Project description:Rheumatoid arthritis (RA) is a severe inflammatory autoimmune disease characterized by the failed spontaneous resolution of inflammation. The induction of immune regulation and resolution of inflammatory pathways are effective in alleviating inflammation in RA. As the oldest medical system in the world, traditional Tibetan medicine (TTM) has a long history of preventing and treating RA. This review provides a comprehensive overview of medicinal plants with anti-RA activity in the TTM system, using classic books of Tibetan medicine, modern research literature, and drug standards. A total of 27 species have been found to be effective in treating RA, including Tinospora sinensis (Lour.) Merr., Terminalia chehula Retz., P. hookeri (C. B. Clarke) Hock.), and Aconitum pendulum Busch. Alkaloids, flavonoids, polyphenols, and terpenoids have turned out to be the major bioactive components for RA treatment. The inhibition of pro-inflammatory cytokine expression by mediating the NF-κB, MAPK, and JAK/STAT pathways is the core mechanism in RA treatment. In conclusion, this review provides key information and research perspectives for further research on the anti-RA effects of TTM.
Project description:Rheumatoid arthritis (RA) is a chronic inflammatory disease that will affect quality of life and, working efficiency, and produce negative thoughts for patients. Current therapy of RA is treated with disease-modifying antirheumatic drugs (DMARDs). Although most of these treatment methods are effective, most patients still have a pleasant experience either due to poor efficacy or side effects or both. Interleukin-6 receptor (IL6R) is important in the pathogenesis of RA. In this study, we would like to detect the potential candidates which inhibit IL6R against RA from traditional Chinese medicine (TCM). We use TCM compounds from the TCM Database@Taiwan for virtually screening the potential IL6R inhibitors. The TCM candidate compound, calycosin, has potent binding affinity with IL6R protein. The molecular dynamics simulation was employed to validate the stability of interaction in the protein complex with calycosin. The analysis indicates that protein complex with calycosin is more stable. In addition, calycosin is known to be one of the components of Angelica sinensis, which has been indicated to have an important role in the treatment of rheumatoid arthritis. Therefore, calycosin is a potential candidate as lead compounds for further study in drug development process with IL6R protein against rheumatoid arthritis.
Project description:Genomic screening is routinely used to guide the treatment of cancer patients in many countries. However, several multi-layered factors make this effort difficult to deliver within a clinically relevant timeframe. Here we share the learnings from the CRUK-funded Stratified Medicine Programme for advanced NSCLC patients, which could be useful to better plan future studies.
Project description:Purpose: To search candidate synergized compounds from Chinese herbal medicine used in RA therapy Methods: Candidate synergized compounds were searched based on multi-information integrative approaches. In vivo experiment in collagen induced arthritis rat was then carried out to evaluate the efficacy and synergism of compounds combination treatment. RNA sequencing and IPA were used to investigate the synergized mechanism of combination treatment. Results: We found a pair of compound combination which could alleviate the symptom of CIA rats. RNA sequencing and IPA analysis revealed that the synergistic mechanism of combination treatment was related to several canonical signaling pathways and key targets LTA, CD83 and SREBF1. Conclusion: A pair of compound combination has been found. RNA sequencing and IPA analysis revealed that the synergistic mechanism of combination treatment was related to several canonical signaling pathways and key targets.
Project description:Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). This post hoc analysis investigated the effect of methotrexate (MTX) dose on the efficacy of tofacitinib in patients with RA. ORAL Scan (NCT00847613) was a 2-year, randomized, Phase 3 trial evaluating tofacitinib in MTX-inadequate responder (IR) patients with RA. Patients received tofacitinib 5 or 10 mg twice daily (BID), or placebo, with low (≤12.5 mg/week), moderate (>12.5 to <17.5 mg/week), or high (≥17.5 mg/week) stable background MTX. Efficacy endpoints (at months 3 and 6) included American College of Rheumatology (ACR) 20/50/70 response rates, and mean change from baseline in Clinical Disease Activity Index (CDAI), Disease Activity Score in 28 joints (DAS28)-4(erythrocyte sedimentation rate [ESR]), Health Assessment Questionnaire-Disability Index (HAQ-DI), and modified Total Sharp score. 797 patients were treated with tofacitinib 5 mg BID (N = 321), tofacitinib 10 mg BID (N = 316), or placebo (N = 160); 242, 333, and 222 patients received low, moderate, and high MTX doses, respectively. At months 3 and 6, ACR20/50/70 response rates were greater for both tofacitinib doses vs placebo across all MTX doses. At month 3, mean changes from baseline in CDAI and HAQ-DI were significantly greater for both tofacitinib doses vs placebo, irrespective of MTX category; improvements were maintained at month 6. Both tofacitinib doses demonstrated improvements in DAS28-4(ESR), and less structural progression vs placebo, across MTX doses at month 6. Tofacitinib plus MTX showed greater clinical and radiographic efficacy than placebo in MTX-IR patients with RA, regardless of MTX dose.
Project description:Rheumatoid arthritis (RA) is a chronic, inflammatory joint disease of unknown etiology and pronounced inter-patient heterogeneity. To characterize RA at the molecular level and to uncover key pathomechanisms, we performed whole-genome gene expression analyses. Synovial tissues from rheumatoid arthritis patients were compared to those from osteoarthritis patients and to normal donors. Keywords: disease state analysis
Project description:Background: Methotrexate (MTX) is one of the most common medications used for rheumatoid arthritis (RA) treatment. Single-nucleotide polymorphisms (SNPs) could potentially predict variability in therapeutic outcomes. Aim: This study aims to assess the impact of SNPs in genes encoding for the MTX pathway for predicting clinical and therapeutic responses to MTX in a cohort of Egyptian patients with RA. Subjects and Methods: Data from 107 Egyptian RA patients (aged 44.4 ± 11.4 years) treated with MTX monotherapy, for a duration of 3.7 ± 3.3 years, were collected. Genotypes of 10 SNPs from four different genes were analyzed using the allelic discrimination PCR technique. Results: The ATIC rs3821353 G/T (p = 0.034) and the C/T and C/C of SLC19A1 rs7279445 (p = 0.0018) were associated with a non-response to MTX, while DHFR rs10072026 C/T and C/C were associated with a good response (p < 0.001). Carriers of the ATIC rs382135 3 G (p = 0.001) and ATIC rs4673990 G (p < 0.001) alleles were more likely to develop RA, while the SLC19A1 rs11702425 T (p < 0.001) and GGH rs12681874 T (p = 0.003) allele carriers were more likely to be protected against RA. Carriers of the ATIC rs4673990 A/G genotype (p < 0.001) were at risk of developing RA, while carriers of the following genotypes were mostly protected against RA: ATIC rs3821353 T/T (p < 0.001), ATIC rs3821353 G/G (p = 0.004), SLC19A1 rs11702425 T/T (p = 0.001), SLC19A1 rs11702425 C/T (p = 0.003), GGH rs12681874 C/T (p = 0.004) and GGH rs12681874 T/T (0.002). Conclusion: The genotyping of genes involved in the MTX pathway may be helpful to predict which RA patients will/will not benefit from MTX, and thus, may help to apply a personalized medicine approach in RA.
Project description:Personalized medicine refers to the utilization of technologies at the molecular level to understand disease processes and improve health outcomes. In rheumatoid arthritis (RA) some factors associated with disease outcome have been identified. These factors have not yet been integrated into a clinically useful tool to predict disease outcome in individual patients. Developments in pharmacogenomics are moving the field forward quite rapidly. Genetic variants, which may have a role in drug metabolism mediating either drug response or toxicity, have been identified for both traditional disease modifying antirheumatic drugs and biologic agents. Choosing a medication based on a patient's characteristics (sociodemographic, clinical, genetic) will result in better utilization of resources and better clinical outcomes. The ethical, political, and legal implications of personalized medicine need to be considered as well.