects of methotrexate (MTX), and their combination with other drugs such as MTX and leflunomide (HWA486) has become an important regimen for the treatment of RA in clinical practice. Therefore, we designed this study protocol to evaluate the adjuvant effect of commonly used traditional Chinese medicine components combined with MTX in the treatment of osteoarticular injury in RA. METHODS: The search time was set from January 2000 to September 2020 in this study. EMBASE database, Cochrane Library, PubMed, Web of Science, Science Direct, Chinese National Knowledge Infrastructure, China Biology Medicine disc (CBM), Chinese Scientifific Journals Database (VIP), and Wanfang Database were used as search sources to select the traditional Chinese medicine components that reduce MMP-3 and use MTX in the treatment of RA. Clinical randomized controlled trials were used, and inclusion criteria and exclusion criteria were set for screening. In this study, MMP-3, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), cyclic peptide containing citrulline (CCP) and rheumatoid factor (RF) were used as the main outcomes, and the improvement of Disease Activity Score 28 (DAS28), joint bone mineral density, Clinical Disease Activity Index (CDAI), and other clinically relevant symptoms was selected as the secondary outcomes. Revman software version 5.3 was used for statistical analysis of data and risk assessment of deviation in this meta-analysis. In this study, one researcher performed study direction selection, literature inquiry, and literature download, and 2 independent reviewers performed literature data extraction and literature quality assessment. Dichotomized data are expressed as relative risk, continuous data are expressed as mean difference or standard mean difference, and finally fixed-effect model or random-effect model is used for synthesis according to the heterogeneity of data. RESULTS: To evaluate the effect of downregulation of MMP-3 level by traditional Chinese medicine components combined with MTX on the progression of bone injury in patients with RA by serum MMP-3, ESR, CRP, CCP, and RF. CONCLUSION: This study protocol can be used to evaluate the efficacy and safety of traditional Chinese medicine components combined with MTX in the treatment of bone injury in patients with RA. ETHICS AND DISSEMINATION: This study is a secondary study based on the published clinical research; therefore, approval from an ethics committee is not required for this study. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocol (PRISMA-P), the results of this study will be published in peer-reviewed scientific journals and conference papers. REGISTRATION NUMBER:: is INPLASY202090064.

Anti-Osteoarthritic Effects of a Mixture of Dried Pomegranate Concentrate Powder, Eucommiae Cortex, and Achyranthis Radix 5:4:1 (g/g) in a Surgically Induced Osteoarthritic Rabbit Model.

In this study, we aimed to determine the synergistic effects of a formula consisting of dried pomegranate concentrate powder, Eucommiae Cortex, and Achyranthis Radix 5:4:1 (g/g) (PCP:EC:AR) in a surgically induced osteoarthritis (OA) rabbit model. PCP:EC:AR was orally administered once per day. Knee thickness, maximum extension of the knee joint, gross articular defect area, and the histopathological appearance of the cartilage were monitored, along with serum collagen type II C-telopeptide (CTX-II), cartilage oligomeric matrix protein (COMP), matrix metalloproteinase (MMP)-3, tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and subchondral IL-1ß and TNF-α levels. Roentgenographic images were also evaluated. PCP:EC:AR significantly inhibited the surgically induced increase in knee thickness, maximum extension of both knees, knee thickness after capsule exposure, gross femoral and tibial articular defect areas, loss of the knee joint area, serum and synovial COMP, CTX-II, and MMP expression, and synovial IL-1ß, and TNF-α expression. In addition, surgically induced narrowing of the knee bones, loss of the joint area, cartilage damage, and osteophyte formation were reduced. PCP:EC:AR suppressed the surgically induced increases in the Mankin score, and subchondral IL-1ß and TNF-α immunolabeled cell numbers. PCP:EC:AR exerted potent OA protective effects in a surgically induced OA rabbit model.

Sensitivity of serum concentration of cartilage biomarkers to 21-days of bed rest.

The objective of the study was to test the hypothesis that serum levels of cartilage oligomeric matrix protein (COMP) would decrease and serum levels of tumor-necrosis factor alpha (TNF-α) and selected matrix metalloproteinases (MMPs) would increase in response to bed rest (BR) and that these changes are unaffected by the intake of potassium bicarbonate or whey protein. Seven and nine healthy male subjects participated in two 21-day 6° head down tilt crossover BR-studies with nutrition interventions. Serum samples were taken before, during, and after BR and biomarker concentrations were measured using commercial enzyme-linked immunosorbent assays. MMP-3 during BR was significantly lower than at baseline (reduction greater 20%; p < 0.001). MMP-3 increased significantly from 14 to 21 days of BR (+7%; p = 0.049). COMP during BR was significantly lower than at baseline (reduction greater 20%; p < 0.001). MMP-3 and COMP returned to baseline within 1 day after BR. MMP-9 on day 3 of BR was significantly lower than at baseline (-31%; p < 0.033) and on days 3, 5, and 14 of BR significantly lower than at the end of and after BR (reduction greater 35%; p < 0.030). The nutritional countermeasures did not affect these results. The observed changes in cartilage biomarkers may be caused by altered cartilage metabolism in response to the lack of mechanical stimulus during BR and inflammatory biomarkers may play a role in changes in biomarker levels. CLINICAL RELEVANCE: Immobilization independently from injury can cause altered cartilage biomarker concentration. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1465-1471, 2018.

Buprenorphine Alters Inflammatory and Oxidative Stress Molecular Markers in Arthritis.

Buprenorphine is recommended for use as an analgesic in animal models including in murine models of collagen-induced arthritis (CIA). However, the effect of buprenorphine on the expression of disease-associated biomarkers is not well defined. We examined the effect of buprenorphine administration on disease progression and the expression of inflammatory and oxidative stress markers, in a murine model of CIA. Buprenorphine administration altered the expression of cytokines, IFN-γ, IL-6, and MMP-3, and oxidative markers, for example, iNOS, superoxide dismutase (SOD1), and catalase (CAT), in the CIA mice. As buprenorphine is an analgesic, we further monitored the association of expression of these biomarkers with pain scores in a human cohort of early rheumatoid arthritis (RA). Serum MMP-3 levels and blood mRNA expression of antioxidants sod1 and cat correlated with pain scores in the RA cohort. We have demonstrated that administration of buprenorphine alters the expression of inflammatory and oxidative stress-related molecular markers in a murine model of CIA. This caveat needs to be considered in animal experiments using buprenorphine as an analgesic, as it can be a confounding factor in murine studies used for prediction of response to therapy. Furthermore, the antioxidant enzymes that showed an association with pain scores in the human cohort may be explored as biomarkers for pain in future studies.

Pomegranate extract alleviates disease activity and some blood biomarkers of inflammation and oxidative stress in Rheumatoid Arthritis patients.

BACKGROUND/OBJECTIVES: Since the main characteristics of Rheumatoid Arthritis (RA) are joint dysfunction caused by inflammation and serious pain, anti-inflammatory agents may alleviate the clinical symptoms in RA. Pomegranate juice is rich in polyphenolic compounds that possess antioxidant and anti-inflammatory activities. This study aimed to determine the beneficial effects of pomegranate extract (POMx) in RA patients. SUBJECTS/METHODS: A total of 55 RA patients were enrolled and randomly allocated to an intervention group (n=30) or a control group (n=25). The intervention group received 2 capsules of 250 mg POMx and the control group 2 capsules of 250 mg cellulose per day for 8 weeks. At the beginning of the study and after 8 weeks, Health Assessment Questionnaire (HAQ) and Disease Activity Score (DAS) 28 were completed and serum concentrations of C-reactive protein (CRP), matrix metalloproteinases 3 (MMP3), malondialdehyde (MDA), glutathione peroxidase (GPx) and erythrocyte sedimentation rate (ESR) were analyzed using standard methods and compared between the two groups. RESULTS: Compared with the placebo group, POMx supplement significantly reduced the score of DAS28 (P<0.001) which could be related to the decrease in swollen (P<0.001) and tender joints (P=0.001) count, pain intensity (P=0.003) and ESR levels (P= 0.03). POMx consumption also decreased HAQ score (P=0.007) and morning stiffness (P=0.04) and increased GPx concentrations (P<0.001). There were no differences in the change in mean MMP3, CRP and MDA levels between two groups. CONCLUSIONS: POMx alleviates disease activity and improves some blood biomarkers of inflammation and oxidative stress in RA patients.

Efficacy and tolerability of an undenatured type II collagen supplement in modulating knee osteoarthritis symptoms: a multicenter randomized, double-blind, placebo-controlled study.

BACKGROUND: Undenatured type II collagen (UC-II) is a nutritional supplement derived from chicken sternum cartilage. The purpose of this study was to evaluate the efficacy and tolerability of UC-II for knee osteoarthritis (OA) pain and associated symptoms compared to placebo and to glucosamine hydrochloride plus chondroitin sulfate (GC). METHODS: One hundred ninety one volunteers were randomized into three groups receiving a daily dose of UC-II (40 mg), GC (1500 mg G & 1200 mg C), or placebo for a 180-day period. The primary endpoint was the change in total Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) from baseline through day 180 for the UC-II group versus placebo and GC. Secondary endpoints included the Lequesne Functional Index (LFI), the Visual Analog Scale (VAS) for pain and the WOMAC subscales. Modified intent-to-treat analysis were performed for all endpoints using analysis of covariance and mixed model repeated measures, while incremental area under the curve was calculated by the intent-to-treat method. RESULTS: At day 180, the UC-II group demonstrated a significant reduction in overall WOMAC score compared to placebo (p = 0.002) and GC (p = 0.04). Supplementation with UC-II also resulted in significant changes for all three WOMAC subscales: pain (p = 0.0003 vs. placebo; p = 0.016 vs. GC); stiffness (p = 0.004 vs. placebo; p = 0.044 vs. GC); physical function (p = 0.007 vs. placebo). Safety outcomes did not differ among the groups. CONCLUSION: UC-II improved knee joint symptoms in knee OA subjects and was well-tolerated. Additional studies that elucidate the mechanism for this supplement's actions are warranted. TRIAL REGISTRATION: CTRI/2013/05/003663 ; CTRI/2013/02/003348 .

Effects of Vitamin K on Matrix Metalloproteinase-3 and Rheumatoid Factor in Women with Rheumatoid Arthritis: A Randomized, Double-Blind, Placebo-Controlled Trial.

OBJECTIVES: Rheumatoid arthritis (RA) is an autoimmune disease characterized by an increase in some autoantibodies and proteolytic enzymes, leading to joint destruction. Although recent investigations have considered vitamin K as an anti-inflammatory nutrient with an important role in bone metabolism, there is currently limited information on its efficacy in RA. We aimed to examine the effects of vitamin K1 (phylloquinone) on the biomarker of joint destruction and autoantibody in patients with RA. MATERIALS AND METHODS: This was a randomized clinical trial in which 64 women with RA who fulfilled the eligibility criteria were randomly allocated to an intervention or a control group. Vitamin K1 or placebo was administered to the participants for 8 weeks. Baseline characteristics and anthropometric measures were obtained. Clinical status using disease activity score in 28 joints (DAS-28), serum levels of matrix metalloproteinase-3 (MMP-3), and rheumatoid factor (RF) were assessed before and after the intervention. RESULTS: The serum level of MMP-3 compared with the baseline values did not change significantly in the groups. However, the serum concentration of RF decreased significantly in the vitamin K1 group (p = 0.041). Intergroup comparison showed no significant change in RF serum level after adjusting for relevant confounders (p > 0.05). CONCLUSIONS: Vitamin K1 supplementation at 10 mg/day for 8 weeks did not alter joint destruction and immune status in the patients with RA compared with the controls.

Biomarkers in Remission According to Different Criteria in Patients with Rheumatoid Arthritis.

OBJECTIVE: Remission is the primary aim in the treatment of patients with rheumatoid arthritis (RA). In this study, we aimed to evaluate biomarker profiles of patients in remission by different criteria and compare these profiles with controls. METHODS: Serum levels of calprotectin, interleukin 6 (IL-6), type II collagen helical peptide, C-terminal crosslinking telopeptide of type I collagen generated by matrix metalloproteinases (ICTP), matrix metalloproteinase 3 (MMP-3), resistin, and leptin were measured by ELISA in 80 patients. The patients were in Disease Activity Score at 28 joints with erythrocyte sedimentation rate (DAS28-ESR) remission, and had these characteristics: female/male 54/26, mean age 51.4 ± 12.1 years, mean disease duration 11.4 ± 8.1 years, rheumatoid factor positivity 68.7% (n = 55), anticyclic citrullinated peptide positivity 60.7% (n = 48). These patients were also evaluated for the American College of Rheumatology/European League Against Rheumatism (Boolean) and Simple Disease Activity Index (SDAI) remissions. Additionally, 80 age-, sex-, and comorbidity-matched individuals without rheumatic diseases were included in the study as controls. RESULTS: At recruitment of 80 patients in DAS28 remission, 33 patients (41.2%) were found in Boolean remission and 39 patients (48.7%) were in SDAI remission. Serum MMP-3, ICTP, resistin, and IL-6 levels of the 80 patients in DAS28 remission were statistically significantly higher than the controls. Patients in Boolean and SDAI remissions had significantly higher serum ICTP, resistin, and IL-6 levels in comparison with the controls. CONCLUSION: The 3 commonly used remission criteria of RA are almost similar with regard to patients' biomarker levels. Biomarker profiles of patients may provide complementary information to clinical evaluation of remission and may help to determine the patients under the risk of progression.

Preventive effects of dietary hydroxytyrosol acetate, an extra virgin olive oil polyphenol in murine collagen-induced arthritis.

SCOPE: Hydroxytyrosol acetate (HTy-Ac), an extra virgin olive oil (EVOO) polyphenol, has recently been reported to exhibit antioxidant and anti-inflammatory effects on LPS-stimulated macrophagesand ulcerative colitis. This study was designed to evaluate dietary HTy-Ac supplementation effects on collagen-induced arthritis (CIA) in mice. METHODS AND RESULTS: DBA-1/J mice were fed from weaning with 0.05% HTy-Ac. After 6 weeks, arthritis was induced by type II collagen. Mice were sacrificed 42 days after first immunization. Blood was recollected and paws were histological and biochemically processed. HTy-Ac diet significantly prevent edarthritis development and decreased serum IgG1 and IgG2a, cartilage olimeric matrix protein (COMP) and metalloproteinase-3 (MMP-3) levels, as well as, pro-inflammatory cytokines levels (TNF-α, IFN-γ, IL-1ß, IL-6 and IL-17A). The activation of Janus kinase-signal transducer and activator of transcription (JAK/STAT), mitogen-activated protein kinases (MAPKs) and nuclear transcription factor-kappa B (NF-κB) pathways were drastically ameliorated whereas nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) protein expressions were significantly up-regulated in those mice fed with HTy-Ac. CONCLUSION: HTy-Ac improved the oxidative events and returned pro-inflammatory proteins expression to basal levels probably through JAK/STAT, MAPKs and NF-κB pathways. HTy-Ac supplement might provide a basis for developing a new dietary strategy for the prevention of rheumatoid arthritis.

Effects of BIS076 in a model of osteoarthritis induced by anterior cruciate ligament transection in ovariectomised rats.

BACKGROUND: Osteoarthritis (OA) is the most frequent articular disease and a leading cause of disability. There is a need for effective treatments able to slow the progression of disease. Some of the available treatments are dietary supplements providing natural components. Recent studies have shown that estrogen deficiency contributes to the pathophysiological events of OA progression. METHODS: We have used the anterior cruciate ligament transection model of OA in ovariectomised rats to study the effects of BIS076, a new formulation of a natural porcine cartilage extract associated with hydroxyapatite (as a source of calcium) and vitamin D3. Cartilage degradation, proteoglycan depletion and synovitis were followed by histochemistry. Effects on bone microstructure were determined by µCT. The levels of biomarkers in serum and inflammatory mediators in knee homogenates were measured by luminex or ELISA. RESULTS: Oral administration of BIS076 reduced articular cartilage damage and serum levels of cartilage degradation markers C-telopeptide of type II collagen and cartilage oligomeric matrix protein, as well as matrix metalloproteinase-3. The local inflammatory response was down-regulated by BIS076 with lower production of pro-inflammatory cytokines and prostaglandin E2 in joint tissues. In addition, BIS076 was effective on metaphyseal bone alterations as this formulation increased volumetric bone mineral density and improved bone micro-architecture. These effects were related to the modification of bone metabolism reflected by changes in bone biomarkers with reductions in the ratio receptor activator of nuclear factor κB ligand/osteoprotegerin and the levels of tartrate-resistant acid phosphatase-5b, suggesting an inhibitory activity of BIS076 on trabecular bone resorption. CONCLUSIONS: We have demonstrated the protective properties of a new formulation (BIS076) on joint lesion and bone alterations in an experimental model of OA in ovariectomised rats. This study supports the interest of BIS076 in OA treatments.

Effects of Alpha-Lipoic Acid Supplementation on Inflammatory Biomarkers and Matrix Metalloproteinase-3 in Rheumatoid Arthritis Patients.

OBJECTIVE: Although many studies have considered alpha-lipoic acid (ALA) as a potent antioxidant with anti-inflammatory functions in oxidative stress-associated inflammatory diseases, few studies have evaluated its efficacy in rheumatoid arthritis (RA). Therefore, we aimed to examine the effects of ALA on serum biomarkers of joint damage and inflammation in women with RA. METHODS: We performed a randomized, double-blind, placebo-controlled clinical trial in which RA patients (n = 70) aged 20-50 years were randomly assigned 1:1 to receive either ALA (1200 mg/day) or placebo for 8 weeks. Fasting blood samples were taken before and after the study to analyze inflammatory biomarkers including serum high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and serum matrix metalloproteinase-3 (MMP-3) as a marker of joint erosion. Moreover, 3-day dietary records, the International Physical Activity Questionnaire (IPAQ), and the Spielberger State-Trait anxiety inventory form Y (STAI-Y) were assessed before and after the intervention. RESULTS: Sixty-five RA patients completed the trial. No statistically significant differences were observed in serum levels of hs-CRP, TNF-α, IL-6, and MMP-3 within and between the ALA and placebo groups (p > 0.05). There were no statistically significant differences in dietary intakes, physical activity, and anxiety levels between groups at baseline and they remained statistically unchanged during the study period (p > 0.05). CONCLUSION: Although in theory ALA supplementation could serve as a beneficial nutraceutical in RA patients, in the present study serum inflammatory biomarkers and MMP-3 were not significantly affected by 8 weeks of ALA supplementation.

The complementary effects of atorvastatin and exercise treatment on the composition and stability of the atherosclerotic plaques in ApoE knockout mice.

AIM: This study aimed to investigate the effects of combined atorvastatin and exercise treatment on the composition and stability of the atherosclerotic plaques in apolipoproteinE (apoE) knockout mice. METHODS: Forty male, apoE-/- mice were fed a high-fat diet for 16 weeks. Thereafter, while maintained on high-fat diet, they were randomized into four (n = 10) groups for 8 additional weeks: Group CO: Control. Group AT: Atorvastatin treatment (10 mg/Kg/day). Group EX: Exercise-training on treadmill. Group AT+EX: Atorvastatin and simultaneous exercise training. At the study's end, plasma cholesterol levels, lipids and triglycerides were measured, along with the circulating concentrations of matrix-metalloproteinases (MMP-2,3,8,9) and their inhibitors (TIMP-1,2,3). Plaque area and the relative concentrations of collagen, elastin, macrophages, smooth muscle cells, MMP-2,3,8,9 and TIMP-1,2,3 within plaques were determined. Lastly, MMP activity was assessed in the aortic arch. RESULTS: All intervention groups showed a lower degree of lumen stenosis, with atheromatous plaques containing more collagen and elastin. AT+EX group had less stenosis and more elastin compared to single intervention groups. MMP-3,-8 -9 and macrophage intra-plaque levels were reduced in all intervention groups. EX group had increased TIMP-1 levels within the lesions, while TIMP-2 was decreased in all intervention groups. The blood levels of the above molecules increased during atherosclerosis development, but they did not change after the therapeutic interventions in accordance to their intra-plaque levels. CONCLUSION: The two therapeutic strategies act with synergy regarding the extent of the lesions and lumen stenosis. They stabilize the plaque, increasing its content in elastin and collagen, by influencing the MMP/TIMP equilibrium, which is mainly associated with the macrophage amount. While the increased MMP-2,-3,-8 -9, as well as TIMP-1 and TIMP-2 circulating levels are markers of atherosclerosis, they are not correlated with their corresponding concentrations within the lesions after the therapeutic interventions, and cannot serve as markers for the disease development/amelioration.

[Significance of serum MMP-3, TIMP-1, and monocyte CD147 in rheumatoid arthritis patients of damp-heat Bi-syndrome and of cold-damp Bi-syndrome].

OBJECTIVE: To explore the clinical significance of serum matrix metalloproteinase-3 (MMP-3), tissue inhibitor of metalloproteinase-1 (TIMP-1), and monocyte CD147 in rheumatoid arthritis (RA) patients of damp-heat Bi-syndrome (DHBS) and of cold-damp Bi-syndrome (CDBS). METHODS: The clinical data of 22 patients from inpatients and outpatients with RA were collected, and their peripheral blood was withdrawal. The disease activity scores [DAS28(4)] were assessed. The serum levels of MMP-3 and TIMP-1 were detected by double antibody sandwich enzyme linked immunosorbent assay (ELISA). The mean fluorescence intensity (MFI) and the expression percentage of CD147 on CD14+ monocytes were detected by flow cytometry. The difference of each index between RA patients of DHBS and RA patients of CDBS was analyzed. RESULTS: The level of serum MMP-3 and the MFI of CD147 on the monocyte surface were obviously higher in RA patients of DHBS than in those of CDBS and the normal control group (P < 0.05). The concentration of serum TIMP-1 was obviously higher in RA patients of DHBS than in those of the normal control group (P < 0.05), while there was no statistical difference between the two syndrome types. The percentage of CD147 expression was obviously lower in DHBS than in those of CDBS and the normal control group (P < 0.05). CONCLUSIONS: Increased serum MMP-3 level of RA patients of DHBS might result in destroy of joint cartilages and sclerotin. The significant increase of MFI and decreased expression percentage of monocyte CD147 might be the results of increased disease activity of RA and monocyte migration to the synovial membrane tissue.

[Effect of acupoint heat-sensitive moxibustion intervention on serum osteopontin and matrix metalloproteinase-3 in patients with acute knee pain].

OBJECTIVE: To observe the clinical effect of acupoint heat-sensitive moxibustion for acut knee arthralgia and to analyze its effect on serum osteopontin (OPN) and matrix metalloproteinase-3 (MMP-3) contents in patients with knee osteoarthritis so as to study its mechanism underlying improving arthralgia. METHODS: One hundred and forty-four patients with acute knee knee osteoarthritis were randomly allocated to acupoint heat-sensitive moxibustion (moxibustion), electroacupuncture (EA) and medication groups. Patients of the moxibustion group were treated by suspended moxibustion over bilateral Weizhong (BL 40) for 40 min each point, once daily for 15 days. Patients of the EA group were treated by EA stimulation of Neixiyan (EX-LE 4), Dubi (ST 35), Xuehai (SP 10) and Liangqiu (ST 34) for 30 min, once daily for 15 days; and those of the medication group treated by oral administration of Sanqi Tongshu capsules (Panax Notoginseng, etc. used for promoting blood circulation and removing blood stasis), 3 times daily for 15 days. Serum OPN and MMP-3 levels were detected with ELISA. RESULTS: Following the treatment, of the 50, 50 and 44 cases in the moxibustion, EA and medication groups, 24, 20 and 14 were excellent, 18, 16 and 13 were good in therapeutic effect, 7, 4, and 3 were effective, and 1, 10, and 14 invalid, with the excellent and good rates being 84%, 72.0% and 61.4%, respectively. Serum OPN content of the moxibistion and EA groups, and serum MMP-3 content of the moxibustion group were reduced considerably in comparison with pre-treatment in the same one group (P < 0.01), while serum OPN level of the medication group and MMP-3 of the EA group were decreased slightly. The effect of moxibustion was evidently superior to that of medication in lowering serum OPN level (P < 0.05) and superior to that of both EA and medication in lowering serum MMP-3 content (P < 0.05). CONCLUSION: Acupoint heat-sensitive moxibustion has a good therapeutic effect in relieving acute knee arthralgia, which may be related to its effects in decreasing serum OPN and MMP-3 levels.

A dietary colorant crocin mitigates arthritis and associated secondary complications by modulating cartilage deteriorating enzymes, inflammatory mediators and antioxidant status.

Articular cartilage degeneration and inflammation are the hallmark of progressive arthritis and is the leading cause of disability in 10-15% of middle aged individuals across the world. Cartilage and synovium are mainly degraded by either enzymatic or non-enzymatic ways. Matrix metalloproteinases (MMPs), hyaluronidases (HAases) and aggrecanases are the enzymatic mediators and inflammatory cytokines and reactive oxygen species being non-enzymatic mediators. In addition, MMPs and HAases generated end-products act as inflammation inducers via CD44 and TLR-4 receptors involved NF-κB pathway. Although several drugs have been used to treat arthritis, numerous reports describe the side effects of these drugs that may turn fatal. On this account several medicinal plants and their isolated molecules have been involved in modern medicine strategies to fight against arthritis. In view of this, the present study investigated the antiarthritic potentiality of Crocin, a dietary colorant carotenoid isolated from stigma of Crocus sativus. Crocin effectively neutralized the augmented serum levels of enzymatic (MMP-13, MMP-3 and MMP-9 and HAases) and non-enzymatic (TNF-α, IL-1ß, NF-κB, IL-6, COX-2, PGE(2) and ROS) inflammatory mediators. Further, Crocin re-established the arthritis altered antioxidant status of the system (GSH, SOD, CAT and GST). It also protected the bone resorption by inhibiting the elevated levels of bone joint exoglycosidases, cathepsin-D and tartrate resistant acid phosphatases. Taken together, Crocin revitalized the arthritis induced cartilage and bone deterioration along with inflammation and oxidative damage that could be accredited to its antioxidant nature. Thus, Crocin could be an effective antiarthritic agent which can equally nullify the arthritis associated secondary complication.

Analysis of early biochemical markers and regulation by tin protoporphyrin IX in a model of spontaneous osteoarthritis.

Age-related changes in joint tissues lead to osteoarthritis (OA). Detection of early changes in OA patients may help to initiate treatments before the establishment of irreversible joint destruction. STR/ort mice develop with age a severe degenerative joint disease that resembles human OA thus allowing the investigation of biochemical markers as well as new treatments in an accelerated time frame. We have analyzed the changes in serum levels of different mediators during the early phases of idiopathic OA in STR/ort mice. Serum levels of matrix metalloproteinase-3 (MMP-3) but not those of tumor necrosis factor-α, interleukin(IL)-1ß, IL-17 or prostaglandin E(2) correlated with histopathological changes in knees of STR/ort mice at 9 weeks. Treatment of animals with tin protoporphyrin IX (SnPP, 12 mg/kg/dayi.p.) for 4 weeks significantly reduced the progression of OA. Our data suggest that MMP-3 is a sensitive biomarker to detect early OA alterations and that SnPP could be a protective agent in OA.

Heme oxygenase-1 regulates the progression of K/BxN serum transfer arthritis.

BACKGROUND: Heme oxygenase-1 (HO-1) is induced in many cell types as a defense mechanism against stress. We have investigated the possible role of endogenous HO-1 in the effector phase of arthritis using the K/BxN serum transfer model of arthritis in HO-1 heterozygous and homozygous knock-out mice. METHODOLOGY/PRINCIPAL FINDINGS: Arthritis was induced in C57/Black-6 xFVB (HO-1(+/+), HO-1(+/-) and HO-1(-/-)) mice by intraperitoneal injection of 150 µl serum from arthritic K/BxN mice at days 0 and 2. Blood was collected and animals were sacrificed at day 10. Histological analysis was performed in ankle sections. The levels of inflammatory mediators were measured in serum and paw homogenates by enzyme-linked immunosorbent assay or Multiplex technology. The incidence of arthritis was higher in HO-1(+/-) and HO-1(-/-) groups compared with HO-1(+/+). The inflammatory response was aggravated in HO-1(+/-) mice as shown by arthritic score and the migration of inflammatory cells that could be related to the enhancement of CXCL-1 production. In addition, the HO-1(+/-) group showed proteoglycan depletion significantly higher than HO-1(+/+) mice. Serum levels of matrix metalloproteinase-3, monocyte chemotactic protein-1, plasminogen activator inhibitor-1, E-selectin and intercellular adhesion molecule-1 were increased in arthritic HO-1(-/-) mice, whereas vascular endothelial growth factor and some cytokines such as interferon-γ showed a reduction compared to HO-1(+/+) or HO-1(+/-) mice. In addition, down-regulated gene expression of ferritin, glutathione S-reductase A1 and superoxide dismutase-2 was observed in the livers of arthritic HO-1(+/-) animals. CONCLUSION/SIGNIFICANCE: Endogenous HO-1 regulates the production of systemic and local inflammatory mediators and plays a protective role in K/BxN serum transfer arthritis.

[Establishment and analysis of chronic periodontitis and atherosclerosis model in Wistar rat].

OBJECTIVE: To investigate the possible correlation between atherosclerosis and chronic periodontitis by establishing an animal model of chronic periodontitis and atherosclerosis in Wistar rat. METHODS: Sixty male Wistar rats were divided into four groups: A (control group), B (chronic periodontitis group), C (atherosclerosis group), D (chronic periodontitis accompany with atherosclerosis group). Every group was accepted the corresponding treatment. Animals were sacrificed after 12 weeks. The periodontal index, levels of serum total cholesterol (TC) and low-density lipoprotein (LDL), the concentration of TNF-alpha and matrix metalloproteinase (MMP-3) were examined. The severity of chronic periodontitis and atherosclerosis was quantified by histopathology. The date were statistically analyzed. RESULTS: Through detection of periodontal tissue of experimental teeth, serum and histopathology, animal models were successful. Histopathologic observation revealed:obvious inflammation of periodontal tissue was observed in group B and D. Attachment loss level in group B [(137.86 +/- 28.39) microm] and D [(162.36 +/- 22.69) microm] was higher than that in group A [(4.26 +/- 1.07) microm] and C [(68.07 +/- 18.25) microm] (P < 0.05), and that in group C was higher than group A (P < 0.05). Atherosclerotic lesions of abdominal aorta were formed in group C and D. The level of TC, LDL in group C and D was higher than that in group A and B (P < 0.05), and that in group D was higher than group C (P < 0.05). Animals in group B and D showed higher level of TNF-alpha, MMP-3 in serum than that in group A and C (P < 0.05). There was no correlation between the level of MMP-3 and TC (P = 0.971) or LDL (P = 0.604). CONCLUSIONS: Chronic periodontitis may be a risk factor and contribute to the pathogenesis of atherosclerosis. MMP-3 may be an independent risk factor of atherosclerosis exclude TC and LDL.

[Effect of the active components of red paeonia and rhizoma chuanxiong on matrix metalloproteinases in rabbits with atherosclerosis].

OBJECTIVE: To investigate the effect of the active components from Red Paeonia and Rhizoma chuanxiong (in Xiongshao Capsule, XSC) on matrix metalloproteinases (MMPs) in rabbit model of atherosclerosis. METHODS: Fifty New Zealand rabbits were randomly divided into the normal control group (A), the model control group (B), the Simvastatin treated group (C), the low-dose XSC treated group (D) and the high-dose XSC treated group (E), 10 in each group. Rabbits in the normal control group were fed with normal diet, while those in the other four groups were fed with high fat diet and duplicated after two weeks feeding into model of abdominal aortic atherosclerosis by balloon angioplasty. In the 6 successive weeks feeding of high fat diet, Simvastatin 2.5 mg/kg, XSC 0.24 g/kg and 0.48 g/kg per day was given respectively to the rabbits in the three treated groups. Blood sample was collected for determining the level of blood lipids; serum MMP-3 and MMP-9, and tissue inhibitor of metalloproteinase-1 (TIMP-1) with enzyme-linked immunoassay; and the protein expression of MMP-3 and cluster of differentiation antigen 40 ligand (CD40L) in plaque were detected with immunohistochemical method. RESULTS: Compared with Group B, the serum levels of MMP-3 and MMP-9; the expression of MMP-3 and CD40L in plaque; and the blood content of total cholesterol in the three treated groups were significantly lower (P < 0.05 or P < 0.01). Besides, the content of triglyceride and low-density lipoprotein cholesterol were significantly reduced in Group C, while the TIMP-1 showed no statistical difference among different groups (P > 0.05). CONCLUSION: The active components of Red Paeonia and Rhizoma chuanxiong play a definite role in stabilizing the atherosclerotic plaque in rabbits, one of their possible mechanisms may be by way of inhibiting the expressions of MMP-3, MMP-9 in vascular walls and blood serum.

Associations of dietary long-chain n-3 polyunsaturated fatty acids and fish with biomarkers of inflammation and endothelial activation (from the Multi-Ethnic Study of Atherosclerosis [MESA]).

The cardioprotective effects of long-chain n-3 polyunsaturated fatty acids (PUFAs) and fish consumption have been observed. However, data on the specific associations of these dietary factors with inflammation and endothelial activation are sparse. A cross-sectional study was conducted of 5,677 men and women from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort, including African Americans, Caucasians, Chinese, and Hispanics aged 45 to 84 years and free of clinical cardiovascular disease. Dietary information was collected using a self-administered food frequency questionnaire. Multivariate linear regression analyses were used to examine relations between the intake of long-chain n-3 PUFAs, nonfried fish, and fried fish and biomarkers of inflammation and endothelial activation. Long-chain n-3 PUFA intake was inversely associated with plasma concentrations of interleukin-6 (p = 0.01) and matrix metalloproteinase-3 (p = 0.03) independent of age, body mass index, physical activity, smoking, alcohol consumption, and dietary variables. Nonfried fish consumption was inversely related to C-reactive protein (p = 0.045) and interleukin-6 (p <0.01), and fried fish consumption was inversely related to soluble intercellular adhesion molecule-1 (p <0.01) but was not associated with other biomarkers after adjustment for potential confounders. In conclusion, the results of this study suggest that the dietary intake of long-chain n-3 PUFAs and fish is inversely associated with concentrations of some biomarkers, reflecting lower levels of inflammation and endothelial activation. These results may partially explain the cardioprotective effects of fish consumption.