AMERICAN JOURNAL OF CHINESE MEDICINE
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2025
·Vol. 53
·期 03
·909-930
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IF 5.5
Ke Li,Ya-Jun Wang,Kun Wei,Wen-Lin Li,Yong-Bo Liu,Jun-Nan Hu,Wen-Guang Chang,Wen-Xuan Zhang,Long Chen,Wei Li
Diabetes mellitus (DM) is considered to be the most widespread epidemic worldwide, and diabetic nephropathy (DN) is one of the most serious diabetic complications. Its complex pathogenesis makes treatment of DN an ongoing medical challenge. Ginseng ( Panax ginseng . C. A Meyer) is a valuable medicinal herb with a long medicinal and culinary history. Ginsenoside Rg2 (Rg2), an important active component in ginseng, has effective inhibitory effects on lipogenesis and hepatic glucose production. However, the potential effect and mechanism of Rg2 on DN remain unclear. In this study, we investigated the effect of Rg2 on DN in high fat diet/streptozotocin (HFD/STZ)-induced type 2 diabetic mice and high glucose (HG)-induced human kidney 2 (HK-2) cells. The results demonstrated that Rg2 significantly improved the levels of FBG, dyslipidemia and impaired kidney function in DN mice. Additionally, Rg2 decreased the phosphorylation levels of IKKβ, IκBα, and NF-κB p65, inhibited the activation of NLRP3 inflammasomes (NLRP3, ASC, and Caspase 1), and restrained release of inflammatory factors (IL-18 and IL-1 β ) . In HG-induced HK-2 cells, Rg2 showed similar inhibitory effects on pyroptosis via NF-κB/NLRP3 signaling pathways. Moreover, the effect of Rg2 on inhibiting the activation of NF-κB/NLRP3 signaling pathways may have a relationship to reducing the overproduction of reactive oxygen species (ROS), which is further supported by the ROS inhibitor N-acetylcysteine (NAC). In conclusion, our findings clearly indicated that Rg2 could prevent the progress of DN by inhibiting the activation of pyroptosis-related NF-κB/NLRP3 signaling pathways in vivo and in vitro , suggesting that Rg2 may be a novel and promising therapeutic agent in the treatment of DN.
研究领域:
药理学
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分子生物学
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糖尿病研究
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DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2025
·
IF 8.2
Xiaomeng Ji,Jingquan Dong,Wenting Zhu,Shasha Zhang,Yaru Chen,Xiao Liu,Yan Cao,Panpan Zhao,Zibo Dong
Background Sepsis-associated encephalopathy (SAE) represents one of the most common neurological complications observed in sepsis patients, contributing to both increased mortality and long-term cognitive impairment. Microglial mitochondrial reactive oxygen species (mtROS) overproduction and NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation were key pathological drivers of SAE. Although PIM-1, a serine/threonine kinase, was known to regulate both mtROS generation and NLRP3 signaling, its specific contribution to SAE remained poorly defined. Methods This study established a SAE mouse model using cecal ligation and puncture (CLP) surgery, and screened the differentially expressed gene PIM-1 through immunohistochemistry, GEO database analysis, and etc. An in vitro model was established using Lipopolysaccharide + Adenosine(LPS + ATP) Triphosphate stimulated Mouse Microglia (BV-2), and the regulation mechanism of PIM-1 was analyzed through siRNA interference, RNA-seq, and etc. Potential drug Urolithin B (UB) targeting PIM-1 inhibition was screened through molecular docking, and its inhibitory effect on PIM-1 and therapeutic potential in SAE were evaluated through thermal stability experiments, behavioral experiments, etc. Results PIM-1 was upregulated in SAE, which was associated with brain damage. PIM-1 knockdown suppressed microglial activation and reduced inflammatory cytokines release. Further investigation indicated that PIM-1 modulated mtROS generation and facilitated NLRP3 inflammasome activation. Notably, pharmacological inhibition of PIM-1 by UB alleviated SAE both in vivo and in vitro , resulting in improved neuronal damage and cognitive impairment. Conclusion PIM-1 played a critical role in SAE progression, potentially through its mediation of microglial activation and neuroinflammation via the mtROS/NLRP3 axis. Notably, pharmacological inhibition of PIM-1 with urolithin B significantly alleviated SAE.
研究领域:
神经免疫学
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重症医学
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分子神经生物学
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炎症与感染
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转化神经科学
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药理学
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DOI
PubMed
高影响因子
TOXICOLOGY MECHANISMS AND METHODS
·
2025
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IF 2.7
Min Li,Zhouli Yue,Menglin Wang,Yan Wang,Peng Xiao,Wei Yuan,Jiduo Shen,Yucheng Li
Crizotinib, a first-generation tyrosine kinase inhibitor, demonstrates excellent clinical efficacy in treating non-small cell lung cancer (NSCLC). However, its clinical application is often limited by severe hepatotoxicity, the underlying mechanisms of which remain poorly understood. This study aimed to investigate the molecular mechanisms of crizotinib-induced hepatotoxicity in mice using transcriptomic analysis. Male ICR mice were orally administered crizotinib at doses of 100, 200, and 300 mg/kg for 7 consecutive days. Hepatotoxicity was assessed by measuring serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, along with histopathological evaluation via hematoxylin and eosin (H&E) staining. Transcriptomic and bioinformatics analyses of liver tissues were conducted to identify potential toxicological pathways. Oxidative stress markers were quantified using biochemical assay kits. Hepatic macrophage activation was examined by F4/80 immunostaining, and protein expression levels were analyzed by western blotting. Crizotinib administration resulted in dose-dependent liver injury, as indicated by elevated serum ALT and AST levels, body weight loss, and histological abnormalities. Transcriptomic profiling revealed significant enrichment of oxidative stress-related pathways, with protein–protein interaction (PPI) analysis identifying Jun as a key hub gene. Crizotinib significantly increased hepatic reactive oxygen species (ROS), malondialdehyde (MDA), and oxidized glutathione (GSSG) levels, while reducing reduced glutathione (GSH) levels and the GSH/GSSG ratio. Additionally, crizotinib significantly upregulated Bax and downregulated Bcl-2 expression, promoted macrophage infiltration, and increased the expression of JNK and NLRP3 proteins. These findings suggest that crizotinib-induced hepatotoxicity may be mediated by ROS-induced activation of the JNK/NLRP3 signaling pathway, which subsequently promotes hepatic inflammation and apoptosis.
研究领域:
药理学
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毒理学
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分子生物学
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肿瘤学
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生物信息学
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DOI
PubMed
高影响因子
CLINICAL AND EXPERIMENTAL IMMUNOLOGY
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2025
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IF 3.8
Su Qiyan,Feng Yingyue,Guo Jin,Cui Xi,Zhu Jiarui,Yang Jumei,Zhang Sigong
BackgroundIdiopathic inflammatory myopathy (IIM) is a progressive autoimmune disease characterized by interstitial lung disease (ILD) with limited therapeutics available. Pirfenidone (PFD), a medication utilized for the treatment of idiopathic pulmonary fibrosis, exhibits notable antioxidant, anti-inflammatory and inhibition of collagen synthesis. This study aims to clarify its efficacy and mechanism in treating IIM-ILD.MethodsA murine myositis-associated interstitial lung disease (MAILD) model was used to assess the therapeutic effect of PFD. The serum levels of IL-1β, IL-6 and TNF-α were detected by ELISA. PFD was utilized to disrupt neutrophil extracellular traps (NETs) formation in vitro, and its inhibitory effect on NETs was assessed through immunohistochemistry of CitH3 and MPO in the lung tissue and the serum cfDNA level in mice. Immunohistochemical and western blot was utilized to examine alterations in epithelial-mesenchymal transition (EMT) and NLRP3 inflammasome markers.ResultsPFD treatment inhibited pulmonary inflammation and fibrosis in the MAILD model. PFD intervention reduced NETs formation in vitro. PFD treatment significantly reduce NETs infiltration in the lung tissue and the level of cfDNA in the serum of mice. Additionally, PFD down-regulated EMT and NLRP3-related proteins in vivo. PFD treatment also notably reduced serum levels of IL-1β, IL-6 and TNF-α. After NETs stimulation, A549 cells exhibited EMT and activation of NLRP3 inflammasome. PFD attenuated EMT in A549 cells and suppressed the activation of NLRP3 inflammasome.ConclusionPFD alleviates ILD in a murine MAILD model by inhibiting NETs formation and NLRP3 inflammasome activation, suggesting that PFD might be a potential therapeutic agent for IIM-ILD.
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
Scientific Reports
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2024
·Vol. 14
·期 1
·1-12
·
IF 3.8
Gao Kexin,Liu Yancui,Sun Cheng,Wang Ying,Bao Hongrong,Liu Guoyang,Ou Jinrui,Sun Ping
Pyroptosis is a gasdermin-mediated pro-inflammatory form of programmed cell death (PCD). Tumor necrosis factor-ɑ (TNF-ɑ) is an inflammatory cytokine, and some studies have shown that TNF-ɑ can cause pyroptosis of cells and exert anti-tumor effects. However, whether TNF-ɑ exerts anti-tumor effects on breast cancer cells by inducing pyroptosis has not been reported. In this study, to explore the impact of TNF-ɑ on pyroptosis in breast cancer cells, we treated MCF-7 cells with TNF-ɑ and found that TNF-ɑ induced cell death. Moreover, we observed that the dead cells were swollen with obvious balloon-like bubbles, which was a typical sign of pyroptosis. Further studies have found that the anti-tumor effect of TNF-ɑ on breast cancer cells in vitro was achieved through the canonical pyroptosis pathway. In addition, TNF-ɑ-induced pyroptosis in MCF-7 cells was associated with mitochondrial dysfunction, in which mitochondrial membrane potential was decreased and mitochondrial ROS production was increased. After inhibiting ROS production, the activation effect of TNF-ɑ on NLRP3/Caspase-1/GSDMD pathway was weakened, and the inhibitory effect of TNF-ɑ on the growth of MCF-7 cells in vitro was also decreased, further confirming the involvement of ROS in TNF-ɑ-induced pyroptosis. Overall, our study revealed a new mechanism by which TNF-ɑ exerts an anti-tumor effect by inducing pyroptosis in MCF-7 cells through the ROS/NLRP3/Caspase-1/GSDMD pathway, which may provide new therapeutic ideas for the treatment of breast cancer.
研究领域:
肿瘤学
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细胞生物学
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免疫学
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DOI
PubMed
高影响因子
Bioactive Materials
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2025
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IF 20.3
Yi Wang,Xuemei Liao,Qinglong Guo,Heng Zhang,Lei Ye,Liangchen Yu,Xiaoming Kong,Yicheng Jiang,Peng Zhao,Kaiyong Cai,Hongwei Cheng
Parkinson's disease (PD), a progressive neurodegenerative disorder, is marked by the degeneration of dopaminergic neurons. Emerging evidence highlights the critical involvement of neuronal ferroptosis and microglial pyroptosis in PD pathogenesis. In this study, we first characterized systemic inflammatory alterations in the peripheral blood of PD patients compared to healthy controls, revealing distinct pro-inflammatory signatures. Based on these findings, we engineered BV2 microglial membrane-camouflaged biomimetic multienzyme gallic acid-selenium nanoparticles (BM@GA-Se nanosomes) and evaluated their neuroprotective potential. In vitro and in vivo experiments demonstrated that BM@GA-Se nanosomes enhanced neuronal survival by simultaneously suppressing ferroptosis of neurons (via GPX4-mediated lipid peroxide reduction) and pyroptosis of microglia (through inhibition of the HSP90/NLRP3/Caspase-1 signaling pathway). These results position BM@GA-Se nanosome as a new dual-pathway targeting therapeutic strategy, offering a promising translational approach to mitigate PD progression by addressing interdependent inflammatory and oxidative mechanisms.
研究领域:
神经退行性疾病
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免疫炎症调节
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纳米医学
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氧化应激
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DOI
PubMed
高影响因子
POULTRY SCIENCE
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2024
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IF 3.8
Xinzhang Chen,Xu Lin
Trimethyl tin (TMT) is a good stabilizer for plastic products but is also a toxic environmental pollutant. Selenium has good antioxidant and anti-inflammatory properties and has been widely used in the poultry industry. However, it has not been reported whether selenium enrichment can antagonize TMT-induced viral hepatitis in poultry. To fill this gap, AA broiler models exposed to TMT for 42 d were established and fed a Se-enriched diet at the same time. H&E staining showed that selenium could significantly alleviate TMT-induced liver inflammation. Further analysis of the underlying mechanism revealed that TMT induced nitrosation stress (RNS), increased NO content and iNOS expression, which in turn activated the NF-κB/NLRP3 pathway and induced pyroptosis. However, selenium enrichment can reverse this situation, that is, reduce the occurrence of RNS, reduce the degree of pyroptosis, and thus alleviate the occurrence of inflammation. In our study, we demonstrated for the first time that TMT could induce hepatotoxicity other than neurotoxicity in poultry and that selenium could antagonize TMT-induced hepatotoxic hepatitis in chickens through the RNS/NF-κB/NLRP3 pathway.
研究领域:
毒理学
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兽医学
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分子生物学
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DOI
PubMed
高影响因子
TOXICOLOGY LETTERS
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2025
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IF 2.9
Leina Jia,Xiaoning Meng,Yu Ma,Jinyu Luo,Xiaoqi Luo,Huifang Yang,Jian Zhou
Cypermethrin (CYP, IUPAC name: [cyano-(3-phenoxyphenyl)methyl] 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropane-1-carboxylate), a type II pyrethroid insecticide, is suggested to have potential adverse effects on human endocrine, immune, and neurotoxic systems. Objectives: In this study, we aimed to investigate whether CYP causes oxidative stress and pyroptosis in thyroid follicle epithelial cells through the activation of the ROS-NFκB-NLRP3 pathway, thereby causing inflammatory responses. Methods: Nthy-ori 3-1 cells were used as an in vitro model and exposed to CYP at different doses (0, 100, 200, 400, 800, and 1600 μmol/L) for 24 h. Results: CYP treatment enhanced oxidative damage in Nthy-ori 3-1 cells, characterized by cellular crumpling, indistinct borders, increased cellular gaps, appearance of intercellular grease droplets, and increased pyroptosis. Subsequent treatment with the caspase-1 inhibitor VX-765 enhanced cell viability in the VX-765+CYP group, improving cell morphology, reducing pyroptotic vesicles, suppressing oxidative stress, and downregulating Interleukin-18(IL-18) (an inflammatory factor) level. Conclusion: The results demonstrate that CYP induces pyroptosis in Nthy-ori 3-1 cells through activation of the reactive oxygen species (ROS)-NF-κB-NLRP3 pathway.
研究领域:
毒理学
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内分泌学
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细胞生物学
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DOI
PubMed
高影响因子
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
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2020
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IF 4.133
Yan Wu,Yacheng Zhang,Jie Zhang,Tingting Zhai,Jingping Hu,Hairong Luo,Haiyan Zhou,Qinghai Zhang,Zhiguang Zhou,Feng Liu
Aims The antimicrobial peptide cathelicidin ( Camp ) has multifunctional immunomodulatory activities. However, its roles in inflammation-related myocardial ischemia/reperfusion (MI/R) injury remain unclear. Methods and results In this study, adult male C57BL/6 wild-type (WT) mice were subjected to MI/R injury by left anterior descending coronary artery ligation for 45 min followed by 3 or 24 h of reperfusion . An abundant cardiac expression of cathelicidin was observed during ischemia and reperfusion, which was mainly derived from heart-infiltrating neutrophils . Knockout of Camp in mice reduced MI/R-induced myocardial inflammation , infarct size, and circulating cTnI levels (an indicator of heart damage). CRAMP (the mature form of murine cathelicidin) administration of WT mice immediately before MI/R exerted detrimental effects on the reperfused heart. CRAMP exacerbates MI/R injury via a TLR4 and P2X 7 R/NLRP3 inflammasome-dependent mechanism, since I/R-induced myocardial infarction was reserved by inhibition of TLR4, P2X 7 R, or NLRP3 inflammasome in CRAMP-treated WT mice. Depletion of neutrophils before MI/R abrogated the amplification of infarct size in CRAMP-treated WT mice. Heart-infiltrating neutrophils were found to be one of major cellular sources of myocardial IL-1β (a “first line” pro-inflammatory cytokine) at the early stage of MI/R. At this stage, CRAMP administration just before MI/R induced pro-IL-1β protein expression in heart-infiltrating neutrophils, but not in non-neutrophils. In vitro experiments showed that LL-37 (the mature form of human cathelicidin) treatment promotes the processing and secretion of IL-1β from human neutrophils via stimulating TLR4 signaling and P2X 7 R/NLRP3 inflammasome. Conclusions Our findings reveal that, at the early stage of MI/R, neutrophil-derived cathelicidin plays an injurious role in the heart. Cathelicidin aggravates MI/R injury by over-activating TLR4 signaling and P2X 7 R/NLRP3 inflammasome in heart-infiltrating neutrophils, which leads to the excessive secretion of IL-1β and subsequent inflammatory injury .
研究领域:
心脏病学
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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
Journal of Inflammation Research
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2025
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IF 4.1
Qi Shi,Tingting Hu,Lixia Xu,Jiayuanyuan Fu,Yehong Fang,Yu Lan,Weijia Fan,Qiaoli Wu,Xiaoguang Tong,Hua Yan
Background Acute lung injury (ALI) is a serious yet common complication in patients with traumatic brain injury (TBI), often associated with poor prognosis. The development of TBI-induced ALI is closely associated with excessive oxidative stress and NLRP3 inflammasome activation. Fingolimod, an immunomodulatory agent, has been reported to attenuate inflammatory responses, restore blood-brain barrier integrity, reduce cerebral edema, and mitigate associated neurological deficits.Objective This study aimed to investigate the mechanistic role of NLRP3 inflammasome activation in TBI-induced ALI and to evaluate the therapeutic potential of fingolimod in targeting this inflammatory pathway.Results A rat TBI model was established using the classical free-fall method, and animals were treated with fingolimod (0.5 or 1 mg/kg) daily for three days. The TBI model rats presented with clear signs of histopathological pulmonary damage, an increase in the permeability of capillaries in the lung, and pulmonary edema that coincided with significantly increased NLRP3, caspase-1, and ASC expression in lung tissue samples. This overexpression of NLRP3 inflammasome machinery resulted in the release of IL-1β. Fingolimod treatment, however, reversed all of these effects such that it suppressed NLRP3 activity and normalized levels of IL-1β, leading to the alleviation of inflammation. In line with these results, LPS and nigericin (NLRP3 agonist)-treated NR8383 cells treated using fingolimod exhibited reductions in reactive oxygen species production and NLRP3 inflammasome activation.Conclusion These findings suggest that NLRP3 inflammasome activation and oxidative stress are key mediators of TBI-induced ALI. Fingolimod exerts protective effects against this condition by inhibiting NLRP3 inflammasome activation, highlighting its potential as a therapeutic agent for TBI-associated pulmonary complications.
研究领域:
医学
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免疫学
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神经科学
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PubMed
高影响因子
FASEB JOURNAL
·
2025
·Vol. 39
·期 9
·e70561
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IF 4.2
Haocong Zhang,Xianyun Qin,Hong Yuan,Liangbi Xiang,Hailong Yu
Neuronal inflammation and apoptosis aggravate the secondary injury after spinal cord injury (SCI). Cathepsin L (CTSL) is a lysosomal cysteine protease with effects on the regulation of inflammation, but its role in SCI remains unclear. The in vivo T10 mouse spinal cord contusion model was established. The results showed that CTSL expression was increased following SCI and then gradually decreased. Moreover, CTSL was mainly expressed in microglia. To detect the function of CTSL, after contusive injury, the mice were immediately injected with lentiviruses carrying CTSL shRNA. The results showed that CTSL depletion promoted functional recovery, accompanied by increased locomotor ability. CTSL deficiency reduced lesion cavity areas by inhibiting neuronal apoptosis and neuroinflammation. Indeed, CTSL deficiency decreased the secretion of TNF-α, IL-6, and MCP-1 and M1 microglia polarization in the spinal cord. CTSL depletion inhibited the expression and assembly of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome. In vitro, CTSL expression was increased in LPS-treated BV2 cells. CTSL silencing repressed LPS-induced M1 polarization, as evidenced by the reduction in TNF-α, IL-6, and MCP-1 expression in the supernatant of BV2 cells. CTSL knockdown induced the downregulation of NLRP3 expression and activation. The inhibition role of CTSL knockdown in microglial inflammation and M1 polarization was reversed by NLRP3 agonist. Collectively, the study suggests that CTSL induces the microglia M1 polarization-mediated inflammation via promoting NLRP3 activation and thereby inhibits functional recovery after SCI. Graphical The inhibition of CTSL improves functional recovery and alleviates neuroinflammation through microglial polarization after spinal cord injury. Mechanically, CTSL knockdown inhibited NLRP3 expression and activation, which repressed the production of pro-inflammatory cytokines in M1 microglia, thereby inhibiting spinal cord injury-induced neuroinflammation.
研究领域:
神经科学
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免疫学
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DOI
PubMed
高影响因子
Scientific Reports
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2025
·Vol. 15
·期 1
·1-16
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IF 3.9
Chen Chunxia,Huang Huan,Zhang Haofeng,Huang Junli,Zhou Xing,Xie Xixiang,Liao Xiaoling,Zhou Yao,Cai Fangqi,Chen Guirong,Xie Yuping,Huang Luying
The TLR4/NLRP3 inflammasome pathway drives lung cancer cell proliferation, migration, and invasiveness. However, no in vivo treatments targeting this pathway in lung cancer exist. Resveratrol, an anti-inflammatory compound, inhibits the NLRP3 inflammasome but requires high doses due to its hydrophobicity and instability. This study aimed to enhance the therapeutic efficacy of resveratrol by encapsulating it in liposomes to effectively target the TLR4/NLRP3 inflammasome pathway in lung cancer. In this study, the efficacy of resveratrol liposome was tested in vitro through cell proliferation and migration assays and gene expression analysis. In vivo effects were evaluated in a lung cancer mouse model using histological and molecular techniques. Resveratrol liposome significantly inhibited lung cancer cell proliferation and migration, and induced apoptosis in orthotopic lung cancer models. Additionally, by suppressing TLR4/NLRP3 inflammasome-related genes, resveratrol liposomes diminished levels of IL-1β and IL-18 both locally at tumor sites and systemically, thus modulating the tumor immune microenvironment by decreasing MDSCs and increasing CD4 + and CD8 + T cells. In conclusion, resveratrol liposome alleviates lung cancer progression by targeting the TLR4/NLRP3 inflammasome pathway and enhancing anti-tumor immune responses, highlighting its potential as a promising therapeutic strategy for lung cancer treatment.
研究领域:
药理学
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肿瘤学
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免疫学
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纳米技术
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分子生物学
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产品关联
DOI
PubMed
高影响因子
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