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Dai X, Zheng Y, Cui J, Zeng Y, Yang B, Zhang Z. Nanodrug delivery systems targeting ferroptosis as an innovative therapeutic approach for Rheumatoid Arthritis. Mater Today Bio 2025; 32:101804. [PMID: 40343168 PMCID: PMC12059336 DOI: 10.1016/j.mtbio.2025.101804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 04/02/2025] [Accepted: 04/24/2025] [Indexed: 05/11/2025] Open
Abstract
Rheumatoid Arthritis (RA) is a chronic inflammatory disease characterized by joint inflammation, progressive cartilage degradation, and bone erosion. Recent research has implicated ferroptosis not only in autoimmune hepatitis but also in the pathogenesis and progression of autoimmune disorders like RA. Consequently, numerous therapeutic strategies have begun to target the ferroptosis pathway, particularly in the design and development of nanodrug delivery systems (NDDSs). While previous reviews have comprehensively discussed the mechanisms of ferroptosis, related signaling pathways, and NDDS materials, recent studies have further elucidated the interplay between ferroptosis and various metabolic pathways, providing a robust theoretical basis for the design of NDDS-based ferroptosis strategies. This review focuses on investigating the role of ferroptosis in the development of RA, aiming to elucidate how targeting ferroptosis can offer novel therapeutic concepts and potential treatments for RA patients. Specifically, it summarizes the design strategies of ferroptosis-based NDDSs via different pathways and highlights the feasibility of RA treatment regimens based on the ferroptosis mechanism. Furthermore, the review critically discusses the current limitations of NDDSs and offers perspectives on future research directions in this field.
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Affiliation(s)
- Xiaolin Dai
- Department of Pharmacy, Chengdu Seventh People's Hospital (Affiliated Cancer Hospital of Chengdu Medical College), Chengdu, China
| | - Yu Zheng
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, PR China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, 646000, PR China
- Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, 646000, PR China
- Sichuan-Chongqing Joint Key Laboratory of Metabolic Vascular Diseases, Luzhou, 646000, PR China
| | - Jianrong Cui
- Department of Pharmacy, Chengdu Seventh People's Hospital (Affiliated Cancer Hospital of Chengdu Medical College), Chengdu, China
| | - Yuqi Zeng
- Department of Pharmacy, Chengdu Seventh People's Hospital (Affiliated Cancer Hospital of Chengdu Medical College), Chengdu, China
| | - Bo Yang
- Department of Pharmacy, Chengdu Seventh People's Hospital (Affiliated Cancer Hospital of Chengdu Medical College), Chengdu, China
| | - Zhanlin Zhang
- Irradiation Preservation and Effect Key Laboratory of Sichuan Province, School of Bioscience and Technology, Chengdu Medical College, Chengdu, 610500, PR China
- The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, 610051, PR China
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Xu HY, Jiang MT, Yang YF, Huang Y, Yang WD, Li HY, Wang X. Microalgae-Based Fucoxanthin Attenuates Rheumatoid Arthritis by Targeting the JAK-STAT Signaling Pathway and Gut Microbiota. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2025; 73:11708-11719. [PMID: 40325616 DOI: 10.1021/acs.jafc.4c12474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/07/2025]
Abstract
Fucoxanthin, an abundant carotenoid in marine algae, has garnered attention for its diverse health benefits, including anti-inflammatory and anticancer properties. Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation and damage. This study investigated the therapeutic potential of fucoxanthin extracted from Phaeodactylum tricornutum in collagen-induced RA. Our results demonstrated that fucoxanthin significantly alleviated RA symptoms, including weight loss, joint swelling, and decreased appetite. Histological analysis revealed that fucoxanthin mitigated synovial inflammation, cartilage damage, and bone erosion. Mechanistically, transcriptomic analysis and cell experiments indicated that fucoxanthin suppressed the JAK-STAT signaling pathway by downregulating the expression of inflammatory cytokines, such as IL-6 and IL-1β. Furthermore, metagenomic analysis suggested that fucoxanthin restored the altered gut microbiota composition associated with RA. These findings highlight the therapeutic potential of fucoxanthin from P. tricornutum in the management of RA by targeting multiple pathways, including inflammation and gut microbiota.
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Affiliation(s)
- Hui-Ying Xu
- Key Laboratory of Eutrophication and Red Tide Prevention of Guangdong Higher Education Institute, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
| | - Meng-Ting Jiang
- Key Laboratory of Eutrophication and Red Tide Prevention of Guangdong Higher Education Institute, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
| | - Yu-Feng Yang
- Biotechnology and Nuclear Technology Research Institute, Sichuan Academy of Agricultural Sciences, Chengdu 610066, China
| | - Yisha Huang
- Key Laboratory of Eutrophication and Red Tide Prevention of Guangdong Higher Education Institute, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
| | - Wei-Dong Yang
- Key Laboratory of Eutrophication and Red Tide Prevention of Guangdong Higher Education Institute, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
| | - Hong-Ye Li
- Key Laboratory of Eutrophication and Red Tide Prevention of Guangdong Higher Education Institute, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
| | - Xiang Wang
- Key Laboratory of Eutrophication and Red Tide Prevention of Guangdong Higher Education Institute, College of Life Science and Technology, Jinan University, Guangzhou 510632, China
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Li Y, Gu Y, Shi Y, Zhang B, Pan S, Chai Y, Chen X, Yuan Y. Application of a dual channel MPTS-modified two-dimensional cell membrane chromatography system for rapid screening of effective ingredients in Saposhnikovia divaricata targeting inflammatory macrophages and fibroblast synovial cells in the treatment of rheumatoid arthritis. J Pharm Biomed Anal 2025; 255:116595. [PMID: 39631165 DOI: 10.1016/j.jpba.2024.116595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 11/27/2024] [Accepted: 11/28/2024] [Indexed: 12/07/2024]
Abstract
Saposhnikovia divaricata (SD) is a traditional Chinese medicine (TCM) which has been commonly used for the treatment of rheumatoid arthritis (RA). However, its active components and mechanism of anti-RA are still unclear. Targeting rheumatoid arthritis-fibroblastoid synovial (RA-FLS) and synovial macrophages are promising strategies for RA treatment, and their membrane receptors are important targets for anti-RA active substances. A dual channel 3-mercaptopropyltrimethoxysilane (MPTS) modified 2D cell membrane chromatography (CMC) system was established to characterize dual-cell membrane binding active components in SD. Nine components retained on RAW-CMC column and 8 components retained on FLS-CMC column were screened out. Among them, 8 components retained well on both CMC columns. We further validate the pharmacological activity of 5-O-methylvisammioside, 3'-O-angeloylhamaudol, imperatorin, phellopterin and anomalin. They could efficiently target both inflammatory macrophages and fibroblast synovial cells, reduce the release of inflammatory factors, inhibit abnormal cell proliferation, and promote cell apoptosis. 5-O-methylvisammioside, which exhibited the best pharmacological ability on both target cells, inhibited the NF-κB pathway. Our results showed that the dual channel MPTS modified 2D CMC system is a practical method for rapid screening the active components in TCM binding on multiple target cells' membrane protein of a disease. The method is very suitable for elucidating the mechanism of TCM with multiple-components and targets, and rapid screening of lead compounds.
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Affiliation(s)
- Yueyue Li
- Department of Pharmacy, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011, China
| | - Yanqiu Gu
- Department of Pharmacy, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011, China
| | - Yuhuan Shi
- Department of Pharmacy, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011, China
| | - Bin Zhang
- Department of Pharmacy, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011, China
| | - Shu Pan
- Department of Pharmacy, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011, China
| | - Yifeng Chai
- Department of Pharmaceutical Analysis, School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Xiaofei Chen
- Department of Pharmaceutical Analysis, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
| | - Yongfang Yuan
- Department of Pharmacy, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011, China.
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Wu Z, Zhang P, Huang W, Zhou Y, Cao Z, Wu C. Qufeng epimedium decoction alleviates rheumatoid arthritis through CYLD-antagonized NF-kB activation by deubiquitinating Sirt1. Immunobiology 2025; 230:152875. [PMID: 39908772 DOI: 10.1016/j.imbio.2025.152875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 12/20/2024] [Accepted: 01/25/2025] [Indexed: 02/07/2025]
Abstract
BACKGROUND Rheumatoid arthritis (RA) is a chronic autoimmune disease that markedly limits the patients´ day-to-day functional abilities and life quality. Currently, there is no known cure for RA. Qufeng epimedium decoction, a traditional Chinese medicine, is widely used in China to treat RA. However, its underlying mechanism remains elusive. METHODS The RA animal model was established to investigate the anti-RA effect and regulatory effect on fibroblast-like synoviocytes (FLS) pyroptosis, qRT-PCR, Western blot, flow cytometry, histology staining, and ELISA were utilized to confirm the gene and protein expressions. The interactions between Sirt1 and CYLD were validated through Co-immunoprecipitation (Co-IP) and RNA-FISH assay. RESULTS Administration with Qufeng epimedium decoction attenuated inflammatory damage, excessive proliferation, and FLSs pyroptosis in an RA rat model. Moreover, treatment of Qufeng epimedium decoction reduced the ubiquitination modification level of Sirt1 in FLSs isolated from an RA rat model. Mechanistically, CYLD, an intermediation for linking Qufeng epimedium decoction and RA, was responsible for Sirt1 deubiquitination to its protein stabilization, thereby deactivating the NF-kB /GSDMD signaling pathway. CONCLUSION Our findings indicate that Qufeng epimedium decoction suppresses FLSs pyroptosis and RA progression via CYLD-mediated Sirt1 deubiquitination and deactivation of the NF-kB /GSDMD signaling pathway. This study sheds light on the underlying mechanism of Qufeng epimedium decoction's effectiveness in RA treatment.
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Affiliation(s)
- Zhiming Wu
- Chinese Medicine Department, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330000, Jiangxi Province, PR China.
| | - Peng Zhang
- Chinese Medicine Department, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330000, Jiangxi Province, PR China
| | - Wenyan Huang
- Day Surgery Center, Jiangxi Maternal and Child Health Care Hospital, Nanchang 330000, Jiangxi Province, PR China
| | - Yifen Zhou
- Chinese Medicine Department, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330000, Jiangxi Province, PR China
| | - Zhengliu Cao
- Chinese Medicine Department, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330000, Jiangxi Province, PR China
| | - Chunhong Wu
- Outpatient Department, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330000, Jiangxi Province, PR China
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Cong S, Wang N, Pei H, Li Z, Meng Y, Maimaitituersun S, Zhao X, Wan R, Wan Q, Luo L, Bian Y, Wen W, Cui H. Syringin inhibits the crosstalk between macrophages and fibroblast-like synoviocytes to treat rheumatoid arthritis via PDE4. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 138:156401. [PMID: 39842374 DOI: 10.1016/j.phymed.2025.156401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 12/28/2024] [Accepted: 01/16/2025] [Indexed: 01/24/2025]
Abstract
BACKGROUND Syringin (SRG) is well-known for its anti-inflammatory effects. However, its pharmacological mechanisms against rheumatoid arthritis (RA) are not fully understood. MATERIALS AND METHODS We assessed the anti-RA effects of SRG using a collagen-induced arthritis (CIA) rat model. And, we employed single-cell RNA sequencing (scRNA-seq) to analyze the changes in cell types and gene expression in the synovial tissues. Building on these observations, we investigated the effects of SRG on M1 macrophage polarization and RA-fibroblast-like synoviocytes (FLS) proliferation. RESULTS Our findings highlighted the anti-RA effects of SRG on CIA rat. scRNA-seq of rat synovial tissues revealed significant changes in M1 and RA-FLS. Specifically, SRG decreased the levels of inflammatory factors in the supernatants of LPS and IFN-γ induced THP-1 cells and downregulated M1-polarized markers in these cells. Further analysis indicated that SRG's regulation of phosphodiesterase 4 (PDE4) and its associated factors was crucial for its anti-M1 polarization effects. Besides, we found that SRG inhibited the activation of FLS in vivo but showed no direct effects on RA-FLS in vitro. However, in RA-FLS, co-cultured with supernatant from SRG-treated M1-polarized THP-1 cells exhibited lower ability of cell proliferation and activation as compared to co-cultured with supernatant from M1-polarized THP-1 cells. CONCLUSION By integrating scRNA-seq analysis with in vivo and in vitro validations, our study revealed that SRG achieved its anti-RA effects by blocking the interaction between macrophages and RA-FLS, with PDE4 playing a central role. This study may provide a novel research paradigm in studying the multi-cell regulatory mechanisms of natural compounds.
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Affiliation(s)
- Shan Cong
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Xinjiang Medical University, Urumchi 830054, China
| | - Ning Wang
- First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming 650500, China
| | - Huan Pei
- School of Basic Medical, Yunnan University of Chinese Medicine, Kunming 650500, China
| | - Zixuan Li
- Medical School, Tibet University, Lhasa 850000, China
| | - Yan Meng
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Xinjiang Medical University, Urumchi 830054, China
| | - Saimire Maimaitituersun
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Xinjiang Medical University, Urumchi 830054, China
| | - Xue Zhao
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Xinjiang Medical University, Urumchi 830054, China
| | - Rong Wan
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Xinjiang Medical University, Urumchi 830054, China
| | - Qianqian Wan
- First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming 650500, China
| | - Li Luo
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Xinjiang Medical University, Urumchi 830054, China.
| | - Yuhong Bian
- School of Integrative Chinese and Western Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
| | - Weibo Wen
- First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming 650500, China.
| | - Huantian Cui
- First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming 650500, China.
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Zhao L, Wu Q, Long Y, Qu Q, Qi F, Liu L, Zhang L, Ai K. microRNAs: critical targets for treating rheumatoid arthritis angiogenesis. J Drug Target 2024; 32:1-20. [PMID: 37982157 DOI: 10.1080/1061186x.2023.2284097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 11/09/2023] [Indexed: 11/21/2023]
Abstract
Vascular neogenesis, an early event in the development of rheumatoid arthritis (RA) inflammation, is critical for the formation of synovial vascular networks and plays a key role in the progression and persistence of chronic RA inflammation. microRNAs (miRNAs), a class of single-stranded, non-coding RNAs with approximately 21-23 nucleotides in length, regulate gene expression by binding to the 3' untranslated region (3'-UTR) of specific mRNAs. Increasing evidence suggests that miRNAs are differently expressed in diseases associated with vascular neogenesis and play a crucial role in disease-related vascular neogenesis. However, current studies are not sufficient and further experimental studies are needed to validate and establish the relationship between miRNAs and diseases associated with vascular neogenesis, and to determine the specific role of miRNAs in vascular development pathways. To better treat vascular neogenesis in diseases such as RA, we need additional studies on the role of miRNAs and their target genes in vascular development, and to provide more strategic references. In addition, future studies can use modern biotechnological methods such as proteomics and transcriptomics to investigate the expression and regulatory mechanisms of miRNAs, providing a more comprehensive and in-depth research basis for the treatment of related diseases such as RA.
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Affiliation(s)
- Lingyun Zhao
- College of Acupuncture, Tuina and Rehabilitation, Hunan University of Chinese Medicine, Changsha, China
| | - Qingze Wu
- College of Acupuncture, Tuina and Rehabilitation, Hunan University of Chinese Medicine, Changsha, China
| | - Yiying Long
- Hunan Traditional Chinese Medical College, Zhuzhou, China
| | - Qirui Qu
- College of Acupuncture, Tuina and Rehabilitation, Hunan University of Chinese Medicine, Changsha, China
| | - Fang Qi
- College of Acupuncture, Tuina and Rehabilitation, Hunan University of Chinese Medicine, Changsha, China
| | - Li Liu
- The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Liang Zhang
- College of Acupuncture, Tuina and Rehabilitation, Hunan University of Chinese Medicine, Changsha, China
| | - Kun Ai
- College of Acupuncture, Tuina and Rehabilitation, Hunan University of Chinese Medicine, Changsha, China
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Li Y, Wang GQ, Li YB. Therapeutic potential of natural coumarins in autoimmune diseases with underlying mechanisms. Front Immunol 2024; 15:1432846. [PMID: 39544933 PMCID: PMC11560467 DOI: 10.3389/fimmu.2024.1432846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 10/14/2024] [Indexed: 11/17/2024] Open
Abstract
Autoimmune diseases encompass a wide range of disorders characterized by disturbed immunoregulation leading to the development of specific autoantibodies, which cause inflammation and multiple organ involvement. However, its pathogenesis remains unelucidated. Furthermore, the cumulative medical and economic burden of autoimmune diseases is on the rise, making these diseases a ubiquitous global phenomenon that is predicted to further increase in the coming decades. Coumarins, a class of aromatic natural products with benzene and alpha-pyrone as their basic structures, has good therapeutic effects on autoimmune diseases. In this review, we systematically highlighted the latest evidence on coumarins and autoimmune diseases data from clinical and animal studies. Coumarin acts on immune cells and cytokines and plays a role in the treatment of autoimmune diseases by regulating NF-κB, Keap1/Nrf2, MAPKs, JAK/STAT, Wnt/β-catenin, PI3K/AKT, Notch and TGF-β/Smad signaling pathways. This systematic review will provide insight into the interaction of coumarin and autoimmune diseases, and will lay a groundwork for the development of new drugs for autoimmune diseases.
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Affiliation(s)
- Yan Li
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Institute of Neuroimmunology, Shandong Provincial Key Medical and Health Laboratory of Neuroimmunology, Jinan, China
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Guan-qing Wang
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Institute of Neuroimmunology, Shandong Provincial Key Medical and Health Laboratory of Neuroimmunology, Jinan, China
| | - Yan-bin Li
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Institute of Neuroimmunology, Shandong Provincial Key Medical and Health Laboratory of Neuroimmunology, Jinan, China
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Zhou S, Xue W, Tan J. Design, Synthesis, and Antirheumatoid Arthritis Mechanism of TLR4 Inhibitors. ACS OMEGA 2024; 9:36232-36241. [PMID: 39220494 PMCID: PMC11359639 DOI: 10.1021/acsomega.4c02344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 07/12/2024] [Accepted: 07/24/2024] [Indexed: 09/04/2024]
Abstract
A total of 12 carbonyl compounds were synthesized, their lipopolysaccharide induced inhibition, and activity of RAW264.7 cells was evaluated. The most active compound 3k inhibited RAW264.7 cells with IC50 value of 1.02 ± 0.08 μM. Compound 3k significantly inhibited the release of TNF-α, IL-1β, and IL-6 in supernatant for RAW264.7 cells. In vivo collagen-induced arthritis model tests administered orally, compound 3k showed effects similar to those of methotrexate in the positive control group. The preliminary mechanism study showed that compound 3k had an effect on abnormal expression for TLR4, TNF-α, NF-κB protein, and genes related to inflammation signaling pathway in RAW264.7 cells. Meanwhile, compound 3k showed a good affinity for the TLR4 receptor in molecular docking simulation. Therefore, compound 3k may be a promising lead compound for the treatment of rheumatoid arthritis.
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Affiliation(s)
- Shiyang Zhou
- Chongqing
Chemical Industry Vocational College, Chongqing 401228, China
- School
of Biological and Chemical Engineering, Chongqing University of Education, Chongqing 400067, China
- Chongqing
Academy of Traditional Chinese Medicine, Chongqing 400065, China
- Key
Laboratory of Tropical Medicinal Plant Chemistry of Hainan Province, Hainan Normal University, Haikou 571158, China
- School
of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China
| | - Weiwei Xue
- School
of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China
| | - Jun Tan
- School
of Biological and Chemical Engineering, Chongqing University of Education, Chongqing 400067, China
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Li Z, Zhang Q, Gao Y, Wan F, Wang Y, Hou B, Cui W, Wang Y, Feng W, Hou Y. Luobitong Potentiates MTX's Anti-Rheumatoid Arthritis Activity via Targeting Multiple Inflammatory Pathways. J Inflamm Res 2024; 17:4389-4403. [PMID: 38994468 PMCID: PMC11236762 DOI: 10.2147/jir.s461093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Accepted: 06/18/2024] [Indexed: 07/13/2024] Open
Abstract
Background The LuoBiTong (LBT) capsule, a novel traditional Chinese medicine formulation, is currently in Phase III clinical trials. Preliminary preclinical and Phase II clinical studies suggest its efficacy and safety in treating rheumatoid arthritis (RA). However, the underlying mechanisms of its action remain to be elucidated.This research aims to explore the effects and mechanisms of LBT in conjunction with a maintenance dose of methotrexate (M-MTX) on RA. Methods A Collagen-Induced Arthritis (CIA) mouse model was used to evaluate the anti-RA effects of LBT combined with M-MTX. Assessments included foot swelling, arthritis scoring, serum inflammatory factor analysis, and histopathological examination of the foot. These effects were compared with those of high-dose MTX (H-MTX). Network pharmacology was employed to construct a compound-target network for RA, based on drug composition, to predict its potential mechanism of action. Flow cytometry, Western Blot, and immunohistochemical analyses in animal models identified multiple inflammatory pathways targeted by LBT to augment the anti-RA effects of MTX. Results The study revealed that LBT combined with M-MTX significantly alleviated CIA-induced arthritis without adverse effects. The combination of LBT and M-MTX showed similar or superior efficacy in regulating macrophage polarization, NF-κB, MAPK signaling pathways, and in the suppression of TH-17 expression in proinflammatory cells. These findings suggest that LBT may exert a multi-pathway therapeutic effect in RA treatment. The predicted pharmacological targets and mechanisms align well with this hypothesis. Conclusion LBT, when combined with MTX, enhances the anti-RA effect by targeting multiple inflammatory pathways, demonstrating significant therapeutic potential.
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Affiliation(s)
- Ziyu Li
- Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, People’s Republic of China
| | - Qiuyan Zhang
- New Drug Evaluation Center, Shijiazhuang Yiling Pharmaceutical Co., Ltd, Shijiazhuang, People’s Republic of China
| | - Yuhe Gao
- Graduate School, Heilongjiang University of Chinese Medicine, Harbin, People’s Republic of China
| | - Fang Wan
- Graduate School, Heilongjiang University of Chinese Medicine, Harbin, People’s Republic of China
| | - Yincang Wang
- Graduate School, Heilongjiang University of Chinese Medicine, Harbin, People’s Republic of China
| | - Bin Hou
- New Drug Evaluation Center, Shijiazhuang Yiling Pharmaceutical Co., Ltd, Shijiazhuang, People’s Republic of China
| | - Wenwen Cui
- National Key Laboratory for Innovation and Transformation of Luobing Theory, Shijiazhuang Yiling Pharmaceutical Co., Ltd, Shijiazhuang, People’s Republic of China
- Key Laboratory of State Administration of TCM (Cardio-Cerebral VesselCollateral Disease), Shijiazhuang, People’s Republic of China
| | - Yanan Wang
- New Drug Evaluation Center, Shijiazhuang Yiling Pharmaceutical Co., Ltd, Shijiazhuang, People’s Republic of China
| | - Wei Feng
- New Drug Evaluation Center, Shijiazhuang Yiling Pharmaceutical Co., Ltd, Shijiazhuang, People’s Republic of China
| | - Yunlong Hou
- National Key Laboratory for Innovation and Transformation of Luobing Theory, Shijiazhuang Yiling Pharmaceutical Co., Ltd, Shijiazhuang, People’s Republic of China
- Key Laboratory of State Administration of TCM (Cardio-Cerebral VesselCollateral Disease), Shijiazhuang, People’s Republic of China
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An M, Zhang J, Zhang X, Zhao Y, Liu Y. Nanomedicine targeted anti-inflammatory therapy to deal with the 'crux' of rheumatoid arthritis. J Drug Target 2024; 32:381-392. [PMID: 38321981 DOI: 10.1080/1061186x.2024.2315475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 01/30/2024] [Indexed: 02/08/2024]
Abstract
Rheumatoid arthritis is a chronic and complex autoimmune disease that is marked by an inflammatory response, synovial hyperplasia, vascularisation, fascial formation, cartilage and bone destruction, which can lead to joint deformity and even loss of function, ultimately affecting a person's health and quality of life. Although the pathogenesis of RA is unclear, growing evidence suggests that inflammation-associated cells infiltrate joints, causing tissue damage, inflammation and pain. This disruption in the balance between host tolerance and immune homeostasis the progression of RA. Existing drug therapy and surgical treatments for RA are unable to completely cure the disease or reverse its accelerated progression. Therefore, the design and development of an appropriate and effective drug delivery system will substantially improve the therapeutic effect. In this review, by describing the inflammatory microenvironment of rheumatoid arthritis and the associated inflammatory cells, the progress of targeting strategies and applications of nanotechnology in the disease is summarised, which will be helpful in providing new ideas for the subsequent treatment of rheumatoid arthritis.
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Affiliation(s)
- Min An
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, Yinchuan, China
| | - Juntao Zhang
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, Yinchuan, China
| | - Xiaojie Zhang
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, Yinchuan, China
| | - Yumeng Zhao
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, Yinchuan, China
| | - Yanhua Liu
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, Yinchuan, China
- Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, Yinchuan, China
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Xiao T, Cheng X, Zhi Y, Tian F, Wu A, Huang F, Tao L, Guo Z, Shen X. Ameliorative effect of Alangium chinense (Lour.) Harms on rheumatoid arthritis by reducing autophagy with targeting regulate JAK3-STAT3 and COX-2 pathways. JOURNAL OF ETHNOPHARMACOLOGY 2024; 319:117133. [PMID: 37690476 DOI: 10.1016/j.jep.2023.117133] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 08/30/2023] [Accepted: 09/04/2023] [Indexed: 09/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Alangium chinense has been used as traditional folk medicine for centuries to treat rheumatoid arthritis (RA) by Guizhou Miao nationality with remarkable clinical effect. But the mechanism of its anti-RA is not fully clarified. AIM OF THE STUDY To explore the effect and underlying mechanism of A. chinense against RA. MATERIAL AND METHODS RA rats were induced by CII/IFA, and oral administrated with or without ethyl acetate extracts of Alangium chinense (ACEE) and tripterygium glycosides (GTW). Then arthritis scores, inflammatory factors in serum and histological evaluation were evaluated to assess the degree of joints disease. Proteomics were conducted via LC-MS/MS to clarify the mechanism of ACEE preliminarily, and further examined by immunohistochemistry, immunofluorescence, western botting, and molecular docking. RESULTS ACEE decreased joints swelling, cell abscission and necrosis of joint tissues arthropathy of RA rats, and attenuated expression of TNF-α, IL-1β, IL-6, PGE2, TGF-β. Meanwhile, differentially expressed proteins in the ACEE treated groups were observed, which were involved in RA, spliceosome, cell adhesion molecules, phagosome and lysosome signaling pathways. Moreover, ACEE significantly ameliorated arthropathy, suppressed JAK-STAT pathway (JAK3, p-JAK3, STAT3, iNOS, RANKL), COX-2 pathway (COX-2, TNF-α, IL-6I, L-1β, 5-LOX), and autophagic signaling pathway (LC3-Ⅰ, LC3-Ⅱ, p62, mTOR). But it showed little effect on the expression of COX-1, JAK1, JAK2, TyK2. CONCLUSION It is the first evidence that A. chinense significantly ameliorates RA, and the underlying immune mechanism involves reducing autophagy with targeting regulate JAK3-STAT3 and COX-2 pathways.
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Affiliation(s)
- Ting Xiao
- The State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550025, China; The Department of Pharmacology of Materia Medica (The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and The High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability), School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550031, China; The Key Laboratory of Optimal Utilization of Natural Medicine Resources (The Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550031, China.
| | - Xingyan Cheng
- The State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550025, China; The Department of Pharmacology of Materia Medica (The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and The High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability), School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550031, China; The Key Laboratory of Optimal Utilization of Natural Medicine Resources (The Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550031, China.
| | - Yuan Zhi
- The State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550025, China; The Department of Pharmacology of Materia Medica (The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and The High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability), School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550031, China; The Key Laboratory of Optimal Utilization of Natural Medicine Resources (The Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550031, China.
| | - Fangfang Tian
- The State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550025, China; The Department of Pharmacology of Materia Medica (The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and The High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability), School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550031, China; The Key Laboratory of Optimal Utilization of Natural Medicine Resources (The Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550031, China.
| | - Ai Wu
- The State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550025, China; The Department of Pharmacology of Materia Medica (The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and The High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability), School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550031, China; The Key Laboratory of Optimal Utilization of Natural Medicine Resources (The Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550031, China.
| | - Feilong Huang
- The State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550025, China; The Department of Pharmacology of Materia Medica (The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and The High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability), School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550031, China; The Key Laboratory of Optimal Utilization of Natural Medicine Resources (The Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550031, China.
| | - Ling Tao
- The State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550025, China; The Department of Pharmacology of Materia Medica (The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and The High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability), School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550031, China; The Key Laboratory of Optimal Utilization of Natural Medicine Resources (The Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550031, China.
| | - Zhenghong Guo
- School of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China.
| | - Xiangchun Shen
- The State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550025, China; The Department of Pharmacology of Materia Medica (The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province and The High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability), School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550031, China; The Key Laboratory of Optimal Utilization of Natural Medicine Resources (The Union Key Laboratory of Guiyang City-Guizhou Medical University), School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550031, China.
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Wang W, Zhou S, Jiang W, Chen G. Design, synthesis and anti-rheumatoid arthritis activity of target TLR4 inhibitors. Bioorg Med Chem 2024; 97:117539. [PMID: 38070351 DOI: 10.1016/j.bmc.2023.117539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 11/17/2023] [Accepted: 11/21/2023] [Indexed: 12/30/2023]
Abstract
A series of 1-(2-oxocyclohexyl)butane-1, 3-dione derivatives were designed and synthesized as TLR4 inhibitors by modifying the core structure of the lead compound ((6, 8-dioxo-1, 2, 3, 4, 6, 7, 8, 8a-octahydronaphthalen-2-yl) carbamate)). In vitro, compound 3p significantly inhibited the proliferation of rat synovial cells, inhibited the proliferation of LPS-induced RAW264.7 cells, and inhibited TLR4 activity, with IC50 values of 1.21 ± 0.09 μM, 0.73 ± 0.05 μM and 0.43 ± 0.03 μM, respectively, which was superior to the positive control methotrexate. In vivo anti-rheumatoid arthritis evaluation, compound 3p can significantly inhibit the inflammatory factors TNF-α, IL-1β and IL-6, so as to achieve the therapeutic purpose. In the preliminary mechanism study, compound 3p has obvious regulatory effects on the abnormal increase of TLR4, JAK2 and STAT3 protein and gene expression related to inflammatory signaling pathway in RAW264.7 cells. In summary, this study aims to develop more effective candidates for rheumatoid arthritis.
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Affiliation(s)
- Wenbin Wang
- Chongqing Chemical Industry Vocational College, Chongqing 401228, China; Chongqing (Changshou) Green Chemical and Material Industry Technology Research Institute, Chongqing 401228, China
| | - Shiyang Zhou
- Chongqing Chemical Industry Vocational College, Chongqing 401228, China; Chongqing (Changshou) Green Chemical and Material Industry Technology Research Institute, Chongqing 401228, China; Key Laboratory of Tropical Medicinal Plant Chemistry of Hainan Province, Hainan Normal University, Haikou 571158, China; Chongqing Academy of Traditional Chinese Medicine, Chongqing 400065, China; Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing 400067, China.
| | - Wenming Jiang
- Chongqing Chemical Industry Vocational College, Chongqing 401228, China; Chongqing (Changshou) Green Chemical and Material Industry Technology Research Institute, Chongqing 401228, China
| | - Guangying Chen
- Key Laboratory of Tropical Medicinal Plant Chemistry of Hainan Province, Hainan Normal University, Haikou 571158, China.
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Wang S, Yin J, Liu Y, Jin M, Wang Q, Guo J, Gao Z. An organic state trace element solution for rheumatoid arthritis treatment by modulating macrophage phenotypic from M1 to M2. Biomed Pharmacother 2024; 170:116025. [PMID: 38113625 DOI: 10.1016/j.biopha.2023.116025] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 12/02/2023] [Accepted: 12/14/2023] [Indexed: 12/21/2023] Open
Abstract
Trace elements (TEs) are essential for the treatment of rheumatoid arthritis (RA). This study aimed to prepare a TEs solution enriched with various organic states to evaluate its preventive, therapeutic effects, and mechanism of action in RA and to provide a treatment method for RA treatment. The TEs in natural ore were extracted and added to 0.5% (W/V) L-alanyl-L-glutamine (LG) to obtain a TEs solution (LG-WLYS), which was examined for its concentration and quality. The antioxidant properties and effects of LG-WLYS on cell behavior were evaluated at the cellular level. The preventive and therapeutic effects and mechanism of action of LG-WLYS in rats with RA were explored. The LG-WLYS solution was clear, free from visible foreign matter, and had a pH of 5.33 and an osmolality of 305.67 mOsmol/kg. LG-WLYS inhibited cell migration and angiogenesis. LG-WLYS solution induced macrophages to change from M1-type to M2-type, increased the content of antioxidant enzymes (glutathione, superoxide dismutase, and IL-10), decreased the levels of nitric oxide, malondialdehyde, TNF-α, IL-1β, IL-6, COX-2, and iNOs, scavenging reactive oxygen species from the lesion site, inhibiting the apoptosis of chondrocytes, regulating inflammatory microenvironment, and decreasing inflammation response to exert the therapeutic effect for RA. In conclusion, LG-WLYS has outstanding therapeutic and preventive effects against RA and has enormous potential for further development.
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Affiliation(s)
- Shuangqing Wang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Jishan Yin
- Beijing JINSHAN Ecological Power element Manufactu Co., Ltd, Beijing 101300, China
| | - Yanhong Liu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Mingji Jin
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Qiming Wang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Jianpeng Guo
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China
| | - Zhonggao Gao
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
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Wu Z, Zhang T, Ma X, Guo S, Zhou Q, Zahoor A, Deng G. Recent advances in anti-inflammatory active components and action mechanisms of natural medicines. Inflammopharmacology 2023; 31:2901-2937. [PMID: 37947913 DOI: 10.1007/s10787-023-01369-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 09/16/2023] [Indexed: 11/12/2023]
Abstract
Inflammation is a series of reactions caused by the body's resistance to external biological stimuli. Inflammation affects the occurrence and development of many diseases. Anti-inflammatory drugs have been used widely to treat inflammatory diseases, but long-term use can cause toxic side-effects and affect human functions. As immunomodulators with long-term conditioning effects and no drug residues, natural products are being investigated increasingly for the treatment of inflammatory diseases. In this review, we focus on the inflammatory process and cellular mechanisms in the development of diseases such as inflammatory bowel disease, atherosclerosis, and coronavirus disease-2019. Also, we focus on three signaling pathways (Nuclear factor-kappa B, p38 mitogen-activated protein kinase, Janus kinase/signal transducer and activator of transcription-3) to explain the anti-inflammatory effect of natural products. In addition, we also classified common natural products based on secondary metabolites and explained the association between current bidirectional prediction progress of natural product targets and inflammatory diseases.
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Affiliation(s)
- Zhimin Wu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Tao Zhang
- College of Animal Science and Technology, Anhui Agricultural University, Hefei, China
| | - Xiaofei Ma
- College of Veterinary Medicine, Gansu Agriculture University, Lanzhou, China
| | - Shuai Guo
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Qingqing Zhou
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Arshad Zahoor
- College of Veterinary Sciences, The University of Agriculture Peshawar, Peshawar, Pakistan
| | - Ganzhen Deng
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.
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15
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He S, Huang C, Tan N, Zhang J. Oridonin Promotes Apoptosis in Rheumatoid Arthritis Fibroblast-like Synoviocytes Through PERK/eIF2α/CHOP of Endoplasmic Reticulum Stress Pathway. DNA Cell Biol 2023; 42:711-719. [PMID: 37862122 PMCID: PMC10712354 DOI: 10.1089/dna.2023.0244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 08/15/2023] [Accepted: 09/06/2023] [Indexed: 10/22/2023] Open
Abstract
Oridonin (ORI), derived from Chinese herbs Rabdosia rubescens, has anti-inflammatory, proapoptotic, anticancer effects. Previous studies have found that ORI induces apoptosis in rheumatoid arthritis fibroblast synovial cells (RA-FLSs), but this mechanism is not clear. We will investigate the apoptosis mechanism of ORI on RA-FLSs. RA-FLSs were treated with various concentrations of ORI (0, 5, 10, 15, 20, 25, and 30 μM) for 24 h. CCK8, LDH, and hochest/PI assay determined the viability, cytotoxicity, and death of ORI on RA-FLSs. The endoplasmic reticulum probe was used to observe structural changes of endoplasmic reticulum in RA-FLSs. RNA expression was detected with RNA sequencing analysis and quantitative real-time PCR. The PERK/eIF2α/CHOP pathway protein of the endoplasmic reticulum was verified with Western Blot. Our results show that ORI induced the apoptosis of RA-FLSs from CCK8, LDH, and Hochest/PI. The endoplasmic reticulum distribution was altered in RA-FLSs after being treated with ORI. Bioinformatics analysis of RNA sequencing data found that 1453 genes were elevated. The PERK/eIF2α/CHOP pathway of the endoplasmic reticulum was regulated from the Gene ontology and KEGG analysis. The results of quantitative real-time PCR and Western blot analysis verified the regulation of PERK/eIF2α/CHOP pathway in RA-FLSs. Our data imply that the endoplasmic reticulum's PERK/eIF2α/CHOP signaling pathway is certainly implicated in the induction of RA-FLS apoptosis by ORI. This study has important implications for the pharmacological effects of ORI and the treatment of RA.
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Affiliation(s)
- Shoudi He
- The Department of Rheumatology, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
- Guangzhou University of Chinese Medicine, Shenzhen, China
- Traditional Chinese Medicine Department of Rheumatism, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, China
| | - Changsheng Huang
- Traditional Chinese Medicine Department of Rheumatism, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, China
| | - Ning Tan
- Traditional Chinese Medicine Department of Rheumatism, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, China
| | - Jianyong Zhang
- The Department of Rheumatology, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
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He Q, Jia L, Wang X, Feng D, Mao T. Knockdown of BUB1 inhibits tumor necrosis factor-α-induced proliferation and migration of rheumatoid arthritis synovial fibroblasts by regulating PI3K/Akt pathway. Int J Rheum Dis 2023; 26:2024-2030. [PMID: 37593912 DOI: 10.1111/1756-185x.14865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 07/17/2023] [Accepted: 07/27/2023] [Indexed: 08/19/2023]
Abstract
BACKGROUND Rheumatoid arthritis (RA) is a common disease with joint cartilage destruction. BUB1 Mitotic Checkpoint Serine/Threonine Kinase (BUB1) is abnormally expressed in synovial tissues of RA patients, but its effect on RA remains unclear. In this study, we explored the role of BUB1 in RA. METHODS An RA cell model was constructed by treating MH7A cells with tumor necrosis factor-α (TNF-α). The levels of BUB1, GAPDH, phosphorylated phosphatidylinositol 3 kinase (p-PI3K)/PI3K, and phosphorylated serine/threonine kinase (p-Akt)/Akt in MH7A cells were examined by Western blot. The MH7A cell proliferation was examined by colony formation assay. Wound healing assay and transwell assay were carried out to detect MH7A cell migration and invasion. The mRNA levels of proinflammatory cytokines were assessed by quantitative reverse transcription polymerase chain reaction. RESULTS The results showed that knockdown BUB1 inhibited TNF-α-induced MH7A cell proliferation, migration, and invasion. Silencing BUB1 repressed the PI3K/Akt pathway in TNF-α-induced MH7A cells. We also found that the TNF-α-induced MH7A cell proliferation, migration, and invasion were repressed by si-BUB1 transfection, whereas these effects were attenuated by 740Y-P (an activator of the PI3K pathway) co-treatment. Knockdown of BUB1 reduced the expression of the proinflammatory cytokines. CONCLUSION Knockdown BUB1 repressed TNF-α-induced MH7A cell proliferation, migration and invasion through the PI3K/Akt pathway.
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Affiliation(s)
- Qian He
- Department of Rheumatism and Immunology, The First Affiliated Hospital of Wannan Medical College, Wuhu, China
| | - Lanlan Jia
- Department of Rheumatism and Immunology, The First Affiliated Hospital of Wannan Medical College, Wuhu, China
| | - Xiaowan Wang
- Department of Rheumatism and Immunology, The First Affiliated Hospital of Wannan Medical College, Wuhu, China
| | - Dandan Feng
- Department of Rheumatism and Immunology, The First Affiliated Hospital of Wannan Medical College, Wuhu, China
| | - Tongjun Mao
- Department of Rheumatism and Immunology, The First Affiliated Hospital of Wannan Medical College, Wuhu, China
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Zhang Y, Cai X, Wang B, Zhang B, Xu Y. Exploring the molecular mechanisms of the involvement of GZMB-Caspase-3-GSDME pathway in the progression of rheumatoid arthritis. Mol Immunol 2023; 161:82-90. [PMID: 37531918 DOI: 10.1016/j.molimm.2023.07.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 07/26/2023] [Accepted: 07/28/2023] [Indexed: 08/04/2023]
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease with an unclear pathogenesis. Granzyme B (GZMB) has been reported as a potential therapeutic target for RA treatment, but its mechanism remains unclear. This study aimed to explore the molecular mechanism of the GZMB-Caspase-3-GSDME pathway in the progression of RA. An SD rat model of RA was constructed, and Western blot analysis was used to verify the high expression of the GZMB gene in RA rats. Functional validation was then performed on two common RA cells, HFLS-RA cells and MH7A cells, by inhibiting the GZMB gene with the GZMB siRNA virus. Cell proliferation function was measured by CCK8 and EDU assays; cell pyroptosis markers were detected by the LDH assay; inflammation factor levels were measured by ELISA; and the expression of GZMB and pathway-related genes and proteins was measured by Western blot. After GZMB silencing, cell proliferation was decreased compared to the control group, and the inflammation factors IL-1b and IL-18, as well as the pyroptosis markers LDH, IL-1b, and IL-18, were all reduced. The GZMB-related proteins GZMB, caspase-3, and Gasdermin E (GSDME) were also decreased. Therefore, GZMB silencing reduces pyroptosis by inhibiting caspase-3 and Gasdermin E decomposition. In summary, GZMB silencing inhibits the activation of caspase-3 and Gasdermin E, thereby delaying inflammation in RA. The GZMB gene may be a potential therapeutic target for RA.
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Affiliation(s)
- Yue Zhang
- Kunming Medical University, No.1168, Chunrong West Road, Yuhua Street,Chenggong District, Kunming 650500, China; Department of Orthopaedics, 920th Hospital of the Joint Logistics Support Force of the Chinese People's Liberation Army, Kunming 650032, China
| | - Xingbo Cai
- Kunming Medical University, No.1168, Chunrong West Road, Yuhua Street,Chenggong District, Kunming 650500, China; Department of Orthopaedics, 920th Hospital of the Joint Logistics Support Force of the Chinese People's Liberation Army, Kunming 650032, China
| | - Bin Wang
- Kunming Medical University, No.1168, Chunrong West Road, Yuhua Street,Chenggong District, Kunming 650500, China; Department of Orthopaedics, 920th Hospital of the Joint Logistics Support Force of the Chinese People's Liberation Army, Kunming 650032, China
| | - Bihuan Zhang
- Kunming Medical University, No.1168, Chunrong West Road, Yuhua Street,Chenggong District, Kunming 650500, China; Department of Orthopaedics, 920th Hospital of the Joint Logistics Support Force of the Chinese People's Liberation Army, Kunming 650032, China
| | - Yongqing Xu
- Department of Orthopaedics, 920th Hospital of the Joint Logistics Support Force of the Chinese People's Liberation Army, Kunming 650032, China.
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Lu H, Lu X, Xie Q, Wan H, Sun Y. TTC4 inhibits NLRP3 inflammation in rheumatoid arthritis by HSP70. Int J Rheum Dis 2023; 26:1751-1759. [PMID: 37431792 DOI: 10.1111/1756-185x.14818] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 05/24/2023] [Accepted: 06/21/2023] [Indexed: 07/12/2023]
Abstract
OBJECTIVE This experiment explored the function of TTC4 in rheumatoid arthritis inflammation and its possible mechanism. METHODS C57BL/6 mice were immunized intradermally with bovine type II collagen. Lipopolysaccharide induction was performed on RAW264.7 cells. RESULTS The mRNA expression of TTC4 in articular tissue of mice with rheumatoid arthritis was downregulated. Sh-TTC4 virus increased arthritis score, morphological change score, paw edema, and spleen index, as well as alkaline phosphatase level in mice with rheumatoid arthritis. Sh-TTC4 virus increased the levels of inflammatory factors and MDA, and decreased anti-oxidant factors in articular tissue of mice with rheumatoid arthritis. TTC4 reduced inflammation and oxidative stress in an in vitro model. TTC4 regulated HSP70 in a rheumatoid arthritis model. The inhibition of HSP70 reduced the effects of sh-TTC4 gene in mice with rheumatoid arthritis. METTL3 reduced the stability of the TTC4 gene. CONCLUSION In this study, the TTC4 gene reduced oxidative response and inflammation in the rheumatoid arthritis model through the HSP70/NLRP3 pathway. Therefore, it can be concluded that TTC4 can be used as diagnosis and prognosis evaluation of rheumatoid arthritis.
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Affiliation(s)
- Hui Lu
- Department of Orthopedics, Nantong Third People's Hospital of Nantong University, Nantong City, China
| | - Xin Lu
- Department of Orthopedics, Nantong Third People's Hospital of Nantong University, Nantong City, China
| | - Qihua Xie
- Department of Endocrinology, Nantong Third People's Hospital of Nantong University, Nantong City, China
| | - Honglai Wan
- Department of Orthopedics, Nantong Third People's Hospital of Nantong University, Nantong City, China
| | - Yuyu Sun
- Department of Orthopedics, Nantong Third People's Hospital of Nantong University, Nantong City, China
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Lin W, Liu Y, Zhang S, Xu S, Qiu Q, Wang C, Liu D, Shen C, Xu M, Shi M, Xiao Y, Chen G, Xu H, Liang L. Schisandrin treatment suppresses the proliferation, migration, invasion, and inflammatory responses of fibroblast-like synoviocytes from rheumatoid arthritis patients and attenuates synovial inflammation and joint destruction in CIA mice. Int Immunopharmacol 2023; 122:110502. [PMID: 37390648 DOI: 10.1016/j.intimp.2023.110502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Revised: 05/30/2023] [Accepted: 06/11/2023] [Indexed: 07/02/2023]
Abstract
BACKGROUND Rheumatoid arthritis (RA) is a systemic autoimmune disease causing joint dysfunction. As disease-modifying anti-rheumatic drugs (DMARDs) have poor efficacy in 20% to 25% of RA patients, additional novel RA medications are urgently needed. Schisandrin (SCH) has multiple therapeutic effects. However, whether SCH is effective against RA remains unknown. PURPOSE To investigate how SCH affects the abnormal behaviours of RA fibroblast-like synoviocytes (FLSs) and further elucidate the underlying mechanism of SCH in RA FLSs and collagen-induced arthritis (CIA) mice. METHODS Cell Counting Kit-8 (CCK8) assays were used to characterize cell viability. EdU assays were performed to assess cell proliferation. Annexin V-APC/PI assays were used to determine apoptosis. Transwell chamber assays were used to measure cell migration and invasion in vitro. RT-qPCR was used to assess proinflammatory cytokine and MMP mRNA expression. Western blotting was used to detect protein expression. RNA sequencing was performed to explore the potential downstream targets of SCH. CIA model mice were used to assess the treatment efficacy of SCH in vivo. RESULTS Treatments with SCH (50, 100, and 200 μΜ) inhibited RA FLSs proliferation, migration, invasion, and TNF-α-induced IL-6, IL-8, and CCL2 expression in a dose-dependent manner but did not affect RA FLSs viability or apoptosis. RNA sequencing and Reactome enrichment analysis indicated that SREBF1 might be the downstream target in SCH treatment. Furthermore, knockdown of SREBF1 exerted effects similar to those of SCH in inhibiting RA FLSs proliferation, migration, invasion, and TNF-α-induced expression of IL-6, IL-8, and CCL2. Both SCH treatment and SREBF1 knockdown decreased activation of the PI3K/AKT and NF-κB signalling pathways. Moreover, SCH ameliorated joint inflammation and cartilage and bone destruction in CIA model mice. CONCLUSION SCH controls the pathogenic behaviours of RA FLSs by targeting SREBF1-mediated activation of the PI3K/AKT and NF-κB signalling pathways. Our data suggest that SCH inhibits FLS-mediated synovial inflammation and joint damage and that SCH might have therapeutic potential for RA.
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Affiliation(s)
- Wei Lin
- Department of Rheumatology and Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong China
| | - Yingli Liu
- Department of Rheumatology and Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong China
| | - Shuoyang Zhang
- Department of Rheumatology and Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong China
| | - Siqi Xu
- Department of Rheumatology and Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong China
| | - Qian Qiu
- Department of Rheumatology and Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong China
| | - Cuicui Wang
- Department of Rheumatology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong China
| | - Di Liu
- Department of Rheumatology and Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong China
| | - Chuyu Shen
- Department of Rheumatology and Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong China
| | - Meilin Xu
- Department of Rheumatology and Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong China
| | - Maohua Shi
- Department of Rheumatology, The First People's Hospital of Foshan, Foshan, Guangdong China
| | - Youjun Xiao
- Department of Rheumatology and Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong China
| | - Guoqiang Chen
- Department of Rheumatology, The First People's Hospital of Foshan, Foshan, Guangdong China.
| | - Hanshi Xu
- Department of Rheumatology and Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong China.
| | - Liuqin Liang
- Department of Rheumatology and Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong China.
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Niu X, Yang Y, Yu J, Song H, Yu J, Huang Q, Liu Y, Zhang D, Han T, Li W. Panlongqi tablet suppresses adjuvant-induced rheumatoid arthritis by inhibiting the inflammatory reponse in vivo and in vitro. JOURNAL OF ETHNOPHARMACOLOGY 2023; 308:116250. [PMID: 36791928 DOI: 10.1016/j.jep.2023.116250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 02/03/2023] [Accepted: 02/06/2023] [Indexed: 06/18/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Panlongqi Tablet is prepared with the ancestral secret recipe provided by Mr. Wang Jiacheng, a famous specialist in orthopedics and traumatology of China. The efficacy and safety of PLQT have been supported by years of clinical practice in the treatment of joint-related conditions. Has remarkable effect for treating rheumatoid arthritis (RA) clinically. However, its mechanism is not entirely clear. AIM OF THE STUDY We aim to evaluate the anti-inflammatory activity of PLQT and explore its mechanism in adjuvant-induced arthritis (AA) mice and LPS-induced Human fibroblast-like synovial (HFLS) cells. MATERIALS AND METHODS To this end, we analyzed the active ingredients in PLQT by HPLC-MS/MS. Furthermore, the anti-RA effect of PLQT was studied through proliferation, apoptosis, foot swelling, cytokine levels, immune organ index, histopathology and related signal pathways in LPS-induced HFLS cells and AA-treated mice. RESULTS HPLC-MS/MS results showed that PLQT contained a variety of active compounds, such as epicatechin, imperatorin, hydroxysafflor yellow A and so on. PLQT significantly inhibited the abnormal proliferation of HFLS cells induced by LPS, promoted cell apoptosis. In AA-treated mice, PLQT alleviated RA symptoms by alleviating paw swelling, synovial hyperplasia, pannus formation, inflammatory cell infiltration, and inhibiting abnormal immune responses. The results showed that PLQT significantly decreased the expression of inflammatory mediators (IL-1β, IL-6, IL-17) in vivo and in vitro, which may be related to the regulation of PI3K/Akt, MAPK and JAK/STAT signaling pathways. CONCLUSION Based on serum pharmacology and in vivo pharmacology studies, PLQT may regulate RA symptoms by regulating inflammatory and immune response-related pathways, which is an effective method for the treatment of RA.
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Affiliation(s)
- Xiaofeng Niu
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, PR China
| | - Yajie Yang
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, PR China
| | - Jinjin Yu
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, PR China
| | - Huixin Song
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, PR China
| | - Jiabao Yu
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, PR China
| | - Qiuxia Huang
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, PR China
| | - Yang Liu
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, PR China
| | - Dezhu Zhang
- Shaanxi Panlong Pharmaceutical Group Limited By Share LTD, Xi'an, PR China
| | - Tengfei Han
- Shaanxi Panlong Pharmaceutical Group Limited By Share LTD, Xi'an, PR China.
| | - Weifeng Li
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, PR China.
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21
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Feng W, Zhong XQ, Zheng XX, Liu QP, Liu MY, Liu XB, Lin CS, Xu Q. The Underlying Mechanism of Duanteng Yimu Decoction in Inhibiting Synovial Hyperplasia in Rheumatoid Arthritis. J Immunol Res 2023; 2023:2340538. [PMID: 37252680 PMCID: PMC10225272 DOI: 10.1155/2023/2340538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 04/19/2023] [Accepted: 05/13/2023] [Indexed: 05/31/2023] Open
Abstract
Dysregulation of microRNAs (miRNAs) is associated with the pathogenesis of rheumatoid arthritis (RA). Our previous studies confirmed that Duanteng Yimu decoction (DTYMT) effectively inhibits RA fibroblast-like synoviocyte (FLS) proliferation. In this study, we investigated the influence of DTYMT on miR-221 in RA individuals. Hematoxylin-eosin (HE) staining was performed to assess histopathological alterations in collagen-induced arthritis (CIA) mice. The expression of miR-221-3p and TLR4 in PBMC, FLS, and cartilage was measured by RT-qPCR. In the in vitro experiments, DTYMT-containing serum was incubated with FLS-transfected miR-221 mimic or inhibitor. CCK-8 was performed to determine FLS proliferation, and the secretion of IL-1β, IL-6, IL-18, and TNF-α was quantified by ELISA assay. In addition, the regulation of miR-221 expression on FLS apoptosis was assessed using flow cytometry. Finally, western blot was employed to reflect TLR4/MyD88 protein levels. HE results showed that DTYMT effectively reduced synovial hyperplasia in the joints of CIA mice. RT-qPCR assay of FLS and cartilage of the model group showed that miR-221-3p and TLR4 significantly increased compared with those in the normal group. All outcomes were improved by DTYMT. The miR-221 mimic reversed the inhibitory effect of DTYMT-containing serum on FLS proliferation, the release of IL-1β, IL-18, IL-6, and TNF-α, and FLS apoptosis, as well as TLR4/MyD88 protein levels. The results showed that miR-221 promotes the activity of RA-FLS by activating TLR4/MyD88 signaling, and DTYMT treats RA by reducing miR-221 in CIA mice.
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Affiliation(s)
- Wei Feng
- The First Clinical Medicine School, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
- Department of Rheumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Xiao-Qin Zhong
- The First Clinical Medicine School, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
- Department of Rheumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Xue-Xia Zheng
- The First Clinical Medicine School, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
- Department of Rheumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Qing-Ping Liu
- The First Clinical Medicine School, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
- Department of Rheumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Min-Ying Liu
- The First Clinical Medicine School, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
- Department of Rheumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Xiao-Bao Liu
- The First Clinical Medicine School, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
- Department of Rheumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Chang-Song Lin
- The First Clinical Medicine School, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
- Department of Rheumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Qiang Xu
- The First Clinical Medicine School, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
- Department of Rheumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, China
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22
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Feng W, Wan X, Fan S, Liu CZ, Zheng XX, Liu QP, Liu MY, Liu XB, Lin CS, Zhang LJ, Li DT, Xu Q. Mechanism underlying the action of Duanteng-Yimu Tang in regulating Treg/Th17 imbalance and anti-rheumatoid arthritis. Heliyon 2023; 9:e15867. [PMID: 37206012 PMCID: PMC10189174 DOI: 10.1016/j.heliyon.2023.e15867] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 04/19/2023] [Accepted: 04/24/2023] [Indexed: 05/21/2023] Open
Abstract
Background Rheumatoid arthritis (RA) is a chronic immune disease characterised by synovitis and cartilage destruction. Currently, many patients experience poor remission after new antirheumatic drug treatments. Duanteng-Yimu Tang (DTYMT), a traditional Chinese medicine, is effective in the treatment of RA. In this research, we designed to investigate the anti-RA effects of DTYMT and explore its potential mechanisms. Methods Network pharmacology was adopted to explore the main pathways of DTYMT in patients with RA. Collagen-induced arthritis models of male DBA/1 mice were established, and their histopathological changes were observed by hematoxylin-eosin staining and micro-CT. qRT-PCR was performed to detect the expression of Foxp3 and RORγt in the serum and synovial tissue and IL-17, IL-1β, TNF-α, and IL-10 mRNA in vivo. The proliferation and invasion of synovial cells were analyzed using Cell Counting Kit-8 and transwell assays, respectively. The ratio of T helper 17 (Th17) to regulatory T (Treg) cells was analyzed by flow cytometry. Results Network pharmacology analysis revealed that Th17 cell differentiation may be the key pathway of DTYMT in RA. DTYMT ameliorated joint damage, inhibited RORγt expression, and increased Foxp3 expression in CIA mice. DTYMT significantly decreased IL-1β, IL-17, and TNF-α mRNA levels, and increased IL-10 mRNA levels in IL-6-induced cells. Additionally, DTYMT inhibited Th17 cell differentiation and promoted Treg cell production, thus improving the Treg/Th17 imbalance. DTYMT also inhibited the proliferation, migration, and invasion of RA fibroblast-like synovial cells. Conclusions These results indicate that DTYMT could regulate the Treg/Th17 cell balance, which is a possible mechanism of DTYMT in treating RA.
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Affiliation(s)
- Wei Feng
- The First Clinical Medicine School, Guangzhou University of Chinese Medicine. Guangzhou 510405, China
- Department of Rheumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine. Guangzhou 510405, China
| | - Xin Wan
- The First Clinical Medicine School, Guangzhou University of Chinese Medicine. Guangzhou 510405, China
| | - Shirong Fan
- The First Clinical Medicine School, Guangzhou University of Chinese Medicine. Guangzhou 510405, China
- Department of Rheumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine. Guangzhou 510405, China
| | - Cui-Zhen Liu
- The First Clinical Medicine School, Guangzhou University of Chinese Medicine. Guangzhou 510405, China
| | - Xue-Xia Zheng
- The First Clinical Medicine School, Guangzhou University of Chinese Medicine. Guangzhou 510405, China
- Department of Rheumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine. Guangzhou 510405, China
| | - Qing-Ping Liu
- The First Clinical Medicine School, Guangzhou University of Chinese Medicine. Guangzhou 510405, China
- Department of Rheumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine. Guangzhou 510405, China
| | - Min-Ying Liu
- The First Clinical Medicine School, Guangzhou University of Chinese Medicine. Guangzhou 510405, China
- Department of Rheumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine. Guangzhou 510405, China
| | - Xiao-Bao Liu
- The First Clinical Medicine School, Guangzhou University of Chinese Medicine. Guangzhou 510405, China
- Department of Rheumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine. Guangzhou 510405, China
| | - Chang-Song Lin
- The First Clinical Medicine School, Guangzhou University of Chinese Medicine. Guangzhou 510405, China
- Department of Rheumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine. Guangzhou 510405, China
| | - Li-juan Zhang
- Department of Otorhinolaryngology, Zhongshan Hospital Affiliated to Guangzhou University of Chinese Medicine, Zhongshan, China
- Department of Pharmacy, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Corresponding author. Department of Pharmacy, the First Affiliated Hospital of Guangzhou University of Chinese Medicine. Guangzhou 510405, China.
| | - De-tang Li
- Department of Pharmacy, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Corresponding author.
| | - Qiang Xu
- The First Clinical Medicine School, Guangzhou University of Chinese Medicine. Guangzhou 510405, China
- Department of Rheumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine. Guangzhou 510405, China
- Corresponding author. Department of Rheumatology, the First Affiliated Hospital of Guangzhou University of Chinese Medicine. Guangzhou 510405, China.
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23
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Jia P, Zhang W, Shi Y. NFIC attenuates rheumatoid arthritis-induced inflammatory response in mice by regulating PTEN/SENP8 transcription. Tissue Cell 2023; 81:102013. [PMID: 36669387 DOI: 10.1016/j.tice.2023.102013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 12/19/2022] [Accepted: 01/04/2023] [Indexed: 01/07/2023]
Abstract
OBJECTIVE To explore whether nuclear factor I C (NFIC) alleviated inflammatory response of synovial fibroblasts (SFs) caused by rheumatoid arthritis (RA) by regulating transcription levels of phosphatase and tension homolog deleted on chromosome 10 (PTEN) and sentrin-specific protease 8 (SENP8). METHODS NFIC, PTEN, and SENP8 levels in RASFs and normal SFs (NSFs) were measured by qRT-PCR and western blotting. The levels of Bax, Bcl-2, MMP-3, and MMP-13, as well as the content of superoxide dismutase (SOD) and malondialdehyde (MDA) were determined in RASFs and NSFs using western blotting and ELISA. The binding of NFIC to promoter sequences of PTEN and SENP8 was predicted and verified. A mouse model of collagen-induced arthritis (CIA) was established and evaluated according to the degree of joint swelling and arthritis index. RESULTS NFIC, PTEN, and SENP8 were downregulated in RASFs. RASFs had increased viability and MDA levels as well as decreased cell apoptosis and SOD content. NFIC was demonstrated to modulate the transcription of PTEN and SENP8 as their transcription factor. NFIC ameliorated the inflammatory response induced by RA in vivo by promoting the transcription of PTEN and SENP8. CONCLUSION NFIC acted as a transcription factor to facilitate the transcription of PTEN and SENP8, thereby inducing apoptosis of RASFs and effectively attenuating inflammatory response in CIA mice.
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Affiliation(s)
- Pengfei Jia
- Department of Spinal Surgery, Suizhou Central Hospital, Hubei University of Medicine, Suizhou, Hubei 441300, PR China
| | - Wen Zhang
- Department of Spinal Surgery, Suizhou Central Hospital, Hubei University of Medicine, Suizhou, Hubei 441300, PR China
| | - Yongyan Shi
- Department of Spinal Surgery, Suizhou Central Hospital, Hubei University of Medicine, Suizhou, Hubei 441300, PR China.
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24
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Wikan N, Tocharus J, Oka C, Sivasinprasasn S, Chaichompoo W, Suksamrarn A, Tocharus C. The capsaicinoid nonivamide suppresses the inflammatory response and attenuates the progression of steatosis in a NAFLD-rat model. J Biochem Mol Toxicol 2023; 37:e23279. [PMID: 36541345 DOI: 10.1002/jbt.23279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 04/28/2022] [Accepted: 12/08/2022] [Indexed: 12/24/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is relatively associated with comorbidities in obesity and metabolic inflammation. Low-grade inflammation following the high-fat diet (HFD)-induced NAFLD can promote the development of nonalcoholic steatohepatitis (NASH) through particularly liver-resident immune cell recruitment and hepatic nuclear factor kappa B (NF-κB) pathway. Therefore, inflammatory intervention may contribute to NASH reduction. Pelargonic acid vanillylamide (PAVA) or nonivamide is one of the pungent capsaicinoids of Capsicum species and has been found in chili peppers. Our previous study demonstrated that PAVA improved hepatic function, decreased oxidative stress and reduced apoptotic cell death but the insight role of PAVA on NAFLD is still unclear. Thus, this study aimed to investigate the underlying anti-inflammatory mechanism of PAVA in an NAFLD-rat model. Male Sprague Dawley rats were fed with normal diet or HFD for 16 weeks. Then high-fat rats were given vehicle or PAVA (1 mg/kg/day) for another 4 weeks. We found that PAVA alleviated hepatic inflammation associated with the reducing toll-like receptor 4/NF-κB pathway, showing significantly lower recruitment of cluster of differentiation 44. PAVA also maintained activity of insulin signaling pathway, and attenuated NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome formation. NAFLD progresses to NASH through transforming growth factor (TGF-β1), and also recovery to simple stage followed by PAVA suppresses pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-1β, interleukin-6, and Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway. Therefore, our findings suggest that PAVA provides a novel therapeutic approach for NAFLD and slows the progression to NASH.
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Affiliation(s)
- Naruemon Wikan
- Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Jiraporn Tocharus
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Chio Oka
- Functional Genomics and Medicine, Division of Biological Science, Nara Institute of Science and Technology, Ikoma, Nara, Japan
| | | | - Waraluck Chaichompoo
- Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok, Thailand
| | - Apichart Suksamrarn
- Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok, Thailand
| | - Chainarong Tocharus
- Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Center for Research and Development of Natural Products for Health, Chiang Mai University, Chiang Mai, Thailand
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25
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Zhou H, Huang L, Zhan K, Liu X. Wenhua Juanbi Recipe Attenuates Rheumatoid Arthritis via Inhibiting miRNA-146a-Mediated Autophagy. BIOMED RESEARCH INTERNATIONAL 2022; 2022:1768052. [PMID: 36440364 PMCID: PMC9683957 DOI: 10.1155/2022/1768052] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 10/16/2022] [Accepted: 10/18/2022] [Indexed: 08/23/2023]
Abstract
Background Wenhua Juanbi Recipe (WJR) is widely used for the treatment of rheumatoid arthritis (RA) in China. However, its mechanism of action remains unclear. This study was designed to investigate the potential therapeutic effects of WJR on the proliferation and apoptosis of synovial fibroblasts in RA and its efficacy in inhibiting miRNA-146a-mediated cellular autophagy. Methods A collagen-induced arthritis (CIA) Wistar rat model was established. The model rats were administered WJR or methotrexate (MTX) to assess the therapeutic effect of the drugs. The chemical components of WJR were analyzed using UPLC-Q/TOF-MS. Histological changes; miRNA-146a, ATG5, ATG7, ATG12, Beclin1, LC3II, Bax, and Bcl2 expression; synovial apoptosis; and cellular proliferation were assessed. Primary synovial fibroblasts (FLS) were cultured in vitro using tissue block and transfected with miRNA-146a; an autophagy inducer was added to FLS, inhibiting the PI3K/AKT/mTOR pathway. FLS were cocultured with WJR-containing serum to observe the effects of miRNA-146a-mediated autophagy via the PI3K/AKT/mTOR pathway on CIA-affected rats. Results Forty and thirty-one compounds were identified in WJR in the positive and negative ion modes, respectively. WJR significantly reduced toe swelling, arthritis scores, and expression of miRNA-146a and autophagy genes (ATG5, ATG7, ATG12, Beclin1, LC32, and Bcl2). Moreover, Bax expression, apoptosis, and attenuated proliferation were observed in rats. WJR could, therefore, regulate autophagy by influencing the miRNA-146a-mediated PI3K/AKT/mTOR pathway, which induces apoptosis and proliferation of FLS. Conclusion WJR can inhibit autophagy, apoptosis, and proliferation in a CIA rat model by inhibiting the miRNA-146a-mediated PI3K/AKT/mTOR pathway.
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Affiliation(s)
- Haili Zhou
- Second Clinical College, Zhejiang Chinese Medicine University, Hangzhou, Zhejiang 310000, China
| | - Liuyun Huang
- Second Clinical College, Zhejiang Chinese Medicine University, Hangzhou, Zhejiang 310000, China
| | - Kuijun Zhan
- Second Clinical College, Zhejiang Chinese Medicine University, Hangzhou, Zhejiang 310000, China
| | - Xide Liu
- Department of Arthropathy, Zhejiang Hospital of Integrated Traditional Chinese and Western Medicine, Hangzhou, Zhejiang 310000, China
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26
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Wu Y, Liu Y, Zhang L, Wen L, Xie Y. Aconiti lateralis radix praeparata total alkaloids exert anti-RA effects by regulating NF-κB and JAK/STAT signaling pathways and promoting apoptosis. Front Pharmacol 2022; 13:980229. [PMID: 36120302 PMCID: PMC9478898 DOI: 10.3389/fphar.2022.980229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 08/05/2022] [Indexed: 11/14/2022] Open
Abstract
Aconiti Lateralis Radix Praeparata (“Fuzi” in Chinese) is one of the traditional herbs widely used to intervene rheumatoid arthritis (RA), while Fuzi total alkaloids (FTAs) are the main bioactive components. However, the treatment targets and specific mechanisms of FTAs against RA have not been fully elucidated. The purpose of the present study was to confirm the anti-rheumatism effects of FTAs and reveal its potential molecular mechanisms. In TNF-α-induced MH7A cells model, we found that FTAs showed inhibitory effects on proliferation. While, FTAs significantly decreased the expression levels of IL-1β, IL-6, MMP-1, MMP-3, PGE2, TGF-β, and VEGF. FTAs also enhanced the progress of apoptosis and arrested the cell cycle at G0/G1 phase to prevent excessive cell proliferation. In addition, FTAs inhibited the hyperactivity of NF-κB and JAK/STAT signaling pathways, and regulated the cascade reaction of mitochondrial apoptosis signaling pathway. The results suggested that FTAs exerted anti-inflammatory effects by inhibiting NF-κB and JAK/STAT signaling pathways, promoted apoptosis by stimulating mitochondrial apoptosis signaling pathway, and inhibited cell proliferation by modulating cell cycle progression.
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Affiliation(s)
- Yeke Wu
- Department of Stomatology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Yi Liu
- Department of Pharmacy, Clinical Medical College & Affiliated Hospital of Chengdu University, Chengdu, Sichuan, China
| | - Lele Zhang
- School of Basic Medical Sciences, Chengdu University, Chengdu, Sichuan, China
| | - Lan Wen
- Department of Digestion and Endocrinology, Sichuan Provincial People’s Hospital Jinniu Hospital, Chengdu, Sichuan, China
| | - Yunfei Xie
- Department of Nuclear Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
- *Correspondence: Yunfei Xie,
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27
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Cai J, Zhang LC, Zhao RJ, Pu LM, Chen KY, Nasim AA, Leung ELH, Fan XX. Chelerythrine ameliorates rheumatoid arthritis by modulating the AMPK/mTOR/ULK-1 signaling pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 104:154140. [PMID: 35752081 DOI: 10.1016/j.phymed.2022.154140] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 04/07/2022] [Accepted: 04/28/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Rheumatoid arthritis (RA) is a long-term, progressive, and disabling autoimmune disease. It causes inflammation, swelling and pain in and around the joints and other body organs. Currently, no cure is available for RA. Clinical interventions can only relieve the condition, and at least 30% of RA patients do not respond to first‑line therapy. This means that the development of more effective therapies against RA is urgently needed. OBJECTIVE This study aimed to assess the anti-rheumatoid arthritis effect of chelerythrine (CLT) and explore its mechanism of action. METHODS The cytotoxic effect of CLT on human rheumatoid arthritis fibroblast-like synoviocyte (HFLS-RA) cells and HFLS-normal cells were measured by MTT assay. The growth and migration of HFLS-RA cells were determined by colony-formation and wound-healing assay. The level of intracellular reactive oxygen species (ROS) was detected using the DCFH-DA reagent. Cell apoptosis was measured by flow cytometry, TUNEL staining, caspase 3 activity, as well as the activation of apoptosis related proteins. In addition, the levels of autophagy related markers such as LC3B and P62 were determined by immunocytochemistry and western blotting. Lastly, the anti-RA effect of CLT was evaluated in an Adjuvant-Induced Arthritis(AIA) rat model and the severity of arthritis was detected and quantified using macroscopic inspection and X‑ray imaging. RESULTS We discovered that treatment with CLT effectively inhibited the migration and colony-formation of the HFLS-RA cells and resulted in cell death. Moreover, CLT increased the intracellular level of ROS and the apoptotic rate of HFLS-RA by activating the AMPK/mTOR/ULK-1 signaling pathways. In vivo study showed CLT effectively ameliorated AIA in rats, protecting them from inflammation and bone damage. CONCLUSION Our study shows CLT is an effective agent for ameliorating RA in vitro and in vivo by modulation of the AMPK/mTOR/ULK-1 signaling pathway. These findings indicate that CLT is a great potential candidate for development as a therapeutic agent for the prevention and treatment of RA.
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Affiliation(s)
- Jun Cai
- Dr.Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau (S.A.R.), China
| | - Lu-Chen Zhang
- Dr.Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau (S.A.R.), China
| | - Ren-Jie Zhao
- Dr.Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau (S.A.R.), China
| | - Li-Min Pu
- Dr.Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau (S.A.R.), China
| | - Ke-Yuan Chen
- Dr.Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau (S.A.R.), China
| | - Ali Adnan Nasim
- Dr.Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau (S.A.R.), China
| | - Elaine Lai-Han Leung
- Dr.Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau (S.A.R.), China; Department of Respiratory and Critical Care Medicine, Taihe Hospital, Hubei University of Medicine, Hubei, China.
| | - Xing-Xing Fan
- Dr.Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau (S.A.R.), China.
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Lin W, Chen G, Mao Y, Ma X, Zhou J, Yu X, Wang C, Liu M. Imperatorin Inhibits Proliferation, Migration, and Inflammation via Blocking the NF-κB and MAPK Pathways in Rheumatoid Fibroblast-like Synoviocytes. ACS OMEGA 2022; 7:29868-29876. [PMID: 36061691 PMCID: PMC9434770 DOI: 10.1021/acsomega.2c02766] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 08/02/2022] [Indexed: 06/15/2023]
Abstract
Rheumatoid arthritis (RA) is a chronic joint inflammatory disease associated with the aberrant activation of fibroblast-like synoviocytes (FLSs). Searching for natural compounds that may suppress the activation of FLSs has become a complementary approach for RA treatment. Here, we investigated the effects and mechanisms of imperatorin (IPT) on proliferation, migration, and inflammation in primary cultured arthritic FLSs. We found that IPT significantly suppressed TNFα-induced proliferation and migration of arthritic FLSs, but showed little effect on survival and apoptosis. In addition, IPT treatment significantly reduced the TNFα-induced expression of pro-inflammatory cytokines (IL-1β, TNFα, IL-6, and IL-8) in arthritic FLSs. Further mechanism studies suggested that IPT inhibited the activations of p38 and extracellular signal-regulated kinase (ERK). Also, IPT blocked the nuclear factor of κB (NF-κB) activation by suppressing the phosphorylation and degradation of IκBα, thereby preventing the translocation of p65. Collectively, our results demonstrated that IPT could inhibit the over-activated phenotypes of arthritic FLSs via the mitogen-activated protein kinase (MAPK) (p38 and ERK) and NF-κB pathways leading to the down-regulation of pro-inflammatory cytokines, which might be beneficial to the anti-proliferative and anti-migratory activities of FLS cells. These findings suggest that IPT has the potential to be developed as a novel agent for RA treatment.
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Affiliation(s)
- Wei Lin
- Jiangsu
Key Laboratory for Molecular and Medical Biotechnology, College of
Life Sciences, Nanjing Normal University, Nanjing 210023, China
- Spine
and Joint Surgery, People’s Hospital
Affiliated to Shandong First Medical University, Jinan 271199, China
| | - Gang Chen
- Jiangsu
Key Laboratory for Molecular and Medical Biotechnology, College of
Life Sciences, Nanjing Normal University, Nanjing 210023, China
| | - Yuhang Mao
- Jiangsu
Key Laboratory for Molecular and Medical Biotechnology, College of
Life Sciences, Nanjing Normal University, Nanjing 210023, China
| | - Xuemei Ma
- Jiangsu
Key Laboratory for Molecular and Medical Biotechnology, College of
Life Sciences, Nanjing Normal University, Nanjing 210023, China
| | - Junnan Zhou
- Jiangsu
Key Laboratory for Molecular and Medical Biotechnology, College of
Life Sciences, Nanjing Normal University, Nanjing 210023, China
| | - Xiaolu Yu
- Jiangsu
Key Laboratory for Molecular and Medical Biotechnology, College of
Life Sciences, Nanjing Normal University, Nanjing 210023, China
| | - Chaoliang Wang
- Spine
and Joint Surgery, People’s Hospital
Affiliated to Shandong First Medical University, Jinan 271199, China
| | - Mei Liu
- Jiangsu
Key Laboratory for Molecular and Medical Biotechnology, College of
Life Sciences, Nanjing Normal University, Nanjing 210023, China
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7-Hydroxyflavone Alleviates Myocardial Ischemia/Reperfusion Injury in Rats by Regulating Inflammation. Molecules 2022; 27:molecules27175371. [PMID: 36080137 PMCID: PMC9458087 DOI: 10.3390/molecules27175371] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 08/17/2022] [Accepted: 08/22/2022] [Indexed: 11/18/2022] Open
Abstract
Inflammation is the primary pathological process of myocardial ischemia/reperfusion injury (MI/RI). 7-Hydroxyflavone (HF), a natural flavonoid with a variety of bioactivities, plays a crucial role in various biological processes. However, its cardioprotective effects and the underlying mechanisms of MI/RI have not been investigated. This study aimed to explore whether pretreatment with HF could attenuate MI/RI-induced inflammation in rats and investigate its potential mechanisms. The results showed that pretreatment with HF could significantly improve the anatomic data and electrocardiograph parameters, reduce the myocardial infarct size, decrease markers of myocardial injury (aspartate transaminase, creatine kinase, lactate dehydrogenase, and cardiac troponin I), inhibit inflammatory cytokines (IL-1β, IL-6, and TNF-α), suppress oxidative stress, and recover the architecture of the cardiomyocytes. The cardioprotective effect of HF was connected with the regulation of the MAPK/NF-κB signaling pathway. What is more, molecular docking was carried out to prove that HF could be stably combined with p38, ERK1/2, JNK, and NF-κB. In summary, this is a novel study demonstrating the cardioprotective effects of HF against MI/RI in vivo. Consequently, these results demonstrate that HF can be considered a promising potential therapy for MI/RI.
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Niu X, Song H, Xiao X, Yang Y, Huang Q, Yu J, Yu J, Liu Y, Han T, Zhang D, Li W. Tectoridin ameliorates proliferation and inflammation in TNF-α-induced HFLS-RA cells via suppressing the TLR4/NLRP3/NF-κB signaling pathway. Tissue Cell 2022; 77:101826. [DOI: 10.1016/j.tice.2022.101826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 04/23/2022] [Accepted: 05/16/2022] [Indexed: 11/26/2022]
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31
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Cheng WJ, Yang HT, Chiang CC, Lai KH, Chen YL, Shih HL, Kuo JJ, Hwang TL, Lin CC. Deer Velvet Antler Extracts Exert Anti-Inflammatory and Anti-Arthritic Effects on Human Rheumatoid Arthritis Fibroblast-Like Synoviocytes and Distinct Mouse Arthritis. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2022; 50:1617-1643. [PMID: 35850642 DOI: 10.1142/s0192415x22500689] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes joint deformity and disability. Deer velvet antler (DA), a traditional Chinese medicine, has been used to treat various types of arthritis for several thousands of years, but the underlying mechanisms are unknown. Herein, we investigated the anti-arthritic and anti-inflammatory effects of DA in vitro and in vivo. The ethyl acetate layer of DA ethanol extract (DA-EE-EA) was used to treat tumor necrosis factor (TNF)-[Formula: see text]-stimulated fibroblast-like synoviocyte MH7A cells, collagen-induced arthritis DBA/1 mice, and SKG mice with zymosan-induced arthritis. DA-EE-EA reduced nitric oxide production, prostaglandin E2 levels, and levels of pro-inflammatory cytokines including interleukin (IL)-1[Formula: see text], IL-6, and IL-8 in MH7A cells. DA-EE-EA also downregulated the phosphorylation of mitogen-activated protein kinase p38 and c-Jun N-terminal kinase and the translocation of nuclear factor kappa B p65. Intraperitoneal injection of DA-EE-EA for 3 weeks substantially reduced clinical arthritis scores in vivo models. Pathohistological images of the hind paws showed that DA-EE-EA reduced immune cell infiltration, synovial hyperplasia, and cartilage damage. The levels of pro-inflammatory cytokines, such as tumor necrosis factor alpha, IL-1[Formula: see text], IL-6, IL-8, IL-17A, and interferon-gamma, decreased in the hind paw homogenates of DA-EE-EA-treated mice. We also identified several potential components, such as hexadecanamide, oleamide, erucamide, and lysophosphatidylcholines, that might contribute to the anti-inflammatory effects of DA-EE-EA. In conclusion, DA-EE-EA has the potential to treat RA by regulating inflammatory responses. However, the individual components of DA-EE-EA and the underlying anti-inflammatory mechanisms need further investigation in future studies.
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Affiliation(s)
- Wei-Jen Cheng
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Hsuan-Tzu Yang
- Division of Thoracic and Cardiovascular Surgery, Department of Surgery, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chih-Chao Chiang
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Puxin Fengze Chinese Medicine Clinic, Taoyuan, Taiwan
| | - Kuei-Hung Lai
- Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Yu-Li Chen
- Research Center for Chinese Herbal Medicine, Research Center for Food and Cosmetic Safety and Graduate Institute of Health Industry Technology, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan
| | - Huei-Lin Shih
- Division of Chinese Internal Medicine, Center of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Jong-Jen Kuo
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Graduate Institute of Traditional Chinese Medicine, School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Tsong-Long Hwang
- Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Research Center for Chinese Herbal Medicine, Research Center for Food and Cosmetic Safety and Graduate Institute of Health Industry Technology, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan
- Department of Chemical Engineering, Ming-Chi University of Technology, New Taipei, Taiwan
| | - Chi-Chien Lin
- Institute of Biomedical Science, College of Life Sciences, National Chung-Hsing University, Taichung, Taiwan
- Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Research China Medical University Hospital, Taichung, Taiwan
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32
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Li Z, Bai X, Fan Y, Jia Q, Zhang H, Hou H. Structure of type II collagen from sturgeon cartilage and its effect on adjuvant-induced rheumatoid arthritis in rats. Food Funct 2022; 13:6152-6165. [PMID: 35582851 DOI: 10.1039/d1fo03929f] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The purpose of this paper was to extract and characterize type II collagen of sturgeon cartilage (SC-CII), and to explore the effects of taking SC-CII orally on rheumatoid arthritis (RA) in rats. SC-CII showed a triple-helix structure (RPN = 0.12), with d1 of 11.82 Å and d2 of 4.08 Å, which was analyzed by FT-IR, CD, XRD, and MS. It was constructed of the repeating tripeptide unit Gly-X-Y, where X and Y are generally Pro or Hyp, proved by amino acid composition and peptide mass fingerprinting. Furthermore, the effects of SC-CII on RA were evaluated. Ankle thickness was significantly decreased in SC-CII groups, with changes in lymphocyte proliferation also observed. Compared with the model control group, there was an evident decrease in TNF-α, IL-1β, COX-2, MCP-1, and TLR-4 mRNA levels, but no remarkable differences in APF, MMP-3, and MyD88 mRNA levels in the SC-CII groups. In addition, TNF-α, IL-1β, RF, Anti-CII Ab were significantly reduced in the SC-CII groups, proved by ELISA. Therefore, SC-CII showed alleviating effects on RA through the TLR4/MyD88-NFκB pathway.
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Affiliation(s)
- Zhaoxia Li
- College of Food Science and Engineering, Ocean University of China, No. 5, YuShan Road, Qingdao, Shandong Province, 266003, P.R. China. .,Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao, Shandong Province, 266071, P.R. China
| | - Xue Bai
- College of Food Science and Engineering, Ocean University of China, No. 5, YuShan Road, Qingdao, Shandong Province, 266003, P.R. China.
| | - Yan Fan
- College of Food Science and Engineering, Ocean University of China, No. 5, YuShan Road, Qingdao, Shandong Province, 266003, P.R. China.
| | - Qiannan Jia
- College of Food Science and Engineering, Ocean University of China, No. 5, YuShan Road, Qingdao, Shandong Province, 266003, P.R. China.
| | - Hongwei Zhang
- Technology Center of Qingdao Customs, No. 83, Xinyue Road, Qingdao, Shandong Province 266109, P.R. China
| | - Hu Hou
- College of Food Science and Engineering, Ocean University of China, No. 5, YuShan Road, Qingdao, Shandong Province, 266003, P.R. China. .,Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao, Shandong Province, 266071, P.R. China
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Proanthocyanidin oligomers extract from hawthorn mediates cell cycle arrest, apoptosis, and lysosome vacuolation on HCT116 cells. Curr Res Food Sci 2022; 5:904-917. [PMID: 36686366 PMCID: PMC9846341 DOI: 10.1016/j.crfs.2022.05.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 05/12/2022] [Accepted: 05/20/2022] [Indexed: 01/25/2023] Open
Abstract
In this study, Hawthorn oligomic procyanidins extracts (HPOE) were evaluated for their anticancer activity on colorectal cancer. Our results showed that HPOE arrested HCT116 cells cycle at G2/M phase through P53-Cyclin B pathway and promoted apoptosis partly via mitochondrial (Caspase 9-Caspase 3) and death receptor (Caspase 8-Caspase 3) pathways. Meanwhile, it was found that HPOE aggravated HCT116 cells death through lysosomal vacuolation, which was verified by inhibitor/activator of P53-ILC3 signaling pathway. Taken together, HPOE exerted anticancer effects which lays the foundation for the development of functional foods for clinical colon cancer patients.
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34
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Tang M, Zheng Y, Li J, Hu Y. The X box binding protein 1/C/EBP homologous protein pathway induces apoptosis of endothelial cells under hyperglycemia. Exp Ther Med 2022; 24:454. [PMID: 35720621 DOI: 10.3892/etm.2022.11381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Accepted: 06/16/2021] [Indexed: 11/06/2022] Open
Affiliation(s)
- Maoshun Tang
- Department of Neurosurgery, Shenzhen Hospital, University of Chinese Academy of Sciences, Shenzhen, Guangdong 518106, P.R. China
| | - Yi Zheng
- Department of Science and Education, Shenzhen Hospital, University of Chinese Academy of Sciences, Shenzhen, Guangdong 518106, P.R. China
| | - Jianping Li
- Department of Cardiology, Shenzhen Hospital, University of Chinese Academy of Sciences, Shenzhen, Guangdong 518106, P.R. China
| | - Yuanlang Hu
- Department of Obstetrics and Gynecology, Shenzhen Hospital, University of Chinese Academy of Sciences, Shenzhen, Guangdong 518106, P.R. China
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35
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Li ZM, Shao ZJ, Qu D, Huo XH, Hua M, Chen JB, Lu YS, Sha JY, Li SS, Sun YS. Transformation Mechanism of Rare Ginsenosides in American Ginseng by Different Processing Methods and Antitumour Effects. Front Nutr 2022; 9:833859. [PMID: 35445056 PMCID: PMC9014012 DOI: 10.3389/fnut.2022.833859] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 01/24/2022] [Indexed: 11/13/2022] Open
Abstract
The mechanism by which ginsenosides from Panax quinquefolium L. transform into rare saponins by different processing methods and their antitumour effects have yet to be fully elucidated. Our study aimed to detect the effect of amino acids and processing methods on the conversion of ginsenosides in American ginseng to rare ginsenosides, using 8 monomeric ginsenosides as substrates to discuss the reaction pathway and mechanism. S180 tumour-bearing mice were established to study the antitumour effects of American ginseng total saponins (AGS-Q) or American ginseng total saponins after transformation (AGS-H) synergistic CTX. The results showed that aspartic acid was the best catalyst, and the thermal extraction method had the best effect. Under the optimal conditions, including a reaction temperature of 110°C, an aspartic acid concentration of 5%, a reaction time of 2.5 h and a liquid-solid ratio of 30 mL/g, the highest conversion of Rk1 and Rg5 was 6.58 ± 0.11 mg/g and 3.74 ± 0.05 mg/g, respectively. In the reaction pathway, the diol group saponins participated in the transformation process, and the triol group saponins basically did not participate in the transformation process. AGS-Q or AGS-H synergistic CTX, or AGS-H synergistic CTX/2 could significantly increase the tumour inhibition rate, spleen index and white blood cell count, had a significant upregulation effect on IL-2 and IL-10 immune cytokines; significantly restored the ratio of CD4+/CD8+; and significantly inhibited the level of CD4+CD25+. AGS-Q or AGS-H synergistic with CTX or CTX/2 can significantly upregulate the expression of Bax and cleaved-Caspase-3 and inhibit the expression of antiapoptotic protein Bcl-2. AGS synergistic CTX in the treatment of S180 tumour-bearing mice can improve the efficacy and reduce toxicity.
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Affiliation(s)
- Zhi-Man Li
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Zi-Jun Shao
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Di Qu
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Xiao-Hui Huo
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Mei Hua
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Jian-Bo Chen
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Yu-Shun Lu
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Ji-Yue Sha
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Shan-Shan Li
- Institute of Biological and Pharmaceutical Engineering, Jilin Agricultural Science and Technology University, Jilin, China
| | - Yin-Shi Sun
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, China
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Wu SS, Hao LJ, Shi YY, Lu ZJ, Yu JL, Jiang SQ, Liu QL, Wang T, Guo SY, Li P, Li F. Network Pharmacology-Based Analysis on the Effects and Mechanism of the Wang-Bi Capsule for Rheumatoid Arthritis and Osteoarthritis. ACS OMEGA 2022; 7:7825-7836. [PMID: 35284738 PMCID: PMC8908527 DOI: 10.1021/acsomega.1c06729] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 01/26/2022] [Indexed: 06/12/2023]
Abstract
Wang-Bi capsule (WB) is a traditional Chinese medicine (TCM)-based herbal formula, and it has been used in the treatment of rheumatoid arthritis (RA) in China for many years. Additionally, WB is also used as a supplement to the treatment of osteoarthritis (OA) in clinical practice. Our research aimed to reveal the therapeutic effects and underling mechanism of WB on RA and OA through computational system pharmacology analysis and experimental study. Based on network pharmacology analysis, a total of 173 bioactive compounds interacted with 417 common gene targets related to WB, RA, and OA, which mainly involved the PI3K-Akt signaling pathway. In addition, the serine-threonine protein kinase 1 (AKT1) might be a core gene protein for the action of WB, which was further emphasized by molecular docking. Moreover, the anti-inflammatory activity of WB in vitro was confirmed by reducing NO production in lipopolysaccharide (LPS)-induced RAW264.7 cells. The anti-RA and OA effects of WB in vivo were confirmed by ameliorating the disease symptoms of collagen II-induced RA (CIA) and monosodium iodoacetate-induced OA (MIA) in rats, respectively. Furthermore, the role of the PI3K-Akt pathway in the action of WB was preliminarily verified by western blot analysis. In conclusion, our study elucidated that WB is a potentially effective strategy for the treatment of RA and OA, which might be achieved by regulating the PI3K-Akt pathway. It provides us with systematic insights into the effects and mechanism of WB on RA and OA.
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Affiliation(s)
- Shan-Shan Wu
- State
Key Laboratory of Natural Medicines, China
Pharmaceutical University, Nanjing 210009, China
| | - Li-Jun Hao
- School
of Science, China Pharmaceutical University, Nanjing 210009, China
| | - Yuan-Yuan Shi
- State
Key Laboratory of Natural Medicines, China
Pharmaceutical University, Nanjing 210009, China
- College
of Pharmacy, Xinjiang Medical University, Urumqi 830011, China
| | - Zhuo-Jian Lu
- State
Key Laboratory of Natural Medicines, China
Pharmaceutical University, Nanjing 210009, China
- College
of Pharmacy, Xinjiang Medical University, Urumqi 830011, China
| | - Jia-Lin Yu
- State
Key Laboratory of Natural Medicines, China
Pharmaceutical University, Nanjing 210009, China
| | - Si-Qi Jiang
- State
Key Laboratory of Natural Medicines, China
Pharmaceutical University, Nanjing 210009, China
| | - Qing-Ling Liu
- State
Key Laboratory of Natural Medicines, China
Pharmaceutical University, Nanjing 210009, China
| | - Ting Wang
- School
of Chinese Materia Medica and Yunnan Key Laboratory of Southern Medicinal
Resource, Yunnan University of Chinese Medicine, Kunming 650000, China
| | - Shi-Ying Guo
- China
Resources Sanjiu Medical & Pharmaceutical Company Ltd., Shenzhen 518110, China
| | - Ping Li
- State
Key Laboratory of Natural Medicines, China
Pharmaceutical University, Nanjing 210009, China
| | - Fei Li
- State
Key Laboratory of Natural Medicines, China
Pharmaceutical University, Nanjing 210009, China
- College
of Pharmacy, Xinjiang Medical University, Urumqi 830011, China
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Zhao J, Jiang P, Guo S, Schrodi SJ, He D. Apoptosis, Autophagy, NETosis, Necroptosis, and Pyroptosis Mediated Programmed Cell Death as Targets for Innovative Therapy in Rheumatoid Arthritis. Front Immunol 2021; 12:809806. [PMID: 35003139 PMCID: PMC8739882 DOI: 10.3389/fimmu.2021.809806] [Citation(s) in RCA: 132] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 12/13/2021] [Indexed: 01/13/2023] Open
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory joint disease that can lead to clinical manifestations of systemic diseases. Its leading features include chronic synovial inflammation and degeneration of the bones and joints. In the past decades, multiple susceptibilities for rheumatoid arthritis have been identified along with the development of a remarkable variety of drugs for its treatment; which include analgesics, glucocorticoids, nonsteroidal anti-inflammatory medications (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDs), and biologic response modifiers (bDMARDs). Despite the existence of many clinical treatment options, the prognosis of some patients remains poor due to complex mechanism of the disease. Programmed cell death (PCD) has been extensively studied and ascertained to be one of the essential pathological mechanisms of RA. Its dysregulation in various associated cell types contributes to the development of RA. In this review, we summarize the role of apoptosis, cell death-associated neutrophil extracellular trap formation, necroptosis, pyroptosis, and autophagy in the pathophysiology of RA to provide a theoretical reference and insightful direction to the discovery and development of novel therapeutic targets for RA.
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Affiliation(s)
- Jianan Zhao
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ping Jiang
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shicheng Guo
- Department of Medical Genetics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
| | - Steven J. Schrodi
- Department of Medical Genetics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
| | - Dongyi He
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Arthritis Institute of Integrated Traditional and Western Medicine, Shanghai Chinese Medicine Research Institute, Shanghai, China
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Junjun Q, Mingdong L. Exploring the Anti-Rheumatoid Arthritis Mechanisms of Curcumin. J BIOMATER TISS ENG 2021. [DOI: 10.1166/jbt.2021.2756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Objective: To research curcumin on rheumatoid arthritis (RA) symptoms. Materials and Methods: Dividing Sixty SD male rats among six groups: normal control group, model group, dexamethasone (DXM) group and curcumin low, medium and high dosage groups (25, 50, 100 mg/kg body
weight) every days. We adopted the CIA (collagen induced arthritis) rat model. All rats were subjected to 28 days of intragastric administration wherein we observed the rats’ state, weight, degree of paw swelling, arthritis index and pathological changes of ankle joints. Their serologic
contents of IL-1β, IL-6 and TNF-α were examined by Elisa method and IKK-α, IKK-β and NF-κB in joint synovial tissues were tested via IHC assay. Results: Curcumin inhibited paw swelling within the CIA rat model, decreasing
the serologic content of IL-1β, IL-6 and TNF-α. It also decreased the protein expressions of IKK-α, IKK-β and and NF-κB in synovial tissues. Its effects were dose-dependent and weaker than those of DXM. Conclusion: Curcumin
is effective against RA by means of transcribing the IKK-α/-β/NF-κB pathway
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Affiliation(s)
- Qin Junjun
- Department of Orthopaedics, The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi Zhang Autonomous Region, 530021, China
| | - Li Mingdong
- Department of Orthopaedics and Traumatology, Hainan General Hospital, Haikou, Hainan, 570311, China
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Wang Y, Chen S, Du K, Liang C, Wang S, Owusu Boadi E, Li J, Pang X, He J, Chang YX. Traditional herbal medicine: Therapeutic potential in rheumatoid arthritis. JOURNAL OF ETHNOPHARMACOLOGY 2021; 279:114368. [PMID: 34197960 DOI: 10.1016/j.jep.2021.114368] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 06/16/2021] [Accepted: 06/23/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease influenced by diverse endogenous and exogenous factors. It is characterized by cartilage and bone destruction. The current conventional allopathic therapy is expensive and carries adverse side effects. Recently, there were some ethnopharmacological studies on RA including anti-RA effects and therapeutic targets of distinct dosage forms of traditional herbal medicines (THMs). AIM OF THE REVIEW This review provides a brief overview of the current understanding of the potential pharmacological mechanisms of THMs (active constituents, extracts and prescriptions) in RA. This study is intended to provide comprehensive information and reference for exploring new therapeutic strategies of THMs in the RA treatment. MATERIALS AND METHODS This review captured scientific literatures invivo and vitro experiments on effects of anti-RA THMs published between 2016 and 2021 from journals and electronic databases (e.g. PubMed, Elsevier, Science Direct, Web of Science and Google Scholar). Relevant literatures were searched and analyzed by using keywords such as 'rheumatoid arthritis AND traditional herbal medicines', 'rheumatoid arthritis AND immune cells', 'rheumatoid arthritis AND inflammation', 'rheumatoid arthritis AND miRNA', 'rheumatoid arthritis AND Angiogenesis', 'rheumatoid arthritis AND oxidative stress', 'rheumatoid arthritis AND osteoclasts', 'rheumatoid arthritis AND CIA model', 'rheumatoid arthritis AND AA model' AND 'rheumatoid arthritis herbal prescription'. RESULTS Experiments in vitro and in vivo jointly demonstrated the potential of THMs in the RA treatment. There are plentiful therapeutic targets in RA. THMs and active ingredients could alleviate RA symptoms through different therapeutic targets, such as immunoregulation, inflammation, fibroblast-like synoviocytes (FLSs), microRNAs (miRNAs), angiogenesis, oxidative stress, osteoclasts and multiple targets interaction. Anti-RA THMs, active ingredients and prescriptions through corresponding therapeutic targets were summarized and classified. CONCLUSIONS Flavonoids, phenolic acids, alkaloids and triterpenes of THMs are identified as the main components to ameliorate RA. Regulation of different and multiple related therapeutic targets by THMs and their active ingredients were associated with greater therapeutic benefits, among which inflammation is the main therapeutic target. Nonetheless, further studies are required to unravel the complexities and in-depth mechanisms of THMs in alleviating RA.
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Affiliation(s)
- Yuan Wang
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Shujing Chen
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Kunze Du
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Chunxiao Liang
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Shuangqi Wang
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Evans Owusu Boadi
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Jin Li
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Xiaoli Pang
- Academy of Nursing, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Jun He
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Yan-Xu Chang
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
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Duan H, Wang W, Li Y, Jilany Khan G, Chen Y, Shen T, Bao N, Hua J, Xue Z, Zhai K, Wei Z. Identification of phytochemicals and antioxidant activity of Premna microphylla Turcz. stem through UPLC-LTQ-Orbitrap-MS. Food Chem 2021; 373:131482. [PMID: 34731817 DOI: 10.1016/j.foodchem.2021.131482] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 09/15/2021] [Accepted: 10/24/2021] [Indexed: 12/17/2022]
Abstract
Premna microphylla Turcz. is a commonly used traditional Chinese medicine totreatdysentery and appendicitis. Present study is focused to explore antioxidants and other compounds in the Premna microphylla Turcz. stem. Assessment of chemical composition was done with high sensitivity UPLC-LTQ-Orbitrap-MS and for Separation Thermo Hypersil Gold (100 mm × 2.1 mm, 1.9 µm) was used while electrospray ionization (ESI) was used for the mass spectrometry. 18 compounds were identified including Vitexin (1), Schaftoside (2), Vicenin-2 (3), Apigenin-6, 8-di-C-arabinoside (4), Apigenin-7-O-β-d-glucoside (5), Carnosic acid (6), Apigenin-8-C-β-d-xylopyranoside (7), Prostratin (8), Aurantio-obtusin-β-d-glucoside (9), Royleanone (10), 5-hydroxy-7,3',4'-Trimethoxy flavonols (11), 6-Hydroxy-5,6-dehydrosugiol (12), 14-deoxycoleon (13), Arucadiol (14), Obtusinone-B (15), Trehalose (16), Citric acid (17) and Betaine (18). Among these, 6 compounds including (6), (8), (9), (16), (17) and (18) were identified first time within this genus and plant. Study highlights the importance of Premna microphylla Turcz. stem extract for strong therapeutic potential against oxidation-related diseases.
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Affiliation(s)
- Hong Duan
- Suzhou Engineering and Technological Research Center of Natural Medicine and Functional Food, School of Biological and Food Engineering, Suzhou University, Suzhou 234000, PR China
| | - Wei Wang
- Suzhou Engineering and Technological Research Center of Natural Medicine and Functional Food, School of Biological and Food Engineering, Suzhou University, Suzhou 234000, PR China; School of Biological and Food Engineering, Anhui Polytechnic University, Wuhu 241000, PR China
| | - Yongxiang Li
- Suzhou Engineering and Technological Research Center of Natural Medicine and Functional Food, School of Biological and Food Engineering, Suzhou University, Suzhou 234000, PR China
| | - Ghulam Jilany Khan
- Department of Pharmacology, Faculty of Pharmacy (FOP), University of Central Punjab, Lahore, Pakistan; National Drug Screening Center of Pharmacokinetics and Pharmacodynamics, School of Pharmacy, China Pharmaceutical University, Nanjing, PR China
| | - Yuan Chen
- Suzhou Engineering and Technological Research Center of Natural Medicine and Functional Food, School of Biological and Food Engineering, Suzhou University, Suzhou 234000, PR China; School of Biological and Food Engineering, Anhui Polytechnic University, Wuhu 241000, PR China
| | - Tianci Shen
- Suzhou Engineering and Technological Research Center of Natural Medicine and Functional Food, School of Biological and Food Engineering, Suzhou University, Suzhou 234000, PR China
| | - Nina Bao
- Suzhou Engineering and Technological Research Center of Natural Medicine and Functional Food, School of Biological and Food Engineering, Suzhou University, Suzhou 234000, PR China
| | - Jing Hua
- Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Guangxi Normal University), Guilin 541004, PR China
| | - Zhenglian Xue
- School of Biological and Food Engineering, Anhui Polytechnic University, Wuhu 241000, PR China
| | - Kefeng Zhai
- Suzhou Engineering and Technological Research Center of Natural Medicine and Functional Food, School of Biological and Food Engineering, Suzhou University, Suzhou 234000, PR China; School of Biological and Food Engineering, Anhui Polytechnic University, Wuhu 241000, PR China; Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Guangxi Normal University), Guilin 541004, PR China.
| | - Zhaojun Wei
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, PR China.
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Zhang Y, Ge L, Song G, Zhang R, Li S, Shi H, Zhang H, Li Y, Pan J, Wang L, Han J. Azithromycin alleviates the severity of rheumatoid arthritis by targeting the UPR component GRP78. Br J Pharmacol 2021; 179:1201-1219. [PMID: 34664264 DOI: 10.1111/bph.15714] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 09/12/2021] [Accepted: 09/27/2021] [Indexed: 12/01/2022] Open
Abstract
BACKGROUND AND PURPOSE Azithromycin (AZM) is a macrolide antibiotic with well-described anti-inflammatory properties. This study aimed to substantiate the treatment potential of AZM in rheumatoid arthritis (RA). EXPERIMENTAL APPROACH Gene expression profiles were collected by RNA sequencing, and the effects of AZM were assessed in functional assays. In vitro and in vivo assays were performed to examine the effects of AZM-mediated blockade of glucose-regulated protein 78 (GRP78). Assays to define the anti-inflammatory activity of AZM using fibroblast-like synoviocytes (FLSs) from RA patients and collagen-induced arthritis (CIA) in DBA/1 mice were performed. Identification and characterization of the binding of AZM to GRP78 was performed using drug affinity responsive target stability assays, proteomics and cellular thermal shift assays. AZM-mediated inhibition of GRP78 and the dependence of the antiarthritic activity of AZM on GRP78 were assessed. KEY RESULTS AZM reduced proinflammatory factor production, cell migration, invasion and chemoattraction and enhanced apoptosis, thereby reducing the deleterious inflammatory response of RA FLSs in vitro. AZM ameliorated the severity of CIA lesions as efficiently as the anti-tumour necrosis factor (anti-TNF) biological agent etanercept (ETC). Transcriptional analyses suggested that AZM treatment impairs signalling cascades associated with cholesterol and lipid biosynthetic processes. GRP78 was identified as a novel target of AZM. AZM-mediated activation of the unfolded protein response (UPR) via the inhibition of GRP78 activity is required not only for inducing the expression of C/EBP-homologous protein (ChOP) but also for the activating sterol-regulatory element binding protein (SREBP) and its targeted genes involved in cholesterol and lipid biosynthetic processes. Furthermore, deletion of GRP78 abolished the antiarthritic activity of AZM. CONCLUSION AND IMPLICATIONS These findings confirmed that AZM is a therapeutic drug for RA treatment.
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Affiliation(s)
- Yongli Zhang
- Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Key Lab for Biotech-Drugs of National Health Commission, Key Lab for Rare & Uncommon Diseases of Shandong Province, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Luna Ge
- Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Key Lab for Biotech-Drugs of National Health Commission, Key Lab for Rare & Uncommon Diseases of Shandong Province, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China.,Department of Rheumatology and Autoimmunology, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Guanhua Song
- Institute of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Ruojia Zhang
- Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Key Lab for Biotech-Drugs of National Health Commission, Key Lab for Rare & Uncommon Diseases of Shandong Province, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Shufeng Li
- Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Haojun Shi
- The second clinical medical college, Henan University of Chinese Medicine, Zhengzhou, China
| | - Hongchang Zhang
- Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Key Lab for Biotech-Drugs of National Health Commission, Key Lab for Rare & Uncommon Diseases of Shandong Province, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Yi Li
- Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Jihong Pan
- Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Key Lab for Biotech-Drugs of National Health Commission, Key Lab for Rare & Uncommon Diseases of Shandong Province, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China.,Department of Rheumatology and Autoimmunology, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Lin Wang
- Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Key Lab for Biotech-Drugs of National Health Commission, Key Lab for Rare & Uncommon Diseases of Shandong Province, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China.,Department of Rheumatology and Autoimmunology, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Jinxiang Han
- Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Key Lab for Biotech-Drugs of National Health Commission, Key Lab for Rare & Uncommon Diseases of Shandong Province, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China.,Department of Rheumatology and Autoimmunology, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
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Wang L, Pan F, Luo T. Sinapic Acid Attenuates Rheumatoid Arthritis Through Reducing Inflammation and Oxidative Stress by Downregulating IκB Kinase. J Interferon Cytokine Res 2021; 41:347-354. [PMID: 34543128 DOI: 10.1089/jir.2021.0044] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Sinapic acid (SA) was reported to protect against inflammation in various types of diseases. However, the role of SA in rheumatoid arthritis remains unclear. This study was designed to investigate the role of SA on rheumatoid arthritis. Rheumatoid arthritis mouse model was established by collagen immunization [collagen-induced arthritis (CIA)]. Histological analysis of articular cartilage tissue was carried out by hematoxylin and eosin (H&E) staining. Serum concentrations of tumor necrosis factor alpha and interleukin 6 were determined through enzyme-linked immunosorbent assay (ELISA). Oxidative damage indexes such as superoxide dismutase activity, malondialdehyde detection, glutathione detection, and catalase were determined by biochemical analysis. The protein levels of related genes were determined using Western blot. In CIA model, SA treatment attenuated paw swelling and clinical score of arthritis, attenuated articular cartilage tissues edema and infiltration of inflammatory cells, suppressed inflammatory cytokines release, and attenuated oxidative damage indexes. Mechanically, SA suppressed immune responses through inhibiting the IκB kinase (IKKs). SA attenuates rheumatoid arthritis through reducing inflammation and oxidative stress by downregulating IKKs.
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Affiliation(s)
- Long Wang
- Department of Traditional Chinese Medicine, Daqing Oilfield General Hospital, Daqing, Heilongjiang, China
| | - Fang Pan
- Department of Rheumatism, Daqing Oilfield General Hospital, Daqing, Heilongjiang, China
| | - Tao Luo
- Department of Rheumatology and Pain, Traditional Chinese Medicine Hospital of Dianjiang Chongqing, Chongqing, China
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Wu Z, Zhang L, Zhao X, Li Z, Lu H, Bu C, Wang R, Wang X, Cai T, Wu D. Protectin D1 protects against lipopolysaccharide-induced acute lung injury through inhibition of neutrophil infiltration and the formation of neutrophil extracellular traps in lung tissue. Exp Ther Med 2021; 22:1074. [PMID: 34447467 DOI: 10.3892/etm.2021.10508] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 01/28/2021] [Indexed: 12/16/2022] Open
Abstract
Protectin D1 (PD1), a DHA-derived lipid mediator, has recently been shown to possess anti-inflammatory and pro-resolving properties. To date, little is known about the effect of PD1 on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. The aim of the present study was to investigate the therapeutic effects of PD1 on LPS-induced ALI and its potential mechanisms of action. ALI was induced via an intraperitoneal injection of LPS, where PD1 (2 ng/mouse) was administered intravenously 30 min after LPS challenge. Mice were sacrificed 24 h after modeling. Lung histopathological changes were assessed using hematoxylin and eosin staining and myeloperoxidase (MPO) activity was tested using immunohistochemistry. Tumor necrosis-α and interleukin-6 levels in the bronchoalveolar lavage fluid (BALF) and serum were measured using ELISA. To detect neutrophil extracellular traps produced by infiltrated neutrophils in the lung tissue, immunofluorescence staining was performed using anti-MPO and anti-histone H3 antibodies. The results indicated that PD1 significantly attenuated histological damage and neutrophil infiltration in lung tissue, reduced the lung wet/dry weight ratio, protein concentration and proinflammatory cytokine levels in BALF and decreased proinflammatory cytokine levels in serum. Moreover, neutrophil citrullinated histone H3 (CitH3) expression was also reduced after PD1 administration. In conclusion, PD1 attenuated LPS-induced ALI in mice via inhibition of neutrophil extracellular trap formation in lung tissue. Therefore, PD1 administration may serve to be a new strategy for treating ALI.
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Affiliation(s)
- Zhiyang Wu
- Department of Critical Care Medicine, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong 266035, P.R. China
| | - Luyao Zhang
- Department of Pathology, School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Xiangyang Zhao
- Department of Critical Care Medicine, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong 266035, P.R. China
| | - Zhi Li
- Department of Critical Care Medicine, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong 266035, P.R. China
| | - Haining Lu
- Department of Critical Care Medicine, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong 266035, P.R. China
| | - Chanyuan Bu
- Department of Critical Care Medicine, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong 266035, P.R. China
| | - Rui Wang
- Department of Critical Care Medicine, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong 266035, P.R. China
| | - Xiaofei Wang
- Department of Critical Care Medicine, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong 266035, P.R. China
| | - Tiantian Cai
- Department of Critical Care Medicine, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong 266035, P.R. China
| | - Dawei Wu
- Department of Critical Care Medicine, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong 266035, P.R. China
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Zhang Z, Chen X, Gao B, Sun G, Wang Y, Wang J, Zhang T, Qian H, Zhang Y, Huang J, Sun R, Wu J, Zhou L. PLD1 knockdown reduces metastasis and inflammation of fibroblast-like synoviocytes in rheumatoid arthritis by modulating NF-κB and Wnt/β-catenin pathways. Autoimmunity 2021; 54:398-405. [PMID: 34431424 DOI: 10.1080/08916934.2021.1963957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Considered as an autoimmune disease, rheumatoid arthritis (RA) is an chronic inflammatory disorder that causes inflammation of the joints. This study is performed with the aim to clarify the expression of phospholipase D1 (PLD1) in RA and its specific regulation role of RA as well as the underlying mechanisms. In this study, synovial tissue samples were collected from RA patients, and RA-fibroblast-like synoviocytes (FLSs) were subsequently isolated. The expression levels of PLD1 and pathway-related proteins were detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blotting or immunohistochemistry (IHC). Upon shPLD1 treatment, cell viability, proliferation, migration, invasion, and the level of inflammation-related factors were measured by Cell Counting Kit-8 (CCK-8), Edu, wound healing, Transwell and enzyme-linked immunosorbent assay (ELISA). Furthermore, C-reactive protein (CRP), rheumatoid factor (RF), arthritis score and synovial tissue lesions were assessed by collecting the blood or tissues from collagen induced arthritis (CIA) model rats. Our results showed that PLD1 level was increased in RA synovial tissues. Cell viability, proliferation, migration, invasion, and the level of inflammatory factors were reduced upon PLD1 knockdown in RA-FLSs. Moreover, p-IκBα/IκBα, β-catenin, p-IKKβ/IKKβ and TCF-4 were inhibited under PLD1 knockdown treatment. PLD1 knockdown alleviated the collagen-induced addition of arthritis score, CRP and RF, as well as the filling of inflammatory cells and proliferation of synovium in CIA model rat. To sum up, knockdown of PLD1 could reduce RA-FLSs metastasis as well as inflammatory response by modulating the activity of NF-κB and Wnt/β-catenin pathways.
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Affiliation(s)
- Zhengyu Zhang
- Department of Rheumatology and Immunology, Affiliated Changzhou No. 2 People's Hospital with Nanjing Medical University, Changzhou, China
| | - Xi Chen
- Department of Rheumatology and Immunology, Affiliated Changzhou No. 2 People's Hospital with Nanjing Medical University, Changzhou, China
| | - Bo Gao
- Department of Rheumatology and Immunology, Affiliated Changzhou No. 2 People's Hospital with Nanjing Medical University, Changzhou, China
| | - Guomin Sun
- Department of Rheumatology and Immunology, Affiliated Changzhou No. 2 People's Hospital with Nanjing Medical University, Changzhou, China
| | - Yan Wang
- Department of Rheumatology and Immunology, Affiliated Changzhou No. 2 People's Hospital with Nanjing Medical University, Changzhou, China
| | - Junke Wang
- Department of Rheumatology and Immunology, Affiliated Changzhou No. 2 People's Hospital with Nanjing Medical University, Changzhou, China
| | - Ting Zhang
- Department of Rheumatology and Immunology, Affiliated Changzhou No. 2 People's Hospital with Nanjing Medical University, Changzhou, China
| | - Hao Qian
- Department of Rheumatology and Immunology, Affiliated Changzhou No. 2 People's Hospital with Nanjing Medical University, Changzhou, China
| | - Yu Zhang
- Department of Rheumatology and Immunology, Affiliated Changzhou No. 2 People's Hospital with Nanjing Medical University, Changzhou, China
| | - Jun Huang
- Department of Echocardiography, Affiliated Changzhou No. 2 People's Hospital with Nanjing Medical University, Changzhou, China
| | - Rurong Sun
- Department of Rheumatology and Immunology, The Third Affiliated Hospital of Suzhou University Changzhou First People's Hospital, Changzhou, China
| | - Jiabiao Wu
- Department of Rheumatology, Immunology and Hematology, Changzhou Wujin Hospital Affiliated to Jiangsu University, Changzhou, China
| | - Lei Zhou
- Department of Rheumatology and Immunology, Affiliated Changzhou No. 2 People's Hospital with Nanjing Medical University, Changzhou, China
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Zhuo Q, Wei L, Yin X, Li H, Qin G, Li S, Peng TT, Liu B, Zhao S, Ye Z. LncRNA ZNF667-AS1 alleviates rheumatoid arthritis by sponging miR-523-3p and inactivating the JAK/STAT signalling pathway. Autoimmunity 2021; 54:406-414. [PMID: 34423698 DOI: 10.1080/08916934.2021.1966770] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND Rheumatoid arthritis (RA) is an autoimmune disease, which compromises the synovial membrane resulting in chronic inflammation. Increasing evidence has demonstrated that long non-coding RNAs (lncRNAs) are implicated in the pathogenesis of RA. This study investigated the role of lncRNA ZNF667-AS1 in RA progression. METHODS Synovial tissues and fibroblast-like synoviocytes (FLSs) were obtained from patients with RA. Gene expression was measured using RT-qPCR. Chondrocytes were treated with lipopolysaccharide (LPS) to establish in vitro models of OA. Cell counting kit-8 (CCK-8), western blot, and enzyme-linked immunosorbent assay (ELISA) were used to examine the proliferation and inflammatory cytokine production in chondrocytes. Animal models of OA were established in SD rats. Peripheral blood mononuclear cells (PBMCs) were isolated from the OA rats. Flow cytometry was used to measure the changes of the inflammatory T-helper cell 17 (Th17) cells. The relationship between ZNF667-AS1 and miR-523-3p was verified by luciferase reporter assay. RESULTS ZNF667-AS1 was downregulated in RA-FLSs and LPS-stimulated chondrocytes. ZNF667-AS1 overexpression significantly promoted cell proliferation and inhibited the production of IL-6, IL-17 and TNF-α in LPS-stimulated chondrocytes. Additionally, ZNF667-AS1 overexpression reduced the generation of CD4 + IL-17+ cells. In mechanism, ZNF667-AS1 acted a sponge for miR-523-3p. MiR-523-3p overexpression reversed the ZNF667-AS1-mediated regulation of cell proliferation and inflammation. Furthermore, miR-523-3p overexpression abolished the inhibitory effects of ZNF667-AS1 on the JAK/STAT signalling activation. CONCLUSION ZNF667-AS1 exerts protective effects during RA development by sponging miR-523-3p and inactivating the JAK/STAT signalling.
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Affiliation(s)
- Qin Zhuo
- The First Clinical College, Hubei University of Chinese Medicine, Wuhan, China.,Department of Rheumatism Immunology, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China
| | - Lu Wei
- Department of Rheumatism Immunology, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China
| | - Xietian Yin
- The First Clinical College, Hubei University of Chinese Medicine, Wuhan, China.,Department of Rheumatism Immunology, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China
| | - Huiling Li
- Department of Rheumatism Immunology, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China
| | - Guifu Qin
- Department of Rheumatism Immunology, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China
| | - Siqi Li
- Department of Rheumatism Immunology, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China
| | - Ting Ting Peng
- Department of Rheumatism Immunology, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China
| | - Bo Liu
- Department of Rheumatism Immunology, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China
| | - Shichao Zhao
- Department of Geriatrics, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China
| | - Zhiqin Ye
- Department of Rheumatism Immunology, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China
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Liu W, Song J, Feng X, Yang H, Zhong W. LncRNA XIST is involved in rheumatoid arthritis fibroblast-like synoviocytes by sponging miR-126-3p via the NF-κB pathway. Autoimmunity 2021; 54:326-335. [PMID: 34165008 DOI: 10.1080/08916934.2021.1937608] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
The role and mechanism of lncRNA XIST (XIST) in the development of rheumatoid arthritis (RA) was explored in this study. RT-qPCRs were performed to detect the expression of XIST and miR-126-3p in synovial tissues and cells. Target gene prediction and luciferase gene reporter assay were used to validate downstream target genes of XIST. MTT assay, EdU staining and Annexin V/PI staining were performed to explore the effects of XIST and miR-126-3p on cell proliferation and apoptosis. Western blotting analysis was used to detect the expression of related proteins. We found that the expression levels of XIST in tissues and cells were significantly higher than that in normal tissues and cells. Down-regulation of XIST could inhibit cell proliferation rate and increase apoptosis rate. Luciferase gene reporter assay showed that miR-126-3p was a downstream target gene of XIST. Overexpression of miR-126-3p significantly inhibited RA-FLS cell proliferation and induced RA-FLS cell apoptosis. In addition, down-regulation of XIST could increase the ratio of caspase-3 and Bax/Bcl-2. In addition, overexpression of miR-126-3p could inhibit the NF-κB signalling pathway by reducing the expression levels of p-p65 and p-IκBα in RA-FLS cells. In conclusion, down-regulation of XIST can inhibit the proliferation of synovial fibroblasts by increasing the expression levels of miR-126-3p/NF-κB, thereby inhibiting the occurrence and development of RA.
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Affiliation(s)
- Wei Liu
- Department of Rheumatology and Immunology, the First hospital of Qiqihar City, Qiqihar City, PR China
| | - Jing Song
- Department of Rheumatology and Immunology, the First hospital of Qiqihar City, Qiqihar City, PR China
| | - Xingyu Feng
- Department of Rheumatology and Immunology, the First hospital of Qiqihar City, Qiqihar City, PR China
| | - Haolong Yang
- Department of Orthopedics, the Third Affiliated Hospital of Qiqihar, Qiqihar City, PR China
| | - Wei Zhong
- Department of Rheumatology and Immunology, the First hospital of Qiqihar City, Qiqihar City, PR China
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Wu X, Xu J, Cai Y, Yang Y, Liu Y, Cao S. Cytoprotection against Oxidative Stress by Methylnissolin-3- O-β-d-glucopyranoside from Astragalus membranaceus Mainly via the Activation of the Nrf2/HO-1 Pathway. Molecules 2021; 26:molecules26133852. [PMID: 34202670 PMCID: PMC8270303 DOI: 10.3390/molecules26133852] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 06/09/2021] [Accepted: 06/16/2021] [Indexed: 11/16/2022] Open
Abstract
Astragalus membranaceus is a famous herb found among medicinal and food plants in East and Southeastern Asia. The Nrf2-ARE assay-guided separation of an extract from Jing liqueur led to the identification of a nontoxic Nrf2 activator, methylnissolin-3-O-β-d-glucopyranoside (MNG, a component of A. membranaceus). Nrf2 activation by MNG has not been reported before. Using Western Blot, RT-qPCR and imaging, we investigated the cytoprotective effect of MNG against hydrogen peroxide-induced oxidative stress. MNG induced the expression of Nrf2, HO-1 and NQO1, accelerated the translocation of Nrf2 into nuclei, and enhanced the phosphorylation of AKT. The MNG-induced expression of Nrf2, HO-1, and NQO1 were abolished by Nrf2 siRNA, while the MNG-induced expression of Nrf2 and HO-1 was abated and the AKT phosphorylation was blocked by LY294002 (a PI3K inhibitor). MNG reduced intracellular ROS generation. However, the protection of MNG against the H2O2 insult was reversed by Nrf2 siRNA with decreased cell viability. The enhancement of Nrf2 and HO-1 by MNG upon H2O2 injury was reduced by LY294002. These data showed that MNG protected EA.hy926 cells against oxidative damage through the Nrf2/HO-1 and at least partially the PI3K/Akt pathways.
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Affiliation(s)
- Xiaohua Wu
- Department of Pharmaceutical Sciences, Daniel K. Inouye College of Pharmacy, University of Hawai’i at Hilo, Hilo, HI 96720, USA; (X.W.); (Y.C.)
| | - Jian Xu
- Hubei Provincial Key Laboratory of Quality and Safety of Traditional Chinese Medicine Health Food, Jing Brand Research Institute, Jing Brand Co., Ltd., Daye 435100, China; (J.X.); (Y.Y.)
| | - Yousheng Cai
- Department of Pharmaceutical Sciences, Daniel K. Inouye College of Pharmacy, University of Hawai’i at Hilo, Hilo, HI 96720, USA; (X.W.); (Y.C.)
- Institute of TCM and Natural Products, School of Pharmaceutical Sciences, Wuhan University, 185 Donghu Road, Wuhan 430071, China
| | - Yuejun Yang
- Hubei Provincial Key Laboratory of Quality and Safety of Traditional Chinese Medicine Health Food, Jing Brand Research Institute, Jing Brand Co., Ltd., Daye 435100, China; (J.X.); (Y.Y.)
| | - Yuancai Liu
- Hubei Provincial Key Laboratory of Quality and Safety of Traditional Chinese Medicine Health Food, Jing Brand Research Institute, Jing Brand Co., Ltd., Daye 435100, China; (J.X.); (Y.Y.)
- Correspondence: (Y.L.); (S.C.); Tel.: +86-71-4876-8056 (Y.L.); +1-808-981-8010 (S.C.)
| | - Shugeng Cao
- Department of Pharmaceutical Sciences, Daniel K. Inouye College of Pharmacy, University of Hawai’i at Hilo, Hilo, HI 96720, USA; (X.W.); (Y.C.)
- Correspondence: (Y.L.); (S.C.); Tel.: +86-71-4876-8056 (Y.L.); +1-808-981-8010 (S.C.)
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Kessler J, Totoson P, Devaux S, Moretto J, Wendling D, Demougeot C. Animal models to study pathogenesis and treatments of cardiac disorders in rheumatoid arthritis: Advances and challenges for clinical translation. Pharmacol Res 2021; 170:105494. [PMID: 34139344 DOI: 10.1016/j.phrs.2021.105494] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 02/08/2021] [Accepted: 02/11/2021] [Indexed: 11/15/2022]
Abstract
Although cardiac diseases such as acute myocardial infarction, heart failure and arrhythmias are the leading cause of cardiovascular complications in rheumatoid arthritis (RA), their pathogenesis is far from being understood and optimal therapeutic options to treat specifically these disorders in RA are lacking. Preclinical studies on animal models of arthritis can help to decipher the complex link between arthritis and the heart, and to identify critical pathways and novel therapeutic targets. This review presented the available data on cardiac disorders in animal models of RA, as well as the current knowledge on pathophysiology and pharmacology of these disorders. Future directions for translational studies in a cardiorheumatic perspective are proposed.
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Affiliation(s)
- Julie Kessler
- PEPITE EA 4267, FHU INCREASE, Univ. Bourgogne Franche-Comté, F-25000 Besançon, France; Service de Rhumatologie, CHU Minjoz, 25000 Besançon, France
| | - Perle Totoson
- PEPITE EA 4267, FHU INCREASE, Univ. Bourgogne Franche-Comté, F-25000 Besançon, France
| | - Sylvie Devaux
- PEPITE EA 4267, FHU INCREASE, Univ. Bourgogne Franche-Comté, F-25000 Besançon, France
| | - Johnny Moretto
- PEPITE EA 4267, FHU INCREASE, Univ. Bourgogne Franche-Comté, F-25000 Besançon, France
| | - Daniel Wendling
- Service de Rhumatologie, CHU Minjoz, 25000 Besançon, France; EA 4266 " Agents Pathogènes et Inflammation ", EPILAB, Univ. Bourgogne Franche-Comté, F-25000 Besançon, France
| | - Céline Demougeot
- PEPITE EA 4267, FHU INCREASE, Univ. Bourgogne Franche-Comté, F-25000 Besançon, France.
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Meng M, Yue Z, Chang L, Liu Y, Hu J, Song Z, Tang Z, Zhou R, Wang C. Anti-Rheumatoid Arthritic Effects of Paris Saponin VII in Human Rheumatoid Arthritis Fibroblast-Like Synoviocytes and Adjuvant-Induced Arthritis in Rats. Front Pharmacol 2021; 12:683698. [PMID: 34122110 PMCID: PMC8194347 DOI: 10.3389/fphar.2021.683698] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 05/14/2021] [Indexed: 12/29/2022] Open
Abstract
In the pathogenesis of rheumatoid arthritis (RA), rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) have tumor-like characteristics, mainly manifested by hyperproliferation and resistance to apoptosis and then it will erode the bone and cartilage, eventually leading to joint destruction. Paris saponin VII (PS VII) is an active compound derived from a traditional herbal medicine named Trillium tschonoskii Maxim, which has anti-tumor, analgesic, and immunomodulatory effects. However, its anti-RA effect has not yet been reported. This study was to investigate the effect of PS VII on two rheumatoid arthritis fibroblast-like synoviocytes lines (RA-FLS and MH7A) and adjuvant-induced arthritis (AIA) in rats. In vitro, the effects of PS VII on the proliferation, cell cycle, and apoptosis of RA-FLS and MH7A cells were detected by MTT, flow cytometry, and western blot analysis. In vivo, the effect of PS VII on the weight of the rat, paw swelling, ankle joint diameter, arthritis index, serum inflammatory cytokines (TNF-α, IL-6, and IL-1β), histopathological assessment and apoptosis proteins in the synovial tissues were evaluated in AIA rats. The in vitro studies showed that PS VII inhibited the proliferation of RA-FLS and MH7A cells, induced S phase arrest and triggered cell apoptosis mainly through the mitochondrial apoptotic pathway and the regulation of JNK and p38 MAPK pathways. The in vivo studies revealed that PS VII could improve ameliorate body weight, paw swelling, ankle joint diameter, reduce the spleen and thymus index, suppress the production of TNF-α, IL-6 and IL-1β, improve histopathological changes and regulate the expressions of apoptosis proteins in AIA Rats. In conclusion, PS VII could inhibit the proliferation and trigger apoptosis of RA-FLS and MH7A cells by regulating the mitochondrial apoptosis pathway and the JNK and p38 MAPK pathways, and alleviate the symptoms of RA, signifying it to be one of the potential anti-RA therapeutics.
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Affiliation(s)
- Mei Meng
- State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), Co-Construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi and Education Ministry, Shaanxi University of Chinese Medicine, Xianyang, China.,Country School of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Zhenggang Yue
- State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), Co-Construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi and Education Ministry, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Lu Chang
- State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), Co-Construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi and Education Ministry, Shaanxi University of Chinese Medicine, Xianyang, China.,Country School of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Yanru Liu
- State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), Co-Construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi and Education Ministry, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Jinhang Hu
- State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), Co-Construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi and Education Ministry, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Zhongxing Song
- State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), Co-Construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi and Education Ministry, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Zhishu Tang
- State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), Co-Construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi and Education Ministry, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Rui Zhou
- State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), Co-Construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi and Education Ministry, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Changli Wang
- Country School of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, China
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50
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Zhang YM, Shen J, Zhao JM, Guan J, Wei XR, Miao DY, Li W, Xie YC, Zhao YQ. Cedrol from Ginger Ameliorates Rheumatoid Arthritis via Reducing Inflammation and Selectively Inhibiting JAK3 Phosphorylation. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:5332-5343. [PMID: 33908779 DOI: 10.1021/acs.jafc.1c00284] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Ginger, as a food spice, is widely applied due to its extensive effects. Cedrol (CE) found in ginger is a sesquiterpene with anti-inflammatory activity. The objective of this research is to discuss the efficacy of CE on ameliorating rheumatoid arthritis (RA). CE inhibited chronic inflammation and pain in a dose-dependent manner accompanied by rapid onset and long duration. Besides, CE treatment effectively ameliorated the paw edema volume and arthritis score with no significant effect on body weight. Organ index, T-cell and B-cell proliferation, histopathology, and immunohistochemistry demonstrated that CE had immunological enhancement and attenuated RA effects. Remarkably, inhibition of phosphorylated-JAK3 protein, thereby abating the secretion of pro-inflammatory cytokines and inflammation-related mediators, was involved in the potential mechanism of CE efficiency through forming a hydrogen bond with ARG953 and ILE955 in the JAK3 active pocket. At the same time, the pharmacokinetic results showed that the absolute bioavailability of CE at 20, 40, and 80 mg/kg was 30.30, 23.68, and 16.11%, respectively. The current results offered clues for mastering the ameliorated RA of CE and further perfected the effective substance basis on the anti-inflammatory effect of ginger, which was beneficial for further applications.
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Affiliation(s)
- Yu-Meng Zhang
- Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Jian Shen
- Zhejiang Respiratory Drugs Research Laboratory of State Food and Drug Administration of China, Zhejiang University, Hangzhou 310000, China
| | - Jun-Ming Zhao
- Liaoning Xinzhong Modern Medicine Company Ltd., Shenyang 110016, China
| | - Jian Guan
- Liaoning Xinzhong Modern Medicine Company Ltd., Shenyang 110016, China
| | - Xin-Rui Wei
- Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Dong-Yu Miao
- Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Wei Li
- Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Yi-Cheng Xie
- Zhejiang Respiratory Drugs Research Laboratory of State Food and Drug Administration of China, Zhejiang University, Hangzhou 310000, China
| | - Yu-Qing Zhao
- Shenyang Pharmaceutical University, Shenyang 110016, China
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