CELLULAR IMMUNOLOGY
·
2024
·
IF 3.7
Jingying Qin,Cheli Wang,Xiaoying Zhou
Reduced glutathione (GSH) is an antioxidant involved in redox homeostasis, and recently regarded as an inducer of Reductive stress. Its immune-regulatory effects on lymphocytes have not been extensively studied. This study is based on the finding that much increased GSH level in collagen-induced arthritis (CIA) rat spleen, and aimed to investigate the effects of GSH (0, 1, 10, 100 mM) on normal and immune-stimulated spleen lymphocytes respectively. The elevated GSH level is associated with the increased levels of inflammatory factors; especially the increased DPP1 activity indicated immune-granulocytes activation in CIA rat spleen. Exogenous GSH had different influences on normal and CIA lymphocytes, affecting intracellular levels of GSH, Glutathione-S-transferases (GSTs) and Reactive oxygen species (ROS); as well as the expressions of NF-κB, MMP-9, Bcl-2, GST, P38, PCNA and TLR4. The increased extracellular GSH level disturbed redox homeostasis and induces reductive stress to spleen lymphocytes, which decreased intracellular GSH concentration and influenced the MAPK/PCNA and NF-κB/MMP-9 signaling pathways, as well as cell cycles respectively, leading to cell senescence/ferroptosis/apoptosis. This study also revealed the multiple faces of GSH in regulating spleen lymphocytes, which depended on its levels in tissue or in cells, and the activation status of lymphocytes. These findings indicate the immune-regulatory role of GSH on spleen-lymphocytes, and the high level GSH in CIA rat spleens may contribute to CIA development.
研究领域:
免疫学
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药理学
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细胞生物学
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风湿病学
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DOI
PubMed
高影响因子
HISTOLOGY AND HISTOPATHOLOGY
·
2026
·Vol. 41
·期 3
·453-465
·
IF 2.2
Xuefei Fan,Suhuan Chen,Haomiao Liu,Nannan Liu,Mengyan Zhang,Mengmeng Chen,Wuqi Chen,Guangyi Chen,Weilu Gao,Tao Yao,Xiaoyu Chen
Background: Rheumatoid arthritis can affect extra-articular organs such as the liver, and the problem of drug-induced liver injury caused by traditional antirheumatic drugs for improving the condition cannot be ignored. This study aims to investigate the therapeutic effects of resveratrol (Res) on hepatic inflammation and oxidative stress in mice with collagen-induced arthritis (CIA) and to elucidate the relationship between the regulatory mechanisms of the nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) signaling pathway. Methods: In this study, we used chicken type II collagen in combination with complete Freund's adjuvant to induce arthritis in a mouse model, and Res was administered by tube feeding to detect the serum biochemical liver function and inflammation levels, oxidative stress, and apoptosis in the livers of mice. An in vitro cellular model of liver inflammation and oxidative stress was established by treating mouse primary hepatocytes (MPHs) with tumor necrosis factor-α (TNF-α) and H 2 O 2 . The intrinsic mechanism of Res in attenuating hepatic inflammation and oxidative stress in CIA mice was explored by treating MPHs with an Nrf2 inhibitor and Keap1 overexpression plasmid. Results: Res significantly reduced the levels of inflammation and oxidative stress in liver tissues of CIA mice as well as in MPHs treated with TNF-α and H 2 O 2 and activated the Nrf2/Keap1 signaling pathway. Inflammation and oxidative stress levels in MPHs were exacerbated by the use of Nrf2 inhibitors and Keap1 overexpression, which promoted apoptosis. Conclusion: This study demonstrated the intrinsic mechanism of Res of attenuating hepatic inflammation and oxidative stress in CIA mice through the Nrf2/Keap1 pathway, which provides a new idea for finding hepatoprotective treatments for rheumatoid arthritis.
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DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2021
·
IF 5.275
Shiyang Zhou,Huiying Zou,Gangliang Huang,Guangying Chen,Xueming Zhou,Shuheng Huang
Four series of double-ring conjugated enones were designed, synthesized and studied for the inhibition of synovial cell activity through the modification of Dysodensiol K core structure, double-ring, double-bond and double-carbonyl groups. For in vitro synovial cell assay of rats, compound 151 and 168 exhibited good inhibitory activities, with IC 50 values of 2.71 ± 0.18 and 2.68 ± 0.16 μM respectively. At the same time, the LDH release and LD 50 test results revealed that the target compounds were low cytotoxicity and acute toxicity. For in vivo CIA model test through the oral administration, compounds 151 and 168 were exhibited similar effect to positive control group methotrexate.
研究领域:
药物化学
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药理学
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风湿病学
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DOI
PubMed
高影响因子
Chinese Journal of Integrative Medicine
·
2024
·
IF 2.2
Liu Xiao-rong,Li Shuo-fu,Mei Wen-ya,Liu Xiang-dan,Zhou Ri-bao
Objective To investigate the effect of isorhamnetin on the pathology of rheumatoid arthritis (RA). Methods Tumor necrosis factor (TNF)- α -induced fibroblast-like synoviocytes (FLS) was exposed to additional isorhamnetin (10, 20 and 40 µ mol/L). Overexpression vectors for matrix metalloproteinase-2 (MMP2) or MMP9 or SRC were transfected to explore their roles in isorhamnetin-mediated RA-FLS function. RA-FLS viability, migration, and invasion were evaluated. Moreover, a collagen-induced arthritis (CIA) rat model was established. Rats were randomly divided to sham, CIA, low-, medium-, and high-dosage groups using a random number table ( n =5 in each group) and administed with normal saline or additional isorhamnetin [2, 10, and 20 mg/(kg·day)] for 4 weeks, respectively. Arthritis index was calculated and synovial tissue inflammation was determined in CIA rats. The levels of MMP2, MMP9, TNF-α, interleukin-6 (IL-6), and IL-1 β, as well as the phosphorylation levels of SRC, extracellular regulated kinase (ERK), and cyclic adenosine monophosphate response element-binding (CREB), were detected in RA-FLS and synovial tissue. Molecular docking was also used to analyze the binding of isorhamnetin to SRC. Results In in vitro studies, isorhamnetin inhibited RA-FLS viability, migration and invasion ( P <0.05). Isorhamnetin downregulated the levels of MMP2, MMP9, TNF-α, IL-6, and IL-1 β in RA-FLS ( P <0.05). The overexpression of either MMP2 or MMP9 reversed isorhamnetin-inhibited RA-FLS migration and invasion, as well as the levels of TNF-α, IL-6, and IL-1 β ( P <0.05). Furthermore, isorhamnetin bound to SRC and reduced the phosphorylation of SRC, ERK, and CREB ( P <0.05). SRC overexpression reversed the inhibitory effect of isorhamnetin on RA-FLS viability, migration and invasion, as well as the negative regulation of MMP2 and MMP9 ( P <0.05). In in vivo studies, isorhamnetin decreased arthritis index scores ( P <0.05) and alleviated synovial inflammation. Isorhamnetin reduced the levels of MMP2, MMP9, TNF-α, IL-6, and IL-1 β, as well as the phosphorylation of SRC, ERK, and CREB in synovial tissue ( P <0.05). Notably, the inhibitory effect of isorhamnetin was more pronounced at higher concentrations ( P <0.05). Conclusion Isorhamnetin exhibited anti-RA effects through modulating SRC/ERK/CREB and MMP2/MMP9 signaling pathways, suggesting that isorhamnetin may be a potential therapeutic agent for RA.
研究领域:
药理学
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免疫学
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风湿病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Pharmaceutics
·
2022
·Vol. 14
·期 7
·1518
·
IF 6.525
Mengchen An,Mengxiao Shi,Jingjing Su,Yueru Wei,Rongrong Luo,Pengchao Sun,Yongxing Zhao
Although the inhibitors of the interleukin-6 receptor (IL-6R) and tumor necrosis factor-α (TNF-α) have achieved a certain success in the clinical treatment of rheumatoid arthritis (RA), great effort should be made to overcome side effects and to improve patient compliance. The present research aimed to address these problems by the co-delivery of tocilizumab (TCZ)—an inhibitor of IL-6R—and an aptamer Apt1-67, which specifically inhibits TNF receptor 1 via separable microneedles (MN). MN were featured with a sustained release of TCZ from needle tips and a rapid release of Apt1-67 from needle bodies by using methacrylate groups grafted hyaluronic acid as the fillings of needle tips and polyvinyl alcohol/polyvinyl pyrrolidone as the fillings of needle bodies. Our results demonstrated that TCZ and Apt1-67 were distributed in MN as expected, and they could be released to the surroundings in the skin. In vivo studies revealed that combined medication via MN (TCZ/[email protected]) was superior to MN loaded with a single drug. Compared with subcutaneous injection, TCZ/[email protected]was of great advantage in inhibiting bone erosion and alleviating symptoms of CIA mice. This study not only provides a novel approach for combined medication with different release properties but also supplies a strategy for improving drug efficacy.Keywords:separable microneedles;tocilizumab;aptamer Apt1-67;rheumatoid arthritis
研究领域:
药学
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生物医学工程
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风湿病学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
·
2016
·Vol. 39
·期 2
·307-316
·
IF 2.348
Yongsheng Yang,Qiumei Dong,Rongheng Li
The induction of apoptosis-resistant rheumatoid synovial tissue cells has been related to constitutively active Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling in rheumatoid arthritis (RA). The excessive proliferation and inherent resistance to apoptosis of fibroblast-like synoviocytes (FLS) is an important mechanism by which RA originates. However, the effects of matrine on FLS in RA is unclear. The present study aimed to investigate the mechanism of action of matrine in a rat model of collagen‑induced arthritis (CIA). The CIA model was established using bovine type II collagen. FLS were isolated from control and CIA rats, cultured in vitro, and confirmed to harbor fibroblast‑like characteristics. After treatment of FLS with varying concentrations of matrine, the JAK2 inhibitor AG490, or a combination of both drugs, cell proliferation, apoptosis rate, expression of apoptotic markers and the activation of the JAK/STAT pathway were assessed. Additionally, CIA rats were administered either matrine or methotrexate by oral gavage to examine the effects of therapeutic intervention on arthritis pathogenesis. The arthritis index (AI) was measured and ankle joint structure was analyzed histologically to determine the severity of CIA. Furthermore, expression levels of apoptotic markers and members of the JAK/STAT family were also examined in vivo. Compared with the CIA group, matrine reduced AI and improved ankle pathology. Matrine also inhibited FLS proliferation, induced G0/G1 cell cycle arrest, and increased the rate of apoptosis in vitro. The effects of matrine on apoptosis induction were further confirmed by observations that Bcl-2 levels were decreased, whereas Bax and caspase-3 levels were increased in the matrine-treated synovial tissues and FLS. Finally, matrine treatment also diminished the phosphorylation, and hence activation of JAK2, STAT1 and STAT3. Our results suggest that matrine induces the apoptosis of FLS from rats with CIA by inhibiting activation of the JAK/STAT signaling pathway.
研究领域:
药理学
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免疫学
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风湿病学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
PeerJ
·
2023
·
IF 2.7
Liang Chen,Yi Xu
Scalp cooling is the most approved treatment for preventing chemotherapy-induced alopecia (CIA). However, the protective mechanism of scalp cooling has rarely been reported. The goal of the present study was to study the relationship between paclitaxel concentration and temperature and the inhibitory effect of low temperature on paclitaxel-induced alopecia. The results showed that the dose of paclitaxel should not exceed 60–70 mg/mL during scalp cooling treatment, and the optimal cooling temperature under different paclitaxel concentrations was determined. Normal human epidermal keratinocytes (NHEK) cells were analyzed by global transcriptome analysis, functional annotation and pathway analysis of differentially expressed genes (DEGs) and ELISA kit to analyze the mechanism of low temperature therapy. The expression of HSPA8, HSPA1A and HSPA1B, which belongs to HSP70, was up-regulated by low temperature. These genes are important target genes of low temperature treatment, which were confirmed by ELISA. The up-regulation of PLK2 and the down-regulation of TXNIP expression are the upstream of mitochondrial dysfunction and ROS, inhibiting the accumulation of ROS and up-regulating the mitochondrial membrane potential. Our research partially elucidates the therapeutic mechanism of scalp cooling, which provides a new idea on the drug research and development in CIA.
研究领域:
肿瘤学
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细胞生物学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2018
·
IF 3.909
Yaoli Guo,Qi Ye,Shuling Yang,Jinzhong Wu,Bingzhu Ye,Yanbin Wu,Zehao Huang,Chengjian Zheng
Anoectochilus roxburghii , a famous Chinese herbal medicine, has been commonly used for the treatment of liver disease, diabetes, and rheumatoid arthritis. Our study aimed to investigate the anti-rheumatoid arthritis effects of A . roxburghii polysaccharides (ARP), using the rat's model of type II collagen-induced arthritis (CIA). ARP was prepared by alcohol sedimentation and structurally characterized based on combined chemical, chromatographic and spectroscopic methods. High Performance Size Exclusion Chromatography-Multiangle Laser Light Scattering-Refrative Index (HPSEC–MALLS–RI) analysis revealed that ARP includes two peaks, and the weight-average molecular weight ( Mw ) of the principal one was estimated as 5.90 kDa with a relative content of 98.2%. Pharmacological results exhibited that ARP significantly decreased the arthritis index and ameliorated the inflammatory cell infiltration and the synovial tissue destruction in CIA rats. Additionally, ARP possessed significant NO production inhibitory effects and antioxidant activity. Further anti-inflammatory mechanism investigations indicated that ARP significantly inhibited the activation of nuclear factor κB (NF-κB) pathway by suppressing the phosphorylation of IκB and p65, which subsequently down-regulated the mRNA expressions of IL-1β and IL-6 in LPS-stimulated RAW 264.7 cells. These findings suggested that ARP has great potential in the development of functional foods and dietary supplements for the treatment of rheumatoid arthritis.
研究领域:
药理学
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免疫学
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分子生物学
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DOI
PubMed
高影响因子
Nano Today
·
2024
·
IF 13.2
Qiaoxuan Wang,Qi Cheng,Guangshuai Yao,Zhaolong Wang,Lingjiang Zhu,Zhiru Zeng,Lingyun Jia,Yan Du,Jing Xue,Changyou Gao
Rheumatoid arthritis (RA) is a chronic inflammatory joint disease primarily driven by inappropriate infiltration and activation of immune cells and pro-inflammatory cytokines. Among them, neutrophils with high plasticity play a pathogenic role in RA by abnormal neutrophil immune activities. As anti-IL-17A therapies failed to achieve long-term ideal therapeutic outcomes in clinical trials, we speculated that the underlying cause may be associated with the abnormal activity of neutrophils that have a direct link to IL-17A. Herein, we created a cationic hydrogel loaded with anti-IL-17A nanobodies (Nbs) capable of synergistically weakening the inflammatory activities of neutrophils and relieving inflammation in RA. Based on the host-guest interaction, the hydrogel was comprised of β-cyclodextrin-modified hyperbranched polylysine (HBPL-CD) and adamantane-modified hyaluronic acid (HA-Ad). The physical properties were adjusted to match the mechanical environment of joints and enable injection. The hydrogel with Nbs could adsorb cell-free DNA (cfDNA) persistently and slowly release anti-IL-17A Nbs, which synergistically alleviated the inflammatory activities of neutrophils via inhibiting the IL-17A stimulated neutrophil extracellular traps (NETs) of neutrophils from RA patients and mice with collagen-induced arthritis (CIA), reducing the level of pro-inflammatory cytokines, and suppressing the inflammatory phenotype of neutrophils in vitro . The ankle injection of the hydrogel with Nbs into a mouse model of CIA could alleviate the RA symptoms in vivo . This novel platform is believed to provide a guideline for treating IL-17A-related diseases by combining Nbs with the immunoregulation of neutrophils.
研究领域:
生物医学工程
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免疫学
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药学
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风湿病学
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DOI
高影响因子
ACS Omega
·
2022
·
IF 4.132
Shan-Shan Wu,Li-Jun Hao,Yuan-Yuan Shi,Zhuo-Jian Lu,Jia-Lin Yu,Si-Qi Jiang,Qing-Ling Liu,Ting Wang,Shi-Ying Guo,Ping Li,Fei Li
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.
研究领域:
药理学
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中医
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风湿病学
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分子生物学
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系统生物学
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产品关联
DOI
PubMed
高影响因子
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