INFLAMMATION
·
2023
·
IF 5.1
Zhu Hong,Zhang Lieliang,Xiao Feng,Wu Lei,Guo Yun,Zhang Zhe,Xiao Yao,Sun Gufeng,Yang Qing,Guo Hua
The aseptic inflammatory response of the central nervous system is one of the important causes of neurodegenerative diseases in individuals and is also recognized in postoperative cognitive dysfunction (POCD). Inflammasome is thought to be closely related to brain homeostasis. However, there are few drugs targeting the inflammasome to suppress inflammation in clinical practice. Here, we showed that the neuroinflammatory response mediated by the NLRP3 (NLR family, pyrin domain containing 3) inflammasome was involved in the pathological process of POCD. Melatonin protected mice from nerve damage by inhibiting activation of the NLRP3-caspase-1-interleukin 1 beta (IL-β) pathway and thus reduced the secretion of IL-1β inflammatory factors in microglia. Further research found that melatonin has a potential binding effect with NLRP3 protein, and at the same time could reduce the phosphorylation of nuclear factor kappa-B (NF-κB) and inhibit its nuclear translocation. The underlying mechanism was that melatonin inhibited the expression of acetylation of histone H3 and melatonin attenuated the binding of NF-κb to the NLRP3 promoter region 1–200 bp, where there are two potential binding target sites of NF-κb and NLRP3, namely the sequences 5′-GGGAACCCCC-3′ and 5′-GGAAATCCA -3′. Therefore, we confirmed a novel mechanism of action of melatonin in the prevention and treatment of POCD.
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Oxidative Medicine and Cellular Longevity
·
2021
·
IF 6.543
Fangzhou Jiao,Yao Wang,Qian Chen,Pan Cao,Chunxia Shi,Maohua Pei,Luwen Wang,Zuojiong Gong
Hepatic encephalopathy (HE) is a neuropsychiatric disorder resulting from acute or chronic liver failure. This study is aimed at investigating the therapeutic effects and mechanisms of SIRT1 in thioacetamide- (TAA-) induced rat HE models. A selective activator (CAY10602) and inhibitor (EX527) of SIRT1 were used in this study. All male rats were separated into control, TAA, CAY10602+TAA, and EX527+TAA groups. Histological damage, liver function, serum ammonia, behavioral changes, and brain oxidative stress were measured in each group. Western blotting was used to measure SIRT1, NLRP3, ASC, and IL-1β protein expression. The results showed that CAY10602 alleviated liver injury, improved neurological decline, reduced microglial activation and brain oxidative stress, and improved the survival rates of HE rats. Moreover, CAY10602 inhibited activation of the NLRP3 inflammasome in microglia of the brain cortex in HE rats. Next, cell experiments confirmed that CAY10602 inhibited activation of the NLRP3 inflammasome in BV2 microglial cells. However, inhibition of SIRT1 by EX527 or lentivirus could enhance activation of the NLRP3 inflammasome in this process. Finally, CAY10602 reduced the neurotoxicity induced by high levels of ammonia in HT22 cells. Taken together, CAY10602 alleviates TAA-induced HE by suppressing microglial activation and the NLRP3 inflammasome and reducing the neurotoxicity of NH4Cl in HT22 cells. A pharmacologic activator of SIRT1 may be a promising approach for the treatment of HE.
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Frontiers in Pharmacology
·
2020
·
IF 4.225
Li Honglian,Lu Ruirui,Pang Yu,Li Jicheng,Cao Yiwen,Fu Hongxin,Fang Guoxing,Chen Qiuhe,Liu Bihao,Wu Junbiao,Zhou Yuan,Zhou Jiuyao
Immunoglobulin A nephropathy (IgAN) is one of the most frequent kinds of primary glomerulonephritis characterized by IgA immune complexes deposition and glomerular proliferation. Zhen-wu-tang (ZWT), a well-known traditional Chinese formula has been reported to ameliorate various kidney diseases. However, its pharmacological mechanism remains unclear. Exosomes have been described in diverse renal diseases by mediating cellular communication but rarely in the IgAN. The purpose of the present study is to explore whether the underlying mechanisms of the effect of ZWT on IgAN is correlated to exosomes. Our results demonstrated that in human renal tubular epithelial cells (HK-2) stimulated by lipopolysaccharide, exosomes are obviously released after ZWT-containing serum treatment especially with 10% ZWT. In addition, once released, HK-2-derived exosomes were uptaked by human mesangial cells (HMC), which impeded the activation of NF-κB/NLRP3 signaling pathway to exert anti-inflammatory effects in a lipopolysaccharide induced proliferation model. Moreover, IgAN rat model was established by bovine serum albumin, CCL4 mixed solution and LPS. We found that 10% ZWT could significantly promote the release of exosomes from HK-2 and inhibit HMC proliferation to improve inflammation. Thus HK-2-derived exosomes treated with 10% ZWT (ZWT-EXO) were administered to the rats by tail vein injection. Our results showed that ZWT-EXO decreased the levels of 24 h proteinuria, urinary erythrocyte, IgA deposition in glomerulus and renal pathological injury which ameliorated the kidney damage. In addition, ZWT was able to dramatically promote secretion of exosomes in renal tissues while blocked NF-κB nuclear translocation as well as activation of NLRP3 inflammasome, leading to the inhibition of IL-1β and caspase-1. In conclusion, our study reveal that ZWT has protective effects on IgAN by regulating exosomes secretion to inhibit the activation of NF-κB/NLRP3 pathway, thereby attenuating the renal dysfunction. These findings may provide a new therapeutic target for the treatment of IgAN.
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JOURNAL OF MEDICINAL CHEMISTRY
·
2025
·
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.
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PHYTOTHERAPY RESEARCH
·
2026
·
IF 8.1
Huaiying Tang,Qin Xiang,Yue Zhang,Yu Zhang,Xiangxiang Fu,Liming Tan,Yongli Zhang,Siqi Li,Dong Gong,Xu Guo,Yonghong Zhang,Li Chen,Tao Zheng,Qibin Wang
Type 2 diabetes mellitus (T2DM) is frequently accompanied by chronic ethanol (ET) consumption, which worsens metabolic dysregulation and organ damage. Cinnamic acid (CA), a natural compound with anti-diabetic and hepatoprotective effects, shows therapeutic potential, but its role in mitigating ET-exacerbated hepatocyte injury in diabetes remains unclear. This study thus investigated whether CA protects against ET-induced hepatocyte pyroptosis under diabetic conditions and explored the underlying mechanisms. In vitro, HepG2 cells cultured under high-glucose (HG) conditions were exposed to ET to simulate a diabetic state with concomitant alcohol intake. Pyroptosis was evaluated by morphological examination and annexin V/PI staining. The involvement of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3)/gasdermin D (GSDMD) pathway and AMP-activated protein kinase (AMPK) activation was assessed via immunoblotting, reactive oxygen species (ROS) detection, and molecular docking. In vivo, a T2DM mouse model was established using a high-fat diet combined with streptozotocin injection, followed by ET exposure and CA treatment. Metabolic parameters, histopathological changes, and hepatic signaling pathways were analyzed. Our results showed that ET exposure significantly increased pyroptotic body formation, ROS production, and NLRP3/GSDMD pathway activation in HG-treated HepG2 cells—all of which were reversed by CA in a concentration-dependent manner. Mechanistically, CA directly bound to and activated AMPK, and the protective effects were abolished by the AMPK inhibitor Compound C. In T2DM mice, ET exposure aggravated insulin resistance, dyslipidemia, hepatic steatosis, and histopathological abnormalities, whereas CA intervention ameliorated these adverse effects and modulated the AMPK-NLRP3/GSDMD signaling axis in liver tissue. Collectively, these findings demonstrate that CA alleviates ET-exacerbated hepatocyte pyroptosis under diabetic conditions by activating AMPK and subsequently inhibiting the NLRP3/GSDMD signaling cascade. This study provides novel insights into the therapeutic potential of CA in T2DM complicated by alcoholic hepatocellular injury.
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Cells
·
2024
·Vol. 13
·期 24
·2070
·
IF 5.1
Wei-Jian Nong,Xin-Yi Tong,Jian-Ming Ouyang
Endoplasmic reticulum stress (ERS) can activate pyroptosis through CHOP and TXNIP; however, the correlation between this process and the formation of kidney stones has not been reported. The purpose is to investigate the effects of calcium oxalate monohydrate (COM) and calcium oxalate dihydrate (COD) on ERS and pyroptosis in HK-2 cells and to explore the formation mechanism of calcium oxalate stones. HK-2 cells were injured by 3 μm COM and COD. COM and COD significantly upregulated the expression levels of GRP78, CHOP, TXNIP, and pyroptosis-related proteins (NLRP3, caspase-1, GSDMD-N, and IL-1β). Fluorescence colocalization revealed that COM induced pyroptosis by inducing the interaction between TXNIP and NLRP3. Both COM and COD crystals can induce ERS and pyroptosis in HK-2 cells. COM induces the interaction with NLRP3 by the upregulation of CHOP and TXNIP and then promotes pyroptosis, while COD only promotes pyroptosis by the upregulation of CHOP. The cytotoxicity and the ability of COM to promote crystal adhesion and aggregation are higher than COD, suggesting that COM is more dangerous for calcium oxalate kidney stone formation.
研究领域:
细胞生物学
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肾脏病学
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泌尿科学
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分子生物学
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病理学
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Pharmaceuticals
·
2026
·Vol. 19
·期 8
·1261
·
IF 5.7
Yongxin Sun,Hao Tan,Jingyu Zhang,Zengyu Zhang,Shuang Huai,Manli Wang
Background:Hyperuricemia is a well-established risk factor for both chronic kidney disease and gout. Currently available urate-lowering drugs, however, are frequently compromised by hepatorenal toxicity and gastrointestinal adverse effects. Cinnamaldehyde, the principal bioactive constituent of the traditional Chinese medicine cinnamon, has documented renoprotective properties, yet its integrated effects on hyperuricemia-associated renal injury remain incompletely defined.Objectives:This study investigated the therapeutic effects of cinnamaldehyde on hyperuricemia and explored the molecular mechanisms involved.Materials and Methods:An in vivo hyperuricemia model was established in KM mice by co-administration of potassium oxonate and hypoxanthine for 14 consecutive days, and an in vitro injury model was generated by exposing HK-2 human renal tubular epithelial cells to uric acid. For the in vivo study, mice were divided into five groups (control, model, febuxostat, low-dose CA, and high-dose CA;n= 9 per group) and were treated by oral gavage. Serum biochemical indices, renal and intestinal histopathology, inflammatory cytokines, renal urate transporter proteins (OAT1, OCT2, ABCG2, and SLC2A9), and components related to AIF1 and CMPK2/NLRP3 inflammasome signaling (ASC, caspase-1, IL-18, and IL-1β) were examined. Western blotting, qPCR, immunofluorescence, apoptosis analysis, mitochondrial membrane potential assessment, transmission electron microscopy, siRNA-mediated knockdown, and 16S rRNA gene sequencing were used to characterize the relevant mechanisms.Results:CA reduced serum uric acid (p≤ 0.001 vs. model), creatinine (p≤ 0.01 vs. model), and blood urea nitrogen (p≤ 0.01 vs. model), alleviated renal and intestinal histopathological injury, and decreased circulating and renal inflammatory cytokines. Cinnamaldehyde increased ABCG2, OAT1, and OCT2 protein expression and reduced SLC2A9 expression (allp≤ 0.05 vs. model). In vivo and in vitro, cinnamaldehyde suppressed AIF1- and CMPK2/NLRP3-related inflammatory proteins, reduced uric acid-induced apoptosis, and preserved mitochondrial membrane potential and ultrastructure. Fecal 16S rRNA sequencing suggested changes in selected microbial taxa, although alpha-diversity and BrayCurtis-based PERMANOVA/ANOSIM analyses did not demonstrate significant global community separation.Conclusions:These findings suggest that CA alleviates hyperuricemia-associated renal injury by regulating renal urate transporters, attenuating AIF1- and CMPK2/NLRP3-related inflammatory signaling, accompanied by compositional shifts in selected gut microbial taxa that warrant further mechanistic investigation. The study provides experimental support for further evaluation of cinnamaldehyde as a multi-target candidate for hyperuricemia-related renal injury.
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2026
·
IF 6.7
Li Liu,Bing Zheng,Hui Ye,Jianhua Xie,Yi Chen,Xiaole Zhao,Yufei Hu,Xiaobo Hu,Qiang Yu
Abstract Although dietary fiber alleviates colonic inflammation, most studies have focused on carbohydrate components, neglecting bound polyphenols (BPs). Rice bran insoluble dietary fiber (RIDF), rich in BPs, improves colitis; however, how BPs work and their specific contributions remain elusive. Our study demonstrates that BPs are important contributors of RIDF in alleviating colitis. Relative to rice bran dietary fiber without BPs (RIDF_DF), RIDF markedly ameliorated colitis symptoms, mitigated endoplasmic reticulum stress (ER stress), restored the gut microbiome and metabolites, and blocked the PI3K/Akt/mTOR cascade and NLRP3 inflammasome activation. 3-MA abolished, whereas RAPA restored, these protective effects via the autophagy-NLRP3 axis, identifying this axis as an important hub. Collectively, BPs served as an important functional component of RIDF. They ameliorated colitis by activating the autophagy-NLRP3 axis, which suppressed ER stress, repaired the intestinal barrier, and restored the gut microbiome and metabolome.
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POULTRY SCIENCE
·
2026
·Vol. 105
·期 12
·107847
·
IF 4.5
Shunxing Liu,Yanling Xiong,Zhentao Cheng,Anchun Cheng,Rutao Lin,Hui Li,Yao Huang,Binlan Zhou,Ting Yang,Chunlan Shan
Mycoplasma gallisepticum ( MG ), a significant pathogen, causes chronic respiratory disease (CRD) in poultry, characterized by coughing, wheezing, and dyspnea. This widespread disease severely impedes the healthy development of the poultry industry. Hydroxytyrosol (HT), a plant-derived monomeric compound, possesses diverse bioactivities, including antibacterial, antioxidant, and cardiovascular protective properties. This study aimed to investigate HT's protective effect against MG -induced inflammatory damage in HD11 cells. The findings revealed that MG infection activated the TLR4/NF-κB signaling pathway and the NLRP3 inflammasome, resulting in macrophage accumulation and inflammatory damage in the lung tissue of chicks. HT mitigated MG -induced inflammatory damage in HD11 cells, inhibited the M1 phenotype shift, and reduced the secretion of pro-inflammatory factors. Molecular docking and molecular dynamics simulations demonstrated HT's stable, spontaneous binding to NLRP3. Further investigations showed that HT alleviates oxidative stress-induced cellular damage, diminishes pathological apoptosis and pore formation, and concurrently reduces NLRP3 activation by regulating the TLR4/NF-κB pathway, thereby downregulating the expression of key pyroptosis factors. In summary, HT reduces NLRP3 inflammasome activation by specifically inhibiting the TLR4/NF-κB signaling axis, consequently alleviating inflammation-induced damage, oxidative stress, and pyroptosis in HD11 cells caused by MG infection.
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JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY
·
2026
·Vol. 40
·期 8
·e71058
·
IF 3.6
Yongmei Li,Yuexin Xu,Wenjie Ye,Zeqi Yu,Zhenkun Wu,Xinyi Liu,Xuhong Huang,Jianxin Pang,Zean Zhao,Ting Wu
Hyperuricaemia (HUA) is a recognized risk factor for cardiovascular and renal diseases. Isobavachin, a dihydroflavone derivative, demonstrates significant efficacy in reducing uric acid levels. This study investigated the nephroprotective and cardioprotective effects and molecular mechanisms of isobavachin. Through integrative network pharmacology, pathway enrichment analysis, and molecular docking, NF‐κB was identified as a potential target of isobavachin in the context of hyperuricemia‐related cardiac and renal injury. Isobavachin treatment inhibited the activation of the NF‐κB pathway, leading to cytoprotection in uric acid (UA)‐stimulated mRTEC and H9C2 cells. In chronic HUA mice, isobavachin treatment significantly improved renal pathology and reduced renal collagen deposition by inhibiting epithelial‐to‐mesenchymal transition. Isobavachin administration demonstrated therapeutic efficacy in attenuating myocardial injury, hypertrophy, and fibrotic remodeling. Notably, the anti‐inflammatory effects of isobavachin were particularly evident in both renal and cardiac tissues, primarily mediated through its dual regulatory capacity in suppressing NF‐κB pathway activation and NLRP3 inflammasome formation. In conclusion, isobavachin ameliorated cardiac and renal damage caused by chronic HUA, suggesting a new strategy to prevent HUA. Isobavachin alleviates HUA‐induced oxidative stress, inflammation, and fibrosis in the kidney and heart, potentially through its dual role in promoting UA excretion and inhibiting NF‐κB signaling and NLRP3 inflammasome activation.
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Journal of Neuroinflammation
·
2026
·
IF 11.5
Hanqi Wang,Yijun Chen,Junna Chang,Zhen Liu,Yang Yu
Depression is one of the most prevalent psychiatric disorders worldwide, yet its pathogenesis remains unclear. Here, we aimed to investigate the effects of formyl peptide receptor 2 (FPR2), a key regulator of innate immunity and inflammation, on lipopolysaccharide (LPS)-induced depression-related behaviors in mice after intraperitoneal administration, and to elucidate its regulatory mechanisms in microglia. FPR2 knockout (Fpr2 -/- ) significantly attenuated LPS-induced depressive and anxiety-like behaviors in mice. LPS markedly increased FPR2 expression in microglia of the prefrontal cortex (PFC) and hippocampus, while only a minimal increase was observed in neurons. FPR2 deficiency alleviated LPS-induced microglial activation and reduced neuronal synaptic alterations. RNA sequencing and validation experiments confirmed that FPR2 deletion substantially decreased LPS-induced microglial NLRP3 inflammasome activation and IL-1β levels in the brain. Mechanistically, FPR2 regulated downstream NLRP3 activation by modulating CSF1, and FPR2/CSF1 activation was governed by its upstream ligand, serum amyloid A (SAA). Analysis of public clinical datasets revealed that SAA1 levels were significantly upregulated in the orbital ventral PFC of patients with major depressive disorder (MDD) and in the plasma of patients with late-life depression. These findings demonstrate that the SAA/FPR2/CSF1/NLRP3 pathway mediates LPS-induced depressive-like behaviors by regulating microglial activation and neuroinflammation.
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INFLAMMATION
·
2026
·Vol. 49
·期 1
·41
·
IF 5
Zheng-qing Hu,Ruijie Ma,Hang Zhang,Jiahao Miao,Jia-qing Sun,Jinlong Yuan,Jiaqiang Liu,Zihuan Zhang,Dayong Xia
This study aims to elucidate the mechanism by which Heat Shock Protein 60 (HSP60) mediates microglial pyroptosis in the context of early brain injury (EBI) following subarachnoid hemorrhage (SAH), and to investigate the effects of HSP60 inhibition on EBI after SAH. A mouse subarachnoid hemorrhage (SAH) model was established using prechiasmatic cistern blood injection. In vitro, microglia were stimulated with 25 µmol/L oxyhemoglobin (OxyHB) to simulate the SAH pathological environment. In vivo, mice received 100 mg/kg Mizoribine, while in vitro, 80 µmol/L Mizoribine was used to suppress SAH-induced HSP60 upregulation. Techniques including Western blotting, immunofluorescence, immunohistochemistry, transmission electron microscopy, ELISA, modified Garcia neurological scoring, beam walking, brain water content measurement, Morris water maze, TUNEL staining, and Nissl staining were employed to systematically investigate the role of HSP60 inhibition in neuroinflammation and microglial pyroptosis after SAH. Compared to the sham group, both in vivo and in vitro studies with blinded, random sampling of six groups demonstrated a significant increase in HSP60 expression post-SAH. In vivo, 100 mg/kg Mizoribine alleviated blood-brain barrier disruption, cerebral edema, neuronal apoptosis/necrosis, and improved neurological deficits and cognitive impairment. In vitro, 80 µmol/L Mizoribine markedly attenuated microglial activation and pyroptosis, downregulated pro-inflammatory cytokines, and mitigated neuroinflammation. The upregulation of HSP60 after SAH promotes NLRP3 inflammasome assembly by activating the TLR4/MyD88/NF-κB signaling pathway, thereby inducing microglial pyroptosis and exacerbating the progression of early brain injury. Inhibition of HSP60 represents a potential therapeutic strategy for ameliorating EBI after SAH.
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