Frontiers in Immunology
·
2023
·
IF 7.3
Ling Yang,Xueyuan Yu,Meng Liu,Yang Cao
Introduction Osteoarthritis (OA) is a chronic disease with high morbidity and disability rates whose molecular mechanism remains unclear. This study sought to identify OA markers associated with synovitis and cartilage apoptosis by bioinformatics analysis. Methods A total of five gene-expression profiles were selected from the Gene Expression Omnibus database. We combined the GEO with the GeneCards database and performed Gene Ontology and Kyoto Encyclopedia of Genes and Genome analyses; then, the least absolute shrinkage and selection operator (LASSO) algorithm was used to identify the characteristic genes, and a predictive risk score was established. We used the uniform manifold approximation and projection (UMAP) method to identify subtypes of OA patients, while the CytoHubba algorithm and GOSemSim R package were used to screen out hub genes. Next, an immunological assessment was performed using single-sample gene set enrichment analysis and CIBERSORTx. Results A total of 56OA-related differential genes were selected, and 10 characteristic genes were identified by the LASSO algorithm. OA samples were classified into cluster 1 and cluster 2 subtypes byUMAP, and the clustering results showed that the characteristic genes were significantly different between these groups. MYOC, CYP4B1, P2RY14, ADIPOQ, PLIN1, MFAP5, and LYVE1 were highly expressed in cluster 2, and ANKHLRC15, CEMIP, GPR88, CSN1S1, TAC1, and SPP1 were highly expressed in cluster 1. Protein–protein interaction network analysis showed that MMP9, COL1A, and IGF1 were high nodes, and the differential genes affected the IL-17 pathway and tumor necrosis factor pathway. The GOSemSim R package showed that ADIPOQ, COL1A, and SPP1 are closely related to the function of 31 hub genes. In addition, it was determined that mmp9 and Fos interact with multiple transcription factors, and the ssGSEA and CIBERSORTx algorithms revealed significant differences in immune infiltration between the two OA subtypes. Finally, a qPCR experiment was performed to explore the important genes in rat cartilage and synovium tissues; the qPCR results showed that COL1A and IL-17A were both highly expressed in synovitis tissues and cartilage tissues of OA rats, which is consistent with the predicted results. Discussion In the future, common therapeutic targets might be found forsimultaneous remissions of both phenotypes of OA.
研究领域:
医学
·
生物信息学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2024
·
IF 4.8
Yasi Deng,Yuxin Chen,Hao Zheng,Bin Li,Ling Liang,Wei Su,Bilal Ahmad,Yupei Yang,Hanwen Yuan,Wei Wang,Huanghe Yu
Ethnopharmacological relevance Synovial inflammatory hyperplasia is the key pathological process that leads to further joint damage in rheumatoid arthritis (RA) progress. Kadsura heteroclita (Roxb) Craib, also called Xuetong in Chinese Tujia ethnomedicine, is utilized for its medicinal properties, including promoting blood circulation, dispelling “wind evil”, and relieving “damp evil”. It has been used in the treatment of arthralgia and RA, within Tujia ethnomedicinal practices. Xuetongsu (XTS), the main component of Xuetong, has been shown to inhibit the proliferation of RA fibroblast-like synovial cells (RAFLS) cells. However, the molecular mechanism of XTS in RA treatment requires further investigation. Aim of the study To observe the therapeutic effect of XTS on synovial inflammatory hyperplasia in rheumatoid arthritis, focusing on its underlying molecular mechanisms involving the janus kinase 2 (JAK2)/transducer/activator of transcription 3 (STAT3) and nuclear factor kappa B (NF-κB) signaling pathways. Materials and methods Protein-protein interaction (PPI) and molecular docking were used to find the main targets of XTS treatment for RA. In lipopolysaccharide (LPS)-induced RAFLS and RAW264.7 cells in vitro models, the levels of inflammatory cytokines were analyzed using enzyme linked immunosorbent assay (ELISA), and the expression of JAK2, STAT3, and NF-κB signaling pathways, as well as cyclooxygenase-2 (COX-2), were analyzed through western blotting test. A hemolysis assay was used to certify the biosecurity of XTS. A model of adjuvant arthritis (AIA) was established in 40 male rats, and different doses of XTS were administered, followed by an automatic blood routine, ELISA assay, hematoxylin and eosin (H&E) staining, and radiological analysis of the effect of no XTS on blood cytokines, histological changes, and improvement of posterior paw bone destruction in AIA rats. The protein levels of inflammatory cytokines were analyzed by immunofluorescence, immunohistochemistry, or western blot. Finally, H&E staining was used to detect the damage of XTS on the heart, liver, spleen, lung, and kidney of AIA rats. Results Our results demonstrate that XTS effectively inhibited LPS-induced inflammatory responses in RAFLS and RAW264.7 cells by modulating the JAK2/STAT3 and NF-κB signaling pathways. Moreover, XTS administration in the AIA rats model significantly ameliorated paw swelling. Histological analysis revealed that XTS also suppressed the inflammatory response in paw tissue by modulating the JAK2/STAT3 and NF-κB signaling pathways. Importantly, during the treatment, XTS exhibited excellent safety profiles, as it did not induce any abnormalities in blood routine parameters or cause organ damage in the rats. Conclusions Our findings highlight XTS as a promising natural agent for inhibiting synovial hyperplasia in RA. XTS holds great potential as an unprecedented natural agent for developing novel therapeutic strategies to target synovial hyperplasia in RA.
研究领域:
药理学
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免疫学
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民族药理学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
ACS Nano
·
2025
·
IF 16
Yanpeng Lin,Hangtian Wu,Jun Wang,Wanling He,Jiahui Hou,Vidmi Taolam Martin,Chencheng Zhu,Yupeng Chen,Junyuan Zhong,Bin Yu,Aiping Lu,Daogang Guan,Genggeng Qin,Weiguo Chen
Chondrocyte senescence, synovitis, and decreased level of lubrication play pivotal roles in the pathogenesis of age-related osteoarthritis (AROA). However, there are currently no effective therapeutic interventions capable of altering the progression of OA until it reaches advanced stages, necessitating joint replacement. In this study, lubricious and drug-loaded hydrogel microspheres were designed and fabricated by utilizing microfluidic technology for radical polymerization of chondroitin sulfate methacrylate and incorporating nicotinamide adenine dinucleotide (NAD)-loaded liposomes modified with lactoferrin that are positively charged. Mechanical, tribological, and drug release analyses demonstrated enhanced lubrication properties and an extended drug dissemination time for the NAD@NPs@HM microspheres. In vitro assays unveiled the ability of NAD@NPs@HM to counteract chondrocyte senescence. RNA sequencing analysis, untargeted metabolomics analysis, and in vitro experiments on macrophages revealed that NAD@NPs@HM can regulate the metabolic reprogramming of synovial macrophages, promoting their repolarization from the M1 to M2 phenotype, thereby alleviating synovitis. Intra-articular injection of NAD@NPs@HM in aged mice reduced the mechanisms associated with AROA. These results suggest that NAD@NPs@HM may provide extended drug release, improved joint lubrication leading to better gait, and attenuation of AROA pathogenic processes, indicating its potential as a therapeutic approach for AROA.
研究领域:
生物材料学
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医学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Bioactive Materials
·
2023
·
IF 18.9
Chunchun Xue,Jia Tian,Zepeng Cui,Yang Liu,Dawei Sun,Mengting Xiong,Nanxing Yi,Kaiqiang Wang,Xiaofeng Li,Yongjun Wang,Hao Xu,Weian Zhang,Qianqian Liang
Osteoarthritis (OA) is a common chronic inflammatory disorder. Effective remodeling of inflammatory microenvironment in the joint is a promising strategy to prevent OA. However, current drugs remain unsatisfactory due to a lack of targeted and effective ways for relieving inflammatory conditions in OA joints. Bortezomib (BTZ), a proteasome inhibitor, could effectively inhibit proinflammatory cytokines but with poor accumulation in the inflammatory tissues. To overcome the shortcomings of BTZ delivery and to improve the efficacy of OA therapy, herein, we designed a novel nanomedicine (denoted as BTZ@PTK) by the co-assembly of BTZ and an amphiphilic copolymer (denoted as PTK) with ROS-cleaved thioketal (TK) linkages. The TK units in BTZ@PTK are first cleaved by the excessive ROS at OA sites, and then triggered the controlled release of BTZ, resulting in the accurate delivery and the inflammatory microenvironment remodeling. Accordingly, BTZ@PTK suppressed ROS generation and proinflammatory cytokines while promoting M1 macrophage apoptosis in lipopolysaccharide (LPS)-activated RAW264.7 macrophages or LPS/IFN-γ-treated primary macrophages, which leads to a better effect than BTZ. In OA mice, BTZ@PTK passively accumulates into inflamed joints to attenuate pain sensitivity and gait abnormality. Importantly, BTZ@PTK treatment successfully ameliorates synovitis with the reduction of synovial hyperplasia and synovitis scores by suppressing M1 macrophage polarization and promoting M1 macrophage apoptosis in the synovium, thereby delaying cartilage damage. Collectively, BTZ@PTK can effectively modulate inflammatory microenvironment for OA recession by activating M1 macrophage apoptosis and inhibiting M1macrophage-mediated inflammatory response.
研究领域:
药理学
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纳米技术
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免疫学
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骨科
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Orthopaedic Surgery
·
2021
·Vol. 13
·期 4
·1398-1407
·
IF 2.071
Ming Li,Yan-bo Xiao,Xin-tao Wang,Jin-peng Zhuang,Chang-long Zhou
Objective To explore the possible way of proline-serine–threonine phosphatase-interacting protein 2 (PSTPIP2) influencing diabetes mellitus-osteoarthritis (DM-OA) progression. Methods In vivo , eight-week-old male Sprague Dawley rats were induced with DM-OA by intraperitoneal injection of streptozotocin with high-fat diet feeding and intra-articular injection of monoiodoacetate. PSTPIP2 overexpression was achieved by intra-articular injection of lentivirus vectors. PSTPIP2 expression was verified by real-time polymerase chain reaction and Western blotting. Histological changes were examined by hematoxylin/eosin and safranin-O/fast-green staining. In vitro , rat synovial fibroblasts were induced DM-OA by stimulation of high glucose (HG) and interleukin (IL)-1β. PSTPIP2 overexpression was achieved by lentivirus infection. U0126 was added as an ERK inhibitor. Levels of tumor necrosis factor (TNF)-α, IL-6, and IL-1β were detected using enzyme-linked immunosorbent assay. Expression of matrix metalloproteinase (MMP)-3, MMP-13, aggrecanase-2 (ADAMTS-5), intercellular cell adhesion molecule (ICAM)-1, extracellular regulated protein kinase (ERK) and phospho-ERK (p-ERK) was detected by Western blotting. Results In DM-OA rats, PSTPIP2 relative messenger RNA (mRNA) level was significantly decreased compared to control rats. The protein expression was also decreased obviously. Inflammation score in synovium was dramatically increased, accompanying with increased TNF-α, IL-6, and IL-1β levels. Osteoarthritis research society international (OARSI) score in cartilage was markedly increased, along with increased MMP-3, MMP-13, ADAMTS-5, ICAM-1, ERK and p-ERK expression. In PSTPIP2-overexpressed DM-OA rats, PSTPIP2 mRNA level and protein expression was increased compared to DM-OA rats received negative-control lentivirus vectors. The inflammation score, as well as TNF-α, IL-6, and IL-1β levels were dramatically decreased. Also, the OARSI score and protein expression of MMP-3, MMP-13, ADAMTS-5, ICAM-1, ERK and p-ERK were decreased. In HG+IL-1β-treated rat synovial fibroblasts, PSTPIP2 protein expression was decreased compared to normal glucose (NG)-treated cells. Levels of TNF-α, IL-6, and IL-1β, as well as expression of MMP-3, MMP-13, ADAMTS-5, ICAM-1, ERK and p-ERK were increased. After cells were infected with PSTPIP2-overexpressed lentivirus, levels of TNF-α, IL-6, and IL-1β, and expression of MMP-3, MMP-13, ADAMTS-5, ICAM-1, ERK and p-ERK were obviously decreased compared to cells infected with NC lentivirus. In addition, ERK inhibitor U0126 treatment also decreased the TNF-α, IL-6, and IL-1βlevels and MMP-3, MMP-13, ADAMTS-5, ICAM-1, ERK and p-ERK expression in HG + IL-1β treated rat synovial fibroblasts. Conclusion Overexpression of PSTPIP2 alleviates synovial inflammation and cartilage injury during DM-OA progression via inhibiting ERK phosphorylation.
研究领域:
医学研究
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风湿病学
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糖尿病学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2024
·Vol. 22
·期 1
·1-19
·
IF 10.6
Huang Lanli,Yao Yi,Ruan Zhuren,Zhang Shengqing,Feng Xianjing,Lu Chun,Zhao Jinmin,Yin Feiying,Cao Cunwei,Zheng Li
Intra-articular drugs used to treat osteoarthritis (OA) often suffer from poor pharmacokinetics and stability. Nano-platforms as drug delivery systems for drug delivery are promising for OA therapy. In this study, we reported an M1 macrophage-targeted delivery system Bai@FA-UIO-66-NH2 based on folic acid (FA) -modified metal-organic framework (MOF) loaded with baicalin (Bai) as antioxidant agent for OA therapy. With outstanding biocompatibility and high drug loading efficiency, Bai@FA-UIO-66-NH2 could be specifically uptaken by LPS-induced macrophages to serve as a potent ROS scavenger, gradually releasing Bai at the subcellular level to reduce ROS production, modulate macrophage polarization to M2, leading to alleviation of synovial inflammation in OA joints. The synergistic effect of Bai@FA-UIO-66-NH2 on macrophage polarization and ROS scavenging significantly improved the therapeutic efficacy of OA, which may provide a new insight into the design of OA precision therapy.
研究领域:
药理学
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纳米技术
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药物递送系统
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免疫学
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骨科
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Chenlu Huo,Shuang Li,Anting Liu,Yujie Hong,Yan Zhu
It has been reported that the symptoms of rheumatoid arthritis (RA) can be ameliorated by acupuncture, an external treatment of traditional Chinese medicine. However, the immune mechanism underlying its action is elusive. Accordingly, this study investigated the role and mechanism of manual acupuncture (MA) in collagen-induced arthritis (CIA) in mice. The results demonstrated that MA or NaB treatment reduced Articular Index scores and right paw thickness and alleviated synovial inflammation and cartilage damage. MA or NaB treatment altered the content and relative abundance of short-chain fatty acids, particularly butyric and propionic acids, in feces. Additionally, MA or NaB treatment elevated SCD1, SREBP1, and GPX4 protein expression in synovial tissues and GSH-px contents in serum while decreasing ROS fluorescence intensity and MDA contents in peripheral blood. A linear correlation was found between the relative expression of SCD1 and SREBP1 in synovial tissues and the contents of propionic acids and butyric acids in feces, as well as between the contents of propionic acids and butyric acids. In summary, MA regulates butyric acids to inhibit ferroptosis, therefore suppressing inflammation in RA.
研究领域:
免疫学
·
风湿病学
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中医
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2023
·
IF 15.1
Huiyun Li,Yusong Yuan,Lingpu Zhang,Chun Xu,Hailin Xu,Zhiwei Chen
Osteoarthritis (OA) is a chronic joint disease characterized by synovitis and joint cartilage destruction. The severity of OA is highly associated with the imbalance between M1 and M2 synovial macrophages. In this study, a novel strategy is designed to modulate macrophage polarization by reducing intracellular reactive oxygen species (ROS) levels and regulating mitochondrial function. A ROS-responsive polymer is synthesized to self-assemble with astaxanthin and autophagy activator rapamycin to form nanoparticles (NP@Poly RHAPM ). In vitro experiments show that NP@Poly RHAPM significantly reduced intracellular ROS levels. Furthermore, NP@Poly RHAPM restored mitochondrial membrane potential, increased glutathione (GSH) levels, and promoted intracellular autophagy, hence successfully repolarizing M1 macrophages into the M2 phenotype. This repolarization enhanced chondrocyte proliferation and vitality while inhibiting apoptosis. In vivo experiments utilizing an anterior cruciate ligament transection (ACLT)-induced OA mouse model revealed the anti-inflammatory and cartilage-protective effects of NP@Poly RHAPM , effectively mitigating OA progression. Consequently, the findings suggest that intra-articular delivery of ROS-responsive nanocarrier systems holds significant promise as a potential and effective therapeutic strategy for OA treatment.
研究领域:
药理学
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生物医学工程
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骨科
·
免疫学
·
纳米技术
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2022
·
IF 5.988
Chuyu Shen,Meilin Xu,Siqi Xu,Shuoyang Zhang,Wei Lin,Hao Li,Shan Zeng,Qian Qiu,Liuqin Liang,Youjun Xiao,Hanshi Xu
Objective: To explore the effect and underlying mechanism of Myricitrin (Myr) in regulating fibroblast-like synoviocyte (FLS)-mediated synovitis and joint destruction in RA. Methods: FLSs were isolated from synovial tissues from patients with RA. Gene expression was measured using quantitative RT-qPCR. Protein expression was detected by immunohistochemistry or Western blot. Cell apoptosis was performed by an Annexin-PI staining assay. EdU incorporation was used to assess the proliferation of RA FLS. Transwell assay was used to characterize the cell migration and invasion ability of RA FLS. The potential target of Myr was identified by RNA sequencing analysis. The in vivo effect of Myr was assessed in a collagen-induced arthritis (CIA) model. Results: Myr treatment inhibited the lamellipodia formation, migration, and invasion, but not the apoptosis and proliferation, of RA FLSs. Myr also reduced the expression of CCL2, IL-6, IL-8, MMP-1, MMP-3, and MMP-13 induced by TNF-α. The RNA-seq results indicated that AIM2 may be a target gene of Myr in RA FLSs. Furthermore, compared to healthy controls, AIM2 expression showed higher levels in synovial tissues and FLSs from RA patients. AIM2 knockdown also inhibited RA FLS migration, invasion, cytokine, and MMP expression. In addition, either Myr treatment or AIM2 knockdown reduced the phosphorylation of AKT induced by TNF-α stimulation. Importantly, Myr administration relieved arthritis symptoms and inhibited AIM2 expression in the synovium of CIA mice. Conclusion: Our results indicate that Myr exerts an anti-inflammatory and anti-invasion effect in RA FLSs and provide evidence of the therapeutic potential of Myr for RA.
研究领域:
风湿病学
·
免疫学
·
药理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Small
·
2024
·
IF 13
Hongtao Zhang,Shiguo Yuan,Boyuan Zheng,Peng Wu,Xiuming He,Yi Zhao,Zhangfeng Zhong,Xiaofang Zhang,Jian Guan,Huajun Wang,Lei Yang,Xiaofei Zheng
Osteoarthritis (OA) is a progressively developing condition primarily characterized by the deterioration of articular cartilage and the proliferation of bone, along with ongoing inflammation. Although the precise pathogenesis remains somewhat elusive, restoring the homeostatic balance of the intra-articular microenvironment is crucial for the management of OA. Intra-articular injection of medication is one of the most direct and effective treatment methods; however, most injectable drugs used for osteoarthritis treatment, due to their rapid breakdown, quick release, poor biological activity, and frequent injections, leading to increased risk of infection and suboptimal therapeutic outcomes. In this study, a lubricating and dual-responsive injectable hydrogel based on zeolitic imidazolate frameworks-8 (ZIF-8) impregnated with Quercetin (Que) is designed, which can facilitate OA treatment by remodeling the microenvironment. The prepared injectable nanocomposite hydrogel (MH/CCM@ZIF-8@Que) exhibits pH and reactive oxygen species (ROS) responsiveness, alongside a controllable release of bioactive substances to modulate the microenvironment of bone tissue, thereby mitigating synovitis and the degeneration of cartilage matrix, while simultaneously facilitating cartilage repair. This developed thermosensitive injectable hydrogel, which effectively balances lubrication with the controlled release of bioactive substances, represents a highly promising therapeutic approach for osteoarthritis.
研究领域:
药学
·
材料科学
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生物医学工程
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骨科
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2024
·
IF 10
Junyi Liao,Zhenglin Zhu,Jing Zou,Senrui Liu,Xuefeng Luo,Wei Bao,Chengcheng Du,Yiting Lei,Wei Huang
Osteoarthritis (OA) is an inflammatory and progressive joint disease characterized by angiogenesis-mediated sustained, chronic, and low-grade synovitis. Anti-angiogenesis is emerging as a strategy for attenuating OA progression, but is often compromised by poor targeted drug delivery and immune clearance. Recent studies have identified macrophages formed a “protective barrier” in the lining layer (LL) of synovium, which blocked the communication of joint cavity and sublining layer (SL) of synovium. Inspired by natural mimicry, macrophage membrane-camouflaged drug delivery is explored to avoid immune clearance. Based on the single cell RNA sequencing, the CD34 + synovial cells are identified as “sentinel cells” for synovium angiogenesis. Consequently, CD34 antibody-modified macrophage membrane is constructed to target new angiogenesis. Hence, a biomimetic multi-layered nanoparticle (NP) is developed that incorporates axitinib-loaded poly(lactic-co-glycolic) acid (PLGA) with CD34 antibody modified macrophage membrane (Atb@NP@Raw@CD34) to specifically deliver axitinib (Atb) to the SL and sustain inhibiting angiogenesis without immune elimination. It is found that the Atb@NP@Raw@CD34 can pass through macrophage “barrier”, specifically targeting CD34 + cells, continuously releasing Atb and anti-angiogenesis in OA synovitis. Furthermore, in vivo data demonstrated that Atb@NP@Raw@CD34 can attenuate joint degeneration by inhibiting synovium angiogenesis-mediated synovitis. In conclusion, local injection of Atb@NP@Raw@CD34 presents a promising approach for clinically impeding OA progression.
研究领域:
药理学
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纳米技术
·
生物医学工程
·
免疫学
·
风湿病学
✓ 已验证
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2024
·
IF 18.5
Wang Han,Mengtong Guan,Xiaoqian Ding,Bo Liao,Jieliang Shen,Xinhe Li,Yi He,Xiaoyu Han,Dingqun Bai,Ying Zhu
The malignant cycle of synovitis considerably impacts the progression of osteoarthritis (OA). Therefore, the precise localization of synovitis, targeted disruption of the inflammatory cycle, and real-time monitoring of its dynamics are crucial for the effective diagnosis and management of OA. Here, porous HAMA/GelMA microspheres are synthesized using microfluidic technology. Interleukin-10 (IL-10) nanobubbles, prepared via double emulsification, are grafted with folic acid (FA) via an amide reaction and subsequently impregnated and adsorbed onto the microspheres, thereby constructing an ultrasonic contrast microsphere system. This system facilitates not only ultrasonic imaging for accurate localization of synovitis but also the targeted and controlled delivery of IL-10 under ultrasound conditions. In vitro, under ultrasound intensities of 0, 0.5, and 1.5 W, the system effectively releases IL-10 at the rates of 19.95%, 30.95%, and 40.67%, respectively. In vivo, the biodegradability of the system facilitates real-time tracking and monitoring of synovitis for at least 14 days. In summary, ultrasonic contrast microspheres enable precise localization and real-time monitoring of synovitis. Under ultrasound conditions, these microspheres enable targeted and controlled drug delivery, effectively disrupting vicious inflammatory cycles. This strategy pioneers new pathways for the management and precise treatment of OA.
研究领域:
生物医学工程
·
药学
·
医学影像
·
炎症生物学
·
骨科
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）