Frontiers in Immunology
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2025
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IF 5.9
Huan Xu,Kaixuan Ma,Ziting Ma,Tianyu Zhuang,Ling Lin
Introduction: Pulmonary fibrosis (PF) is a fatal pathological subtype of interstitial lung disease, frequently manifests as a pulmonary complication of connective tissue disease. Iguratimod (IGU) is a new class of anti-rheumatic drugs used in the treatment of rheumatoid arthritis (RA). Studies have reported that RA patients treated with IGU have better lung function, and IGU effectively ameliorates PF. However, the mechanism by which IGU improves PF is still unclear. This study aims to elucidate the therapeutic efficacy and mechanisms of IGU in PF through in vivo and in vitro investigations, so as to provide a new treatment method for PF.Methods: In our research, bleomycin (BLM)-induced PF of mice were used to observe the therapeutic effect of different concentrations of IGU. And the effects of IGU on macrophage polarization and activation pathway TLR4/NF-κB in lung tissue were analyzed. In addition, Raw264.7 macrophages were induced to M1 and M2 polarization in vitro, and the effects of IGU on Raw264.7 macrophage polarization and related pathways were observed.Results: In our study, database analysis suggested that macrophage polarization-relative genes and pathways as well as TLR4 activation played important roles in BLM-induced PF in mice. Besides, we found that IGU effectively ameliorated BLM-induced PF and epithelial-mesenchymal transition in mice, and inhibited the polarization of M1/M2 macrophages at different stages of PF. Moreover, In vitro studies further demonstrated that IGU suppressed M1 polarization of Raw264.7 and its activation pathway TLR4/NF-κB.Discussion: In summary, IGU inhibits the activation of macrophages and M1 polarization through inhibiting the TLR4/NF-κB pathway, thereby improving BLM-induced pulmonary inflammation and fibrosis in mice. It is suggested that IGU may be a new therapeutic option for interstitial pulmonary fibrosis.
研究领域:
免疫学
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呼吸病学
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药理学
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DOI
PubMed
高影响因子
CELL BIOCHEMISTRY AND BIOPHYSICS
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2024
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IF 1.8
Zhang Qi,Yang Xi-Rui,Deng Yao
Iguratimod (T-614) is a compound widely used as anti-rheumatic drug. This study investigated the effect and underlying mechanism of T-614 on experimental Sjögren’s syndrome (ESS). ESS mice model was established by injection of submandibular gland protein. Mice were randomly divided into control, experimental Sjögren’s syndrome (ESS), ESS + T-614 (10 mg/kg), ESS + T-614 (20 mg/kg), and ESS + T-614 (30 mg/kg) groups. Human submandibular gland (HSG) were cultured with 0, 0.5, 5, or 50 μg/ml T-614 in the absence or presence of interferon-α (IFN-α). Haematoxylin and eosin (H&E) and cytokine levels were used to detect immune cells activation in submandibular glands. Apoptosis in submandibular glands tissues and cells was determined by TUNEL and flow cytometry. Apoptosis and NLRP3 inflammasome-related proteins were detected by western blotting. T-614 treatment attenuated submandibular gland damage in ESS mice. T-614 administration inhibited submandibular gland cell apoptosis in ESS mice. Furthermore, T-614 blocked inflammatory factor levels and NLRP3 inflammasome activation in the submandibular glands. In vitro, results corroborated that T-614 could protect HSG cells from IFN-α-induced cell apoptosis and inflammation by inhibiting NLRP3 inflammasome activation. Our results expounded that T-614 alleviated ESS by inhibiting NLRP3 inflammasome activation.
研究领域:
免疫学
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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
EXPERIMENTAL NEUROLOGY
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2023
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IF 5.3
Qian Wang,Jiang Yi,Hao Liu,Mingran Luo,Guoyong Yin,Zhenfei Huang
Destruction of the blood-spinal cord barrier (BSCB) after spinal cord injury (SCI) is an important factor promoting the progression of the injury. This study addressed how to repair the BSCB in order to promote the repair of injured spinal cords. Iguratimod (IGU), an anti-rheumatic drug, has been approved for clinical use. A spinal cord injury mouse model and TNF-α-stimulated bEnd.3 cells were used to investigate the effect and mechanism of IGU on injured BSCB. An intracerebroventricular osmotic pump was used to administer drugs to the SCI mouse model. The results showed that the SCI mice in the treatment group had better recovery of neurological function than the control group. Examination of the tissue revealed better repair of the BSCB in injured spinal cords after medication. According to the results from the cell model, IGU promoted the expression of tight junction proteins and reduced cell permeability. Further research found that IGU repaired the barrier function by regulating glycolysis levels in the injured endothelial cells. In studying the mechanism, IGU was found to regulate HIF-1α expression through the NF-κB pathway, thereby regulating the expression of the glycolytic enzymes related to endothelial injury. In summary, IGU promoted functional recovery in vivo by repairing the BSCB. In vitro, IGU regulated the level of glycolysis in the damaged endothelium through the NF-κB pathway, thereby repairing the tight junctions between the endothelium. Therefore, IGU may become a potential drug for treating spinal cord injury.
研究领域:
神经科学
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药理学
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细胞生物学
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DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
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2024
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IF 5.4
Du Li,Jindian Dong,Tong Xiong,Xingyu Zhou,Yanhui Li,Chuncheng Chen,Shijie Li,Zhuoyue Song,Nenggui Xu,Mingjing Yang,Xiaoxia Yan,Tao Liu,Shihui Liu
This study introduces a novel approach of repetitive modeling to simulate the pathological process of recurrent gout attacks in humans. This methodology addresses the instability issues present in rat models of gout, providing a more accurate representation of the damage recurrent gout episodes inflict on human skeletal systems. A soluble nanoneedle system encapsulating colchicine and iguratimod ethosomal formulations was developed. This system aims to modulate inflammatory cytokines and inhibit osteoclast activity, thereby treating inflammatory pain and bone damage associated with recurrent gout. Additionally, a comprehensive evaluation of the microneedles' appearance, morphology, mechanical properties, and penetration capability confirmed their effectiveness in penetrating the stratum corneum. Dissolution tests and skin irritation assessments demonstrated that these microneedles dissolve rapidly without irritating the skin. In vitro permeation studies indicated that transdermal drug delivery via these microneedles is more efficient and incurs lower drug loss compared to traditional topical applications. In vivo pharmacodynamic assessments conducted in animal models revealed significant analgesic and anti-inflammatory effects when both types of microneedles were used together. Further analyses, including X-ray imaging, hematoxylin and eosin (H&E) staining, Safranin-O/fast green staining, tartrate-resistant acid phosphatase staining, and quantification of osteoclasts, confirmed the bone-protective effects of the microneedle combination. In conclusion, the findings of this research underscore the potential of this novel therapeutic approach for clinical application in the treatment of recurrent gout.
研究领域:
药理学
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生物医学工程
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炎症研究
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DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
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2024
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IF 6.9
Yang Ya-qi,Liu Yi-jun,Qiao Wen-xuan,Jin Wei,Zhu Shun-wei,Yan Yu-xi,Luo Qiong,Xu Qiang
Primary Sjögren’s syndrome (pSS) is a chronic inflammatory autoimmune disease with an unclear pathogenesis, and there is currently no approved drug for the treatment of this disease. Iguratimod, as a novel clinical anti-rheumatic drug in China and Japan, has shown remarkable efficacy in improving the symptoms of patients with pSS in clinical studies. In this study we investigated the mechanisms underlying the therapeutic effect of iguratimod in the treatment of pSS. Experimental Sjögren’s syndrome (ESS) model was established in female mice by immunizing with salivary gland protein. After immunization, ESS mice were orally treated with iguratimod (10, 30, 100 mg·kg −1 ·d −1 ) or hydroxychloroquine (50 mg·kg −1 ·d −1 ) for 70 days. We showed that iguratimod administration dose-dependently increased saliva secretion, and ameliorated ESS development by predominantly inhibiting B cells activation and plasma cell differentiation. Iguratimod (30 and 100 mg·kg −1 ·d −1 ) was more effective than hydroxychloroquine (50 mg·kg −1 ·d −1 ). When the potential target of iguratimod was searched, we found that iguratimod bound to TEC kinase and promoted its degradation through the autophagy-lysosome pathway in BAFF-activated B cells, thereby directly inhibiting TEC-regulated B cells function, suggesting that the action mode of iguratimod on TEC was different from that of conventional kinase inhibitors. In addition, we found a crucial role of TEC overexpression in plasma cells of patients with pSS. Together, we demonstrate that iguratimod effectively ameliorates ESS via its unique suppression of TEC function, which will be helpful for its clinical application. Targeting TEC kinase, a new regulatory factor for B cells, may be a promising therapeutic option.
研究领域:
免疫学
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药理学
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自身免疫疾病
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DOI
PubMed
高影响因子
Small
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2023
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IF 13.3
Cheng Tao,Feifei Li,Zhenzhen Ma,Xiaoming Li,Yali Zhang,Yuan Le,Jiexin Wang,Jinxia Zhao,Chaoyong Liu,Jianjun Zhang
Rheumatoid arthritis (RA), a systemic autoimmune disease, poses a significant human health threat. Iguratimod (IGUR), a novel disease-modifying antirheumatic drug (DMARD), has attracted great attention for RA treatment. Due to IGUR’s hydrophobic nature, there’s a pressing need for effective pharmaceutical formulations to enhance bioavailability and therapeutic efficacy. The high-gravity nanoprecipitation technique (HGNPT) emerges as a promising approach for formulating poorly water-soluble drugs. In this study, IGUR nanodrugs (NanoIGUR) are synthesized using HGNPT, with a focus on optimizing various operational parameters. The outcomes revealed that HGNPT enabled the continuous production of NanoIGUR with smaller sizes (ranging from 300 to 1000 nm), more uniform shapes, and reduced crystallinity. In vitro drug release tests demonstrated improved dissolution rates with decreasing particle size and crystallinity. Notably, in vitro and in vivo investigations showcased NanoIGUR’s efficacy in inhibiting synovial fibroblast proliferation, migration, and invasion, as well as reducing inflammation in collagen-induced arthritis. This study introduces a promising strategy to enhance and broaden the application of poorly water-soluble drugs.
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产品关联
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PubMed
高影响因子
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