Advancement of Natural Compounds as Anti- Rheumatoid Arthritis Agents: Focus on Their Mechanism of Actions

2021 ◽  
Vol 21 ◽  
Author(s):  
Huanghe Yu ◽  
Yixing Qiu ◽  
Shumaila Tasneem ◽  
Muhammad Daniyal ◽  
Bin Li ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Molecular Mechanisms ◽  
Bone Destruction ◽  
Inflammatory Cells ◽  
Chronic Inflammatory Disease ◽  
Mechanisms Of Action ◽  
Pannus Formation ◽  
Synovial Hyperplasia ◽  
Naturally Occurring ◽  
Natural Plants

: Rheumatoid arthritis (RA) is a chronic inflammatory disease categorized by infiltration of inflammatory cells, synovial hyperplasia, pannus formation and bone destruction, leading to disability worldwide. Despite the presence of the commercial availability of anti-RA agent on the market, the application of these drugs is limited due to its side effects. Anti-rheumatic drugs are more effective and safer being investigated by many researchers, especially, natural products with anti-RA have been identified and the underlying molecular mechanisms of action of novel and known compounds have been reported. In this review, we intend to provide a comprehensive view and updated on naturally occurring compounds known and novel that has the effect of anti-RA, and then classify them according to their molecular mechanisms of action in regulating the anti-RA lane main. The safety of compounds from natural plants and western medicine has also been briefly compared. In addition, the clinical trials with anti-RA compounds isolated from natural plants in RA were also summarized in this manuscript.

VEGFR-1 (Flt-1) Tyrosine Kinase Signaling Enhances Hematopoiesis, Proliferation/Differentiation and Immunity of Monocyte/Macrophage from Bone Marrow Hematopoietic Stem Cells, and Promotes Rheumatoid Arthritis.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 778-778
Author(s):  
Masato Murakami ◽  
Shinobu Iwai ◽  
Sachie Hirasuka ◽  
Yoichiro Iwakura ◽  
Yoshiro Maru ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Bone Marrow ◽  
Mouse Model ◽  
Tyrosine Kinase ◽  
Vascular Tissue ◽  
Systemic Disease ◽  
Bone Destruction ◽  
Inflammatory Cells ◽  
Vegf Receptor ◽  
Hematopoietic Stem

Abstract VEGF and its receptor family including VEGFR-1(Flt-1) are well known to be a crucial regulatory system for normal development and pathological angiogenesis. Rheumatoid arthritis(RA) is a chronic systemic disease characterized by an inflammatory erosive synovicitis, which show marked neovascularization, inflammatory cell infiltration and synovial hyperplasia, then produce a pannus of inflammatory vascular tissue and lead to irreversible cartilage and bone destruction. We have already shown VEGFR-1 is expressed not only in vascular endothelial cells but also in inflammatory cells, especially in monocyte/macrophage. A recent report suggests the involvement of VEGFR-1 in RA by using collagen induced RA mouse model. To examine whether the signaling from VEGFR-1 is important for the pathological process of RA, we used VEGFR-1 tyrosine kinase(−/−) mice which cannot generate the signaling from this receptor, and an arthritis mouse model system carrying Human T-cell leukemia virus(HTLV-1) pX transgene. VEGFR-1 TK(−/−) mice with pX gene clearly showed a reduction in the incidence and the degree of clinical symptom of arthritis. Furthermore, the heterozygote VEGFR-1 TK(+/−) with pX transgene showed a partial decrease in the degree of clinical as well as pathological scores. To explain the reason of reduction of clinical symptoms, we investigated involvement of VEGFR-1 TK signal in lineage of bone marrow hematopoietic stem cell(HSC) to monocyte/macrophage proliferation and differentiation and their immunity. VEGFR-1 TK activities are not associated in number of HSC in bone marrow. However, VEGFR-1 TK(−/−) HSC toward multi-lineage proliferation is suppressed in colony-formation. In addition, failures of monocyte/macrophage faculties are observed in immunological reaction, phagocytosis, cytokine secretion(IL-6, VEGF) and migration. Furthermore, expressions of hematopoiesis and inflammation related genes in VEGFR-1 TK(−/−) macrophage are downregulated by microarray analysis. Next we treated with small molecule inhibitors of VEGF receptor(VEGFR-1 and VEGFR-2) of tyrosine kinase, KRN951, in RA model(pX transgenic model and type II collagen Ab cocktail model) for treatment. Treatment with KRN951 strongly attenuated the disease symptom through inhibiting recruitment of BM hematopoietic cells into peripheral inflammatory cells. These observations indicate that VEGFR-1 signals play an important role in both RA mouse model. The tyrosine kinase activity and the signaling of VEGFR-1 enhances hematopoiesis, proliferation/differentiation and immunity of monocyte/macrophage from bone marrow HSC, and promotes rheumatoid arthritis, which may be a new possibilities for the treatment of RA in humans. Figure Figure

scholarly journals Pathogenesis and Function of Interleukin-35 in Rheumatoid Arthritis

2021 ◽  
Vol 12 ◽  
Author(s):  
Pan Lin Xin ◽  
Li Fan Jie ◽  
Qian Cheng ◽  
Du Yi Bin ◽  
Cheng Wen Dan
Keyword(s):  
Rheumatoid Arthritis ◽  
Inflammatory Cell ◽  
T Regulatory Cells ◽  
Therapeutic Potential ◽  
Bone Destruction ◽  
Pathological Process ◽  
Interleukin 12 ◽  
Synovial Hyperplasia ◽  
And Function ◽  
Anti Inflammatory Cytokine

It is well known that RA (Rheumatoid arthritis) is an autoimmune disease characterized by multiple and symmetric arthropathy. The main pathological features of RA are synovial hyperplasia, angiogenesis, pannus formation, inflammatory cell infiltration, articular cartilage, bone destruction, and ultimately joint dysfunction, even deformity. IL-35 (Interleukin-35) is a new member of the IL-12 (Interleukin-12) family, which is an immunosuppressive and anti-inflammatory cytokine secreted mainly by Treg (T regulatory cells). There is evidence suggested that IL-35 can attenuate the progression of RA through influencing the immune and pathological process. It suggests that IL-35 played an important role in the pathogenesis of RA, and can be used as a potential target for the future treatment of RA. This review summarizes the recent advances of IL-35 in the pathological roles and the therapeutic potential roles in RA.

scholarly journals Effects of Biological Therapies on Molecular Features of Rheumatoid Arthritis

2020 ◽  
Vol 21 (23) ◽  
pp. 9067
Author(s):  
Chary Lopez-Pedrera ◽  
Nuria Barbarroja ◽  
Alejandra M. Patiño-Trives ◽  
Maria Luque-Tévar ◽  
Eduardo Collantes-Estevez ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Molecular Mechanisms ◽  
Adaptive Immune System ◽  
Autoimmune Disorder ◽  
Synovial Fibroblasts ◽  
Chronic Inflammatory Disease ◽  
Pharmacological Therapy ◽  
Biologic Dmards ◽  
Molecular Features ◽  
Specific Effects

Rheumatoid arthritis (RA) is an autoimmune and chronic inflammatory disease primarily affecting the joints, and closely related to specific autoantibodies that mostly target modified self-epitopes. Relevant findings in the field of RA pathogenesis have been described. In particular, new insights come from studies on synovial fibroblasts and cells belonging to the innate and adaptive immune system, which documented the aberrant production of inflammatory mediators, oxidative stress and NETosis, along with relevant alterations of the genome and on the regulatory epigenetic mechanisms. In recent years, the advances in the understanding of RA pathogenesis by identifying key cells and cytokines allowed the development of new targeted disease-modifying antirheumatic drugs (DMARDs). These drugs considerably improved treatment outcomes for the majority of patients. Moreover, numerous studies demonstrated that the pharmacological therapy with biologic DMARDs (bDMARDs) promotes, in parallel to their clinical efficacy, significant improvement in all these altered molecular mechanisms. Thus, continuous updating of the knowledge of molecular processes associated with the pathogenesis of RA, and on the specific effects of bDMARDs in the correction of their dysregulation, are essential in the early and correct approach to the treatment of this complex autoimmune disorder. The present review details basic mechanisms related to the physiopathology of RA, along with the core mechanisms of response to bDMARDs.

scholarly journals Apoptosis of Rheumatoid Arthritis Fibroblast-Like Synoviocytes: Possible Roles of Nitric Oxide and the Thioredoxin 1

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Huili Li ◽  
Ajun Wan
Keyword(s):  
Rheumatoid Arthritis ◽  
Nitric Oxide ◽  
Molecular Mechanisms ◽  
Caspase 3 ◽  
Joint Destruction ◽  
Redox System ◽  
Chronic Inflammatory Disease ◽  
Thioredoxin 1 ◽  
Fibroblast Like Synoviocytes

Rheumatoid arthritis is a chronic inflammatory disease characterized by synovial hyperplasia and progressive joint destruction. The impaired apoptosis of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) is pivotal in this process. However, the molecular mechanisms responsible for the reduced apoptosis are not fully understood. Both nitric oxide and thioredoxin 1 as two important mediators are widely investigated in the pathogenesis of rheumatoid arthritis. Interestingly, studies have showed that thioredoxin 1 may serve as a master regulator of S-nitrosylation of caspase-3 to fine-tune apoptosisin vivo. Thus, it is anticipated that further investigations on the role of thioredoxin 1 in the S-nitrosylation and denitrosylation of caspase-3 in RA-FLS will likely provide a novel understanding of mechanisms implicated in the impaired apoptosis of RA-FLS. In this paper, we will provide an overview on pathways involved in the reduced apoptosis of RA-FLS and then discuss specially the possible roles of nitric oxide and the thioredoxin 1 redox system associated with apoptosis of RA-FLS.

scholarly journals Ets-2 Propagates IL-6 Trans-Signaling Mediated Osteoclast-Like Changes in Human Rheumatoid Arthritis Synovial Fibroblast

2021 ◽  
Vol 12 ◽  
Author(s):  
Anil K. Singh ◽  
Mahamudul Haque ◽  
Bhanupriya Madarampalli ◽  
Yuanyuan Shi ◽  
Benjamin J. Wildman ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Bone Destruction ◽  
Metabolic Reprogramming ◽  
Mass Spectrometry Analysis ◽  
Tartrate Resistant Acid Phosphatase ◽  
Positive Staining ◽  
Human Rheumatoid Arthritis

Rheumatoid arthritis synovial fibroblasts (RASFs) contribute to synovial inflammation and bone destruction by producing a pleiotropic cytokine interleukin-6 (IL-6). However, the molecular mechanisms through which IL-6 propels RASFs to contribute to bone loss are not fully understood. In the present study, we investigated the effect of IL-6 and IL-6 receptor (IL-6/IL-6R)-induced trans-signaling in human RASFs. IL-6 trans-signaling caused a significant increase in tartrate-resistant acid phosphatase (TRAP)-positive staining in RASFs and enhanced pit formation by ~3-fold in the osteogenic surface in vitro. IL-6/IL-6R caused dose-dependent increase in expression and nuclear translocation of transcription factor Ets2, which correlated with the expression of osteoclast-specific signature proteins RANKL, cathepsin B (CTSB), and cathepsin K (CTSK) in RASFs. Chromatin immunoprecipitation (ChIP) analysis of CTSB and CTSK promoters showed direct Ets2 binding and transcriptional activation upon IL-6/IL-6R stimulation. Knockdown of Ets2 significantly inhibited IL-6/IL-6R-induced RANKL, CTSB, and CTSK expression and TRAP staining in RASFs and suppressed markers of RASF invasive phenotype such as Thy1 and podoplanin (PDPN). Mass spectrometry analysis of the secretome identified 113 proteins produced by RASFs uniquely in response to IL-6/IL-6R that bioinformatically predicted its impact on metabolic reprogramming towards an osteoclast-like phenotype. These findings identified the role of Ets2 in IL-6 trans-signaling induced molecular reprogramming of RASFs to osteoclast-like cells and may contribute to RASF heterogeneity.

scholarly journals LncRNAs and Rheumatoid Arthritis: From Identifying Mechanisms to Clinical Investigation

2022 ◽  
Vol 12 ◽  
Author(s):  
Wentao Huang ◽  
Xue Li ◽  
Chen Huang ◽  
Yukuan Tang ◽  
Quan Zhou ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Clinical Investigation ◽  
Cartilage Damage ◽  
Bone Matrix ◽  
Poor Response ◽  
Mechanisms Of Action ◽  
Current Therapy ◽  
Synovial Hyperplasia ◽  
Drug Intolerance ◽  
Therapy Strategies

Rheumatoid arthritis (RA) is a systemic chronic autoinflammatory disease, and the synovial hyperplasia, pannus formation, articular cartilage damage and bone matrix destruction caused by immune system abnormalities are the main features of RA. The use of Disease Modifying Anti-Rheumatic Drugs (DMARDs) has achieved great advances in the therapy of RA. Yet there are still patients facing the problem of poor response to drug therapy or drug intolerance. Current therapy methods can only moderate RA progress, but cannot stop or reverse the damage it has caused. Recent studies have reported that there are a variety of long non-coding RNAs (LncRNAs) that have been implicated in mediating many aspects of RA. Understanding the mechanism of LncRNAs in RA is therefore critical for the development of new therapy strategies and prevention strategies. In this review, we systematically elucidate the biological roles and mechanisms of action of LncRNAs and their mechanisms of action in RA. Additionally, we also highlight the potential value of LncRNAs in the clinical diagnosis and therapy of RA.

scholarly journals IL-6-PAD4 axis in the earliest phase of arthritis in knock-in gp130F759 mice, a model for rheumatoid arthritis

RMD Open ◽  
2019 ◽  
Vol 5 (2) ◽  
pp. e000853 ◽  
Author(s):  
Ayano Yahagi ◽  
Taro Saika ◽  
Hiroyasu Hirano ◽  
Miwa Takai-Imamura ◽  
Fumio Tsuji ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Molecular Mechanisms ◽  
Clinical Score ◽  
Careful Examination ◽  
Synovial Hyperplasia ◽  
Reactive Protein ◽  
Preclinical Phase ◽  
Haematopoietic Cells ◽  
Common Receptor

ObjectiveAnimal models for human diseases are especially valuable for clarifying molecular mechanisms before or around the onset. As a model for rheumatoid arthritis (RA), we utilise knock-in mice gp130F759. They have a Y759F mutation in gp130, a common receptor subunit for interleukin 6 (IL-6) family cytokines. Definitive arthritis develops around 8 months old and the incidence reaches 100% around 1 year old. Careful examination in the clinical course revealed very subtle resistance in flexibility of joints at 5 months old. Therefore, pathophysiological changes in gp130F759 were examined to dissect molecular mechanisms for preclinical phase of RA.MethodsSeverity of arthritis in gp130F759 was evaluated with a clinical score system and histological quantification. Serum cytokines, autoantibodies and C reactive protein (CRP) were measured. Changes in the synovium were analysed by real-time PCR, flow cytometry and immunohistochemistry.ResultsAround 5 months old, various types of cytokines, rheumatoid factor (RF), anti-circular citrullinated peptide IgM and CRP increased in the sera of gp130F759. Enhancement of neovascularisation, synovial hyperplasia and fibrosis was observed. Also, increases in haematopoietic cells dominated by innate immune cells and gene expression of Il6 and Padi4 were detected in the joints. Il6 was expressed by non-haematopoietic synovial cells, whereas PAD4 protein was detected in the synovial neutrophils. Padi4 is induced in neutrophils in vitro by IL-6. Increases of phospho-STAT3 and PAD4 protein were detected in the synovium. Deletion of IL-6 in gp130F759 normalised the amount of PAD4 protein in the joints.ConclusionThe IL-6-PAD4 axis operates in the earliest phase of arthritis in gp130F759, implicating it in early RA.

scholarly journals Pyridinone Derivatives as Interesting Formyl Peptide Receptor (FPR) Agonists for the Treatment of Rheumatoid Arthritis

Molecules ◽  
2021 ◽  
Vol 26 (21) ◽  
pp. 6583
Author(s):  
Letizia Crocetti ◽  
Claudia Vergelli ◽  
Gabriella Guerrini ◽  
Maria Paola Giovannoni ◽  
Liliya N. Kirpotina ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Cartilage Damage ◽  
Bone Destruction ◽  
Joint Inflammation ◽  
Chronic Inflammatory Disease ◽  
New Drugs ◽  
Formyl Peptide Receptor ◽  
Pyridine Derivative ◽  
Pharmacological Tests ◽  
Formyl Peptide

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint inflammation, cartilage damage and bone destruction. Although the pharmacological treatment of RA has evolved over the last few years, the new drugs have serious side effects and are very expensive. Thus, the research has been directed in recent years towards new possible targets. Among these targets, N-formyl peptide receptors (FPRs) are of particular interest. Recently, the mixed FPR1/FPR2 agonist Cpd43, the FPR2 agonist AT-01-KG, and the pyridine derivative AMC3 have been shown to be effective in RA animal models. As an extension of this research, we report here a new series of pyridinone derivatives containing the (substituted)phenyl acetamide chain, which was found to be essential for activity, but with different substitutions at position 5 of the scaffold. The biological results were also supported by molecular modeling studies and additional pharmacological tests on AMC3 have been performed in a rat model of RA, by repeating the treatments of the animals with 10 mg/kg/day of compound by 1 week.

scholarly journals Glycolysis Rate-Limiting Enzymes: Novel Potential Regulators of Rheumatoid Arthritis Pathogenesis

2021 ◽  
Vol 12 ◽  
Author(s):  
Jianlin Zuo ◽  
Jinshuo Tang ◽  
Meng Lu ◽  
Zhongsheng Zhou ◽  
Yang Li ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Autoimmune Disease ◽  
Molecular Level ◽  
Bone Destruction ◽  
Chronic Inflammatory Disease ◽  
Hexokinase Ii ◽  
Rheumatoid Arthritis Pathogenesis ◽  
Synovial Proliferation ◽  
Rate Limiting ◽  
Glycolytic Rate

Rheumatoid arthritis (RA) is a classic autoimmune disease characterized by uncontrolled synovial proliferation, pannus formation, cartilage injury, and bone destruction. The specific pathogenesis of RA, a chronic inflammatory disease, remains unclear. However, both key glycolysis rate-limiting enzymes, hexokinase-II (HK-II), phosphofructokinase-1 (PFK-1), and pyruvate kinase M2 (PKM2), as well as indirect rate-limiting enzymes, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), are thought to participate in the pathogenesis of RA. In here, we review the latest literature on the pathogenesis of RA, introduce the pathophysiological characteristics of HK-II, PFK-1/PFKFB3, and PKM2 and their expression characteristics in this autoimmune disease, and systematically assess the association between the glycolytic rate-limiting enzymes and RA from a molecular level. Moreover, we highlight HK-II, PFK-1/PFKFB3, and PKM2 as potential targets for the clinical treatment of RA. There is great potential to develop new anti-rheumatic therapies through safe inhibition or overexpression of glycolysis rate-limiting enzymes.

The Impact of Proinflammatory Cytokynes of Rheumatoid Polyarthritis on the Generalized Loss of Bone Mass

2018 ◽  
Vol 69 (9) ◽  
pp. 2541-2545
Author(s):  
Raluca Barzoi ◽  
Elena Rezus ◽  
Codruta Badescu ◽  
Razan Al Namat ◽  
Manuela Ciocoiu
Keyword(s):  
Rheumatoid Arthritis ◽  
Immune Cells ◽  
Osteoclast Differentiation ◽  
Bone Destruction ◽  
Nuclear Factor ◽  
Receptor Activator ◽  
Level Function ◽  
Rheumatoid Polyarthritis ◽  
The Impact ◽  
Nuclear Factor Kb

There is a bidirectional interaction between most immune cells and osteoblasts, osteoclasts and their precursor cells. The receptor activator of nuclear factor-kB ligand (RANKL)/RANK/osteoprotegerin (OPG) system plays an essential role in the formation of osteoblasts, but it also has implications in osteoclast biology and implicitly on the diseases characterized by bone loss. Proinflammatory cytokines existing at synovial level function as direct or indirect stimulators of osteoclast differentiation, but also of its survival or activity, although some cytokines may also play an antiosteocastogenic role. The fate of bone destruction is determined by the balance between osteoclastogenic and antiosteoclastogenic mediators. Our study has shown that the early initiation of the therapy with anti-TNF and anti-IL6 biological agents, in patients with rheumatoid arthritis, inhibits bone destruction, regardless of the anti-inflammatory activity in patients with rheumatoid arthritis.

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