JOURNAL OF MEDICINAL CHEMISTRY
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2025
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IF 6.8
Xinlin Zhu,Yi Dong,Ya Zhang,Chenghai Gao,Lijian Ding,Yonghong Liu,Zhiran Ju
Gouty arthritis, driven by monosodium urate (MSU) crystal deposition and dysregulated inflammation, remains a therapeutic challenge due to the limitations of current treatments. Here, we investigate Herdmanine D (HDD), a marine-derived alkaloid from the ascidian Herdmania momus. It was optimized via structure–activity relationship (SAR) studies and computational modeling to enhance its binding to peroxisome proliferator-activated receptor γ (PPAR-γ), which regulates the PPAR-γ/NF-κB signaling pathway in gout pathogenesis. The optimized HDD derivative 9a demonstrated potent PPAR-γ binding affinity and pharmacokinetic properties, effectively suppressing NF-κB-driven pro-inflammatory cytokines in vitro. In murine MSU-induced gouty arthritis models, 9a alleviated synovial inflammation and tissue damage. Mechanistically, 9a activated PPAR-γ to inhibit NF-κB and attenuate NLRP3 inflammasome assembly. This work highlights HDD as a unique marine scaffold for next-generation antigout therapeutics, merging marine natural product safety with rational design to address unmet clinical needs.
研究领域:
药理学
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海洋天然产物
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炎症性疾病
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药物设计与开发
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风湿病学
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DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
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2026
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IF 5.4
Lili Wu,Siyu Chen,Qiyuan Yang,Xing Li,Lingyan Liu,Shengjun Ji,Shuaiyuan Tang,Sihui Zhang,Yan Wang,Runzhi Chen,Zhikun Zhan
Emodin, a bioactive compound abundant in Chinese medicinal herbs, possesses broad therapeutic potential but raises safety concerns due to conflicting reports of hepatotoxicity. This study investigated the toxicological mechanisms underlying emodin-induced liver injury. Emodin (25-100 μM) elicited dose-dependent cytotoxicity in HepG2 cells, with the cytochrome P450 (CYP) enzymes CYP1A2 and CYP3A4 identified as the primary enzymes metabolizing emodin into hydroxylated products (M1-M3). The comparative cytotoxicity assay of emodin and its metabolites in HepG2 cells indicated that CYP-mediated metabolism functions as a critical detoxification pathway. Moreover, inhibition of CYP with 1-aminobenzotriazole (ABT, 500 μM) markedly enhanced emodin (12.5-100 μM) cytotoxicity in HepG2 cells. Similarly, ABT (50 mg/kg) markedly exacerbated emodin (400 mg/kg)-induced hepatotoxicity in mice following three weeks of co-administration. Transcriptomic profiling and validation experiments demonstrated that activation of the NF-κB/NLRP3 signaling axis contributes to emodin-induced hepatic injury. Metabolomic analyses further revealed perturbations in key pathways, including lipopolysaccharide (LPS) biosynthesis, sphingolipid metabolism, and cholesterol metabolism. Integrated multi-omics analysis identified a significant positive correlation between these metabolites (LPS, sphingosine, cholesterol) and NF-κB/NLRP3 pathway genes. These findings suggest that emodin-mediated upregulation of LPS, sphingosine, and cholesterol activates the NF-κB/NLRP3 pathway, subsequently triggering hepatic injury. Collectively, this study delineates the metabolic detoxification routes of emodin and provides mechanistic insight into its hepatotoxic potential.
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PubMed
高影响因子
MICROVASCULAR RESEARCH
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2025
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IF 2.7
Xiao Xu,Xiaohu Ge,Hongbo Ci,Maitiseyiti Abulaihaiti,JianPing Yang,YangYang Li,Feng Zhu
Background Thromboangiitis obliterans (TAO, Buerger's disease) is a chronic inflammatory disorder that affects small and medium-sized vessels in the limbs. Although the pathogenesis of TAO remains incompletely understood, elevated levels of plasminogen activator inhibitor-1 (PAI-1) have been associated with cardiovascular diseases. This study investigates the mechanism by which PAI-1 activates the NF-κB/NLRP3 inflammatory pathway in vascular endothelial cells through hypoxia-inducible factor-1α (HIF-1α), contributing to the progression of TAO. Methods Proteomic analysis was performed on plasma samples from 5 TAO patients and 5 healthy controls to identify differentially expressed proteins (DEPs). In vitro, human umbilical vein endothelial cells (HUVECs) were subjected to 1 % hypoxia to mimic TAO conditions. Interventions included PAI-1 knockdown using lentiviral vectors and treatment with the HIF-1α agonist dimethyloxalylglycine (DMOG). Cell viability was assessed using the CCK-8 assay, apoptosis was measured by flow cytometry, and inflammatory factor levels were detected by enzyme-linked immunosorbent assay (ELISA). Protein expression was analyzed by Western blotting. In vivo, a TAO rat model was established by sodium laurate injection. The severity of limb ischemia was evaluated using gross lesion grading and infrared thermography, while pathological changes were assessed by hematoxylin and eosin (H&E) staining and Masson's trichrome staining. Results Elevated levels of PAI-1, HIF-1α, and key molecules in the NLRP3/NF-κB pathway were observed in both TAO rats and hypoxic HUVECs. PAI-1 knockdown significantly improved limb ischemia and suppressed the NLRP3/NF-κB pathway in TAO rats. Compared with the DMOG intervention group, combined treatment with PAI-1 knockdown and DMOG effectively alleviated ischemic symptoms, increased body weight, and reduced the expression of HIF-1α and inflammatory pathway molecules in TAO rats. Conclusion PAI-1 promotes the progression of TAO by activating the NF-κB pathway via HIF-1α. Targeted inhibition of PAI-1 represents a potential therapeutic strategy for TAO.
研究领域:
心血管医学
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分子生物学
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炎症研究
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血管生物学
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DOI
PubMed
高影响因子
JOURNAL OF DRUG TARGETING
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2019
·
IF 3.277
Yan Jiang,Hongjiao Du,Xue Liu,Xi Fu,Xiaodong Li,Qian Cao
There is increasing evidence that atherosclerosis is the significant risk factor for cardiovascular diseases, which are the leading causes of morbidity and mortality worldwide. Artemisinin is a natural endoperoxides quiterpene lactone compound in Artemisia annua L with vasculoprotective effects. The primary aim of this study was to investigate whether artemisinin could be conferred an anti-atherosclerotic effect in high-fat diet (HFD)-fed ApoE–/– mice and explore the possible mechanism. We found that treatment with artemisinin (50 and 100 mg/kg) effectively ameliorated atherosclerotic lesions, such as foam cell formation, hyperplasia and fibrosis in the aortic intima. Atherosclerotic mice treated with artemisinin showed reduced inflammation by up-regulating adenosine 5′-monophosphate (AMP) activated protein kinase (AMPK) activation and by down-regulating nuclear factor-κB (NF-κB) phosphorylation and nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome expression in the aortas. In addition, artemisinin was found to promote AMPK activity in macrophages and its anti-inflammatory effect was neutralised by AMPK silence using specific siRNA. In conclusion, we demonstrate that artemisinin may protect the aortas from atherosclerotic lesions by suppression of inflammatory reaction via AMPK/NF-κB/NLRP3 inflammasomes signalling in macrophages.
研究领域:
心血管疾病
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药理学
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2022
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IF 5.714
Haihua Zhang,Jing Wang,Wuying Lang,Hongli Liu,Zhiqiang Zhang,Tonglei Wu,Hongqiang Li,Liya Bai,Qiumei Shi
Methotrexate (MTX) treats various diseases but also damages intestinal barrier and leads to enteritis. Albiflorin (ALB) has a variety of pharmacological effects, including antioxidant, anti-inflammation and anti-apoptosis. In the present study, we evaluated the therapeutic effect of ALB on MTX-induced enteritis and investigated the possible mechanisms involved. Male SD rats were intraperitoneally injected with 7 mg/kg MTX for three consecutive days to establish the enteritis model. ALB (20 or 40 mg/kg/day) was intragastrically administrated since two days prior MTX treatment and lasted for six days. We found that ALB treatment increased body weight and intestinal weight of rats with MTX injection. The disease activity index (DAI) score was also decreased after ALB administration. In histological examination, ALB treatment attenuated inflammatory cells infiltration and promoted survival of goblet cells. In detection of inflammatory-associated factors, ALB treatment decreased CD68 + cells infiltration, inhibited myeloperoxidase activity, and suppressed intercellular cell adhesion molecule-1 and cyclooxygenase-2 expression. Additionally, ALB reduced malondialdehyde, glutathione levels, inhibited superoxide dismutase activity and suppressed reactive oxygen species production. Moreover, ALB treatment effectively inhibited NLRP3, as well as caspase 1 p20 and interleukin (IL)-1β and 18 expression. Finally, nuclear factor-κB (NF-κB) p65 phosphorylation and nuclear translocation were also demonstrated to be blocked upon ALB treatment. In conclusion, our findings indicated that ALB alleviated MTX-induced enteritis via inhibiting the NF-κB/NLRP3 pathway.
研究领域:
药理学
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免疫学
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胃肠病学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2024
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IF 6.7
Miaomiao Sun,Honghong Zhan,Xiaoliang Long,Ali M. Alsayed,Zhe Wang,Fancheng Meng,Guowei Wang,Jingxin Mao,Zhihua Liao,Min Chen
Background Irinotecan (CPT-11) is used as chemotherapeutic drug for treatment of colorectal cancer. However, without satisfactory treatments, its gastrointestinal toxicities such as diarrhea and intestinal inflammation severely restrained its clinical application. Roots of Aucklandia lappa Decne. are used as traditional Chinese medicine to relieve gastrointestinal dysfunction and dehydrocostus lactone (DHL) is one of its main active components. Nevertheless, the efficacy and mechanism of DHL against intestinal mucositis remains unclear. Purpose The present study aimed to investigate the protective effects of DHL on CPT-11-induced intestinal mucositis and its underlying mechanisms. Methods The protective effect of DHL was investigated in CPT-11-induced mice and lipopolysaccharide (LPS)+CPT-11 induced THP-1 macrophages. Body weight, diarrhea score, survival rate, colon length, and histopathological changes in mice colon and jejunum were analyzed to evaluate the protective effect of DHL in vivo . And DHL on reducing inflammatory response and regulating TLR4/NF‐κB/NLRP3 pathway in vivo and in vitro were explored. Moreover, DHL on the interaction between TLR4 and MD2 was investigated. And silencing TLR4 targeted by siRNA was performed to validate the mechanisms of DHL on regulating the inflammation. Results DHL prevented CPT-11-induced intestinal damage, represented by reducing weight loss, diarrhea score, mortality rate and the shortening of the colon. Histological analysis confirmed that DHL prevented intestinal epithelial injury and improved the intestinal barrier function in CPT-11 induced mice. Besides, DHL significantly downregulated the level of inflammatory cytokines by inhibiting TLR4/NF-κB/NLRP3 signaling pathway in CPT-11-induced mice and LPS+CPT-11-induced THP-1 macrophages. In addition, DHL blocked TLR4/MD2 complex formation. Molecular docking combined with SIP and DARTS assay showed that DHL could bind to TLR4/MD2 and occludes the hydrophobic pocket of MD2. Furthermore, Silencing TLR4 abrogated the effect of DHL on LPS+CPT-11 induced inflammatory response in THP-1 macrophages. Additionally, DHL ameliorate the CPT-11-induced intestinal mucositis without affecting the anti-tumor efficacy of CPT-11 in the tumor xenograft mice. Conclusion This study found that DHL exhibited the anti-inflammatory effects in CPT-11-induced intestinal mucositis by inhibiting the formation of TLR4/MD2 complex and then regulation of NF-κB/NLRP3 signaling pathway. DHL is potentially served as a novel strategy of combined medication with CPT-11.
研究领域:
药理学
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免疫学
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肿瘤学
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胃肠病学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Immunology
·
2025
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IF 5.9
You Zhou,Kai Yang,Jian Wang,Ruijuan Guan,Wei Liu,Chaowei Wen,Liang Yuan,Tiange Zhang,Wei Feng,Yuanyuan Li,Jingyi Xu,Wenju Lu
Backgrounds: Exposure to fine particulate matter (PM2.5) triggers airway inflammation through the activation of the Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling pathway, contributing to the pathogenesis of various acute and chronic respiratory diseases. Mucin 1 (MUC1), a transmembrane glycoprotein highly expressed on airway epithelial cells, is known to modulate TLR-mediated inflammatory responses. However, the specific role and molecular mechanism by which MUC1 regulates PM2.5-induced airway inflammation remain inadequately understood.Methods: Lung injury models were established using Muc1+/+ and Muc1-/- rats via intranasal instillation of PM2.5. Histopathological changes and inflammatory responses were evaluated following treatment. In parallel, human bronchial epithelial cells (16HBE) were transfected with MUC1 overexpression and knockdown plasmids, along with corresponding controls. An IRAK4-specific inhibitor was employed to explore the mechanistic role of MUC1 in regulating the TLR4/IRAK4/NF-κB signaling cascade and associated pyroptosis.Results: PM2.5 exposure caused notable epithelial disruption, inflammatory infiltration, and submucosal fibrosis in Muc1-/- rats compared to Muc1+/+ controls. While TLR4 expression was not significantly altered, NF-κB and NLRP3 inflammasome activity were markedly elevated in Muc1-deficient rats. In 16HBE cells, MUC1 overexpression attenuated, whereas MUC1 knockdown exacerbated, PM2.5-induced activation of the IRAK4/NF-κB signaling axis and pyroptosis-related markers (IL-1β, IL-18, NLRP3, GSDMD). Furthermore, pharmacological inhibition of IRAK4 mitigated these effects, confirming the involvement of the IRAK4 pathway in MUC1-mediated protection.Conclusions: MUC1 is upregulated in airway epithelial cells upon PM2.5 exposure and serves as a key endogenous inhibitor of airway inflammation. It exerts its anti-inflammatory and anti-pyroptotic effects by suppressing IRAK4 phosphorylation, thereby modulating downstream NF-κB/NLRP3/GSDMD signaling. These findings highlight MUC1 as a potential therapeutic target for PM2.5-induced airway inflammatory diseases.
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高影响因子
BIOORGANIC CHEMISTRY
·
2026
·
IF 5.1
Hui Li,Hengli Luo,Xin Zhang,Jianchun Luo,Chenglin Zhan,Xiaofang Gong,Minghua Liu,Xiangfeng Chen,Ge Zhao
Rhoifolin alleviated pathological and histological changes in DNCB-induced Balb/c mice with AD-like responses. • Rhoifolin suppressed pro-inflammatory chemokine and cytokine production in TNF-α/IFN-γ-stimulated HaCaT cells. • Rhoifolin regulated skin barrier function and inflammation via PPARα-mediated NF-κB/NLRP3 pyroptosis signaling. Rhoifolin (ROF), a naturally occurring flavonoid glycoside, has been documented to possess a broad spectrum of biological properties, including anticancer, antioxidant, neuroprotective, hepatoprotective, anti-inflammatory, and antiviral activities. Atopic dermatitis (AD) is a persistent, recurring inflammatory skin illness that frequently greatly compromises the patients' quality of life. Nevertheless, the role of ROF in AD pathogenesis and the associated molecular events have yet to be elucidated. Our findings revealed that ROF administration substantially ameliorated the 1-chloro-2,4-dinitrobenzene (DNCB)-induced AD-like phenotypes, as reflected by decreased mast cell accumulation, reduced CD4 + and CD8 + T cells infiltration within lesional skin, lowered serum immunoglobulin E (IgE) concentrations, attenuated epidermal and dermal thickening, suppressed histamine liberation and pruritic episodes, improved SCORAD indices, concomitant restoration of skin barrier protein expression, and curtailed the production of multiple inflammatory factors. Mechanistic investigations, integrating network pharmacology forecasts, transcriptomic profiling, and pharmacological blockade experiments with specific antagonists, further confirmed that the anti-inflammatory action of ROF operates through the PPARα-regulated NF-κB/NLRP3 signaling cascade. Collectively, these observations demonstrate that ROF exerts favorable inhibitory effects against AD-like inflammation both in vivo and in vitro , underscoring its potential as a viable therapeutic option for managing AD and other inflammatory cutaneous disorders. Download: Download high-res image (81KB) Download: Download full-size image
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DOI
PubMed
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2024
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IF 4.3
Xin Zhao,Chao Chen,Weina Han,Min Liang,Yuanyuan Cheng,Yingjie Chen,Defeng Pang,Haoqi Lei,Xuefei Feng,Shifeng Cao,Zhixiong Li,Jinhui Wang,Yan Zhang,Baofeng Yang
Lung cancer is a leading cause of cancer-related deaths worldwide. Recent studies have identified pyroptosis, a type of programmed cell death, as a critical process in the development and progression of lung cancer. In this study, we investigated the effect of EEBR, a new compound synthesized by our team, on pyroptosis in non-small cell lung cancer cells (NSCLC) and the underlying molecular mechanisms. Our results demonstrated that EEBR significantly reduced the proliferation and metastasis of NSCLC cells in vitro. Moreover, EEBR-induced pyroptosis in NSCLC cells, as evidenced by cell membrane rupture, the release of cytokines such as interleukin-18 and interleukin-1 beta and the promotion of Gasdermin D cleavage in a Caspase-1-dependent manner. Furthermore, EEBR promoted the nuclear translocation of NF-κB and upregulated the protein level of NLRP3. Subsequent studies revealed that EEBR-induced pyroptosis was suppressed by the inhibition of NF-κB. Finally, EEBR effectively suppressed the growth of lung cancer xenograft tumours by promoting NSCLC pyroptosis in animal models. Taken together, our findings suggest that EEBR induces Caspase-1-dependent pyroptosis through the NF-κB/NLRP3 signalling cascade in NSCLC, highlighting its potential as a candidate drug for NSCLC treatment.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
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2026
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IF 12.5
Yana Ma,Wen Luo,Weijia Zhu,Zhichao Deng,Shijun Xu,Hang Yuan,Wei-jun Fan,Quanjun Yao,Wei Yao,Ho-Young Song,Mingzhen Zhang,Jizhao Wang,Hongtao Hu
Oxidative stress, resulting from excessive reactive oxygen species (ROS), is critically involved in the development and progression of inflammatory diseases such as inflammatory bowel disease. Therefore, targeting ROS for the treatment of inflammation holds great potential, and the underlying mechanism is of great significance for clinical medication. In this work, carbon dots (C-dots) based on chrysanthemum as carbon source were obtained through a hydrothermal method. The as-prepared C-dots exhibited favorable ROS scavenging capacity and biocompatibility. The ROS level and the oxidative damage were reversed, the expression of proinflammatory factors was reduced, and the disrupted barrier was recovered by chrysanthemum-derived C-dots in the cellular inflammatory model. The anti-inflammatory effects were also validated in mice colitis model. Mechanistically, the chrysanthemum-derived C-dots regulated the Keap1/Nrf2 antioxidant signaling and inhibited the NF-κB/NLRP3 inflammasome-mediated inflammatory signaling, thereby restoring redox homeostasis and modulating the inflammatory microenvironment. Collectively, the C-dots from chrysanthemum with preferable biocompatibility hold a bright prospect in inflammation resolution through remodeling redox and inflammatory microenvironment.
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高影响因子
BIOCHEMICAL PHARMACOLOGY
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2026
·
IF 6.5
Xia Wu,Chun-Feng Liu
Septic cardiomyopathy (SCM) is a prevalent complication among septic patients, accompanied by high mortality. Estrogen‐related receptor alpha (ERRα), a transcription factor, is implicated in various cardiovascular diseases. Nonetheless, its role in SCM remains unclear. Here, the cecum ligation and puncture (CLP) procedure was used to construct a mouse sepsis model. We found that the ERRα expression was downregulated in septic hearts. Adeno-associated virus-9 (AAV-9)-mediated cardiomyocyte-specific ERRα overexpression improved the survival rate of septic mice. Additionally, ERRα overexpression ameliorated CLP-induced cardiac dysfunction and myocardial pathological damage. In vitro , HL-1 mouse cardiomyocytes were transduced with an ERRα overexpression adenovirus before LPS stimulation. The results demonstrated that ERRα overexpression mitigated LPS-induced inflammatory cytokines (IL-6, IL-1β, TNF-α, IL-18) and apoptosis (Bax, cleaved caspase-3/9) in HL-1 cells. Mechanistically, ERRα inhibited the NF-κB/NLRP3 inflammasome activation in septic hearts and LPS-stimulated HL-1 cells. Furthermore, we overlapped the differentially expressed genes of septic hearts (GSE125042) and ERRα KO hearts (GSE7196) to identify the downstream target genes. Meteorin like, glial cell differentiation regulator (METRNL) was identified as the target gene of ERRα. Notably, ERRα bound to the METRNL promoter and upregulated its activity, which was confirmed via dual-luciferase reporter assay, ChIP-qPCR, and oligonucleotide pull-down assay. Knockdown of METRNL prevented the effects of ERRα overexpression on the apoptosis and inflammatory response of cardiomyocytes induced by LPS. Our findings underscore the role of ERRα in mitigating myocardial injury in SCM, indicating its potential as a new therapeutic approach.
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高影响因子
International Journal of Environmental Research and Public Health
·
2019
·Vol. 17
·期 1
·138
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IF 2.468
Chang Liu,Yaohui Zhu,Zhenxiang Lu,Weina Guo,Bayaer Tumen,Yalan He,Chao Chen,Shanshan Hu,Kangzhi Xu,Yan Wang,Lei Li,Shenghe Li
Acute Cadmium (Cd) exposure usually induces hepatotoxicity. It is well known that oxidative stress and inflammation causes Cd-induced liver injury. However, the effect of nuclear factor erythroid 2-related factor 2 (Nrf2) in Cd-induced liver injury is not completely understood. In this study, we observed Cd-induced liver damage and the potential contribution of Nrf2, nuclear factor-κB (NF-κB), Nod-like receptor 3 (NLRP3), and mitogen-activated protein kinases (MAPKs) signaling pathways. Changes in serum transaminases and proinflammatory cytokines expression showed that Cd could induce acute hepatotoxicity. Moreover, Nrf2 and its downstream heme oxygenase 1 (HO-1) were inhibited by Cd exposure, and Kelch-like ECH-associated protein 1 (Keap1), the inhibitory protein of Nrf2, was increased. Furthermore, NF-κB, NLRP3, and MAPKs signaling pathways were all activated by Cd intoxication. In conclusion, the inhibition of Nrf2, HO-1, and the activation of NF-κB, NLRP3, and MAPKs all contribute to Cd-induced liver injury.Keywords:Cadmium;acute liver injury;Nrf2;NLRP3;NF-κB;MAPKs
研究领域:
毒理学
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分子生物学
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免疫学
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产品关联
DOI
PubMed
高影响因子
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