Central and peripheral effects of environmental enrichment in a mouse model of arthritis.

This study analyzed whether environmental enrichment (EE) modulates the nociceptive and inflammatory responses in the mouse model of arthritis induced by Complete Freund's Adjuvant (CFA). Ninety male mice (C57BL/6-JUnib, 4-weeks-old; 20-25 g) were distributed into EE and standard (SE) groups. For EE, mice were kept in bigger cages using an alternation of materials to chew (wood and paper), for nesting (cotton), to use as hiding places (plastic tunnels), and for voluntary exercise (wheel running). Arthritis was induced by an injection of CFA (50 µL) into the right hind paw or saline solution in the control group. Separate groups received the anti-inflammatory drug dexamethasone (0.5 mg/kg; every 48 h). Inflammatory and pain measurements were performed from 1 to 35 days after CFA administration. EE per se reduced the acute paw edema formation and arthritis scores. The serum levels of tumor necrosis factor (TNF) were undetectable in any experimental groups. EE diminished the immunopositivity for the microglia marker IBA1 in the pre-frontal cortex, with slight changes for hippocampal GFAP-positive activated astrocytes. Finally, EE induced a marked increment of brain-derived nerve factor (BDNF) expression in the hippocampus, an effect that was fully prevented by dexamethasone. These data bring novel evidence on the peripheral and central effects of EE in a mouse arthritis model.

Low-Salt Diet Attenuates B-Cell- and Myeloid-Cell-Driven Experimental Arthritides by Affecting Innate as Well as Adaptive Immune Mechanisms.

A link between high sodium chloride (salt) intake and the development of autoimmune diseases was previously reported. These earlier studies demonstrated exacerbation of experimental autoimmune encephalomyelitis and colitis by excess salt intake associated with Th17- and macrophage-mediated mechanisms. Little is known about the impact of dietary salt intake on experimental arthritides. Here, we investigated if salt restriction can exert beneficial effects on collagen-induced arthritis (CIA) and K/BxN serum transfer-induced arthritis (STIA). CIA depends on both adaptive and innate immunity, while STIA predominantly mimics the innate immune cell-driven effector phase of arthritis. In both models, low salt (LS) diet significantly decreased arthritis severity compared to regular salt (RS) and high salt (HS) diet. We did not observe an aggravation of arthritis with HS diet compared to RS diet. Remarkably, in STIA, LS diet was as effective as IL-1 receptor blocking treatment. Complement-fixing anti-CII IgG2a antibodies are associated with inflammatory cell infiltration and cartilage destruction. LS diet reduced anti-CII IgG2a levels in CIA and decreased the anti-CII IgG2a/IgG1 ratios pointing toward a more Th2-like response. Significantly less inflammatory joint infiltrates and cartilage breakdown associated with reduced protein concentrations of IL-1 beta (CIA and STIA), IL-17 (CIA), and the monocyte chemoattractant protein-1 (MCP-1) (CIA) were detected in mice receiving LS diet compared to HS diet. However, we did not find a reduced IL-17A expression in CD4+ T cells upon salt restriction in CIA. Analysis of mRNA transcripts and immunoblots revealed a link between LS diet and inhibition of the p38 MAPK (mitogen-activated protein kinase)/NFAT5 (nuclear factor of activated T-cells 5) signaling axis in STIA. Further experiments indicated a decreased leukodiapedesis under LS conditions. In conclusion, dietary salt restriction ameliorates CIA and STIA, indicating a beneficial role of LS diet during both the immunization and effector phase of immune-mediated arthritides by predominantly modulating the humoral immunity and the activation status of myeloid lineage cells. Hence, salt restriction might represent a supportive dietary intervention not only to reduce cardiovascular risk, but also to improve human inflammatory joint diseases like rheumatoid arthritis.

Deciphering the metabolic profile and pharmacological mechanisms of Achyranthes bidentata blume saponins using ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry coupled with network pharmacology-based investigation.

ETHNOPHARMACOLOGICAL RELEVANCE: Achyranthes bidentata Blume (AB) is a traditional Chinese medicine (TCM) widely used as a dietary supplement and anti-arthritis drug. Pharmacological studies have shown that Achyranthes bidentata Blume saponins (ABS) are the main bioactive ingredient. However, the metabolic profile and mechanisms of action of ABS against rheumatic arthritis (RA) remain to be established. AIM OF THE STUDY: Our main objective was to investigate the metabolic profile and pharmacological activities of ABS against RA. MATERIALS AND METHODS: In this study, an analytical method based on ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) coupled with a metabolism platform was developed for metabolic profiling of ABS in rat liver microsomes and plasma. Then, the in vivo metabolites of ABS and their targets associated with RA were used to construct the network pharmacological analysis. Gene ontology (GO) enrichment, KEGG signaling pathway analyses and pathway network analyses were performed. The therapeutic effect of ABS on RA was further evaluated using an adjuvant arthritis (AA) model and network pharmacology results validated via Western blot. RESULTS: Overall, 26 and 21 metabolites of ABS were tentatively characterized in rat liver microsomes and plasma, respectively. The metabolic pathways of ABS mainly included M+O, M+O-H2, M+O2, and M+O2-H2. Data form network pharmacology analysis suggested that MAPK, apoptosis, PI3K-AKT and p53 signaling pathways contribute significantly to the therapeutic effects of ABS on RA. In pharmacodynamics experiments, ABS ameliorated the symptoms in AA rats in a dose-dependent manner and restored the homeostasis of pro/anti-inflammatory factors. Western blot results further demonstrated a significant ABS-induced decrease in phosphorylation of ERK in the MAPK pathway (P < 0.01). CONCLUSION: Application of an analytical method based on UPLC-QTOF/MS, network pharmacology and validation experiments offers novel insights into the components and mechanisms of ABS that contribute to its therapeutic effects against RA, providing useful directions for further research.

Galactomannan of Delonix regia seeds reduces nociception and morphological damage in the rat model of osteoarthritis induced by sodium monoiodoacetate.

This study investigated the effects of the protein-free galactomannan obtained from Delonix regia seeds (GM-DR) in an experimental osteoarthritis (OA) model. GM-DR was obtained from water-homogenized endosperms by collection of the supernatant and precipitation with ethanol. The remaining proteins in the galactomannan were removed by alkaline hydrolysis. Weight average molar mass (Mw) of the galactomannan was estimated in 5.8 × 105 g mol-1, presenting mannose:galactose ratio of 2.39:1. Rats received sodium monoiodoacetate (OA groups, 1 mg/25 µL) or saline (sham group) in the right tibio-tarsal joint. GM-DR (30-300 µg) was administered by intra-articular route at days 14 and 21 after OA induction. Hypernociception was evaluated daily by the measurement of the mechanical threshold required to cause joint flexion and paw withdrawal reflex. The 56-day animal groups were euthanized for joint histopahological analysis using the OARSI score system. Lower doses of GM-DR (30 and 100 µg) promoted antinociception from day 15 until the endpoint at day 56. Joint damage was reduced by GM-DR administration (100 µg) in OA-subjected animals, compared to the vehicle-treated OA group (5.9 ± 1.8 vs 19.0 ± 1.8, respectively, p < 0.05). Conclusion: Both antinociception and damage reduction suggest that Delonix regia galactomannan is a promising approach for osteoarthritis therapy.

Suppression of Rheumatoid Arthritis by Enhanced Lymph Node Trafficking of Engineered Interleukin-10 in Murine Models.

OBJECTIVE: Rheumatoid arthritis (RA) is a major autoimmune disease that causes synovitis and joint damage. Although clinical trials have been performed using interleukin-10 (IL-10), an antiinflammatory cytokine, as a potential treatment of RA, the therapeutic effects of IL-10 have been limited, potentially due to insufficient residence in lymphoid organs, where antigen recognition primarily occurs. This study was undertaken to engineer an IL-10-serum albumin (SA) fusion protein and evaluate its effects in 2 murine models of RA. METHODS: SA-fused IL-10 (SA-IL-10) was recombinantly expressed. Mice with collagen antibody-induced arthritis (n = 4-7 per group) or collagen-induced arthritis (n = 9-15 per group) were injected intravenously with wild-type IL-10 or SA-IL-10, and the retention of SA-IL-10 in the lymph nodes (LNs), immune cell composition in the paws, and therapeutic effect of SA-IL-10 on mice with arthritis were assessed. RESULTS: SA fusion to IL-10 led to enhanced accumulation in the mouse LNs compared with unmodified IL-10. Intravenous SA-IL-10 treatment restored immune cell composition in the paws to a normal status, elevated the frequency of suppressive alternatively activated macrophages, reduced IL-17A levels in the paw-draining LN, and protected joint morphology. Intravenous SA-IL-10 treatment showed similar efficacy as treatment with an anti-tumor necrosis factor antibody. SA-IL-10 was equally effective when administered intravenously, locally, or subcutaneously, which is a benefit for clinical translation of this molecule. CONCLUSION: SA fusion to IL-10 is a simple but effective engineering strategy for RA therapy and has potential for clinical translation.

Clinical features and outcomes in children with bone and joint infections of the ankle or foot.

BACKGROUND: The foot and ankle are uncommon sites of bone and joint infections (BJIs) in children. The objectives of the present study were to determine the clinical and bacteriologic features of BJIs and to assess any associated complications and orthopedic sequelae. METHODS: We performed a retrospective, single-center study of children treated for foot or ankle BJIs between 2008 and 2018 in a French university medical center. A total of 23 children were included. The median age at diagnosis was 9.1 years. Osteomyelitis was noted in 14 cases; it involved the calcaneus in seven cases, the distal fibula in four cases, the first metatarsal in two cases, and the distal tibia in one case. Arthritis affected the ankle in six cases and the cuneiform-cuboidal joint in one case. In two cases, osteoarthritis of the ankle was associated with distal osteomyelitis of the tibia. Clinical, radiological, and bacteriological parameters, surgical procedures, complications, and sequelae were recorded and analyzed. RESULTS: The median (range) time to diagnosis was 3.18 days (0-10), and trauma was reported in four cases. Fever was present on admission in 18 cases, and the serum C-reactive protein level was elevated in 22 cases. Standard X-rays showed osteolysis in one case and bone sequestration in another. Staphylococcusaureus was identified in 10 cases. Surgery was performed in 17 cases. A subperiosteal abscess that required surgical drainage complicated 10 cases of osteomyelitis. No recurrence was observed. At the last follow-up, the median (range) age was 11.9 years (1.5-19). Sequelae (spontaneous tibia-talus fusion, first metatarsal epiphysis fusion, and varus deformity of the hindfoot) were observed in three cases, all of which were initially complicated by an abscess. CONCLUSION: Physicians should be aware that pediatric BJIs of the lower limb may involve the foot and ankle. S. aureus is frequently involved. In cases of osteomyelitis, complications are closely associated with subperiosteal abscesses justifying an early diagnosis. These BJIs must be treated rapidly, and the risk of sequelae justifies long-term follow-up.

Anti-rheumatic activity of Phenethyl isothiocyanate via inhibition of histone deacetylase-1.

Rheumatoid Arthritis (RA) affects approximately 1% of the total world population. Despite incessant research and development of new therapeutic agents, management of RA is still a troublesome affair. Histone Deacetylase 1 (HDAC1) is an epigenetic regulator which play important role in pathogenesis of RA. In present study, we hypothesized that Phenethyl isothiocyanate (PEITC), a potent inhibitor of HDAC1, may ameliorate RA. Efficacy of PEITC was evaluated in Complete Freund's Adjuvant (CFA) induced arthritis model in rats. CFA (0.1 ml) was injected subplantarly in the left hind paw on day 0 to all the groups except normal control. The administration of test drug PEITC (10, 24 & 50 mg/kg) and standard drug Ibuprofen started simultaneously and was continued for 21 days. Paw edema, total arthritic index, mobility score, stair climbing ability, behavioral parameters, and bone erosion were evaluated. Further, radiographic studies, TNF-alpha as well as HDAC1 levels in synovial tissue homogenate and histological analysis were performed. Prophylactic treatment of PEITC attenuated paw edema, total arthritic index, mobility score, stair climbing ability, behavioral parameters, and bone erosion in dose dependent manner. Furthermore, there was significant decrease in TNF-alpha as well as HDAC1 levels in synovial tissue homogenate. Histological analysis revealed no cartilage damage, bone erosion, hyperplasia at synovial lining as well as infiltration of inflammatory cells in treatment group. Results of this study suggest potent anti-rheumatoid arthritis activity of Phenethyl isothiocyanate in CFA induced RA model in rats.

Evaluation of rohitukine-enriched fraction of Dysoxylum binectariferum Hook.f. (leaves) as anti-arthritic phytopharmaceutical candidate: Chemical standardization, in-vivo validation, formulation development and oral pharmacokinetics.

ETHNOPHARMACOLOGICAL RELEVANCE: Rheumatoid arthritis is a chronic inflammatory disease of joints. Dysoxylum binectariferum Hook.f (Family: Meliaceae) is a Indian medicinal plant which is traditionally being used to heal inflammation of joints. AIM OF THE STUDY: This work was aimed to carry out chemical standardization, in-vitro/in-vivo validation, oral pharmacokinetics and formulation development of anti-arthritic botanical lead, the rohitukine-enriched fraction of D. binectariferum. MATERIALS AND METHODS: The rohitukine-enriched fraction of D. binectariferum was standardized using four chemical markers and was checked for microbial load, heavy metal content, aflatoxins and pesticides. Its in-vitro inhibitory effect on the lipopolysaccharide (LPS) induced production of pro-inflammatory cytokines TNF-α and IL-6 was studied in THP-1 cells. The in-vivo anti-arthritic activity was investigated in collagen-induced arthritis model in DBA/1J mice. The sustained release capsule formulation was developed and characterized for physicochemical and pharmacokinetic properties. RESULTS: Rohitukine and schumaniofioside A were found to be major chemical constituents of the botanical lead. The rohitukine-enriched fraction of D. binectariferum significantly reduced the production of both pro-inflammatory cytokines TNF-α and IL-6 (>50% inhibition at 3.12 µg/mL) in THP-1 cells. In LPS-treated wild-type mice model, the rohitukine-enriched fraction at 200 mg/kg (PO, QD) completely reduced serum TNF-α levels. In transgenic mice model (collagen-induced arthritis in DBA/1J mice), rohitukine-enriched fraction at 100 mg/kg (PO, QD) dose has resulted in >75% reduction of TNF-α/IL-6 serum levels, 68% reduction in anti-mouse type II collagen IgG1 antibody levels, decreased joint proteoglycan loss and reduced paw edema in DBA/1J mice. The sustained release capsule formulation of rohitukine-enriched fraction showed sustained-release of rohitukine over the period of 24 h, and resulted in an improved plasma-exposure of rohitukine in SD rats. CONCLUSIONS: The data presented herein demonstrated anti-arthritic potential of rohitukine-enriched fraction of D. binectariferum and this study will serve as the benchmark for further research on this botanical lead and developed sustained release capsule formulation.

Conventional versus ultrasound treat to target: no difference in magnetic resonance imaging inflammation or joint damage over 2 years in early rheumatoid arthritis.

OBJECTIVE: To investigate whether an ultrasound-guided treat-to-target strategy for early RA would lead to reduced MRI inflammation or less structural damage progression compared with a conventional treat-to-target strategy. METHODS: A total of 230 DMARD-naïve early RA patients were randomized to an ultrasound tight control strategy targeting DAS <1.6, no swollen joints and no power Doppler signal in any joint or a conventional strategy targeting DAS <1.6 and no swollen joints. Patients in both arms were treated according to the same DMARD escalation strategy. MRI of the dominant hand was performed at six time points over 2 years and scored according to the OMERACT RA MRI scoring system. A total of 218 patients had baseline and one or more follow-up MRIs and were included in the analysis. The mean MRI score change from baseline to each follow-up and the 2 year risk for erosive progression were compared between arms. RESULTS: MRI bone marrow oedema, synovitis and tenosynovitis improved over the first year and was sustained during the second year of follow-up, with no statistically significant differences between the ultrasound and the conventional arms at any time point. The 2 year risk for progression of MRI erosions was similar in both treatment arms: ultrasound arm 39%, conventional arm 33% [relative risk 1.16 (95% CI 0.81, 1.66), P = 0.40]. CONCLUSION: Incorporating ultrasound information in treatment decisions did not lead to reduced MRI inflammation or less structural damage compared with a conventional treatment strategy. The findings support that systematic use of ultrasound does not provide a benefit in the follow-up of patients with early RA. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov, http://clinicaltrials.gov, NCT01205854.

Pigmented villous nodular synovitis mimicking metastases on 18F-FDG PET/CT in a patient with rectal mucosal melanoma: a case report.

BACKGROUND: Mucosal melanomas are rare and have a high potential for metastasizing. Surgical resection is the treatment of choice for single distant metastases. Malignant melanoma usually shows the highest uptake of fluorine-18 fluorodeoxyglucose (18F-FDG). 18F- FDG positron emission tomography /computed tomography (PET/CT) is usually used for melanoma staging. An extensive literature review revealed only 4 published case reports and an original paper involving 8 cases (12 cases in total) of patients with skin melanomas in whom pigmented villous nodular synovitis (PVNS) mimicked metastatic melanoma, however, none of the melanomas reported were of rectal mucosal origin. CASE PRESENTATION: A 60-year-old woman presented with recent diagnosis of rectal mucosal melanoma, two additional 18F-FDG-avid lesions in the left ankle and left foot were detected on 18F-FDG PET/CT. Metastases were initially suspected; however, the final diagnosis was PVNS. CONCLUSIONS: This is the first report of PVNS mimicking metastases on 18F-FDG PET/CT in a patient with rectal mucosal melanoma. Although high 18F-FDG-avid lesions in patients with rectal mucosal melanoma are highly suspected to be metastasis and warrant an meticulous examination, the present case is a reminder that in such patients, not all lesions with high 18F-FDG uptake, especially those near a joint, are metastases and that more extensive resection is unnecessary.

Quantitative analysis of therapeutic response in psoriatic arthritis of digital joints with Dual-energy CT iodine maps.

The aim of this study was to investigate the feasibility of quantitative assessment of the therapeutic response in psoriatic arthritis (PsA) by measuring iodine uptake using a Dual-energy CT (DECT) iodine map. The study included 74 symptomatic and 74 matching non-symptomatic joints of 26 consecutive PsA patients who underwent two contrast enhanced DECTs of the hand or foot, pre and post medical interventions. Symptomatic and matched non-symptomatic control joints were scored with the PsA DECT Scoring System (PsADECTS), which was derived by modifying the PsA MRI Scoring System (PsAMRIS), a recently validated scoring system that assesses PsA changes on MRI. Quantified iodine uptake measured using the DECT iodine map was compared to the PsADECTS score. Efficacy of PsA treatment was confirmed by the improved clinical findings. Both PsADECTS and iodine uptake also showed significant improvement after treatment (Wilcoxon signed-rank test: z = 7.38, p < 0.005; z = 6.20, p < 0.005, respectively). The treatment effects of PsADECTS score and iodine uptake showed a good correlation with each other (Spearman's ρ = 0.58 p < 0.005). Inter-reader agreement for PsADECTS score and iodine uptake were either moderate or good. In conclusion, our study showed that the DECT iodine map is a valid tool for quantitative assessment of the therapeutic response of PsA.

Relationship of callosities of the forefoot with foot deformity, Health Assessment Questionnaire Disability Index, and joint damage score in patients with rheumatoid arthritis.

Objectives: We aimed to investigate the relationship of callosities of the forefoot with foot deformity, the Health Assessment Questionnaire Disability Index (HAQ-DI) and modified total Sharp score (TSS) in patients with rheumatoid arthritis (RA).Methods: A total of 202 patients and 404 feet were enrolled. We examined the prevalence of callosities. Clinical data included the HAQ-DI, TSS, hallux valgus angle (HVA), and calcaneal pitch angle (CPA). The analysis of factors associated with callosities of the forefoot was performed by comparing patients with and without callosities of the forefoot.Results: The prevalence of callosities was 31.2% of all patients and 24.0% of all feet. The patients with callosities of the forefoot had significantly higher TSS of the foot. The presence of callosities affected the HAQ-DI walking score. HVA and CPA were identified as being associated with callosities of the forefoot. Analyzing from the cutoff values, the odds ratios of HVA, CPA, and HVA and (combined) CPA were 4.64, 1.73, and 2.99, respectively.Conclusion: Hallux valgus and flatfoot were related to callosities of the forefoot in RA. This study suggested that to prevent callosities of the forefoot, early diagnosis and foot care for hallux valgus and flatfoot are needed in daily practice.

ACPA-positive versus ACPA-negative rheumatoid arthritis: two distinct erosive disease entities on radiography and ultrasonography.

The objective of this study is to assess the prevalence, localization, and severity of bone erosions on radiography (RX) and ultrasonography (US) according to ACPA status in patients with rheumatoid arthritis (RA). 78 patients with ACPA-positive (ACPA+) RA and 30 patients with ACPA-negative (ACPA-) RA fulfilling the ACR 1987 and/or ACR/EULAR 2010 criteria were consecutively included. On RX, a modified Sharp erosion score (SHSe) was evaluated by two blinded readers and one adjudicator for discordant cases (number of eroded joints ≤ three). On US, erosions were scored on six bilateral joints (MCP2, 3, 5; MTP2, 3, 5) with a four-point scale to calculate the total US score for erosions (USSe). The mean total SHSe and USSe were 3.7 and 4.4 times higher in the ACPA+ group than in the ACPA- group, respectively (P < 0.001). On both RX and US, the most discriminating joint between the two groups was MTP5, especially in cases with bilateral erosion. Based on multivariate analyses, ACPA + status was associated with erosive RA on RX according to the EULAR 2013 definition criteria [OR 4.4 (95% CI 1.2-16.4)], and on US according to the following two definitions: the presence of at least two eroded joint facets [OR 3.7 (95% CI 1.4-9.9)] or at least one grade 2 joint facet erosion [OR 9.0 (95% CI 2.8-28.4)]. Compared to ACPA- RA, ACPA + RA is associated independently with more severe erosive disease on RX and US. Both US and RX bilateral erosions in MTP5 joints are highly discriminant for ACPA + RA patients (97.8% in US and 100% in RX).

Ginsenoside metabolite compound-K regulates macrophage function through inhibition of ß-arrestin2.

Ginsenoside metabolite compound-K (C-K), which is an active metabolite of ginsenoside in vivo, can produce anti-inflammatory affects by activating glucocorticoid receptors (GRs) to inhibit the expression of ß-arrestin2. Studies have shown that C-K can inhibit the function of immune cells including macrophage polarization and phagocytosis. However, the mechanism by which C-K regulates macrophage polarization is currently unclear. Toll-like receptors (TLRs) are the pattern recognition receptors on the membrane of immune cells, with TLR4 being especially important in polarization of macrophages. The Gαi-mediated activation of nuclear factor-κB (NF-κB) by TLR4 promotes inflammation and phagocytosis in macrophages by increasing the proportion of type I phenotypic macrophages (M1). Whether C-K inhibits the signal transduction of TLR4-Gαi-NF-κB and how that effects macrophage polarization regulation in murine models of RA is not reported. The coupling of G proteins with receptors is regulated by ß-arrestin2, but it has been unclear whether C-K modulates the TLR4 interaction with G proteins by inhibiting the expression of ß-arrestin2. To explore these questions, the collagen-induced arthritis (CIA) mouse model was employed, and mice were treated with C-K (112 mg/kg/day). The results depict that C-K treatment inhibits macrophage phagocytosis and reduces the proportion of M1. C-K decreases the overexpressed ß-arrestin2, Gαi, TLR4 and NF-κB in macrophages of CIA mice, while increasing the expression of Gαs. Furthermore, C-K promotes TLR4-Gαs coupling and inhibits TLR4-Gαi coupling through ß-arrestin2 regulation in macrophages, leading to a decrease in the proportion of M1 to M2 macrophages and improved outcomes in CIA mice.

Therapeutic effect of Parmotrema tinctorum against complete Freund's adjuvant-induced arthritis in rats and identification of novel Isophthalic ester derivative.

The present study reveals the anti-arthritic potential of traditionally used Parmotrema tinctorum (Pt) on experimental rats and purification of novel Isophthalic ester derivative. Arthritis was induced in rats using Freund's complete adjuvant (CFA) and subsequently treated with Pt extract (100 & 200 mg/kg.b.w). Assessment of antiarthritic activity was carried out using paw volume, arthritic score, haematological, biochemical, tissue antioxidant, histopathology and radiological analyses of ankle joints. The results revealed that continuous administration of Pt reduces the complication associated with arthritis by inhibiting the edema formation and arthritic score significantly (P < 0.05). The altered changes in biochemical parameters were brought back with an improvement in free radical scavenging ability after treatment with Pt significantly. Further purification of Pt using conventional column chromatography led to the isolation of four compounds and the structure of these isolated compounds were elucidated on the basis of spectral data's FT-IR, 1H NMR, 13C NMR, DEPT-NMR spectroscopy, COSY & HSQC-NMR spectroscopy and LC-MS. The spectral data revealed that the three compounds were found to be Methyl-γ-Orsellinate, Atranorin, and usnic acid (CI-III) along with a novel secondary metabolite, (C-IV)4-Hydroxy-5-methyl-isophthalicacid3-(3,4-dihydroxy-5-methyl-phenyl)ester (C16H14O7,318.1amu). The present study reveals that Parmotrema tinctorum reduces complications associated with arthritis and the compounds were isolated for the first time.

Foot structure, pain and functional ability in people with gout in primary care: cross-sectional findings from the Clinical Assessment Study of the Foot.

BACKGROUND: Gout frequently affects the foot yet relatively little is known about the effects of gout on foot structure, pain and functional ability. This study aimed to describe the impact of gout in a UK primary care population. METHODS: A cross-sectional study was nested within an observational cohort study of adults aged ≥50 years with foot pain. Participants with gout were identified through their primary care medical records and each matched on age (±2 years) and gender to four participants without gout. Differences in person-level variables (SF-12 Physical Component Score, Manchester Foot Pain and Disability Index and Short Physical Performance Battery) between gout and non-gout participants were determined using regression models. Differences in foot-level variables (pain regions, skin lesions, deformities, foot posture, and non-weightbearing range of motion) were determined using multi-level regression models. All models were adjusted for body mass index. Means and probabilities with 95% confidence intervals were calculated. RESULTS: Twenty-six participants with gout were compared to 102 participants without gout (77% male; mean age 66 years, standard deviation 11). Subtalar joint inversion and eversion and 1st metatarsophalangeal joint (MTPJ) dorsiflexion range of motion were significantly lower in the gout participants compared to the non-gout participants. Gout participants were more likely to have mallet toes and less likely to have claw toes compared to non-gout participants. There were no statistically significant differences in person-level variables, foot posture, ankle dorsiflexion range of motion, hallux valgus, pain regions, or skin lesions. CONCLUSIONS: Non-weightbearing range of motion at the subtalar joint and 1st MTPJ was reduced in people with gout. Patients with gout who present with chronic foot problems should therefore undergo appropriate clinical assessment of foot structure.

Clinical Assessment and Management of Foot and Ankle Osteoarthritis: A Review of Current Evidence and Focus on Pharmacological Treatment.

Foot and ankle osteoarthritis (OA) is a common and disabling problem that adversely affects physical function and significantly reduces quality of life. Although the knee was considered to be the lower-limb site most often affected by OA, recent population data showed foot OA is as prevalent as knee OA, and rates increase with advancing years. The most common foot OA sites include the first metatarsophalangeal joint and the midfoot, with the ankle affected less often. Despite the high prevalence and disabling nature of foot and ankle OA, the condition has been neglected by clinical researchers, and there are very few trials investigating non-surgical foot or ankle OA treatment options. There are no accepted clinical diagnostic criteria for foot or ankle OA so imaging remains common. Clinical guidelines based on knee and hip OA research recommend education, exercise, and weight loss in the first instance. Topical non-steroidal anti-inflammatory drugs (NSAIDs) or capsaicin may be used as an adjunct. Failing these approaches, acetaminophen (paracetamol) should be recommended; however, if there is inadequate symptomatic relief, then clinicians should trial an oral NSAID or a cyclo-oxygenase-2 inhibitor. Given that adverse events and co-morbidities are common in the elderly, older patients should be closely monitored. Some studies have investigated intra-articular injections for foot and ankle OA, and there is some evidence to suggest hyaluronic acid may be effective in the short term for ankle OA. With the lack of research on foot or ankle OA treatments, however, robust clinical trials are urgently needed.

Early supplemental α2-macroglobulin attenuates cartilage and bone damage by inhibiting inflammation in collagen II-induced arthritis model.

OBJECTIVE: To determine if early supplemental intra-articular α2-macroglobulin (A2M) has a chondroprotective effect in a collagen II-induced arthritis (CIA) mice model. METHODS: DBA/1 mice were randomized into four groups (n = 15/group): (a) CIA + 1.2 µg of A2M; (b) CIA + 0.8 µg of A2M; (c) CIA + 0.4 µg of A2M; (d) vehicle + phosphate-buffered saline (PBS). A2M was injected into right ankles and PBS was injected into the left ankles simultaneously as internal control at days 36, 43 and 50. The CIA inflammation clinical score and ankle thickness were recorded every other day starting on day 21 until sacrifice. Changes in inflammation were monitored by in vivo fluorescence molecular tomography (FMT). Inflammation, cartilage and bone damage were assessed with X-ray, histology and immunohistochemistry. Cartilage and inflammation-related gene expression was quantified by real-time polymerase chain reaction (PCR). RESULTS: All mice showed ankle inflammation on day 33. After day 43, lower clinical scores, ankle thickness and Sharp/van der Heijde method scores in A2M-treated ankles compared with PBS-treated ankles. FMT data indicated that the inflammation markers MMPSense and ProSense were significantly elevated in the PBS-treated ankles than A2M-treated ankles. Histology and X-ray analyses indicated that A2M administration resulted in lower levels of inflammatory infiltration and synovial hyperplasia, as well as more typical cartilage and bone organization with increased COL II and Aggrecan staining when compared with PBS-treated ankles. In addition, real-time PCR showed that,matrix metalloproteinase-3, -9, -13, COL X and Runx2 were significantly less expressed in A2M-treated groups than PBS-treated animals. CONCLUSION: Early supplemental intra-articular A2M exerts an anti-inflammatory effect and attenuates cartilage and bone damage in a CIA model.

Butyrate inhibit collagen-induced arthritis via Treg/IL-10/Th17 axis.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder demanding the development of novel therapeutic strategy. Butyrate is a functional short-chain fatty acid produced by the anaerobic intestinal microbiota. This study aimed to investigate the attenuation of butyrate on RA. The collagen-induced arthritis (CIA) mouse model was established and butyrate was administered in drinking water along with the collagen immunization. The histopathological features, clinical score, paw swelling, as well as the production of pro-inflammatory cytokines including interleukin (IL)-1ß, IL-6 and IL-17A were measured to determine the amelioration of butyrate on arthritis. The differentiation of Treg cells and Th17 cells in the splenic cells was assessed by flow cytometry. The expression of Foxp3, IL-10, Rorγt and IL-17A were detected by RT-PCR and FACS immunostaining. Anti-IL10R antibody was used in the CIA and CD4+ cell cultures to mediate the effects of butyrate. Butyrate significantly inhibited expressions of IL-1ß, IL-6 and IL-17A, but promoted the expression of IL-10. Butyrate also increased systematical Treg cells and reduced Th17 cells. Mechanism study revealed that butyrate directly enhanced the polarization of Treg cells but not Th17 cells. All effects of butyrate on RA were inversed by the co-administered anti-IL10R antibody. This study showed that butyrate administration inhibited arthritis in CIA mice model, suppressed the expression of inflammatory cytokines. The modulation may be mediated the differentiation of CD4 T cells towards Treg cells, which produce anti-inflammatory cytokine IL-10, and thus influenced the function of Th17 cells.