INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2024
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IF 7.7
Jun Weng,Geng Miaomiao,Xiaoyu Hu,Yang Hu,Yi Yang,Banbin Xing,Wu Zhiyong,Zigong Wei
TNFα inhibitors have been successfully developed and used in the clinical treatment of autoimmune disorders. However, the use of TNFα blockade may be accompanied by side effects. The cases of bacterial and viral infections, lymphoproliferative disorders, and anti-TNFα-induced lupus, have been reported among the rheumatoid arthritis or Crohn's disease patients treated with TNFα blockers. Therefore, alternative therapeutic strategy is highly desirable. TNFα signaling via TNFR1 induces proinflammatory responses, and selective inhibition of TNFR1 signaling may be beneficial for managing autoimmune diseases. To this end, we developed minibinder proteins targeting soluble ectodomain of TNFR1 (sTNFR1) by de novo computational designing. Top-rated designed minibinders targeting to two hydrophobic sites on sTNFR1 were selected and expressed in E. coli . Purified top-ranked minibinders are thermostable in solution and presented micromolar to sub-micromolar affinity to sTNFR1. All designs showed the potency of blocking TNFα signaling in L929 cell-based assays, and one of the designs targeting to hydrophobic Site I called S1B2 exhibited higher potency than other minibinders with IC 50 of 4.32 nM. Our work provided a new approach to develop TNFR1 antagonist and S1B2 should be a promising lead molecule of TNFR1 antagonist for further development.
研究领域:
生物化学
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免疫学
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药物开发
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产品关联
DOI
PubMed
高影响因子
CLINICAL IMMUNOLOGY
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2025
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IF 3.8
Shuang Pan,Mengshu Yu,Bowei Fan,Bin Wang,Xinrui Yang,Jiawen Zhang,Xiaoqi Liu,Xiaojian Hong,Wei Yang
Autoimmune myocarditis refers to the inflammation of myocardial tissue caused by innate and adaptive immune responses, characterized by elevated levels of tumour necrosis factor-α (TNF-α), a classic pro-inflammatory factor. Although hydrogen exhibits anti-inflammatory and antioxidant properties, its therapeutic effects in autoimmune myocarditis have not been evaluated. Therefore, the present study aimed to explore whether hydrogen can alleviate autoimmune myocarditis via TNF-α. An experimental autoimmune myocarditis (EAM) model was established in BALB/c mice via subcutaneous injection of pig-derived myocardial myoglobin emulsified with complete Freund's adjuvant. The treatment group received 2 % hydrogen inhalation twice a day (3 h each time) for 21 days. CD4+ T cell expression was higher in the EAM group than in the Control group, and this increase was attenuated following treatment with hydrogen. Additionally, the levels of TNF-α and related inflammatory factors were substantially higher in the EAM group than in the Control group, and these changes were reversed following hydrogen treatment. Echocardiography assessments demonstrated a significant improvement in heart function following treatment with hydrogen compared to that in the EAM group. Pathological results revealed significant inflammatory cell infiltration and fibrosis in the hearts of the untreated EAM group. Tissue immunofluorescence and protein immunoblotting indicated elevated necroptosis markers in the EAM group, which were downregulated after treatment with hydrogen. This study demonstrates that hydrogen effectively ameliorated autoimmune myocarditis by modulating necroptosis via the TNF/TNFR1 signalling pathway, making it a promising novel therapeutic strategy for myocarditis.
研究领域:
免疫学
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心脏病学
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分子生物学
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炎症研究
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2025
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IF 6.2
Hao Zhang,Jia-Gen Cui,Ming-Shan Chen,Jia-Xin Wang,Xiao-Han Sun,Yi Zhao,Jin-Long Li
Di(2-ethylhexyl) phthalate (DEHP), which is widely used in agricultural plastics, accumulates in humans and animals through the food chain over time, resulting in liver toxicity. Recent studies have reported that pyroptosis and mitochondrial damage are closely related to a variety of liver diseases, but the specific mechanism is still unclear. To address this issue, in vitro and in vivo hepatotoxicity models were established. The results demonstrated that exposure to DEHP caused a buildup of MEHP in livers, altered liver metabolite composition, and caused pyroptosis-like changes in hepatocytes. After DEHP treatment, REDOX homeostasis was unbalanced, and mitochondrial reactive oxygen species (mtROS) were overproduced. MEHP exposure activates pyroptosis mediated by TNF/TNFR1 signaling and upregulates the perforating protein GSDMD-N to destroy the mitochondrial membrane of hepatocytes. Above all, this study elucidates the potential involvement of TNF/TNFR1 signaling-mediated pyroptosis in mitochondrial damage and confirms that the regulation of pyroptosis is helpful in maintaining normal mitochondrial function.
研究领域:
毒理学
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细胞生物学
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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
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2025
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IF 4.7
Li Wang,Tao Gu,Chunguang Yu,Yingying Gao,Tingting Xuan,Kaichun Shen,Guowei Wang,Zhenhai Wang
Kaempferol (Kae) is a flavonoid that has antioxidant, anti-inflammatory and neuroprotective effects. In recent years, there have been increasing reports on viral infection-induced Guillain-Barré syndrome (GBS) with high rates of disability and fatality. Therefore, in order to search for effective peripheral nerve injury repair drugs, we used rats with experimental autoimmune neuritis (EAN) as the typical animal model for GBS, and implemented Kae treatment intervention on EAN rats. Real-time quantitative polymerase chain reaction (qPCR), western blotting (WB) and immunofluorescence (IF) were utilized to detect the changes of inflammatory factors and signaling pathway proteins in peripheral nerve of rats. The impact of Kae on peripheral nerve damage in EAN rats was evaluated in multiple dimensions by clinical symptom score and neuroelectrophysiology examination, and the protective impact and mechanism of Kae on peripheral nerve injury were revealed. Our results showed that Kae increased the expression of sciatic myelin basic protein (MBP), decreased the expression of peripheral nerve macrophage infiltration and inflammatory cytokines, including TNF-α, IL-1β and IL-6, and down-regulated the expression levels of TNFR1. Additionally, it suppressed the activation of the JNK and p38 pathways. It can alleviate sciatic nerve symptoms and pathological injury in EAN rats. Therefore, we believe that Kae can be used as an adjunct drug in the treatment of GBS.
研究领域:
药理学
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神经科学
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免疫学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACOLOGICAL SCIENCES
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2025
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IF 2.9
Jingwei Liu,Cheng Qiu,Xiaoxiong Wang,Ziqian Xiang,Junyuan Sun,Mingzheng Chang,Qingliang Ma,Yan Zhuang,Yunpeng Zhao,Qiang Yang,Lianlei Wang,Xinyu Liu
Fracture is a common type of traumas and alternative therapies to boost bone fracture healing is necessary. The aim of this study is to elucidate the role of sulfasalazine in bone fracture healing by using MC3T3-E1 cells in vitro and murine femoral fracture model in vivo . Western blotting, flow cytometry, RNA sequencing, Calcein AM/PI staining, Alizarin-Red-S staining, ALP activity assay, transmission electron microscope, histological staining, immunohistochemistry, immunofluorescence and Surface plasmon resonance analysis were performed in this study. Sulfasalazine failed to elicit ferroptosis in osteoblasts within acceptable dose manner while promoted osteogenic differentiation. Furthermore, sulfasalazine was identified to inhibit inflammation by declination of inflammatory biomarkers. Besides, TNFα was verified as a potential downstream target for sulfasalazine and the adverse effect of TNFα on osteogenic differentiation could be largely salvaged by sulfasalazine due to direct binding between these two molecules. RNA-seq further implied decreased transcription of genes related to NF-κB pathway. Murine study showed sulfasalazine promotes fracture healing as evidenced by increased bone remodeling both histologically and radiologically. Overall, sulfasalazine accelerates osteogenic differentiation and promotes bone healing by direct binding to and thus inhibiting TNFα, which subsequently suppresses NF-κB signaling. Therefore, sulfasalazine shows a promising outcome for the treatment of bone fracture.
研究领域:
药理学
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分子生物学
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免疫学
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骨科学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2024
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IF 4.8
Jiale Mao,Houxing Lei,Pingcui Xu,Shuang Liu,Jiwang Zhou,Mingrong Mei,Nani Wang,Xiaoqin Zhang
Ethnopharmacological relevance Melastoma dodecandrum (MD), a traditional ethnomedicine, has been widely used for the treatment of fractures, osteoarthritis, and osteoporosis due to its remarkable anti-inflammatory activity. However, the specific active components responsible for its therapeutic effects on orthopedic conditions remain unidentified. Aim of the study This study aimed to screen and identify key active components in MD using a combination of cell membrane chromatography and mass spectrometry, followed by cellular validation. Materials and methods A TNF-α-induced osteoblast injury model and an osteoblast membrane chromatography screening system were established to select and identify chemical components of MD that directly act on osteoblasts. The protective effects of MD on osteoblasts were assessed by evaluating cell viability, alkaline phosphatase (ALP) activity, cell mineralization and the expression of osteogenesis-related proteins OCN, RUNX2, and the TNF-α receptor protein TNFR1. Validation of the activity of individual components was also conducted. Results MD significantly improved the viability of osteoblasts under TNF-α-induced injury, enhanced ALP activity, stimulated the expression of OCN and RUNX2 proteins, and decreased the expression of TNFR1. Cell membrane chromatography screening identified 32 chemical components, including 21 flavonoids, 6 organic acids, 2 phenylpropanoids, 2 terpenes, and 1 nucleotide. Molecular docking revealed that isovitexin could bind to the specific receptor TNFR1 on the cell membrane. Furthermore, cellular validation demonstrated that isovitexin significantly protected osteoblasts. Conclusions MD and its pharmacologically active component, isovitexin, exhibit protective effects against TNF-α-induced inflammatory injury in osteoblasts, laying a solid foundation for future drug development.
研究领域:
药理学
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民族药理学
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细胞生物学
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质谱学
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色谱学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2020
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IF 3.943
Jia-Hui Cheng,Xiang Xu,Ying-Biao Li,Xu-Dong Zhao,Fumie Aosai,Su-Yun Shi,Cheng-Hua Jin,Jing-Shu Piao,Juan Ma,Hu-Nan Piao,Xue-Jun Jin,Lian-Xun Piao
Toxoplasma gondii ( T. gondii ) is a known neurotropic protozoan that remains in the central nervous system and induces neuropsychiatric diseases in intermediate hosts. Arctigenin (AG) is one of the major bioactive lignans of the fruit Arctium lappa L. and has a broad spectrum of pharmacological activities such as neuroprotective, anti-inflammatory and anti- T. gondii effects. However, the effect of AG against depressive behaviors observed in T. gondii -infected hosts has not yet been clarified. In the present study, we analyzed the effects of AG against T. gondii -induced depressive behaviors in intermediate hosts using a microglia cell line (BV2 cells) and brain tissues of BALB/c mice during the acute phase of infection with the RH strain of T. gondii . AG attenuated microglial activation and neuroinflammation via the Toll-like receptor/nuclear factor-kappa B (NF-κB) and tumor necrosis factor receptor 1/NF-κB signaling pathways, followed by up-regulating the dopamine and 5-hydroxytryptamine levels and inhibiting the depression-like behaviors of hosts. AG also significantly decreased the T. gondii burden in mouse brain tissues. In conclusion, we elucidated the effects and underlying molecular mechanisms of AG against depressive behaviors induced by T. gondii infection.
研究领域:
神经科学
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药理学
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传染病学
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免疫学
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DOI
PubMed
高影响因子
PSYCHOPHARMACOLOGY
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2025
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IF 3.3
Ren Yan,Chen Weikang,Wang Jinhui,Wu Shasha,Linghu Ting,Ge Jinyin,Zhang Ruiping
Objective Studies have demonstrated a close association between alterations in the immune system and major depressive disorder (MDD), with MDD potentially inducing neuroinflammation, hippocampal atrophy, and depression-like behaviors. Matrix metalloproteinase-8 (MMP8) contributes to the onset of depression, but it has not been studier yet. This study aims to investigate the mechanistic role of the MMP8 inhibitor (M8I) in alleviating depression induced by chronic unpredictable mild stress (CUMS) in rats. The objectives include evaluating the ameliorative effects of M8I on CUMS-induced depression-like behaviors and exploring its impacts on the TNF-α/TNFR1/NF-κB signaling pathway, NLRP3 inflammasome activation, expression levels of GFAP and IBA-1, oxidative stress pathways, apoptosis, regulation other neurotransmitters, and acetylcholinesterase(AChE) expression. Methods The CUMS model was employed to induce depressive-like behaviors in rats, followed by a one-week treatment with M8I. Behavioral tests were performed to assess depressive-like behaviors. Western blot, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, immunohistochemistry, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), and near-infrared II (NIR-II) imaging were utilized to evaluate the expression levels of proteins involved in the TNF-α/TNFR1/NF-κB signaling pathway, NLRP3 inflammasome, GFAP and IBA-1 expression in astrocytes and microglia, oxidative stress markers (SOD, GSH, PI3K/AKT), apoptosis-related proteins (Bax, Bcl-2), as well as brain neurotransmitters regulation and AChE activity. Results CUMS induced depressive-like behaviors in rats, upregulated the expression of TNF-α and its associated proteins (TNFR1, NF-κB), NLRP3 inflammasome-related proteins (p-P38, caspase-1), GFAP, and IBA-1 in the hippocampal tissue, and downregulated the expression of SOD, GSH, and PI3K/AKT. Additionally, it disrupted the balance of apoptosis-related proteins (Bax, Bcl-2), brain neurotransmitters regulation, and AChE activity. Treatment with M8I reversed these alterations; however, certain neurotransmitters, such as norepinephrine and dopamine, did not fully return to normal levels. Conclusion M8I effectively alleviates CUMS-induced depressive-like behaviors by modulating the TNF-α/TNFR1/NF-κB signaling pathway, inhibiting the NLRP3 inflammasome activation, and suppressing astrocytes and microglia activation, thereby attenuating inflammatory responses, oxidative stress pathways, and apoptosis-related processes. These findings provide novel insights into M8I as a potential therapeutic strategy for depression and futher elucidate the molecular mechanisms underlying its anti-inflammatory effects.
研究领域:
神经科学
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精神病学
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免疫学
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分子生物学
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药理学
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神经炎症
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转化医学
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产品关联
DOI
PubMed
高影响因子
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