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 Vitamin D as a Principal Factor in Mediating Rheumatoid Arthritis-Derived Immune Response

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Muhammad M. Aslam ◽  
Peter John ◽  
Attya Bhatti ◽  
Sidrah Jahangir ◽  
M. I. Kamboh
Keyword(s):  
Rheumatoid Arthritis ◽  
Vitamin D ◽  
Immune Responses ◽  
Molecular Mechanisms ◽  
Genetic Factors ◽  
Autoimmune Disorder ◽  
Serum Levels ◽  
Principal Factor ◽  
Phosphate Homeostasis ◽  
Low Serum

Rheumatoid arthritis (RA) is a systemic multifactorial autoimmune disorder. The interactions between diverse environmental and genetic factors lead to the onset of this complex autoimmune disorder. Serum levels of vitamin D (VD) are involved in the regulation of various immune responses. Vitamin D is a key signaling molecule in the human body that maintains calcium as well as phosphate homeostasis. It also regulates the functions of the immune system and, thus, can play a substantial role in the etiology of various autoimmune disorders, including RA. Low serum VD levels have been found to be associated with a higher risk of RA, although this finding has not been replicated consistently. The molecular mechanisms by which VD influences autoimmunity need to be further explored to understand how variation in plasma VD levels could affect the pathogenesis of RA. This mini-review focuses on the influence of VD and its serum levels on RA susceptibility, RA-associated complexities, treatment, and transcriptome products of key proinflammatory cytokines, along with other cytokines that are key regulators of inflammation in rheumatoid joints.

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.

scholarly journals CXCL1 contributes to IL-6 expression in osteoarthritis and rheumatoid arthritis synovial fibroblasts by CXCR2, c-Raf, MAPK, and AP-1 pathway

2020 ◽  
Vol 22 (1) ◽  
Author(s):  
Sheng-Mou Hou ◽  
Po-Chun Chen ◽  
Chieh-Mo Lin ◽  
Mei-Ling Fang ◽  
Miao-Ching Chi ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Proinflammatory Cytokine ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Synovial Fibroblasts ◽  
Dependent Manner ◽  
Tissue Samples ◽  
Chemical Inhibitors ◽  
Shrna Plasmid ◽  
Signal Cascades

Abstract Background Osteoarthritis (OA) and rheumatoid arthritis (RA) are common joint disorders that are considered to be different diseases due to their unique molecular mechanisms and pathogenesis. Chemokines and their corresponding receptors have been well characterized in RA progression, but less so in OA pathogenesis. Methods The human primary synovial fibroblasts (SFs) were obtained from human OA and RA tissue samples. The Western blot and qPCR were performed to analyze the expression levels of CXCL1, as well as CXCL-promoted IL-6 expression in both OASFs and RASFs. The signal cascades that mediate the CXCL1-promoted IL-6 expression were identified by using chemical inhibitors, siRNAs, and shRNAs. Results Here, we found that both diseases feature elevated levels of CXCL1 and interleukin (IL)-6, an important proinflammatory cytokine that participates in OA and RA pathogenesis. In OASFs and RASFs, CXCL1 promoted IL-6 expression in a dose- and time-dependent manner. In OASFs and RASFs overexpressing CXCL1 or transduced with shRNA plasmid, IL-6 expression was markedly upregulated. CXCR2, c-Raf, and MAPKs were found to regulate CXCL1-induced IL-6 expression in OASFs and RASFs. Finally, CXCL1 triggered the transcriptional activities of c-Jun (which regulates the expression of proinflammatory proteins) in OASFs and RASFs. Conclusions Our present work suggests that the CXCL1/CXCR2 axis helps to orchestrate inflammatory responses in OA and RA SFs.

scholarly journals Clinical and Pathological Implications of Concurrent Autoimmune Thyroid Disorders and Papillary Thyroid Cancer

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
L. L. Cunha ◽  
R. C. Ferreira ◽  
M. A. Marcello ◽  
J. Vassallo ◽  
L. S. Ward
Keyword(s):  
Thyroid Cancer ◽  
Molecular Mechanisms ◽  
Autoimmune Disorder ◽  
Chronic Lymphocytic Thyroiditis ◽  
Papillary Thyroid ◽  
Potential Significance ◽  
Autoimmune Thyroid ◽  
Molecular Features ◽  
Precise Relationship ◽  
Concurrent Cancer

Cooccurrences of chronic lymphocytic thyroiditis (CLT) and thyroid cancer (DTC) have been repeatedly reported. Both CLT and DTC, mainly papillary thyroid carcinoma (PTC), share some epidemiological and molecular features. In fact, thyroid lymphocytic inflammatory reaction has been observed in association with PTC at variable frequency, although the precise relationship between the two diseases is still debated. It also remains a matter of debate whether the association with a CLT or even an autoimmune disorder could influence the prognosis of PTC. A better understanding about clinical implications of autoimmunity in concurrent thyroid cancer could raise new insights of thyroid cancer immunotherapy. In addition, elucidating the molecular mechanisms involved in autoimmune disease and concurrent cancer allowed us to identify new therapeutic strategies against thyroid cancer. The objective of this article was to review recent literature on the association of these disorders and its potential significance.

scholarly journals CXCL1 contributes to IL-6 expression in osteoarthritis and rheumatoid arthritis synovial fibroblasts by CXCR2, c-Raf, MAPK and AP-1 pathway

2020 ◽  
Author(s):  
Sheng-Mou Hou ◽  
PoChun Chen ◽  
Chieh-Mo Lin ◽  
Mei-Ling Fang ◽  
Miao-Ching Chi ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Proinflammatory Cytokine ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Synovial Fibroblasts ◽  
Dependent Manner ◽  
Tissue Samples ◽  
Chemical Inhibitors ◽  
Shrna Plasmid ◽  
Signal Cascades

Abstract Background: Osteoarthritis (OA) and rheumatoid arthritis (RA) are common joint disorders that are considered to be different diseases due to their unique molecular mechanisms and pathogenesis. Chemokines and their corresponding receptors have been well-characterized in RA progression, but less so in OA pathogenesis.Methods: The human primary synovial fibroblasts (SFs) were obtained from human OA and RA tissue samples. The Western blot and qPCR were performed to analyze expression levels of CXCL1, as well as CXCL-promoted IL-6 expression in both OASFs and RASFs. The signal cascades that mediate the CXCL1-promoted IL-6 expression were identified by using chemical inhibitors, siRNAs and shRNAs.Results: Here, we found that both diseases feature elevated levels of CXCL1 and interleukin (IL)-6, an important proinflammatory cytokine that participates in OA and RA pathogenesis. In OASFs and RASFs, CXCL1 promoted IL-6 expression in a dose- and time-dependent manner. In OASFs and RASFs overexpressing CXCL1 or transduced with shRNA plasmid, IL-6 expression was markedly upregulated. CXCR2, c-Raf and MAPKs was found to regulate CXCL1-induced IL-6 expression in OASFs and RASFs. Finally, CXCL1 triggered the transcriptional activities of c-Jun (which regulates the expression of proinflammatory proteins) in OASFs and RASFs.Conclusions: Our present work suggests that the CXCL1/CXCR2 axis helps to orchestrate inflammatory responses in OA and RA SFs.

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 The dual inhibitor of lipoxygenase and cyclooxygenase ML3000 decreases the expression of CXCR3 ligands

2007 ◽  
Vol 67 (4) ◽  
pp. 524-529 ◽  
Author(s):  
C Ospelt ◽  
M Kurowska-Stolarska ◽  
M Neidhart ◽  
B A Michel ◽  
R E Gay ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Polymerase Chain Reaction ◽  
Molecular Mechanisms ◽  
Synovial Fibroblasts ◽  
Target Cells ◽  
Chain Reaction ◽  
Dual Inhibitor ◽  
Protein Levels ◽  
Polymerase Chain ◽  
The Impact

Objective:To find previously unknown properties of ML3000, a competitive inhibitor of the cyclooxygenase and the lipoxygenase (LO) pathway.Methods:Gene expression of ML3000 treated and untreated rheumatoid arthritis synovial fibroblasts were measured with Affymetrix gene arrays. Downregulation of chemokine (C-X-C motif) ligands CXCL9, CXCL10 and CXCL11 was verified with Real-time polymerase chain reaction, CXCL10 protein levels were determined with ELISA. Rheumatoid arthritis synovial fibroblasts were treated with the cyclooxygenase inhibitor naproxen, the 5-LO inhibitor BWA4C and the 5-lipoxygenase-activating protein (FLAP) inhibitor MK886, and consecutive changes in CXCL10 protein levels measured. 5-LO expression was determined by polymerase chain reaction and Western blot.Results:In synovial fibroblasts and monocyte-derived macrophages ML3000 inhibited the tumour necrosis factor induced expression of CXCL9, CXCL10 and CXCL11, which are all ligands of the chemokine receptor CXCR3. No effect was observed in monocytes. Whereas inhibition of the cyclooxygenase pathway or the FLAP protein showed no effect, blockade of 5-LO significantly downregulated CXCL10 protein levels. 5-LO mRNA was detected in monocytes and in monocyte-derived macrophages. All tested cell types expressed 5-LO protein.Conclusions:ML3000 effectively downregulates CXCR3 ligands. This study confirms that a thorough analysis of the impact of a drug on its target cells cannot only reveal unexpected properties of a substance, but also helps to understand the underlying molecular mechanisms. Accordingly, our data provide the basis for further clinical studies testing the application of ML3000 in diseases such as rheumatoid arthritis or multiple sclerosis.

scholarly journals CXCL1 contributes to IL-6 expression in osteoarthritis and rheumatoid arthritis synovial fibroblasts by CXCR2, c-Raf, MAPK and AP-1 pathway

2020 ◽  
Author(s):  
Sheng-Mou Hou ◽  
PoChun Chen ◽  
Chieh-Mo Lin ◽  
Mei-Ling Fang ◽  
Miao-Ching Chi ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Proinflammatory Cytokine ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Synovial Fibroblasts ◽  
Dependent Manner ◽  
Tissue Samples ◽  
Chemical Inhibitors ◽  
Shrna Plasmid ◽  
Signal Cascades

Abstract Background: Osteoarthritis (OA) and rheumatoid arthritis (RA) are common joint disorders that are considered to be different diseases due to their unique molecular mechanisms and pathogenesis. Chemokines and their corresponding receptors have been well-characterized in RA progression, but less so in OA pathogenesis. Methods: The human primary synovial fibroblasts (SFs) were obtained from human OA and RA tissue samples. The Western blot and qPCR were performed to analyze expression levels of CXCL1, as well as CXCL-promoted IL-6 expression in both OASFs and RASFs. The signal cascades that mediate the CXCL1-promoted IL-6 expression were identified by using chemical inhibitors, siRNAs and shRNAs. Results: Here, we found that both diseases feature elevated levels of CXCL1 and interleukin (IL)-6, an important proinflammatory cytokine that participates in OA and RA pathogenesis. In OASFs and RASFs, CXCL1 promoted IL-6 expression in a dose- and time-dependent manner. In OASFs and RASFs overexpressing CXCL1 or transduced with shRNA plasmid, IL-6 expression was markedly upregulated. CXCR2, c-Raf and MAPKs was found to regulate CXCL1-induced IL-6 expression in OASFs and RASFs. Finally, CXCL1 triggered the transcriptional activities of c-Jun (which regulates the expression of proinflammatory proteins) in OASFs and RASFs. Conclusions: Our present work suggests that the CXCL1/CXCR2 axis helps to orchestrate inflammatory responses in OA and RA SFs.

scholarly journals CXCL1 contributes to IL-6 expression in osteoarthritis and rheumatoid arthritis synovial fibroblasts by CXCR2, c-Raf, MAPK and AP-1 pathway

2020 ◽  
Author(s):  
PoChun Chen ◽  
Sheng-Mou Hou ◽  
Ju-Fang Liu
Keyword(s):  
Rheumatoid Arthritis ◽  
Proinflammatory Cytokine ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Synovial Fibroblasts ◽  
Dependent Manner ◽  
Tissue Samples ◽  
Chemical Inhibitors ◽  
Shrna Plasmid ◽  
Signal Cascades

Abstract Background Osteoarthritis (OA) and rheumatoid arthritis (RA) are common joint disorders that are considered to be different diseases due to their unique molecular mechanisms and pathogenesis. Chemokines and their corresponding receptors have been well-characterized in RA progression, but less so in OA pathogenesis. Methods The human primary synovial fibroblasts (SFs) were obtained from human OA and RA tissue samples. The Western blot and qPCR were performed to analyze expression levels of CXCL1, as well as CXCL-promoted IL-6 expression in both OASFs and RASFs. The signal cascades that mediate the CXCL1-promoted IL-6 expression were identified by using chemical inhibitors, siRNAs and shRNAs. Results Here, we found that both diseases feature elevated levels of CXCL1 and interleukin (IL)-6, an important proinflammatory cytokine that participates in OA and RA pathogenesis. In OASFs and RASFs, CXCL1 promoted IL-6 expression in a dose- and time-dependent manner. In OASFs and RASFs overexpressing CXCL1 or transduced with shRNA plasmid, IL-6 expression was markedly upregulated. CXCR2, c-Raf and MAPKs was found to regulate CXCL1-induced IL-6 expression in OASFs and RASFs. Finally, CXCL1 triggered the transcriptional activities of c-Jun (which regulates the expression of proinflammatory proteins) in OASFs and RASFs. Conclusions Our present work suggests that the CXCL1/CXCR2 axis helps to orchestrate inflammatory responses in OA and RA SFs.

scholarly journals Pim-2/mTORC1 Pathway Shapes Inflammatory Capacity in Rheumatoid Arthritis Synovial Cells Exposed to Lipid Peroxidations

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Geng Yin ◽  
Yan Li ◽  
Min Yang ◽  
Xiao-min Cen ◽  
Qi-bing Xie
Keyword(s):  
Rheumatoid Arthritis ◽  
Molecular Mechanisms ◽  
Synovial Fibroblasts ◽  
Systemic Autoimmune Disease ◽  
Human Rheumatoid Arthritis ◽  
Synovial Cells ◽  
Inflammatory Reactions ◽  
Rheumatoid Arthritis Development ◽  
Ectopic Activation ◽  
Mtorc1 Pathway

Rheumatoid arthritis is a systemic autoimmune disease characterized by chronic inflammation of multiple joints, with disruption of joint cartilage. The proliferation of synovial fibroblasts in response to multiple inflammation factors is central to the pathogenesis of rheumatoid arthritis. Our previous studies showed that 4-HNE may induce synovial intrinsic inflammations by activating NF-κB pathways and lead to cell apoptosis. However, the molecular mechanisms of how synovial NF-κB activation is modulated are not fully understood. Here, the present findings demonstrated that 4-HNE may induce synovial intrinsic inflammations by mTORC1 inactivation. While ectopic activation of mTORC1 pathway by the overexpression of Pim-2 may disrupt the initiation of inflammatory reactions and maintain synovial homeostasis, our findings will help to uncover novel signaling pathways between inflammations and oxidative stress in rheumatoid arthritis development and imply that Pim-2/mTORC1 pathway may be critical for the initiation of inflammatory reactions in human rheumatoid arthritis synovial cells.

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