Effective Treatment For Rheumatoid Arthritis Research Articles

Cardiovascular Risk Factor and Atherosclerosis in Rheumatoid Arthritis (RA).

To highlight advancements in managing traditional and rheumatoid arthritis (RA) specific risk factors and the impact of RA treatments on cardiovascular outcomes. Advancements in rheumatoid arthritis management have paralleled declining trends in cardiovascular disease risks. Biomarkers like CRP, Lipoprotein(a), Apolipoprotein B 100, and imaging tools such as coronary artery calcium scoring enhance cardiovascular risk stratification, particularly in intermediate-risk RA patients. While effective RA treatments, have demonstrated substantial cardiovascular benefits, subclass differences were noted in high-risk patients. Increased risk of cardiovascular disease is driven by chronic inflammation, altered lipid metabolism, and traditional risk factors. Effective RA treatment significantly lowers cardiovascular events. Standard treatment of hypertension, diabetes and hypercholesterolemia are effective and lowers RA disease activity and inflammatory markers. While RA is considered a risk enhancing state in calculating CV risk scores, currently there exists no RA disease -specific blood pressure, blood sugar or lipid targets.

Harnessing the Power of Machine Learning Guided Discovery of NLRP3 Inhibitors Towards the Effective Treatment of Rheumatoid Arthritis.

The NLRP3 inflammasome, plays a critical role in the pathogenesis of rheumatoid arthritis (RA) by activating inflammatory cytokines such as IL1β and IL18. Targeting NLRP3 has emerged as a promising therapeutic strategy for RA. In this study, a multidisciplinary approach combining machine learning, quantitative structure-activity relationship (QSAR) modeling, structure-activity landscape index (SALI), docking, molecular dynamics (MD), and molecular mechanics Poisson-Boltzmann surface area MM/PBSA assays was employed to identify novel NLRP3 inhibitors. The ChEMBL database was used to retrieve compounds with known IC50 values to train machine learning (ML) models using the Lazy Predict package. After data pre-processing, 401 non-redundant structures were selected for exploratory data analysis (EDA). PubChem and MACCS fingerprints were used to predict the inhibitory activities of the compounds. SALI was used to identify structurally similar compounds with significantly different biological activities. The compounds were docked using MOE to assess their binding affinities and interactions with key residues in NLRP3. The models were evaluated, and a comparative analysis revealed that the ensemble Random Forest (RF) model (PubChem fingerprints) with RMSE (0.731), R2 (0.622), and MAPE (8.988) and bootstrap aggregating model (MACCS fingerprints) with RMSE (0.687), R2 (0.666), and MAPE (9.216) on the testing set performed well, in accordance with the Organization for Economic Cooperation and Development (OECD) guidelines. Out of all docked compounds, the two most promising compounds (ChEMBL5289544 and ChEMBL5219789) with binding scores of -7.5 and -8.2 kcal/mol were further investigated by MD to evaluate their stability and dynamic behavior within the binding site. MD simulations (200 ns) revealed strong structural stability, flexibility, and interactions in the selected complexes. MM/PBSA binding free energy calculations revealed that van der Waals and electrostatic forces were the key drivers of the binding of the protein with ligands. The outcomes obtained can be used to design more potent and selective NLRP3 inhibitors as therapeutic agents for the treatment of inflammatory diseases such as RA. However, concerns related to the lack of large datasets, experimental validation, and high computational costs remain.

Oral Bioefficacy Enhancement of Capsaicin for the Effective Treatment of Rheumatoid Arthritis

Oral Bioefficacy Enhancement of Capsaicin for the Effective Treatment of Rheumatoid Arthritis

Exploring Rheumatoid Arthritis: Unraveling Signaling Pathways, Advancing Management, and Charting Future Perspectives

Rheumatoid arthritis (RA) is a chronic autoimmune disorder in which inflammation occurs in the synovial joint and synovial membrane, and in severe condition, it leads to erosion of cartilage and bone. The etiology of RA is still indescribable; generally, RA is a multifactorial disease, wherein complex interactions between patients and different factors such as environmental, genetic, and epigenetic factors determine the overall risk of disease. RA is classified based on the stage of disease. Treatment for RA is still a challenge for doctors and researchers. Effective treatment for RA can be achieved by decreasing disease activity or reduction of RA to other patients using currently available treatment options. This article gives a comprehensive perspective of data regarding different signaling pathways involved in RA development, factors affecting RA, stages of RA, and other treatments of RA. This article also suggests future research perspectives that would be helpful for the development of RA treatment (medicine) with more efficacy, safety profiles, and lower financial costs.

Graphene oxide quantum dots-loaded sinomenine hydrochloride nanocomplexes for effective treatment of rheumatoid arthritis via inducing macrophage repolarization and arresting abnormal proliferation of fibroblast-like synoviocytes

The characteristic features of the rheumatoid arthritis (RA) microenvironment are synovial inflammation and hyperplasia. Therefore, there is a growing interest in developing a suitable therapeutic strategy for RA that targets the synovial macrophages and fibroblast-like synoviocytes (FLSs). In this study, we used graphene oxide quantum dots (GOQDs) for loading anti-arthritic sinomenine hydrochloride (SIN). By combining with hyaluronic acid (HA)-inserted hybrid membrane (RFM), we successfully constructed a new nanodrug system named HA@RFM@GP@SIN NPs for target therapy of inflammatory articular lesions. Mechanistic studies showed that this nanomedicine system was effective against RA by facilitating the transition of M1 to M2 macrophages and inhibiting the abnormal proliferation of FLSs in vitro. In vivo therapeutic potential investigation demonstrated its effects on macrophage polarization and synovial hyperplasia, ultimately preventing cartilage destruction and bone erosion in the preclinical models of adjuvant-induced arthritis and collagen-induced arthritis in rats. Metabolomics indicated that the anti-arthritic effects of HA@RFM@GP@SIN NPs were mainly associated with the regulation of steroid hormone biosynthesis, ovarian steroidogenesis, tryptophan metabolism, and tyrosine metabolism. More notably, transcriptomic analyses revealed that HA@RFM@GP@SIN NPs suppressed the cell cycle pathway while inducing the cell apoptosis pathway. Furthermore, protein validation revealed that HA@RFM@GP@SIN NPs disrupted the excessive growth of RAFLS by interfering with the PI3K/Akt/SGK/FoxO signaling cascade, resulting in a decline in cyclin B1 expression and the arrest of the G2 phase. Additionally, considering the favorable biocompatibility and biosafety, these multifunctional nanoparticles offer a promising therapeutic approach for patients with RA.Graphical abstract

Sulfonated Bovine Serum Albumin Hydrogel for Anti-inflammatory Treatment of Rheumatoid Arthritis via Restoring Macrophage Phenotype

Rheumatoid arthritis (RA) is an autoimmune disease with high rates of late-stage disability. Unfortunately, effective treatments for RA are limited by side-effects and high cost of clinical drugs. Bovine serum albumin (BSA) with high biocompatibility and low cost is widely used as the carrier for drug delivery. Here, sulfonated BSA (sBSA) was first time synthesized and its hydrogel system with HA matrix (sBSA/HA) was prepared for RA treatment. In RAW 264.7 cells, sBSA, but not bare BSA, significantly reduced the generation of reactive oxygen species and pro-inflammatory cytokines induced by LPS to the normal levels or even below. The scavenger receptor on macrophages was identified responsible for the enhanced uptake of sulfonated BSA. In vivo, 3% sBSA/HA showed the abilities of anti-inflammation, bone protection and restoring clinical scores and claw thickness of healthy rats in collagen-induced arthritis (CIA). Compared with the positive control (methotrexate), sBSA/HA had significant advantages in terms of speed of action, treatment effectiveness, and duration. Notably, both sBSA and sBSA/HA promoted M2 polarization (P＜0.001) by reducing the M1(CD86)/M2(CD206) phenotype ratio, suggesting the possible immune-modulation mechanism of sBSA in treating RA. Conclusively, sBSA was verified as a promising candidate for RA treatment.

The steroid-sparing effect of JAK inhibitors across multiple patient populations.

JAK-inhibitors (JAK-i) represent an effective treatment in Rheumatoid Arthritis (RA) and Psoriatic Arthritis (PsA). Oral glucocorticoids (OGC) are commonly used in combination with JAK-i to reach therapeutic target. We aimed to assess, in a real-life setting, the reduction of OGC dose during JAK-i treatment in active RA and PsA patients. We prospectively enrolled 103 patients (88 RA, 15 PsA) treated with JAK-i: 24% bio-naïve (b-naïve), 76% bDMARD-insufficient responders (bDMARD-IR) and 40% difficult to treat (D2T), defined as failure of ≥2 bDMARDs with different mechanism of action. Disease activity (DAS28 and DAPSA, VAS-pain, GH) and OGC dose was collected at baseline and after 3, 6 and 12 months (T3, T6, T12) of treatment. In all the cohort and in b-naïve patients we reported a reduction of OGC dose at all time-points; bDMARD-IR patients were able to reduce OGC dose at T3 and T12; D2T ones only at T3. We reported an improvement of disease activity and withdrawal of OGC as early as three months of therapy, at all time-points, regardless of line of bDMARD treatment. Chronic OGC may cause detrimental bone, metabolic, cardiovascular side effects and infections; therefore JAK-i steroid-sparing effect may be beneficial for patients in long-term treatment.

Ionic Liquid Transdermal Patches of Two Active Ingredients Based on Semi-Ionic Hydrogen Bonding for Rheumatoid Arthritis Treatment.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that leads to deformities and disabilities in patients. Conventional treatment focuses on delaying progression; therefore, new treatments are necessary. The present study reported a novel ionic liquid transdermal platform for efficient RA treatment, and the underlying mechanism was elucidated using FTIR, 1H-NMR, Raman, XPS, and molecular simulations. The results showed that the reversibility of the semi-ionic hydrogen bonding facilitated high drug loading and enhanced drug permeability. Actarit's drug loading had an approximately 11.34-times increase. The in vitro permeability of actarit and ketoprofen was improved by 5.46 and 2.39 times, respectively. And they had the same significant effect in vivo. Furthermore, through the integration of network pharmacology, Western blotting (WB), and radiology analyses, the significant osteoprotective effects of SIHDD-PSA (semi-ionic H-bond double-drug pressure-sensitive adhesive transdermal patch) were revealed through the modulation of the JAK-STAT pathway. The SIHDD-PSA significantly reduced paw swelling and inflammation in the rat model, and stimulatory properties evaluation confirmed the safety of SIHDD-PSA. In conclusion, these findings provide a novel approach for the effective treatment of RA, and the semi-ionic hydrogen bonding strategy contributes a new theoretical basis for developing TDDS.

Efficacy of Virechana and Erandmooladi Niruha Basti in the management of Aamvata (rheumatoid arthritis): A case report

Aamvata, also known as rheumatoid arthritis, is a common inflammatory condition that affects about 1% of the global population. It is more prevalent in females, with a 3:1 ratio to males. This systemic autoimmune disease primarily affects the joints, specifically the small joints in the hands and feet. However, it can be challenging to diagnose due to its differential diagnosis and patient presentations. Early treatment is often difficult due to delays in seeking medical attention, diagnosis, and specialist referral. Unfortunately, modern medicine still lacks a completely safe and effective treatment for rheumatoid arthritis without any side effects. The study aims to evaluate the effectiveness of Virechana and Erandmooladi Niruha Basti in treating Aamvata. In a recent clinical study, a 25-year-old female patient with Aamvata was treated with Ayurveda management. This treatment was based on the approach given by Chakradatta in Chikitsa Siddhant. The patient was examined before and after the treatment, and her condition improved tremendously.

Liposomes: An Emerging Strategy for the Effective Treatment of Rheumatoid Arthritis.

A Liposomal delivery system is a novel and distinguishing way of organized medicine administration. The advancements in liposomal technology allow for controlled drug distribution to treat rheumatoid arthritis effectively. Liposomes are microscopic lipid-based vesicles that have shown promise in transporting substances, such as superoxide dismutase, hemoglobin, erythrocyte interleukin-2, gamma interferon, and smaller compounds. Liposomes are biocompatible, nontoxic, biodegradable, non-immunogenic, and flexible, with sizes ranging from 0.025 to 2.5 micrometers. LDS is normally employed to distribute drugs through topical conduits, but fresh investigation has shown that it offers promise for oral, ocular, and parenteral administration. Our major objective is to gather information about liposomes, focusing on their applicability in rheumatoid arthritis treatment. In the current review, we have tried to cover the preparation techniques, clinical trials, patents, marketed formulations, vesicle types, formulations used to treat rheumatoid arthritis and other ailments, and layered liposomal formulations with improved characteristics. Research has established LDS as a biocompatible, sustainable, non-toxic, adaptable material. Researchers working on LDS technology in rheumatoid arthritis will find this review particularly useful as it may unclutter novel ways for therapeutic intercessions in treating the disease.

Inflammation-Responsive Nanoagents for Activatable Photoacoustic Molecular Imaging and Tandem Therapies in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) severely lowers the life quality by progressively destructing joint functions and eventually causing permanent disability, representing a pressing public health concern. The pathogenesis of RA includes the excessive production of proinflammatory cytokines and harmful oxygen-derived free radicals, such as nitric oxide (NO), which constitute vital targets for precise diagnosis and effective treatment of RA. In this study, we introduce an advanced nanoagent that integrates the RA microenvironment-activatable photoacoustic (PA) imaging with multitarget synergistic treatment for RA. A highly sensitive organic probe with NO-tunable energy transformation and molecular geometry is developed, which enables strong near-infrared absorption with a turn-on PA signal, and the active intramolecular motion could further boost PA conversion. The probe is coassembled with an inflammation-responsive prodrug to construct the theranostic nanoagent, on which a macrophage-derived cell membrane with natural tropism to the inflammatory sites is camouflaged to improve the targeting ability to inflamed joints. The nanoagent could not only sensitively detect RA and differentiate the severity but also efficiently alleviate RA symptoms and improve joint function. The combination of activatable probe-mediated NO scavenging and on-demand activation of anti-inflammatory prodrug significantly inhibits the proinflammatory factors and promotes macrophage repolarization from M1 to M2 phenotype. This meticulously designed nanoagent ingeniously integrates RA-specific PA molecular imaging with synergistic multitarget therapy, rendering tremendous promise for precise intervention of RA-related diseases.

The NLRP3 Inflammasome as a Pathogenic Player Showing Therapeutic Potential in Rheumatoid Arthritis and Its Comorbidities: A Narrative Review.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease characterized by chronic synovitis and the progressive destruction of cartilage and bone. RA is commonly accompanied by extra-articular comorbidities. The pathogenesis of RA and its comorbidities is complex and not completely elucidated. The assembly of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activates caspase-1, which induces the maturation of interleukin (IL)-1β and IL-18 and leads to the cleavage of gasdermin D with promoting pyroptosis. Accumulative evidence indicates the pathogenic role of NLRP3 inflammasome signaling in RA and its comorbidities, including atherosclerotic cardiovascular disease, osteoporosis, and interstitial lung diseases. Although the available therapeutic agents are effective for RA treatment, their high cost and increased infection rate are causes for concern. Recent evidence revealed the components of the NLRP3 inflammasome as potential therapeutic targets in RA and its comorbidities. In this review, we searched the MEDLINE database using the PubMed interface and reviewed English-language literature on the NLRP3 inflammasome in RA and its comorbidities from 2000 to 2023. The current evidence reveals that the NLRP3 inflammasome contributes to the pathogenesis of RA and its comorbidities. Consequently, the components of the NLRP3 inflammasome signaling pathway represent promising therapeutic targets, and ongoing research might lead to the development of new, effective treatments for RA and its comorbidities.

A Peripheral Blood Signature of Increased Th1 and Myeloid Cells Combined with Serum Inflammatory Mediators Is Associated with Response to Abatacept in Rheumatoid Arthritis Patients.

Abatacept (CTLA4-Ig)-a monoclonal antibody which restricts T cell activation-is an effective treatment for rheumatoid arthritis (RA). Nevertheless, only 50% of RA patients attain clinical responses, while predictors of response are rather limited. Herein, we aimed to investigate for early biomarkers of response to abatacept, based on a detailed immunological profiling of peripheral blood (PB) cells and serum proteins. We applied flow cytometry and proteomics analysis on PB immune cells and serum respectively, of RA patients starting abatacept as the first biologic agent. After 6 months of treatment, 34.5% of patients attained response. At baseline, Th1 and FoxP3+ T cell populations were positively correlated with tender joint counts (p-value = 0.047 and p-value = 0.022, respectively). Upon treatment, CTLA4-Ig effectively reduced the percentages of Th1 and Th17 only in responders (p-value = 0.0277 and p-value = 0.0042, respectively). Notably, baseline levels of Th1 and myeloid cell populations were significantly increased in PB of responders compared to non-responders (p-value = 0.009 and p-value = 0.03, respectively). Proteomics analysis revealed that several inflammatory mediators were present in serum of responders before therapy initiation and strikingly 10 amongst 303 serum proteins were associated with clinical responses. Finally, a composite index based on selected baseline cellular and proteomics' analysis could predict response to abatacept with a high sensitivity (90%) and specificity (88.24%).

Mannose-modified celastrol liposomes targeted activated macrophages for rheumatoid arthritis treatment in vitro and in vivo evaluation

Rheumatoid arthritis (RA) is an autoimmune illness characterized by symmetrical polyarthritis as the primary clinical symptom. A substantial number of synovial macrophages are activated in RA patients, resulting in synovial inflammation, joint inflammation, and cartilage degradation. The goal of this study is to develop a novel therapy for the effective treatment of RA. We prepared mannose-modified celastrol liposomes (MAN-CSL-lips) by thin-film hydration method. The particle size of the prepared liposomes was (95.37 ± 0.16) nm, and the zeta potential was (−5.4 ± 0.40) mV. The experimental results showed that MAN-CSL-lips had low cytotoxicity and could be efficiently taken up by macrophages, suppress osteoclast formation, and reduce the level of inflammatory factors. In addition, in vivo animal experiments, liposomes can prolong the systemic circulation time of drugs, reduce the joint score and serum inflammatory factor expression in arthritic rats, and have significant cartilage protection and anti-inflammatory effects, making it a promising therapeutic method for treating RA.

Infection incidence, timing, and dose dependency in rheumatoid arthritis patients treated with rituximab: a retrospective cohort study.

Rituximab (RTX) is a safe and effective treatment for rheumatoid arthritis (RA). However, there are some concerns about infection risk and preliminary data suggest dose and time dependency. This study aims to determine the infection incidence in a large real-life population of RA patients using RTX, with special focus on (ultra-)low dosing and time since last infusion. RA patients treated with 1000, 500 or 200 mg RTX per cycle between 2012 and 2021 at the Sint Maartenskliniek were included in a retrospective cohort study. Patient-, disease-, treatment- and infection characteristics were retrieved from electronic health records. Infection incidence rates, dose and time relations with RTX infusion were analysed using mixed-effects Poisson regression. Among 490 patients, we identified 819 infections in 1254 patient years. Most infections were mild and respiratory tract infections were most common. Infection incidence rates were 41, 54 and 71 per 100 patient years for doses of 200, 500 and 1000 mg. Incidence rate ratio (IRR) was significantly lower for 200 mg compared to 1000 mg (adjusted IRR 0.35, 95% CI 0.17-0.72, p = 0.004). In patients receiving 1000 or 500 mg RTX, infections seemed to occur more frequently within the first two months after infusion compared to later on in the treatment cycle, suggesting an association with peak concentration. Ultra-low dosing (200 mg) of RTX is associated with a lower risk of infections in RA. Future interventions focusing on ultra-low dosing and slow release of RTX (e.g. by subcutaneous administration) may lower infection risk.

Effect of autologous bone marrow derived mesenchymal stem cells in treatment of rheumatoid arthritis

IntroductionChronic inflammation causes articular bone and cartilage degeneration in people with rheumatoid arthritis (RA). Despite recent advancements in the management of RA, adverse side effects and ineffective treatments remain a problem. Effective treatment is usually hampered by financial issues. As a result, less expensive medications that reduce both inflammation and bone resorption are required. Mesenchymal stem cells (MSCs) have recently been identified as a potential therapy for RA. Aim of the studyThis study aimed to examine the anti-arthritic effect of rat bone marrow-derived mesenchymal stem cells (rBM-MSCs), oligosaccharides (Os), and human placental extract (HPE), individually and combined, on an RA model, using Complete Freund's adjuvant (CFA)-induced arthritis in rats. Materials and methodsIn female rats, RA was induced by injecting CFA in the paw of the hind limb. Rat bone marrow-MSCs, oligosaccharides, and human placental extract (HPE) were given individually and in combination via the intraperitoneal route. A complete blood count (CBC), erythrocyte sedimentation rate (ESR), serum cortisol, urea, uric acid, and other biochemical parameters were measured to determine the safety and efficacy of the different treatments. Histopathological analysis of bone sections was carried out. ResultsCombining oligosaccharides and HPE therapy with the infusion of rat-bone marrow MSCs had beneficial antiarthritic and anti-inflammatory effects in CFA-induced arthritis in rats: overall such triple therapy significantly reduced serum levels of IL-6, IL-10, and TNF-alpha in comparison with all other combinations (all P > 0.05). Meanwhile, the triple therapy did not have negative effects on levels of CBC, serum cortisol, ESR, and liver enzymes (all NS) as well as on renal functions (NS). Also, the histopathological analysis showed significant improvements in the healing and remodelling of osteoporotic lesions in arthritic rats. As shown by counting apoptotic cells as a histopathological substitute for measuring apoptotic or regeneration markers, the lowest count was found in the group treated with a triple therapy of rat bone marrow-derived mesenchymal stem cells (rBM-MSCs), oligosaccharides, and HPE. ConclusionThe combination of rat MSCs, oligosaccharides, and HPE has the potential to be an effective treatment for rheumatoid arthritis.

TNFipred: a classification model to predict TNF-α inhibitors.

Rheumatoid arthritis (RA), characterized by severe inflammation in the joint lining, is a progressive, chronic, autoimmune disorder with high morbidity and mortality rates. There are several mechanisms responsible for joint damage, but overproduction of TNF-α is a significant mechanism that results in excess swelling and pain. Drugs acting on TNF-α are known to significantly reduce the disease progression and improve the quality of life in many RA patients. Hence, inhibiting TNF-α is considered one of the most effective treatments for RA. Currently, there are only a few FDA-approved TNF-α inhibitors, which are mainly monoclonal antibodies, fusion proteins, or biosimilars with disadvantages such as poor stability, difficulty in route of administration (often given as injection or infusion), cost-prohibitive large-scale production, and increased side effects. There are just a handful of small compounds known to have TNF- inhibitory capabilities. Thus, there is a dire need for new drugs, especially small molecules in the market, such as TNF-α inhibitors. The conventional method of identifying TNF-α inhibitors is expensive, labor, and time intensive. Machine learning (ML) can be used to solve existing drug discovery and development problems. In this study, four classification algorithms-naïve Bayes (NB), random forest (RF), k-nearest neighbor (kNN), and support vector machine (SVM)-were used to train ML models for classifying TNF-α inhibitors based on three sets of features. The performance of the RF model was found to be best when using 1D, 2D, and fingerprints as features, with an accuracy of 87.96 and a sensitivity of 86.17. To our knowledge, this is the first ML model for TNF-α inhibitor prediction. The model is available at http://14.139.57.41/tnfipred/.

Biomimetic Epigallocatechin Gallate-Cerium Assemblies for the Treatment of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an autoimmune and inflammatory disease that is so far incurable with long-term health risks. The high doses and frequent administration for the available RA drug always lead to adverse side effects. Aiming at the obstacles to achieving effective RA treatment, we prepared macrophage cell membrane-camouflaged nanoparticles (M-EC), which were assembled from epigallocatechin gallate (EGCG) and cerium(IV) ions. Due to its geometrical similarity to the active metal sites of a natural antioxidant enzyme, the EC possessed a high scavenge efficiency to various types of reactive oxygen species (ROS) and reactive nitrogen species (RNS). The macrophage cell membrane assisted M-EC in escaping from the immune system, being uptaken by inflammatory cells, and specifically binding IL-1β. After tail vein injection to the collagen-induced arthritis (CIA) mouse model, the M-EC accumulated at inflamed joints and effectively repaired the bone erosion and cartilage damage of rheumatoid arthritis by relieving synovial inflammation and cartilage erosion. It is expected that the M-EC can not only pave a new way for designing metal-phenolic networks with better biological activity but also provide a more biocompatible therapeutic strategy for effective treatment of RA.

Tubson-2 decoction ameliorates rheumatoid arthritis complicated with osteoporosis in CIA rats involving isochlorogenic acid A regulating IL-17/MAPK pathway

BackgroundOsteoporosis (OP) is considered as one of the major comorbidities of rheumatoid arthritis (RA), and is responsible for fragility fracture. However, there is currently no effective treatment for RA complicated with OP. Tubson-2 decoction (TBD), a Mongolian medicine also known as Erwei Duzhong Decoction, has been shown to exert a preventive effect on post-menopausal osteoporosis (PMOP). The preventive effects of TBD on RA-induced OP, as well as the bioactive compound responsible and the underlying mechanisms, remain to be elucidated. ObjectiveTo explore the effects of TBD on RA-induced OP in vivo, and to elucidate the mechanism of isochlorogenic acid A (ICA), the effective component of TBD, in vitro. MethodsTo evaluate the anti-arthritic and anti-osteoporotic effects of TBD, we conducted H&E straining and safranine O/fast green, TEM, immunohistochemistry (IHC), bone histomorphometry, micro-CT imaging, and biomechanical testing in collagen induced arthritis (CIA) rats. The active ingredient in TBD was identified using network pharmacology and molecular docking. The identification was supported by in vivo IHC assay, and further confirmed using qRT-PCR, Western blot, and SEM analysis in TNF-α-treated MH7A cells and/or in LPS-exposed RAW264.7 cells. ResultsOral administration of TBD attenuated the severity of arthritis and osteopenia as well as poor bone quality, in CIA rats. Additionally, TBD and the positive control, tripterygium glycosides (TG), exhibited similar effects in reducing inflammation in both the synovium and ankle joint. They also were both effective in improving bone loss, microarchitecture, and overall bone quality. TBD reduced the expression of MMP13, IL-17, and p-JNK protein in the synovium of CIA rats. ICA, which was screened, suppressed TNF-α or LPS-triggered inflammatory responses via down-regulating IL-17 signaling, involving in MMP13, IL-1β, IL-23, and IL-17, and the MAPK pathway including p-ERK, p-JNK, and p-P38, both in MH7A cells and in RAW264.7 cells. Furthermore, ICA prevented osteoclasts from differentiating and bone resoprtion in a dose-dependent manner in vitro. ConclusionThis study provides the first evidence that TBD exerts intervening effects on RA-induced OP, possibly through the downregulation of the IL-17/MAPK signaling pathway by ICA. The findings of our study provides valuable insights for further research in this area.

A Non-targeted Metabolomics Reveals Therapeutical Effect and Mechanism of Sanmiao Pill on Adjuvant-induced Arthritis Rats.

Rheumatoid arthritis (RA) is an increasingly serious disease worldwide that can damage the joints and bones of sufferers. Sanmiao Pill (SMP), a classical traditional Chinese medicine (TCM) prescription, has been used for effective treatments for RA in the clinic. To comprehensively illuminate the therapeutic mechanism of SMP in the treatment of RA, the effects of SMP on biomarkers and metabolic pathways in rats with adjuvant-induced arthritis (AIA) were examined. > Methods: Sprague Dawley rats were randomly divided into two control (CC, Control) groups, two model (MM, Model) groups, a methotrexate group (MTX, 7.6 mg/kg body weight per week), and two SMP groups (San-L, 28.7 mg/kg body weight per day and San-H, 57.4 mg/kg body weight per day). Rats' body weight, paw swelling, arthritis scores, biochemical parameters, histopathology, and so on were used to evaluate the success of the model and the therapeutic effects of SMP. The metabolic techniques were used to characterize the metabolic profile and biomarkers of the serum and urine samples of rats to reveal the metabolic changes that occurred after SMP treatment. > Results: After 21 days of treatment, SMP improved weight gain, reduced the severity of paw swelling, lowered the levels of biochemical indicators (CCP-Ab, IL-6, TNF-α, RF), decreased destruction of articular cartilage and bone erosion, and protected the affected joints.Additionally, 17 and 19 potential biomarkers associated with RA were identified in the serum and urine, respectively. SMP significantly reversed 14 potential biomarkers, such as arachidonic acid, lysoPC(20:4(5Z,8Z,11Z,14Z)), L-tryptophan, 9-cis-Retinoic acid, hippuric acid, pyridoxine, and pantothenic acid. These metabolites are associated with arachidonic acid metabolism, glycerophospholipid catabolism, tryptophan metabolism, phenylalanine metabolism, vitamin B6 metabolism, etc. > Conclusion: These results indicated that RA-related biomarkers reflected the metabolic profile of AIA rats. Meanwhile, SMP could effectively treat RA mainly by reducing inflammation and regulating abnormal lipid metabolic pathways and amino acid metabolisms. It showed that metabolomics could be used to analyze the metabolic profiles involved in RA and reveal the mechanism of SMP treatment of RA.>.