Pharmaceutics
·
2023
·Vol. 15
·期 5
·1500
·
IF 5.4
Yi Lu,Ting Xiao,Rongrong Lai,Ziyi Liu,Weixuan Luo,Yixuan Wang,Shijia Fu,Guihong Chai,Jinjing Jia,Yuehong Xu
Rheumatoid arthritis (RA) is an autoimmune disease of synovial inflammation that affects populations worldwide. Transdermal drug delivery systems for treating RA have increased but remain challenging. We fabricated a dissolving microneedle (MN) system with photothermal (PT) polydopamine (PDA) to co-load the non-steroidal anti-inflammatory drug loxoprofen (Lox) and the Janus kinase inhibitor tofacitinib (Tof), with the aim of co-delivering Lox and Tof directly to the articular cavity, aided by the combination of MN and PT. In vitro and in vivo permeation studies showed that the PT MN significantly promoted drug permeation and retention in the skin. An in vivo visualization of the drug distribution in the articular cavity showed that the PT MN significantly promoted drug retention in the articular cavity. Importantly, compared to the intra-articular injection of Lox and Tof, the application of the PT MN to a carrageenan/kaolin-induced arthritis rat model exhibited superior performance in reducing joint swelling, muscle atrophy, and cartilage destruction. Furthermore, the PT MN downregulated the mRNA expression levels of proinflammatory cytokines, including TNF-α, IL-1β, iNOS, JAK2, JAK3, and STAT3. The results show that the PT MN transdermal co-delivery of Lox and Tof is a new synergetic therapy with high compliance and good therapeutic efficacy for RA.Keywords:loxoprofen;tofacitinib;microneedle;photothermal therapy;rheumatoid arthritis
研究领域:
药学
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生物医学工程
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免疫学
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产品关联
DOI
PubMed
高影响因子
CURRENT PHARMACEUTICAL DESIGN
·
2025
·Vol. 31
·期 23
·1885-1902
·
IF 2.8
Ying Cai,Sifan Guo,Chunsheng Lin,Yan Wang,Chao Wang,Zhibo Wang,Dandan Xie,Yu Guan,Shi Qiu,Hui Dong,Aihua Zhang
BackgroundSimiao Pill (SMP) has been demonstrated to suppress inflammation and modulate immune function, thereby influencing the onset and progression of rheumatoid arthritis (RA). Nonetheless, the specific molecular mechanisms and targets through which SMP mediates metabolic regulation and enhances immune function have yet to be fully elucidated.ObjectiveIn this study, we employed an integrated approach combining the analysis of dysregulated metabolites and proteins to identify, screen, and validate the metabolic regulatory targets of SMP in adjuvant-induced arthritis (AIA) rats by using pseudotargeted metabolomics and 4D-DIA quantitative proteomics methodologies.MethodsAn AIA rat model was developed, and SMP was administered to AIA rats. Subsequently, assessments were conducted on paw edema, arthritis scores, histopathological changes and IL-1 β content of inflammatory factors in AIA rats. UHPLC-QTOF-MS/MS was employed to analyze endogenous metabolites in the serum. Metabolic pathway and protein profile were performed on the biomarkers. The protein-lipid-phenotype map for the SMP-treated rats was constructed and the primary target closely related to the metabolic regulation of SMP was further screened and verified.ResultsPseudotargeted metabolomics analysis revealed that SMP can mitigate the down-regulation of lipid levels in AIA rats. Pathway enrichment analysis identified arachidonic acid metabolism as the most significantly affected metabolic pathway and SMP was found to substantially ameliorate the dysregulation of this pathway in AIA rats. Subsequent protein profiling led to the identification of five key proteins, with noteworthy obvious corrective effects observed on Ptges3 and Alox15 due to SMP treatment. A comprehensive protein-lipid-phenotypic landscape of SMP-treated rats was analyzed for the specific molecular expressions associated with the arachidonic acid pathway. According to the correlation matrix of dysregulated metabolite/protein, we found that Ptges3 was ranked as the primary target closely related to the metabolic regulation of SMP, a finding further validated through immunofluorescence staining in rat joint and synovial cells.ConclusionOur study confirmed that SMP exerts an anti-arthritic effect by modulating the arachidonic acid metabolic network via the Ptges3 protein in rat joints and human rheumatoid arthritis synovial fibroblasts. This finding offers a novel mechanistic insight into the pharmacological action of SMP in AIA rats. It informs future research on the therapeutic potential of SMP in RA.
研究领域:
药理学
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代谢组学
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蛋白质组学
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免疫学
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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 IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Nannan Xu,Wenyi Fu,Jiake Wu,Shuai Zhao,Chunyang Tian
Rheumatoid arthritis (RA) is one of the most common chronic inflammatory autoimmune diseases, and ferroptosis has been associated with its pathogenesis. TRIM16 belongs to the TRIM protein family and possesses various biological function. However, the role of TRIM16 in RA has not been reported. Our results showed that TRIM16 was upregulated in collagen-induced arthritis (CIA) mice, and TRIM16 overexpression alleviated joint inflammation. Notably, the level of 4-HNE was decreased in CIA mice, whereas TRIM16 overexpression restored it. The expression of GPX4 and SLC7A11 was upregulated in CIA mice, whereas TRIM16 overexpression significantly suppressed their levels, suggesting that TRIM16 promotes ferroptosis. We then detected TRIM16 expression in TNF-α-induced fibroblast-like synoviocytes (FLS), and found that TNF-α stimulation reduced TRIM16 expression. Overexpression of TRIM16 increased the lipid ROS, Fe 2+ levels, and LDH activity, while reducing GSH-PX and GSH activities. Moreover, TNF-α treatment increased GPX4 and SLC7A11 expression but decreased ACSL4 levels, and TRIM16 overexpression reversed these effects. TRIM16 knockdown reduced lipid ROS levels and increased GPX4 and SLC7A11 expression. Furthermore, Fer-1 treatment reduced lipid ROS levels and increased GPX4 and SLC7A11 expression. Mechanistically, TRIM16 directly binds to Snai1, promoted its K48-linked ubiquitination, and specifically ubiquitinates Snai1 at the K146 site. Overexpression of Snai1 decreased the lipid ROS levels and increased the GSH content. Our study identifies TRIM16 as a promoter of ferroptosis in TNF-α-induced FLS by enhancing Snai1 ubiquitination and degradation. In summary, our study presented that TRIM16 plays a protective role in RA.
研究领域:
免疫学
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分子生物学
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风湿病学
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细胞死亡机制
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信号转导
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DOI
PubMed
高影响因子
Nanoscale
·
2023
·
IF 6.7
Yaqing Liu,Zongzhang Wang,Yiru Wang,Yushuo Feng,Mengjiao Xu,Xiaoqian Ma,Qianqian Shi,Huaping Deng,Fangfang Ren,Yong Chen,Hongmin Chen
Rheumatoid arthritis (RA) is a common autoimmune disease, and the inflammatory response during its development can lead to joint cartilage and bone damage up to disability. Dexamethasone (DEX) can effectively alleviate the inflammatory response in RA, but the severe adverse effects that occur after long-term administration limit its clinical development. Herein, we propose a Ca-DEX biomineralization-inducing nut (CaCO3-DEX) with controlled-release properties for mitigating the toxic side effects of DEX in RA treatment, especially the damage to cartilage and bone. CaCO3-DEX releases the drug and Ca2+ preferentially in an inflammatory environment. Both in vitro and in vivo studies demonstrate that CaCO3-DEX significantly reduces the secretion of pro-inflammatory factors and inhibits ROS production in vitro, as well as demonstrates superior pro-biomineralization and osteogenic differentiation potential. In the collagen-induced rheumatoid arthritis model (CIA model), CaCO3-DEX significantly reduces the clinical score of arthritis in mice, and imaging results show a noticeable relief of edema and bone erosion in CIA model mice treated with CaCO3-DEX, while inflammatory factors at the injury areas are significantly reduced, which provides favorable protection to cartilage and bone.
研究领域:
药理学
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风湿病学
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材料科学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6.8
Tingting Han,Ye Sun,Chao Zhao,Hai-Yan Wang,Hui Yu,Yi Liu
Rheumatoid arthritis (RA) is a destructive autoimmune disease, where nitric oxide (NO) is closely implicated in the inflammatory processes of RA. Therefore, direct visualization of NO is essential to assess the pathological changes in RA. Herein, a mitochondrial-targeted near-infrared ratiometric fluorescent probe (NFL-NH2), based on the intramolecular charge transfer effect, was synthesized and applied to monitor the changes of NO content in early RA. Specially, probe NFL-NH2 showed a 44-fold fluorescent intensity ratio (I705/I780) response toward NO with a detection limit of 0.536 nM, enabling qualitative and quantitative analysis of NO. Additionally, NFL-NH2 can accurately target mitochondria and sensitively detect exogenous and endogenous NO in RAW 264.7 cells. Notably, in vivo RA monitoring assays demonstrated that NFL-NH2 can rapidly detect NO levels associated with the inflammatory damage degree in RA mice models by ratiometric fluorescence imaging. These results validate that NFL-NH2 holds significant potential for diagnosing NO-mediated RA diseases.
研究领域:
生物医学工程
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药理学
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免疫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2024
·
IF 3.3
Bo Cai,Zelin He,Dandan Liu,Yuping Zhang,Zikang Yin,Weijia Bao,Qiaoyi Le,Ju Shao,Hongyan Du,Ligang Jie
The elevated risk of cardiovascular disease (CVD) associated with inflammatory rheumatic diseases has long been recognized. Patients with established rheumatoid arthritis (RA) have a higher mortality rate compared to the general population due to abnormal platelet activation. Thymidine phosphorylase (TYMP) plays a crucial role in platelet activation and thrombosis, following bridging the link between RA and CVD. Data from Gene Expression Omnibus (GEO) database exhibited that TYMP levels were highly expressed in synovial tissues, immune cells, and whole blood of RA patients especially those with high levels of inflammation. Platelet count (PLT) and plateletcrit (PCT) were positively correlated with the severity of inflammation in rheumatoid arthritis while platelet distribution width (PDW) and mean platelet volume (MPV) were adverse. Levels of CD62P and TYMP in platelets of patients with active RA were significantly elevated compared to patients in the inactive phase. In vivo experiments showed that reducing TYMP expression levels of platelets could relieve inflammation in Adjuvant-Induced Arthritis (AIA) mice. Platelet activation was significantly elevated in AIA model mice, along with increased levels of intracellular calcium (Ca 2+ ), reactive oxygen species (ROS), and decreased Mitochondrial Membrane Potential (ΔΨm). However, treatment with Tipiracil hydrochloride (TPI) or the utilization of Tymp −/− mice reversed these effects. In vitro stimulation of wild type (WT) mouse platelets with tumor necrosis factor-alpha (TNF-α) promoted platelet activation, elevated levels of intracellular Ca 2+ as well as ROS while decreased ΔΨm. Platelets of WT mice treated with TPI or platelets of Tymp −/− mice exhibited the adverse results. Our study illustrates the vital role of TYMP in promoting RA inflammation and platelet activation, suggesting that TYMP may be a potential therapeutic target for RA.
研究领域:
免疫学
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分子生物学
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风湿病学
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产品关联
DOI
PubMed
高影响因子
Biomaterials Advances
·
2022
·
IF 0
Qiying Shen,Quan Hu,Ting Tang,Xiaoying Ying,Gaofeng Shu,Jiawei Shen,Chong Teng,Yongzhong Du
Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease without effective treatment. Tofacitinib (TOF) is a JAK inhibitor that can be used for RA therapy, but it still faces the problems of nonspecific distribution and relatively low therapeutic effect. Herein, ICAM-1-modified TOF-loaded P(AN-co-AAm)-PEG micelles (AI-TM) were developed, which can result in an enhanced RA therapy when combining with microwave hyperthermia (MH). It was found that AI-TM could rapidly release the encapsulated TOF under a thermal condition of >43 °C, which was due to the fact that the polymeric micelles has an upper critical solution temperature (UCST) of 43 °C. AI-TM could specifically distribute into the inflamed joints of RA mice, which is associated with the high affinity between anti-ICAM-1 and overexpressed ICAM-1 receptors. Moreover, the combination of AI-TM and MH could result in a remarkably enhanced anti-rheumatic activity, which was related to the RA-targeted ability of AI-TM, the rapid TOF release under MH, and the combined effect between TOF and MH treatment. Our study definitely provides a novel strategy for effective treatment of RA.
研究领域:
药理学
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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
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
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DOI
PubMed
高影响因子
Nanoscale
·
2021
·Vol. 13
·期 47
·20170-20185
·
IF 7.79
Yanqin Song,Muhammad Ismail,Qi Shan,Jianing Zhao,Yanping Zhu,Leiming Zhang,Yuan Du,Longbing Ling
Rheumatoid arthritis (RA) is an autoimmune inflammatory disorder that has seriously affected human health worldwide and its current management requires more successful therapeutic approaches. The combination of nanomedicines and pathophysiology into one system may provide an alternative strategy for precise RA treatment. In this work, a practical ROS-mediated liposome, abbreviated as Dex@FA-ROS-Lips that comprised synthetic dimeric thioether lipids (di-S-PC) and a surface functionalized with folic acid (FA), was proposed for dexamethasone (Dex) delivery. Incorporation with thioether lipids and a FA segment significantly improved the triggered release and improved the triggered release of cytotoxic Dex as well as the active targeting of RA, altering its overall pharmacokinetics and safety profiles in vivo. As proof, the designed Dex@FA-ROS-Lips demonstrated effective internalization by LPS-activated Raw264.7 macrophages with FA receptor overexpression and released Dex at the inflammatory site due to the ROS-triggered disassembly. Intravenous injection of this Dex@FA-ROS-Lips into adjuvant-induced arthritis (AIA) mice led to its incremental accumulation in inflamed joint tissues and significantly alleviated the cartilage destruction and joint swelling via suppression of proinflammatory cytokines (iRhom2, TNF-α and BAFF), as compared to the effect of commercial free Dex. Importantly, the Dex@FA-ROS-Lips nanoformulation showed better hemocompatibility with less adverse effects on the body weight and immune organ index of AIA mice. The anti-inflammatory mechanism of Dex@FA-ROS-Lips was further studied and it was found that it is possibly associated with the down-regulation of iRhom2 and the activation of the TNF-α/BAFF signaling pathway. Therefore, the integration of nanomedicines and the RA microenvironment using multifunctional Dex@FA-ROS-Lips shall be a novel RA treatment modality with full clinical potential, and based on the enhanced therapeutic effect, the signaling pathway of iRhom2/TNF-α/BAFF reasonably explained the mechanism of Dex@FA-ROS-Lips in anti-RA, which suggested a molecular target for RA therapy and other inflammatory diseases.
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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风湿病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
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2022
·
IF 18.027
Bowen Li,Chunrui Yang,Mingming Guo,Shuchao Wang,Wenchang Peng,Qinglu Guo,Dong Ming,Yue Teng,Bin Zheng
Excess reactive oxygen species (ROS) produced by abnormal mitochondria is one of the critical triggers of rheumatoid arthritis (RA). Existing nanocatalytic therapies can only catalyze the breakdown of ROS but cannot address the root cause of ROS production, i.e., abnormal mitochondria. Here, we designed an ultrasound (US) piezoelectric catalytic therapy, which can induce mitophagy in a spatiotemporally controlled manner to treat RA. The prepared two-dimensional piezoelectric nanosheets (NSs) Fe/BiOCl with US catalytic activity can efficiently generate electrons under US stimulation to meet the purpose of consuming H+ in the outer mitochondrial membrane and disturbing the H+ supply in the mitochondrial matrix. This causes depolarization of the mitochondrial membrane potential (MMP), triggering the autophagy of mitochondria in regions of inflammation to eliminate the source of ROS regeneration. Analysis of cellular and RA model-related experiments showed that piezoelectric US-catalyzed therapy involving Fe/BiOCl NSs alleviated RA by inducing mitophagy. This provides an explanation of the mechanism for piezoelectric US catalytic therapy and suggests promising strategies for biomedical applications of US piezoelectric materials.
研究领域:
生物医学工程
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纳米技术
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风湿病学
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治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Anatomical Record-Advances in Integrative Anatomy and Evolutionary Biology
·
2018
·Vol. 301
·期 7
·1179-1188
·
IF 1.373
Wei Cao,Junqiang Zhang,Gaoyuan Wang,Jinsen Lu,Taorong Wang,Xiaoyu Chen
In rheumatoid arthritis patients, the fibroblast-like synovial cells (FLS) growth is not controlled normally, but is similar to the tumor cells proliferation in histology. Our previous studies have shown that resveratrol inhibits the proliferation of FLS and promotes FLS apoptosis. However, the molecular mechanisms involved in resveratrol-induced FLS apoptosis have not been determined yet. Here, we showed that the FLS cell viability (following pretreatment with 5 µM H 2 O 2 for 24 hr) exhibited better proliferation performance than at other concentrations via the CCK-8 assay. The cell apoptotic rate increased with the increasing concentration of resveratrol (0, 40, 80, 160, 320 μM), as detected by TdT-mediated dUTP nick-end labeling (TUNEL) staining and western blotting. Furthermore, the expression level of autophagy-related proteins (LC3A/B, ATG-5) decreased with the increased concentration of resveratrol, as determined by immunofluorescence and western blot analysis. We also showed that resveratrol induced FLS mitochondrial morphology change. Moreover, mitochondrial function detection showed that the mitochondrial membrane potential was lost with the increased concentration of resveratrol as examined by the JC-1 assay. The production of ATP in cells was positively and negatively correlated with the resveratrol concentration. Simultaneously, the intracellular calcium release and calcium influx decreased gradually with the increase in resveratrol concentration. Therefore, we proposed that resveratrol can reduce the level of autophagy in FLS. The decrease in the autophagy level can lead to the accumulation of reactive oxygen species, which may result in mitochondrial dysfunction and promotion of FLS apoptosis. Anat Rec, 301:1179–1188, 2018. © 2018 Wiley Periodicals, Inc.
研究领域:
药理学
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细胞生物学
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免疫学
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风湿病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Chemistry
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2023
·
IF 5.5
Chen Qi,Wu Chengyuan,Wang Siwei,Wang Qiang,Wu Peiyun,Wang Lei,Yan Peiyu,Xie Ying
Introduction: Rheumatoid arthritis is an autoimmune disease characterized by chronic joint inflammation. Methotrexate is one of the most effective drugs for rheumatoid arthritis, but the adverse reactions caused by oral methotrexate greatly limit its clinical application. Transdermal drug delivery system is an ideal alternative to oral methotrexate by absorbing drugs into the human body through the skin. However, methotrexate in the existing methotrexate microneedles is mostly used alone, and there are few reports of combined use with other anti-inflammatory drugs.Methods: In this study, glycyrrhizic acid was first modified onto carbon dots, and then methotrexate was loaded to construct a nano-drug delivery system with fluorescence and dual anti-inflammatory effects. Then hyaluronic acid was combined with nano-drug delivery system to prepare biodegradable soluble microneedles for transdermal drug delivery of rheumatoid arthritis. The prepared nano-drug delivery system was characterized by transmission electron microscopy, fluorescence spectroscopy, laser nanoparticle size analyzer, ultraviolet-visible absorption spectroscopy, Fourier transform infrared spectroscopy, differential scanning calorimeter and nuclear magnetic resonance spectrometer. The results showed that glycyrrhizic acid and methotrexate were successfully loaded on carbon dots, and the drug loading of methotrexate was 49.09%. The inflammatory cell model was constructed by lipopolysaccharide-induced RAW264.7 cells. In vitro cell experiments were used to explore the inhibitory effect of the constructed nano-drug delivery system on the secretion of inflammatory factors by macrophages and the cell imaging ability. The drug loading, skin penetration ability, in vitro transdermal delivery and in vivo dissolution characteristics of the prepared microneedles were investigated. The rat model of rheumatoid arthritis was induced by Freund's complete adjuvant.Results: The results of in vivo animal experiments showed that the soluble microneedles of the nano drug delivery system designed and prepared in this study could significantly inhibit the secretion of pro-inflammatory cytokines and had a significant therapeutic effect on arthritis.Discussion: The prepared glycyrrhizic acid-carbon dots-methotrexate soluble microneedle provides a feasible solution for the treatment of Rheumatoid arthritis.
研究领域:
药剂学
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药物递送系统
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风湿病学
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）