METABOLIC BRAIN DISEASE
·
2025
·Vol. 40
·期 5
·1-13
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IF 3.5
Huang Ping,Sun Hao,Wang Yan,Wang Ning
Background . The post-stroke inflammatory response denotes the inflammatory damage inflicted upon brain tissue following stroke. Plasma fibrinogen (FIB) can permeate the compromised blood-brain barrier (BBB) after ischemic stroke, leading to the activation of the NLRP3 inflammasome. Tong-Qiao-Huo-Xue-Decoction (TQHXD), a traditional formula used to promote blood circulation and resolve blood stasis, has shown potential in this context. Nevertheless, the precise therapeutic mechanisms of TQHXD in mitigating cerebral ischemia-reperfusion injury remain to be fully elucidated. Objective . To examine the reparative effects and underlying mechanisms of TQHXD-CSF on inflammatory damage in BV-2 cells subjected to oxygen and glucose deprivation/reoxygenation (OGD/R) injury. Methods . To establish an in vitro model of OGD/R injury and an inflammatory BV-2 cells model induced by FIB. The protective effects of TQHXD-CSF on OGD/R-injured cells were verified using CCK-8 and LDH assays. Immunofluorescence, SEM, Western blotting, and CHIP-PCR were employed to confirm that TQHXD reduces the inflammatory response by downregulating FIB levels. Pull-down and co-immunoprecipitation (CO-IP) assays were conducted to detect the interaction between FIB and NLRP3. Results . TQHXD-CSF can significantly inhibit the abnormal increase in LDH levels induced by OGD/R, enhance cell viability, and mitigate cell pyroptosis. Additionally, TQHXD-CSF reversed the marked upregulation of FIB, NLRP3, and GSDMD fluorescence intensity and protein expression caused by the FIB inflammation model, demonstrating an effect comparable to that of lumbrokinase, a fibrinolytic agent for FIB. Furthermore, it notably reduced the acetylation of H3 and H4 in the NLRP3 promoter. Importantly, the pull-down and CO-IP results indicated a robust binding affinity between FIB and NLRP3. Conclusion . TQHXD-CSF can inhibit inflammation by downregulating the FIB-NLRP3 pathway and exert a protective effect on BV-2 cells under OGD/R and FIB inflammatory injury. Graphical abstract
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2019
·
IF 3.361
Runxiao Lv,Lili Du,Xueyong Liu,Fenghua Zhou,Zhiqiang Zhang,Lixin Zhang
Polydatin is a glucoside of resveratrol with lots of functional properties in the central nervous system , such as anti-edema, anti-oxidation and anti-inflammation. The purpose of this study was to evaluate the effects of polydatin on traumatic spinal cord injury (SCI) and explore the relative mechanisms. SCI models were established using the weight-drop method in rats, additionally, single polydatin administration (20, 40 mg/kg body weight) remarkably improved motor function of SCI rat, along with decreased nitric oxide (NO) generation and inflammatory factor (IL-1β, IL-6 and TNF-α) production in spinal cord tissues. Similar to the results of in vivo experiments, the inflammatory response was aggravated with the intervention of lipopolysaccharide (LPS) in BV2 microglia . However, polydatin treatment (1, 2 and 4 μM) inhibited iNOS expression, decreased NLRP3 inflammasome activation, which subsequently relieved microglial inflammation. Above all, our data indicated that polydatin possessed neuroprotective effects in SCI rats, possibly by suppressing iNOS expression and NLRP3 inflammasome activation in microglia.
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Aging-US
·
2019
·
IF 5.515
Shi Zilu,Huang Qian,Wu Haibin,Ge Chenxu,Lou Deshuai,Li Qiang,Hu Linfeng,Tan Jun,Xu Minxuan
Increasing evidence indicates that prolonged fat-rich diet (HFD) ingestion is a predisposing factor for metabolic disorder-associated system inflammation and oxidative stress injury, which contributes to the occurrence of non-alcoholic fatty liver disease (NAFLD). NACHT, LRR and PYD domains-containing protein 3 (NLRP3)-mediated inflammatory infiltration was determined to participate in NAFLD. X-linked inhibitor of apoptosis protein (XIAP) was recently confirmed as an essential regulator for apoptosis in cells. However, the role of XIAP in HFD-induced NAFLD is still not understood. Here, XIAP was characterized with respect to HFD-induced NLRP3 inflammasome activation and reactive oxygen species (ROS) generation in vivo and palmitate (PA)-treated cells in vitro . After HFD administration, hepatic injury was confirmed via histological assessment (grading and staging of NAFLD) and biochemical parameters, oxidative stress, and reduced antioxidant activity. Up-regulated hepatic dysfunction were further indicated by elevated dyslipidemia, lipid accumulation, and decreased fatty acid β-oxidation associated gene expression. Moreover, in the absence of XIAP, NLRP3 signaling activated by HFD-triggered oxidative stress was up-regulated, accompanied by reduction in antioxidants including HO-1, NQO-1, GST, SOD and Nrf2 activity. The detrimental effects of XIAP blocking on hepatic steatosis and related pathologies were also confirmed in PA-treated mouse liver cells. In contrast, overexpression of XIAP by transfection in vitro restrained PA-stimulated hepatic steatosis by suppression of oxidative stress, NLRP3 related inflammatory response, and impairment of Nrf2 activity, further alleviating abnormal metabolic disorder associated NAFLD. Taken together, the present study helped to elucidate how HFD-induced hepatic steatosis was regulated by XIAP, possibly via the inhibition of NLRP3 signaling and oxidative stress injury.
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Biochemistry and Cell Biology
·
2021
·Vol. 99
·期 5
·
IF 3.626
Xin Wang,Yu Hu,Yaguang Wang,Dapeng Shen,Guizhou Tao
Increasing evidence has shown that the NOD-like receptor protein 3 (NLRP3) inflammasome and pyroptotic cell death play vital roles in the pathophysiology of myocardial infarction (MI), a common cardiovascular disease characterized by cardiac dysfunction. C-type lectin member 5A (CLEC5A) has been reported to be strongly associated with activation of the NLRP3 inflammasome and pyroptosis. In this study, an in vivo MI model was established by ligation of the left anterior descending coronary artery in male C57BL/6 mice, and CLEC5A knockdown was further achieved by intra-myocardial injection of adenovirus delivering shRNA-CLEC5A. CLEC5A was found to be highly expressed in the left ventricle of MI mice, while CLEC5A knockdown alleviated cardiac dysfunction in MI mice. In addition, MI-induced classical activation of macrophages was significantly inhibited after CLEC5A silencing. Additionally, CLEC5A knockdown dramatically inhibited MI-triggered activation of NLRP3 inflammasome, pyroptosis, and NF-κB signaling in the left ventricle of mice. In vitro experiments further validated that CLEC5A knockdown suppressed M1 polarization in LPS/IFNγ-stimulated RAW264.7 cells and inhibited the polarized RAW264.7-induced activation of NLRP3 inflammasome/pyroptosis signaling in co-cultured cardiomyocytes. In conclusion, CLEC5A knockdown protects against MI-induced cardiac dysfunction by regulating macrophage polarization, NLRP3 inflammasome, and cell pyroptosis.
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Frontiers in Pharmacology
·
2022
·
IF 5.988
Chenxi Wu,Fenfen Li,Xiaoxi Zhang,Wenjing Xu,Yan Wang,Yanjing Yao,Ziwei Han,Daozong Xia
Background: Gouty arthritis is a common and complex inflammatory disease that will reduce the life quality of human beings (−)-Epicatechin (EC) is famous for antioxidant and anti-inflammatory activities. Thus, the aim of this study was to investigate the therapeutic effect of EC on gouty arthritis and its mechanisms. Methods and results: EC was added into a monosodium urate (MSU)-stimulated THP-1 cell that was induced by phorbol 12-myristate 13-acetate and lipopolysaccharide (LPS) in advance to establish a gout model in vitro . The efficiency of EC on acute gouty arthritis mice induced by MSU was further investigated. The results showed that EC concentration-dependently improved the cell viability of LPS and MSU stimulated THP-1 cells, and significantly alleviated MSU-induced ankle edema in mice in a dose-dependent manner. In addition, EC inhibited the infiltration of inflammatory cells and local cascular congestion in ankle joint tissue. Furthermore, the secretion of inflammatory cytokines (IL-1β, IL-18, IL-6, and TNF-α) activation of NLRP3 inflammasome and NF-κB signaling pathway were markedly suppressed by EC in vitro and in vivo . Conclusion: These results indicated that EC could effectively improve MSU-induced acute gouty arthritis via inhibiting NLRP3 inflammasome and the NF-κB signaling pathway in vitro and in vivo , which suggested that EC might be a promising active ingredient for the prevention and treatment of gouty arthritis.
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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2026
·Vol. 27
·期 20
·9297
·
IF 5.6
Yuqing Jiang,Weili Hu,Lingxiao Yi,Minal Thacker,Qiyun Wu,Yuan Li,En Gao,Jingfang Bian,Chi Wai Do,Liping Zhou
Given the escalating global prevalence of dry eye disease (DED) and the inadequacy of current palliative management, this study was to evaluate thetherapeutic potential of recombinant lysozyme (rlysozyme) and investigate underlying mechanisms. Human corneal epithelial cells (HCEC) were subjected to hyperosmotic stress and treated with graded rlysozyme. Cell viability, wound healing, barrier integrity, oxidative stress, cytokines, and mitochondrial function were evaluated by MTS and scratch assays, immunofluorescent staining, ELISA, qRT-PCR, and flow cytometry. Results: No cytotoxicity was observed at any of the tested concentrations (2.76 × 10−9–2.76 × 10−4M) in HCEC. In hyperosmolarity-induced DED cells, rlysozyme at the highest concentrations (2.76 × 10−4M) significantly increased cell viability by 12.30% (p< 0.001) and promoted corneal repair by 45.04% (p< 0.05), which were comparable to those of 0.4% hyaluronic acid (the positive control). It also improved via restoring ZO-1 organization. Mechanistically, qRT-PCR results revealed that rlysozyme reduced mRNA expression of IL-1β (by 28.7%), TNF (by 39.2%) and key NLRP3 inflammasome components, including NLRP3 (by 62.0%) and PYD and CARD domain-containing protein gene(PYCARD, 21.4%), while caspase-1 (CASP1) and IL-6 expression remained unchanged. Moreover, oxidative stress was attenuated, as evidenced by significant decreases in reactive oxygen species (ROS, by 59.1%), 8-hydroxy-2-deoxyguanosine levels (8-OHdG, by 23.6%) and total matrix metalloproteinase-9 (MMP-9, by 64.3%) protein levels (p< 0.001), while mitochondrial membrane potential was assessed qualitatively. In conclusion, this study demonstrates thatrlysozyme effectively enhanced corneal epithelial cell viability, promoted wound healing, and restored ZO-1 structural organization without inducing cytotoxicity. These protective effects were associated with downregulation of NLRP3 inflammasome-related genes and attenuation of oxidative stress, supporting further investigation of its therapeutic potential in DED.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2022
·
IF 5.714
Airu Huang,Ling Ji,Yilong Huang,Qian Yu,Yufeng Li
MicroRNAs (miRNAs) are important modulators in the evolvement and progression of neuropathic pain (NP). According to reports, miR-185-5p contributes to various diseases and inflammatory responses. However, it is not clear whether miR-185-5p mediates neuroinflammation and NP following chronic constrictive injury (CCI). The CCI model was constructed in rats to induce NP. Paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were employed to evaluate pain threshold in CCI rats. The expression of miR-185-5p, GFAP, Iba1, Caspase-3-positive cells, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL)-labeled apoptotic neurons, inflammatory mediators, including interleukin (IL)-6, IL-1β and tumor necrosis factor-α (TNF-α) in lumbar portion (L4-L6) of CCI rats were determined. Furthermore, the targets of miR-185-5p were predicted by the Starbase, and the binding association between miR-185-5p and MyD88, miR-185-5p and CXCR4 was verified by the dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. As shown by the data, miR-185-5p was distinctly reduced in L4-L6 spinal cord tissues of rats after CCI. Up-regulating miR-185-5p alleviated mechanical and thermal hyperalgesia, inactivated microglia and astrocytes accumulation, and abated the contents of IL-1β, IL-6 and TNF-α in L4-L6 spinal cord tissues of CCI rats. Bioinformatics analysis suggested that MyD88 and CXCR4 were potential target genes of miR-185-5p. Increasing miR-185-5p expression notably impeded the expression of MyD88, CXCR4 and NLRP3 inflammasome in BV2 microglia, while attenuating miR-185-5p expression exerted the opposite effects. Notably, down-regulating MyD88 and CXCR4 significantly enhanced the miR-185-5p-mediated anti-inflammatory effects, and reversed miR-185-5p inhibitor-mediated proinflammatory effects. Additionally, up-regulating miR-185-5p repressed BV2-induced neuronal apoptosis and increased neuronal viability. In conclusion, this study suggested that miR-185-5p chokes CCI-induced NP and neuroinflammation by targeting MyD88 and CXCR4, indicating that miR-186-5p is an underlying therapeutic target for NP.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2026
·
IF 5.6
Yu Zhang,Yue Zhang,Qin Xiang,Xiangxiang Fu,Yongli Zhang,Liming Tan,Huaiying Tang,Siqi Li,Dong Gong,Xu Guo,Yonghong Zhang,Qibin Wang,Li Chen,Tao Zheng
Type 2 diabetes mellitus (T2DM) and prostate cancer are closely linked, affecting overlapping age groups of predominantly male populations. Flutamide (FLU) is metabolized in the liver to hydroxyflutamide (OHF), exerting anti-androgenic effects and is mainly used for prostate cancer treatment. During its use, occasional adverse reactions such as elevated blood glucose and worsening conditions in T2DM patients have been observed, but the cause remains unknown. This study aims to investigate the effects and mechanisms of FLU on hepatic insulin resistance under T2DM conditions. In vitro , a primary mouse hepatocyte model of insulin sensitivity impairment induced by high glucose (HG) was established to observe the effects of FLU/OHF on cellular lipid accumulation, reactive oxygen species (ROS) production, NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) signaling, and insulin signaling. NLRP3 inhibitors, ROS scavengers, and hepatocytes from Nlrp3 -knockout mice were used to explore the mechanisms of FLU. In vivo , a high-fat diet (HFD)/streptozotocin (STZ) induced-T2DM mouse model was established to observe the effects of FLU gavage on glucose and lipid metabolism, insulin sensitivity, and histopathology. The results showed that FLU exposure exacerbated lipid accumulation, ROS production, over-activation of NLRP3 signaling, and impaired insulin signaling in HG-treated hepatocytes. Inhibition of NLRP3, scavenging of ROS, or knockout of Nlrp3 eliminated the above effects of FLU/OHF. FLU exacerbated glucose and lipid metabolism disorders in HFD/STZ induced-T2DM mice, increased hepatic insulin resistance, and activated the hepatic NLRP3 signaling pathway. The results of this study suggest that FLU treatment is associated with exacerbated hepatic insulin resistance in mice with T2DM, an effect that may be mediated through ROS overproduction and activation of NLRP3 signaling.
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CHEMICAL ENGINEERING JOURNAL
·
2026
·
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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BIOCHEMICAL PHARMACOLOGY
·
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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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2026
·
IF 8.7
Chunyu Wang,Yixin Zheng,Qingwen Cui,Yuxin Jiang,Jinhe Wang,Tianyu Zhang,Yuxin Song,Xiao Guo,Manli Wang,Liping An
Portulaca oleracea acidic polysaccharide (POPW-A) demonstrates significant efficacy in anti-inflammatory and immune-enhancing properties. Intervention with POPW-A reduced blood uric acid levels and significantly up-regulated uric acid transporter expression in hyperuricemic (HUA) model mice. Additionally, it suppressed the activation of the NLRP3 inflammasome by down-regulating AIF-1 and CMPK2 protein expression, thereby alleviating renal inflammation. The polysaccharide components of POPW-A were screened after purifying. Among them, the POPW-Ab component effectively enhanced the expression of uric acid transport proteins and suppressed the activation of the NLRP3 inflammasome. Structural analysis confirmed that POPW-Ab is a pectin polysaccharide composed primarily of a homogalacturonan (HG) domain with a backbone of →4)-α-D-GalpA-(1→, along with a minor rhamnogalacturonan-I (RG-I) domain containing side chains of →5)-α-L-Araf-(1→. After silencing the CMPK2 gene in model cells, the protective effects of POPW-Ab were counteracted. Conversely, overexpression of the CMPK2 gene restored the intervention efficacy of POPW-Ab. Therefore, POPW-Ab is likely the fundamental material basis for the bioactivity of Portulaca oleracea polysaccharides. The underlying mechanism involves targeted down-regulation of CMPK2 gene expression, thereby inhibiting NLRP3 inflammasome activation and subsequent release of pro-inflammatory cytokines. These findings suggest that POPW-Ab holds promise as a potential therapeutic agent for HUA and its associated renal complications.
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JOURNAL OF ETHNOPHARMACOLOGY
·
2026
·
IF 6.8
Qianqian Du,Zhimei Chen,Xian Ma,Yayu Zhang,Yongqiang Fan
Ethnopharmacological relevance Notoginsenoside R1 (NGR1), a primary bioactive constituent of P. notoginseng , has potent anti-inflammatory and immunomodulatory functions, but its role and mechanism in UC remain incompletely understood and warrant further exploration. The global prevalence of ulcerative colitis (UC) is rising steadily, threatening human health. Despite advances in modern therapies, UC treatments remain limited. Aim of the study This work investigated whether NGR1 alleviates DSS-induced colitis by inhibiting the PGAM5-NEK7 interaction and NLRP3 inflammasome activation in macrophages, providing new mechanistic insights and therapeutic targets for UC. Materials and methods UC model was established via 3% DSS administration to assess the protective efficacy of NGR1. Disease activity index (DAI), body weight and colon length were determined to assess disease severity and intestinal injury. HE staining, ELISA and immunofluorescence assays were employed to assess pathological changes in the colon and liver. Macrophages were depleted via tail vein injection of clodronate liposomes. RT-qPCR, ELISA, immunofluorescence and WB were performed to quantify macrophage markers, pro-inflammatory genes and NLRP3 inflammasome-related proteins. In vitro , LPS/ATP-stimulated bone marrow-derived macrophages (BMDMs) demonstrated that NGR1 exerts a potent inhibitory effect on NLRP3 inflammasome activation. After cell treatment, CCK-8, ELISA, RT-qPCR, and WB assays were performed to detect cell viability, inflammatory cytokine levels, and the expression of related genes and proteins. Meanwhile, molecular docking was utilized to verify the interactions among PGAM5, NEK7 and NLRP3. Co-IP in 293T cells overexpressing PGAM5, NEK7 and NLRP3 further verified their interplay. Results Compared with the Model group, NGR1 intervention markedly reduced the DAI scores, ameliorated body weight loss and colon shortening, alleviated colonic and hepatic pathological damage, upregulated the expression of intestinal barrier tight junction proteins (ZO-1, Occludin and Claudin-1), and decreased LPS levels and the release of TNF-α, IL-1β and IL-6 in serum and tissues. Macrophage depletion was observed to markedly abolish protective effects of NGR1, and reduced PGAM5, NEK7, NLRP3, Caspase-1, C-Caspase-1 levels. In vitro , NGR1 inhibited inflammatory factor secretion and NLRP3 inflammasome activation in LPS/ATP-stimulated BMDMs, these effects were partially blocked after PGAM5 or NEK7 gene silencing. Co-IP assays confirmed endogenous interactions between PGAM5, NEK7 and NLRP3. And the molecular docking showed NGR1 could bind to PGAM5, and NGR1 intervention significantly suppressed the expression of the ternary complex formed by the three proteins. Conclusion This study revealed that NGR1 disrupted the PGAM5-NEK7 interaction, restrained NLRP3 inflammasome assembly in macrophages, and relieved colonic damage triggered by DSS, providing a novel target for UC treatment.
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