Anti-rheumatic Effects Research Articles

Flemingia Strobilifera– An Updated Review on its Pharmacognostic and Pharmacological Properties

Background: Our health care system greatly benefits from the use of old medical techniques. In Ayurvedic medicine to improve manhood, Flemingia strobilifera (Lam.) is utilized as an herb. The Fabaceae family, which includes Flemingia strobilifera (Palas), is widely cultivated throughout India. There are more than forty species of Flemingia throughout the globe; out of which 15 species of this genus are in India. Objective: To learn more details about this plant and various species of Flemingia, specifically the chemical makeup of the plant, its species, and/or its elements, traditional and medical uses for the plant. This review article also focuses on the origin, history, classification, phytochemistry, morphology, microscopy, and pharmacological aspects. Methods: A detailed and extensive literature survey through research findings, review articles, Google sources, database etc was done to explore the aspect of Flemingia species for its various physical, chemical, pharmacological, phytochemistry and related fields. Results: Our findings report that several representatives of this genus have been employed as vermifuges and remedies for fever, diarrhea, indigestion in traditional medicine. The plant's anthelmintic, anticancer, antirheumatic, antiinflammatory, antioxidant and antihistaminic effects are well documented. According to literature reports, the chemical constituents of this genus' are flavonoids, glycosides, chalcones, epoxy chromenes, and pterocarpans. Rural and ethnic people regularly use this plant to treat a range of diseases. Conclusion: Research on Flemingia strobilifera has a bright future thanks to its strong natural origin. The uniqueness and usefulness of Flemingia strobilifera was obscured. In future, many more potential of Flemingia could be investigated in combination with other herbs.

Nutrition and fasting

Patients with rheumatic diseases often enquire about the options for nutritional therapy. Nutritional factors have been empirically described that are associated with the occurrence of inflammatory rheumatic diseases or flare-ups or improved disease states. Agrowing number of epidemiological and clinical studies deal with the evaluation of nutrition and dietary restriction in rheumatology. Narrative presentation of the evidence of nutritional interventions and fasting and its clinical implications. Only limited data from smaller clinical studies are available for evidence assessment. Abenefit in terms of symptoms and quality of life in rheumatoid arthritis was shown for the Mediterranean and plant-based diet as well as the anti-inflammatory diet. The effect sizes are small to moderate and the effectiveness in the context of complex lifestyle programs is probably sustainable. The evidence for elimination diets is weak. Initial clinical studies indicate amoderate benefit of plant-based nutrition for osteoarthritis in the context of the metabolic syndrome. There is moderate evidence for the benefit of dietary weight normalization in psoriasis. There is clear experimental evidence of asignificant anti-inflammatory effect of prolonged fasting. Several clinical studies demonstrated asymptomatic benefit of prolonged modified fasting (therapeutic fasting) in rheumatoid arthritis (RA). If fasting is followed by avegan and vegetarian diet, lasting effects of up to 1year have been documented. Cardiometabolic but not antirheumatic effects have been proven for intermittent fasting. Nutrition and fasting can be classified as apossible useful addition to conventional treatment but are currently only rarely taken into account in practice.

Qing-Luo-Yin Eased Adjuvant-Induced Arthritis by Inhibiting SIRT1-Controlled Visfatin Production in White Adipose Tissues.

Nicotinamide adenine dinucleotide (NAD)-dependent deacetylase SIRT1 regulates both metabolism and immune functions. This study investigated if SIRT1 inhibitory property of herbal formula Qing-Luo-Yin (QLY) contributed to its anti-rheumatic effects. Adjuvant-induced arthritis (AIA) rats were treated by QLY and nicotinamide mononucleotide (NMN, a biosynthesis precursor of NAD) for 38 days. After sacrifice, blood, paws, liver and white adipose tissues (WAT) were collected. Pre-adipocytes were cultured by the rats' serum. The medium was used for monocytes culture. Some pre-adipocytes were treated by QLY-derived SIRT1 inhibitors. SIRT1 was silenced or overexpressed beforehand. The samples were subjected to kits-based quantification, polymerase-chain reaction, western-blot, immunofluorescence, and histology experiments. AIA rats experienced significant fat loss in liver and WAT. Expression of many SIRT1-related signals like PPARγ, PGC-1α, HSL, ATGL and CPT-1A were altered. QLY attenuated all these abnormalities and joint injuries. By pan-acetylation up-regulation, visfatin was obviously reduced in QLY-treated AIA rats' blood (from 191.8 to 127.0 pg/mL). NMN sustained SIRT1 activation by replenishing NAD, and weakened these effects. QLY-containing serum and the related compounds showed similar impacts on pre-adipocytes, resembling the changes in QLY-treated AIA rats' WAT. These treatments suppressed AIA serum-induced visfatin secretion (from 49.3 to 36.1 and 30.7 pg/mL). This effect was impaired by SIRT1 overexpression. The medium from the compounds-treated pre-adipocytes impaired NF-κB activation in AIA serum-cultured monocytes. Besides fat depletion, SIRT1 up-regulation in rheumatic subjects' WAT promotes visfatin production, and exacerbates inflammation. SIRT1 inhibition in WAT is an anti-rheumatic way of QLY independent of immune regulation.

Trivalent chromium versus baricitinib for rheumatoid arthritis treatment: first phase 2/3 randomized controlled trial, is trivalent chromium the upcoming immune-modulator?

BackgroundRheumatoid arthritis (RA) is a debilitating disease mainly treated by DMARDs. Baricitinib is one of the emerging DMARDs with strong anti-rheumatic effects but has serious side effects. Trivalent chromium (Cr III) is a natural element with anti-inflammatory properties. Trivalent chromium (Cr III) is introduced for the first time to study its effect and safety in treatment of RA patients and compared to those of baricitinib.MethodsThis is a phase 2/3 randomized controlled trial where RA patients were divided in a ratio of 2:1 according to the newly introduced medication either Cr (III) (group A) or baricitinib (group B). Patients attended three visits on day 0, after 3 weeks and 12 weeks, disease activity was scored. Hands ultrasound was done and reassessed. Side effects were monitored throughout the study.ResultsDAS28-CRP improved by 26.9% and 11.8% on third visit for Cr III and baricitinib, respectively (p = 0.001). DAS28-ESR improved by 25.6% and 7.74% on third visit for Cr III and baricitinib, respectively (p = < 0.001). ACR 50 was 18.8% for Cr III and 5.7% for baricitinib on second visit. ACR 70 was 25% for Cr III and 0% for baricitinib on third visit (P = < 0.001). Ultrasound GLOESS, SH, PDUS, joints effusions improved by 38.9%, 38.4%, 56.7% and 74.8% for Cr III, while by 10.5%, 3.75%, 59.6% and worsening of joints effusions happened with baricitinib on third visit. p = 0.022 and 0.002 between groups for GLOESS and SH improvement, respectively.ConclusionsCr III has shown very promising fast clinical and sonographic results in treating RA patients which were surprisingly superior to baricitinib in most aspects. Furthermore, Cr III is potentially safe with evidently fewer side effects than baricitinib and other DMARDs, however, long-term safety is still not established.(IRB No.: 00012098- FWA No.: 00018699, Serial number: 040457) ClinicalTrials.gov ID: NCT05545020.

A simple nonparametric least-squares-based causal inference for heterogeneous treatment effects

Estimating treatment effects is a common practice in making causal inferences. However, it is a challenging task for observational studies because the underlying models for outcome and treatment assignment are unknown. The concept of potential outcomes has been widely adopted in the literature on causal inferences. Building on potential outcomes, we propose a simple nonparametric least-squares spline-based causal inference method to estimate heterogeneous treatment effects in this manuscript. We use empirical process theory to study its asymptotic properties and conduct simulation studies to evaluate its operational characteristics. Based on the estimated heterogeneous treatment effects, we further estimate the average treatment effect and show the asymptotic normality of the estimator. Finally, we apply the proposed method to assess the biological anti-rheumatic treatment effect on children with newly onset juvenile idiopathic arthritis disease using electronic health records from a longitudinal study at Cincinnati Children's Hospital Medical Center.

Screening of potentially active compounds against rheumatoid arthritis in the Juan-Bi decoction using systems pharmacology and animal experiments.

Background: The Juan-Bi decoction (JBD) is a classic traditional Chinese medicines (TCMs) prescription for the treatment of rheumatoid arthritis (RA). However, the active compounds of the JBD in RA treatment remain unclear. Aim: The aim of this study is to screen effective compounds in the JBD for RA treatment using systems pharmacology and experimental approaches. Method: Botanical drugs and compounds in the JBD were acquired from multiple public TCM databases. All compounds were initially screened using absorption, distribution, metabolism, excretion, and toxicity (ADMET) and physicochemical properties, and then a target prediction was performed. RA pathological genes were acquired from the DisGeNet database. Potential active compounds were screened by constructing a compound-target-pathogenic gene (C-T-P) network and calculating the cumulative interaction intensity of the compounds on pathogenic genes. The effectiveness of the compounds was verified using lipopolysaccharide (LPS)-induced RAW.264.7 cells and collagen-induced arthritis (CIA) mouse models. Results: We screened 15 potentially active compounds in the JBD for RA treatment. These compounds primarily act on multiple metabolic pathways, immune pathways, and signaling transduction pathways. Furthermore, in vivo and in vitro experiments showed that bornyl acetate (BAC) alleviated joint damage, and inflammatory cells infiltrated and facilitated a smooth cartilage surface via the suppression of the steroid hormone biosynthesis. Conclusion: We screened potential compounds in the JBD for the treatment of RA using systems pharmacology approaches. In particular, BAC had an anti-rheumatic effect, and future studies are required to elucidate the underlying mechanisms.

Anti-rheumatic property and physiological safety of KMU-11342 in in vitro and in vivo models

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder characterized by joint destruction due to synovial hypertrophy and the infiltration of inflammatory cells. Despite substantial progress in RA treatment, challenges persist, including suboptimal treatment responses and adverse effects associated with current therapies. This study investigates the anti-rheumatic capabilities of the newly identified multi-protein kinase inhibitor, KMU-11342, aiming to develop innovative agents targeting RA. In this study, we synthesized the novel multi-protein kinase inhibitor KMU-11342, based on indolin-2-one. We assessed its cardiac electrophysiological safety using the Langendorff system in rat hearts and evaluated its toxicity in zebrafish in vivo. Additionally, we examined the anti-rheumatic effects of KMU-11342 on human rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS), THP-1 cells, and osteoclastogenesis in RAW264.7 cells. KMU-11342 demonstrated the ability to inhibit LPS-induced chemokine inhibition and the upregulation of pro-inflammatory cytokines, cyclooxygenase-2, inducible nitric oxide synthase, p-IKKα/β, p-NF-κB p65, and the nuclear translocation of NF-κB p65 in RA-FLS. It effectively suppressed the upregulation of NLR family pyrin domain containing 3 (NLRP3) and caspase-1 cleavage. Furthermore, KMU-11342 hindered the activation of osteoclast differentiation factors such as RANKL-induced TRAP, cathepsin K, NFATc-1, and c-Fos in RAW264.7 cells. KMU-11342 mitigates LPS-mediated inflammatory responses in THP-1 cells by inhibiting the activation of NLRP3 inflammasome. Notably, KMU-11342 exhibited minimal cytotoxicity in vivo and electrophysiological cardiotoxicity ex vivo. Consequently, KMU-11342 holds promise for development as a therapeutic agent in RA treatment.

Mechanism of Huangqin Qingre Chubi Capsules in improving rheumatoid arthritis based on METTL3-SFRP4/Wnt/β-catenin pathway

The effect and mechanism of Huangqin Qingre Chubi Capsules(HQC) on rheumatoid arthritis(RA) were studied.Seventy male SPF rats were randomly divided into normal group, model group, low-(0. 18 g·kg~(-1)), middle-(0. 36 g·kg~(-1)), and high-(0. 72 g·kg~(-1)) dose groups of HQC, methotrexate group(MTX, 0. 75 mg·kg~(-1)), and negative control group(NC group, model +saline). Adjuvant arthritis fibroblast-like synoviocytes(AA-FLS) were divided into normal group, model group, low-, middle-, and high-dose groups of HQC, and negative control group. RT-qPCR and Western blot were used to detect the m RNA and protein expressions of METTL3, SFRP4, β-catenin, CCND1, c-Myc, MMP3, and fibronectin. The protein expression of MMP3 and β-catenin was detected by immunofluorescence. The gene expression level of METTL3 on AA-FLS was knocked down to further examine the expression of each gene. ELISA measured the levels of IL-1β, IL-6, and IL-8. The results showed that compared with the normal group, rats in the model group found redness and swelling in their limbs and significantly increased joint swelling. Compared with the model group, the joint swelling degree of each treatment group significantly decreased(P&lt;0. 05). The paw retraction threshold and body weight mass index both significantly increased(P&lt;0. 05). METTL3 was highly expressed on AA and negatively correlated with the expression of SFRP4. After treatment, the m RNA and protein expression of METTL3, β-catenin, CCND1, c-Myc, fibronectin, and MMP3 were significantly decreased on AA-FLS(P&lt; 0. 05). Compared with the model group, knocking down METTL3 resulted in reduced m RNA and protein expression of β-catenin, CCND1, c-Myc, fibronectin, and MMP3(P&lt; 0. 05). At the same time, the m RNA and protein expressions of β-catenin, CCND1, c-Myc, fibronectin, and MMP3 in the HQC+METTL3 knockdown group were significantly lower than those in the METTL3 knockdown group(P&lt;0. 05). HQC could reduce the levels of IL-1β, IL-6, and IL-8 to varying degrees(P&lt;0. 05). The results indicate that HQC has a significant improvement effect on arthritis in AA rats. The expression of METTL3 is significantly increased in synovial tissue and AA-FLS of AA rats, which may be a potential target for the diagnosis and treatment of RA. HQC improves RA through the METTL3-SFRP4/Wnt/β-catenin signaling pathway and has significant antiinflammatory and anti-rheumatic effects.

Synthesized pyrrole ester ameliorates adjuvant‑induced arthritis in Wistar rats by alleviating inflammation and downregulating the pro‑inflammatory cytokines.

Piperine is an amide alkaloid responsible for producing the pungent smell that comes from black pepper. Piperine has been explained to exhibit significant properties such as anti-rheumatic, anti-inflammatory, and antihypertensive effects. The aim of the study was to synthesize pyrrole ester from piperine and evaluate its anti-arthritis effects in adjuvant-induced arthritis female Wistar rats. In this study, pyrrole ester (AU-5) was designed, synthesized and evaluated for ant-arthritic activity in adjuvant-induced arthritis Wistar rats. The synthesized pyrrole ester (AU-5) was administered in three selected doses (20, 10 and 5mg/kg) to the arthritic-induced model. The administered ester significantly inhibited the increase in arthritis index, paw and ankle joint swelling compared to the arthritic control group. Similarly, the treated rats exhibited a remarkable increase in body weight increase, improved haematological, biochemical, histopathological and radiological parameters. Moreover, the excess production of rheumatoid factor (RF), C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) was noticeably attenuated in all AU-5-treated rats. However, the spleen index, tumour necrosis factor (TNF-α) and interleukin-6 (IL-6) were distinctly lowered compared to arthritic control rats. Moreover, AU-5 showed promising liver protection by lowering the level of liver function markers Serum glutamic pyruvic transaminase (SGPT), Serum glutamic-oxaloacetic transaminase (SGOT) and alkaline phosphatase (ALP) in serum. Henceforth, it might be concluded that AU-5 has an anti-arthritic effect which can be credited to the down regulation of inflammatory markers and the pro-inflammatory cytokines.

Formulation and evaluation of hydrocortisone micro beads

The current study aimed to develop hydrocortisone mucoadhesive microbeads to prolong the drug's action in the gastrointestinal system, targeting Crohn's disease treatment. Hydrocortisone, known for its anti-inflammatory and anti-rheumatic effects, was utilized in bead form to enhance therapeutic efficacy, extend residence time, and reduce dosage frequency. Using sodium alginate, HPMC, and Eudragit L-100 as adhesive polymers, and calcium chloride and aluminium chloride as cross-linking agents, the study crafted microbeads with an entrapment efficiency between 57.23% and 91.69%. Evaluations focused on in vitro drug release, particle size, surface characteristics, entrapment efficiency, and the role of cross-linking ions. Of the formulations, HCS-8 (with sodium alginate and Eudragit L-100 using aluminium chloride as the gelling solution) and HCS-2 showed optimal drug release profiles. Notably, HCS-8 achieved a 12-hour drug release delay, attributed to aluminium chloride's cross-linking action. Drug release kinetics revealed a zero-order linearity (R2=0.99), suggesting super case 2 transport as the primary release mechanism.

Traditional Uses, Phytochemistry, and Pharmacological Activities of Coleus amboinicus: A Comprehensive Review.

Coleus amboinicus Benth., also known as Plectranthus amboinicus (Lour.) Spreng., is a perennial plant from the Lamiaceae family commonly found in tropical and warm regions of Africa, Asia, and Australia. Folk medicine commonly employs this remedy to address various ailments, including but not limited to asthma, headaches, skin disorders, coughs, constipation, colds, and fevers. Several phytoconstituents from various phytochemical classes, such as phenolics, terpenoids, phenolic acids, flavonoids, flavones, and tannins, have been identified in Coleus amboinicus up to the present time. Numerous pharmacological properties of Coleus amboinicus crude extracts have been documented through both in vitro and in vivo studies, including but not limited to antitumor, antibacterial, antifungal, antiprotozoal, anti-inflammatory, antioxidant, antidiabetic, wound healing, analgesic, antirheumatic, and various other therapeutic effects. Due to its extensive history of traditional usage, the diverse array of bioactive phytochemicals, and numerous established pharmacological activities, Coleus amboinicus is widely regarded as having significant potential for clinical applications and warrants further exploration, development, and exploitation through research. With this context, the present study gathers information on the occurrence, biological description, cultivation, and nutritional values of Coleus amboinicus. Furthermore, it thoroughly discusses various phytoconstituents, along with their classes, present in Coleus amboinicus, followed by detailed descriptions of their pharmacological activities based on recent literature.

Medicinal value of Phytoestrogens in Trigonella foenum-graecum L (Fenugreek) - Review

Trigonella foenum-graecum known as fenugreek, is a widely used spice and an abundant source of phytoestrogens. Fenugreek has a wide range of pharmacological effects, such as hypoglycemic, hypolipidemic, obesity, antioxidant activity, osteoporosis, anti-inflammatory, and antirheumatic effects. Phytoestrogens are one of the constituents of fenugreek. These are nonsteroidal compounds that resemble the structure of 17β -estradiol and can bind to the ERα and ERβ estrogen receptors. It acts as an estrogen receptor modulator, producing antiestrogenic and/or estrogenic effects. The protective effect was also apparent in the cellular architecture of the kidney, liver, and common carotid artery. Several beneficial effects are ascribed to the phytoestrogens present in fenugreek. In the present review, we focused on the medicinal values of phytoestrogens in fenugreek

Ticari Zerdeçal Kapsüllerinde Kurkumin Tayini için RP-HPLC Yöntemi Geliştirme

Curcumin is a natural polyphenol product isolated from the rhizome of the Curcuma longa plant and is the most active ingredient of this plant. Curcumin has hepatoprotective, nephroprotective, thrombosis-suppressing, cardioprotective, antidiabetic and antirheumatic effects. This study aimed to develop an HPLC method for analyzing curcumin in its commercial capsules. Supelco Discovery 5 µm C18 Column (4.6mm x 5.0 µm) was used for chromatographic separation. The mobile phase was acetonitrile (ACN), 20 mM phosphate buffer, pH 6 (40:60 v/v), the flow rate was 1.5 mL min-1, and U.V. detection was 262 nm. The retention time was about 6.13 minutes for curcumin. The developed method was validated according to the ICH guidelines. The method was selective under experimental conditions. It was linear within the range of 0.05 - 50.0 μg mL-1. The intraday and inter-day studies showed that the RSD% was lower than 2.0 for intraday and 2.0 for interday, and the Bias% was lower than 2.0 for intraday, and 2.0 for interday. The method could be successfully used in curcumin-loaded commercial capsules' quality control.

Ångstrom-scale silver particles ameliorate collagen-induced and K/BxN-transfer arthritis in mice via the suppression of inflammation and osteoclastogenesis.

Nanoparticles (NPs) hold a great promise in combating rheumatoid arthritis, but are often compromised by their toxicities because the currently used NPs are usually synthesized by chemical methods. Our group has previously fabricated Ångstrom-scale silver particles (AgÅPs) and demonstrated the anti-tumor and anti-sepsis efficacy of fructose-coated AgÅPs (F-AgÅPs). This study aimed to uncover the efficacy and mechanisms of F-AgÅPs for arthritis therapy. We evaluated the efficacy of F-AgÅPs in collagen-induced arthritis (CIA) mice. We also compared the capacities of F-AgÅPs, the commercial AgNPs, and the clinical drug methotrexate (MTX) in protecting against K/BxN serum-transfer arthritis (STA) mice. Moreover, we evaluated the effects of F-AgÅPs and AgNPs on inflammation, osteoclast formation, synoviocytes migration, and matrix metalloproteinases (MMPs) production in vitro and in vivo. Meanwhile, the toxicities of F-AgÅPs and AgNPs in vitro and in vivo were also tested. F-AgÅPs significantly prevented bone erosion, synovitis, and cartilage damage, attenuated rheumatic pain, and improved the impaired motor function in mouse models of CIA or STA, the anti-rheumatic effects of which were comparable or stronger than AgNPs and MTX. Further studies revealed that F-AgÅPs exhibited similar or greater inhibitory abilities than AgNPs to suppress inflammation, osteoclast formation, synoviocytes migration, and MMPs production. No obvious toxicities were observed in vitro and in vivo after F-AgÅPs treatment. F-AgÅPs can effectively alleviate arthritis without notable toxicities and their anti-arthritic effects are associated with the inhibition of inflammation, osteoclastogenesis, synoviocytes migration, and MMPs production. Our study suggests the prospect of F-AgÅPs as an efficient and low-toxicity agent for arthritis therapy.

Mitochondrion-NLRP3 inflammasome activation in macrophages: A novel mechanism of the anti-inflammatory effect of Notopterygium in rheumatoid arthritis treatment

ObjectiveThe mechanism by which Notopterygium (NE) regulates the nucleotide‐binding, oligomerization domain (NOD)‐like receptor family and pyrin domain-containing 3 (NLRP3) inflammasome to treat rheumatoid arthritis (RA) was investigated to reveal the scientific implications of NE in RA treatment. MethodsAdjuvant arthritis (AA) rats were replicated. After NE intervention, the anti-inflammatory efficacy of NE in vivo was determined. The mechanism of NE in RA treatment was predicted by network pharmacology, and the key target for further experiments was found through the analysis of Kyoto Encyclopedia of Genes and Genomes (KEGG). The effect of NE on the NLRP3 inflammasome in AA rats was verified. Furthermore, with the induction of inflammation in RAW264.7 cells by lipopolysaccharide (LPS), several techniques, such as Griess assay, enzyme linked immunosorbent assays, electron microscopy, and fluorescence probe technology, were used to investigate the anti-inflammatory and related mechanisms of NE in RA treatment. ResultsNE could inhibit inflammation in AA rats. KEGG results showed that NLRP3 participated in the top three pathways of NE in RA treatment. Through Western blotting and immunofluorescence assays, this study demonstrated that NE can regulate NLRP3, pro-Caspase-1, Caspase-1, and CD11b in the ankle joint of AA rats. NE may significantly reduce the LPS-induced inflammatory response of RAW264.7 cells by alleviating mitochondrial damage, reducing the number of mitochondrial deoxyribonucleic Acid and mitochondrial reactive oxygen species, inhibiting NLRP3 inflammasome activation. ConclusionThe anti-inflammatory and antirheumatic effect of NE may involve regulating NLRP3 inflammasome activation through mitochondria. NLRP3 is probably the key target molecule of NE in the treatment of RA.

Efficacy of montelukast as an adjuvant therapy in rheumatoid arthritis patients: A randomized controlled study

ObjectiveThis study aimed to evaluate the efficacy of montelukast in conjunction with non-biologic disease modifying anti-rheumatic drugs (nDMARDs) in rheumatoid arthritis (RA) patients. MethodsThis study was a single-center randomized double-blinded placebo-controlled study. Adult RA patients were included if they had moderate to severe disease activity and were receiving monotherapy or combination of nDMARDs. Eligible patients were randomized, in 1:1 ratio, to receive either 10 mg montelukast or placebo, once daily for 16 weeks. The primary endpoint was the change in the 28-joints disease activity score (DAS28) 16 weeks after treatment. The patients’ quality of life (QoL) was assessed by the Arabic version of the Health Assessment Questionnaire-Disability Index. Moreover, serum levels of vascular adhesion molecule-1 (VCAM-1) were measured. ResultsA total of 87 patients completed the study; 44 in the montelukast arm and 43 in the control arm. After 16 weeks of treatment, disease activity decreased significantly in the montelukast arm with mean change in DAS28 (95% CIs) of −1.5 (−1.7, −1.2) while the control arm showed no improvement (0.2 (0.0, 0.4), p < 0.01). The QoL of the patients improved significantly from baseline in the montelukast arm (p < 0.01) but not in the control arm (p = 0.08). The median (IQR) serum levels of VCAM-1 were significantly lower in the montelukast arm (22.8 (15.0–32.7)) than in the control arm (28.9 (15.4–42.8), p = 0.004). ConclusionThe co-administration of montelukast with nDMARDs in RA patients enhanced the anti-rheumatic effect which was reflected clinically by decreased disease activity.

Therapeutic effects of shikonin on adjuvant-induced arthritis in rats and cellular inflammation, migration and invasion of rheumatoid fibroblast-like synoviocytes via blocking the activation of Wnt/β-catenin pathway

BackgroundShikonin (SKN), the main bioactive component isolated from Lithospermum erythrorhizon Sieb et Zucc, has multiple activities including anti-rheumatic effect, but its specific roles and the precise mechanisms in regulating biological properties of rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) are unclear and need further clarification. PurposeThis study explored the therapeutic roles of SKN on rat adjuvant-induced arthritis (AIA) and cellular inflammation, migration and invasion of TNF-α-induced RA FLS (MH7A cells), and further demonstrated the involved mechanisms. MethodsSKN was intraperitoneally given to AIA rats and its therapeutic role was valued. The effects of SKN in vivo and in vitro on the production of pro-inflammatory factors were examined by ELISA and western blot. Wound-healing, transwell and phalloidin staining assay were carried out to evaluate the effects of SKN on TNF-α-induced migration and invasion in RA FLS. The involvement of Wnt/β-catenin pathway was checked by immunohistochemistry or immunofluorescence assay for β-catenin and western blot for pathway-related proteins. ResultsSKN treatment in AIA rats reduced paw swelling, arthritis index and pathological damage of ankle joints, indicating its anti-arthritic effect in vivo. SKN had anti-inflammatory roles in vivo and in vitro, evidenced by inhibiting the production of pro-inflammatory factors (like IL-1β, IL-6, IL-8, TNF-α, MMP-2 and MMP-9) in sera and synovium of AIA rats, and in TNF-α-induced MH7A cells. Gelatin zymography result revealed the suppression of SKN on TNF-α-induced MMP-2 activity in vitro. Moreover, SKN inhibited TNF-α-induced migration, invasion and cytoskeletal reorganization in MH7A cells. Mechanistically, SKN suppressed the activation of Wnt/β-catenin signaling in AIA rat synovium and in TNF-α-induced MH7A cells, indicated by the reduced protein levels of Wnt1, p-GSK-3β (Ser9) and β-catenin, the raised protein level of GSK-3β and the decreased nuclear translocation of β-catenin. Interestingly, the combination of LiCl (Wnt/β-catenin agonist) canceled the therapeutic functions of SKN on cellular inflammation, migration and invasion in TNF-α-induced MH7A cells, whereas XAV939 (Wnt/β-catenin inhibitor) enhanced the therapeutic roles of SKN. ConclusionSKN showed therapeutic effects on rat AIA and cellular inflammation, migration and invasion of TNF-α-stimulated RA FLS via interrupting Wnt/β-catenin pathway.

Anti-rheumatic effect of KMU-11361 in various rheumatoid arthritis-related cells targeting multiple protein kinase

Abstract Protein kinases important for regulating protein phosphorylation, which is a promising therapeutic target for inflammatory disease, such as rheumatoid arthritis (RA). In this study, we synthesized a novel multi-protein kinase inhibitor, KMU-11361, a derivative of indolin-2-one and investigated the mechanisms of anti-inflammatory and anti-rheumatic effects using THP-1 cells, RAW264.7 cells, Jurkat T cells, and human RA fibroblast-like synoviocytes (RA-FLS). Our results revealed that KMU-11361 inhibited LPS-induced upregulation of inducible iNOS, and COX-2, and suppressed LPS-induced phosphorylation of TAK1, JNK, inhibitor of NF-κB kinase α/β (IKKα/β), IκBα, and NF-κB p65 as well as nuclear translocation of NF-κB p65 in THP-1 cells. Furthermore, KMU-11361 attenuated proinflammatory cytokines such as IL-1β, TNF-α, and IL-6, and, remarkably, inhibited LPS-induced activation of the NLRP3 inflammasome in THP-1 cells. Additionally, in activated Jurkat T cells, KMU-11361 inhibited the TAK1-IKKα-mediated NF-κB pathway as well as the phosphorylation of MAPKs. Moreover, KMU-11361 inhibited anti-CD3/CD28 antibodies-induced upregulation of proinflammatory cytokine IL-2. Moreover, it suppressed LPS-induced upregulation of proinflammatory cytokines, p-TAK1, p-IKKα/β, and p-NF-κB p65 in RA-FLS. Surprisingly, KMU-11361 also inhibited the receptor activator of NF-κB-induced osteoclast differentiation and up-regulation of nuclear factor of activated T-cells, NFATc-1 and c-Fos in RAW264.7 cells. Taken together, our results suggest that KMU-11361 has anti-inflammatory and anti-rheumatic effects in various RA-related cells and could be developed as a potent anti-rheumatic drug.

Metabolite profiling, in vitro antioxidant and xanthine oxidase inhibitory properties of six Sumatran sidaguri (Sida L.)

Context: The Sida genus, part of the Malvaceae family, is commonly used in traditional medicine due to its many beneficial properties, such as antigout, anti-rheumatic, anti-inflammatory, antitumor, and hepatoprotective effects. Various species of Sida are found in Indonesia, particularly on the island of Sumatra, and may hold potential for future drug development. Aims: To assess and compare the methanol leaf extracts of three Sida species (S. acuta, S. rhombifolia, and S. cordifolia) from West Sumatra and South Sumatra, Indonesia, for their chemical content in metabolite profiling, in vitro antioxidant capacity, and xanthine oxidase inhibitory activity. Methods: The LC-MS/MS method was used to determine metabolite profiling, while spectrophotometry was used to assess total phenolic content, flavonoid content, antioxidant capacity, and xanthine oxidase inhibitor activity. Results: The results showed that S. rhombifolia (WS) had the highest total phenolic (64.872 ± 1.525 mg GAE/g) and flavonoid contents (13.890 ± 0.816 mg QE/g), S. acuta (SS) exhibited the highest antioxidant activity (IC50 147.295 ± 3.364 µg/mL), and S. cordifolia (WS) showed the highest xanthine oxidase inhibitor activity (IC50 110.087 ± 15.637 µg/mL). Conclusions: These findings suggest that S. acuta, S. rhombifolia, and S. cordifolia may be potential sources of polyphenols and antioxidants and could also serve as promising natural plant sources for developing antigout remedies.

Anti-rheumatoid arthritis potential of Rhododendron molle G. Don leaf extract in adjuvant induced arthritis rats.

The aim of this study was to test the anti-rheumatic arthritis effects of Rhododendron molle G. Don leaf extract in arthritis rats and inflammatory RAW 264.7cells. Preliminary analysis and comparison of potential medicinal components of three polar extracts by HPLC and UHPLC-Q-TOF-MS. SD rats were subcutaneously injected with complete Freund's adjuvant (CFA) to induce inflammation on the right hind paw. RAW 264.7cells were induced by lipopolysaccharide (LPS) to established cell inflammatory model. The volume of rat hind paw was measured with a volume meter to detect swelling, and the weight of rats was measured with an electronic balance. The severity of arthritis in rats was evaluated by arthritis score. The pathological sections of rat hind paw joints were observed by hematoxylin-eosin staining, and the contents of IL-6 and IL-1β in serum were detected. qRT-PCR was used to detect the expression of IL-1β, IL-6, TNF-α and COX-2 genes in RAW 264.7cells. The release of nitric oxide was measured by Griess reaction. The expression levels of IL-6 and IL-1β were detected by Western-Blot. and discussion: The chloroform extract from R. molle leaves (CERL), Ethyl acetate extract from R. molle leaves (EERL), n-butanol extract from R. molle leaves (BERL) could significantly inhibit hind paws swelling and reduce arthritis index in arthritis rats. And it showed dose dependence. Compared with tripterygium glycosides (TG) tablets, an effective drug of RA treatment, CERL have better anti-RA effect after administration. In addition, the three kinds of the polar extracts of Rhododendron molle leaves (PERL) had lower toxicity, with the LD50 279.87, 239.65, 500.08 (mg/kg) respectively, while TG group's LD50 was 96.00 (mg/kg). In vitro experiments showed that the three PERLs can significantly inhibit the level of pro-inflammatory factors and inflammatory mediator, such as TNF-α, IL-1β, IL-6, COX-2 and NO, which were consistent with their anti-RA ability. Among the three kinds of PERLs, CERL showed the best inhibitory activity. The R. molle leaf is a potential medicinal part for the treatment of RA. This study explored the anti-RA and anti-inflammatory activities of CERL, EERL, BERL, which laid a foundation for further promoting the clinical application of R. molle.