MEDIATORS OF INFLAMMATION
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2018
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IF 3.549
Dacheng Wu,Keyan Wu,Qingtian Zhu,Weiming Xiao,Qing Shan,Zhigang Yan,Jian Wu,Bin Deng,Yan Xue,Weijuan Gong,Guotao Lu,Yanbing Ding
Formononetin is a kind of isoflavone compound and has been reported to possess anti-inflammatory properties. In this present study, we aimed to explore the protective effects of formononetin on dextran sulfate sodium- (DSS-) induced acute colitis. By intraperitoneal injection of formononetin in mice, the disease severity of colitis was attenuated in a dose-dependent manner, mainly manifesting as relieved clinical symptoms of colitis, mitigated colonic epithelial cell injury, and upregulations of colonic tight junction proteins levels (ZO-1, claudin-1, and occludin). Meanwhile, our study found that formononetin significantly prevented acute injury of colonic cells induced by TNF-α in vitro, specifically manifesting as the increased expressions of colonic tight junction proteins (ZO-1, claudin-1, and occludin). In addition, the result showed that formononetin could reduce the NLRP3 pathway protein levels (NLRP3, ASC, IL-1β) in vivo and vitro, and MCC950, the NLRP3 specific inhibitor, could alleviate the DSS-induced mice acute colitis. Furthermore, in the foundation of administrating MCC950 to inhibit activation of NLRP3 inflammasome, we failed to observe the protective effects of formononetin on acute colitis in mice. Collectively, our study for the first time confirmed the protective effects of formononetin on DSS-induced acute colitis via inhibiting the NLRP3 inflammasome pathway activation.
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DIGESTIVE DISEASES AND SCIENCES
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2025
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IF 2.5
Gao Tao,Zhang Huaisheng,Xu Yuan,He Guosong,Ma Huicong,Zheng Chuanming,Li Lei,Cheng Feng,Dou Hehe,Zhang Fulong,Zhao Heng,Qiu Zhaolei
Background Severe Acute Pancreatitis (SAP) is associated with significant intestinal injury and inflammation. Hypoxia-Inducible Factor-1α (HIF-1α) and NLRP3 inflammasome have been implicated in this process, but their specific roles remain unclear. Objective This study aims to elucidate the roles of HIF-1α and NLRP3 in the pathogenesis of SAP and their effects on intestinal injury, barrier function, and inflammatory responses. Methods A SAP rat model was established, and histological changes were assessed via HE staining. Western blot was used to analyze HIF-1α and NLRP3 expression in intestinal mucosa. The effects of HIF-1α modulation were examined using the activator DMOG and inhibitor BAY87-2243. Immunohistochemistry, ELISA, and TUNEL staining were used to evaluate intestinal barrier function, permeability markers, and apoptosis. Results HIF-1α and NLRP3 expression significantly increased in SAP rats, peaking at 72 h. HIF-1α activation aggravated intestinal injury and barrier dysfunction, decreasing tight junction protein levels and increasing epithelial apoptosis. Enhanced intestinal permeability and elevated pro-inflammatory cytokines were also observed. Furthermore, HIF-1α activation promoted NLRP3 inflammasome assembly, resulting in increased caspase-1 and IL-1β expression. Conclusion HIF-1α exacerbates intestinal injury and inflammation in SAP, likely through NLRP3 inflammasome activation. Targeting HIF-1α may offer a potential therapeutic approach for SAP-induced damage and inflammation.
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International Journal of Ophthalmology
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2025
·Vol. 18
·期 1
·39
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IF 1.8
Lin-Ping Xue,Hai-Song Feng
AIM To explore the neuroprotective effects of high mobility group box 2 ( HMGB2 ) knockdown on retinal ganglion cells (RGCs) in the retinal ischemia-reperfusion injury (RIRI). METHODS Oxygen-glucose deprivation (OGD)-injured RGCs from postnatal three-day C57BL/6 mice pups and high intraocular pressure (IOP)-induced RIRI mice were used as cellular and animal models of RIRI. The expression of HMGB2 in the retina of RIRI mice and OGD-injured RGCs was detected through reverse transcription-polymerase chain reaction (RT-qPCR) and Western blotting. The effects of HMGB2 silencing on the morphological changes, RGCs survival, and cell apoptosis in mouse retinal tissues were observed through H&E staining, immunofluorescence staining with RNA-binding protein with multiple splicing (RBPMS) antibody, and TUNEL staining, respectively. RGC viability and apoptosis were examined by CCK-8 and flow cytometry assays. The levels of proteins associated with NOD-like receptor thermal protein domain associated protein 3 (NLRP3)-mediated pyroptosis [NLRP3, Caspase-1, GSDMD-N, interleukin (IL)-1β, IL-18] in vivo and in vitro were measured by Western blotting. RESULTS HMGB2 protein and NLRP3 were upregulated in the retina of RIRI mice and OGD-injured RGCs ( P <0.001). The retina was edematous, accompanied by disorganized cell arrangement and decreased thickness of all layers, and obvious vacuoles in ganglion cell layer. HMGB2 silencing alleviated the reduction in total retinal thickness and the severity of retinal tissue damage as well as suppressed RGC loss and retinal cell apoptosis in RIRI mice. OGD-induced RGC apoptosis was ameliorated after downregulation of HMGB2 in vitro . Intravitreal injection of the AAV-sh-HMGB2 and si-HMGB2 resulted in significantly decrease of NLRP3, Caspase-1, GSDMD-N, IL-1β, and IL-18 protein levels in the retinal tissues of RIRI mice and OGD-injured RGCs, respectively (all P <0.001). CONCLUSION HMGB2 knockdown protects against RGC apoptosis and pyroptosis after RIRI through suppressing NLRP3 inflammasome activation.
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BIOMATERIALS
·
2024
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IF 12.8
Xudan Xing,Zunlei Gong,Chuke Chen,Yeyin Lin,Peiyi Liu,Tianhua Xiao,Hui Yu,Yuanxin Li,Yucong Lin,Guoxin Tan,Chengyun Ning,Zenghui Wu,Le Wang,Lei Zhou
Diabetes is associated with excessive inflammation, which negatively impacts the fracture healing process and delays bone repair. Previously, growing evidence indicated that activation of the nod-like receptor (NLR) family, such as nod-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome induces a vicious cycle of chronic low-grade inflammatory responses in diabetic fracture. Here, we describe the synthesis of a bone adhesive hydrogel that can be locally injected into the fracture site and releases a natural inhibitor of NLRP3 (rutin) in response to pathological cue reactive oxygen species activity (ROS). The hydrogel (denoted as RPO) was facilely formed by the cross-linking of rutin-functionalized gelatin, poly(vinyl alcohol), and oxidized starch based on the dynamic schiff base and boronate ester bond. Specifically, rutin is conjugated in the RPO hydrogel via a ROS linker and is released as the linker is cleaved by active ROS. In vitro studies demonstrate that RPO hydrogel effectively mitigates oxidative stress, alleviates mitochondrial dysfunction, and limits the overactivation of NLRP3 inflammasome in bone marrow derived macrophages, thereby promoting osteogenic differentiation of bone marrow mesenchymal stem cells. In a diabetic rat fracture model, RPO hydrogel significantly accelerates bone repair by modulating the inflammatory microenvironment. Our results demonstrate that local, on-demand NLRP3 inhibition for the treatment of diabetic fracture is achievable by using an injectable bioresponsive adhesive RPO hydrogel.
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MOLECULAR AND CELLULAR ENDOCRINOLOGY
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2024
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IF 3.8
Zhaoqing Xi,Ling Shu,Lingling Xiao,Xuesheng Fang,Mingyan Dai,Jing Wang,Yuan Wu,Junxia Zhang,Mingwei Bao
Obesity-associated cardiac remodeling is characterized by cardiac sympathetic nerve over-activation and pro-inflammatory macrophage infiltration. We identified norepinephrine (NE), a sympathetic neurotransmitter, as a pro-inflammatory effector to activate macrophage NLRP3 inflammasome, which contributed to cardiac inflammation. In vivo, Sprague-Dawley (SD) rats were fed a high-fat diet (HFD) for 12 weeks to establish obese rat models. Obese rats exhibited marked cardiac hypertrophy compared to the normal rats. The expression of NLRP3 and interleukin (IL)-1β was upregulated, accompanied by CD68 + NLRP3 + macrophages infiltration in hearts of the obese rats. The obese rats also showed increased sympathetic nerve activity. β-adrenergic receptor (AR) inhibition mitigated these changes. In vitro, sympathetic neurotransmitter NE significantly exacerbated palmitic acid (PA)-induced macrophage polarization toward pro-inflammatory type and NLRP3 inflammasome activation in THP-1 macrophages. It was further found that the pro-inflammatory role of NE is dependent on the activation of protein kinase A (PKA) and subsequently inhibition of β-arrestin2, which is an important regulator of nuclear factor-kappa B (NF-κB) pathway. This study identifies the neuro-immune axis as an important mediator in obesity-associated cardiac remodeling. Targeting the neuro-immune system may open therapeutic opportunities for the treatment of cardiac remodeling in obesity.
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JOURNAL OF DAIRY SCIENCE
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2025
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IF 4.4
Shuang Guan,Yuanmeng Wang,Ranran Zhang,Xinyu Yao,Shujing Lu,Xuming Deng,Jing Lu
Alcohol, one of the most widely popular and consumed beverages worldwide, often leads to acute alcoholic liver injury (AALI) when excessively consumed within a short timeframe. It can further induce alcoholic hepatitis, posing a serious risk to human health and public health safety. Pyroptosis, a typical mode of programmed cell death, is closely associated with the body's inflammatory response and plays a central role in AALI. However, the role of yogurt in acute alcohol-induced pyroptosis and inflammation is unclear. In this study, we found that yogurt and its metabolite d -lactate effectively mitigate alcohol-induced liver damage in mice, reducing hepatocyte pyroptosis and attenuating the inflammatory response. For the specific mechanism, further studies have shown that yogurt may inhibit autophagy through its substance d -lactate, leading to the accumulation of P62 protein in cells. This accumulation subsequently triggers the activation of Nrf2 through nonclassical pathways. Nrf2 translocates to the nucleus to play its antioxidant role, thereby reducing intracellular reactive oxygen species levels, inhibiting the activation of the alcohol-induced NLRP3 inflammasome, and ultimately alleviating pyroptosis and inflammation. Overall, this study reveals the potential protective effect of yogurt and its metabolite d -lactate in alleviating AALI, offering new insights and scientific basis for yogurt as a dietary strategy to improve AALI.
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TOXICOLOGY MECHANISMS AND METHODS
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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.
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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.
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TOXICOLOGY AND APPLIED PHARMACOLOGY
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2025
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IF 3.4
Xing-Jie Zhang,Peng-Yun Yang,Ling Ding,Jun Wang,Xiao-Li Li,Wei-Lie Xiao
Photodamage, a type of skin inflammation caused by excessive exposure to solar radiation, leads to skin redness, inflammation, and even the development of skin cancer, posing a severe threat to individuals living at high altitudes. UVB radiation is considered the primary factor contributing to photodamage. It stimulates macrophages within the epidermis, triggers inflammasome activation, and increases the inflammatory cytokine interleukin-1β (IL-1β) production. This study examined the protective effects of the compound isolicoflavonol (ILF) and its mechanism against UVB-induced photodamage. We irradiated UVB to create a photodamage model in mice and macrophages. Next, we assessed ILF's ability to protect the skin and cells from UVB photodamage and its inhibitory effects on UVB-mediated NLRP3 inflammasome. Our findings indicated that ILF reduced UVB-induced skin injury and inflammation in mouse skin, decreased cell death, NLRP3 inflammasome activation, ROS production, and mitochondrial dysfunction. These results suggest that ILF may be a potent agent for protecting the skin against UVB-induced photodamage.
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PHYTOMEDICINE
·
2025
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IF 8.3
Shuhui Lei,Kaiqun Liu,Cong Liu,Ran An,Zilu Bao,Huan Zhang,Min Zou,Jianqiu Chen,HuiHui Zhang,Liangkai Wei,Zhou Lan,Lvyi Chen
s Background Inflammation is a vital biological defense mechanism, yet uncontrolled or prolonged inflammation can cause tissue damage. The NLRP3 inflammasome, a central component of innate immunity, drives inflammation by activating caspase-1 and promoting the release of cytokines like IL-1β. Monosodium urate (MSU) crystals are potent NLRP3 inflammasome activators implicated in diseases such as gout. While resveratrol, a natural polyphenol, exhibits anti-inflammatory properties, the specific mechanisms by which its cis-isomer (Cis-Resv) inhibits NLRP3 inflammasome activation remain poorly understood. Purpose This study aims to investigate the inhibitory effect of Cis-Resv on MSU-induced NLRP3 inflammasome activation and elucidate the underlying molecular mechanisms. Methods Bone marrow-derived macrophages (BMDMs) from C57BL/6J mice were stimulated with MSU crystals. The effects of Cis-Resv on IL-1β secretion, caspase-1 activation, and ASC oligomerization were evaluated using ELISA, Western blot, and immunoprecipitation, respectively. Transcriptomic analysis was employed to identify potential signaling pathways involved. The in vivo efficacy of Cis-Resv was assessed in MSU-induced acute gouty arthritis and air-pouch models by measuring joint swelling, inflammatory cytokines levels, and histopathological changes. Results Cis-Resv significantly inhibited MSU-induced NLRP3 inflammasome activation in BMDMs, reducing caspase-1 activation, IL-1β secretion, andassociated pyroptosis. Furthermore, Cis-Resv impeded ASC oligomerization, a critical step in inflammasome assembly. Transcriptomic analysis and subsequent functional validation revealed that Cis-Resv exerts these effects primarily through the TRPV4-Ca²⁺-phagocytosis-ROS signaling axis. Specifically, Cis-Resv inhibited macrophage TRPV4 channel activity, leading to decreased Ca²⁺ influx, impaired MSU crystal phagocytosis, and attenuated reactive oxygen species (ROS) accumulation. This reduction in ROS modulated the ROS-TXNIP pathway, diminishing the interaction between TXNIP and NLRP3, thereby suppressing inflammasome activation. In vivo , Cis-Resv effectively alleviated MSU-induced joint swelling, lowered IL-1β and TNF-α levels, and ameliorated histopathological damage in both gouty arthritis and air-pouch models. Conclusion Cis-Resv suppresses MSU-induced NLRP3 inflammasome activation by targeting the TRPV4-Ca²⁺-phagocytosis-ROS axis. This study identifies a novel mechanism and suggests Cis-Resv as a potential therapeutic agent for NLRP3-driven inflammatory conditions like gout.
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ZOOLOGICAL RESEARCH
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2024
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IF 4
Na Zhao,Xiu Chen,Qiu-Gu Chen,Xue-Ting Liu,Fan Geng,Meng-Meng Zhu,Fu-Ling Yan,Zhi-Jun Zhang,Qing-Guo Ren
Emerging evidence indicates that sleep deprivation (SD) can lead to Alzheimer’s disease (AD)-related pathological changes and cognitive decline. However, the underlying mechanisms remain obscure. In the present study, we identified the existence of a microbiota-gut-brain axis in cognitive deficits resulting from chronic SD and revealed a potential pathway by which gut microbiota affects cognitive functioning in chronic SD. Our findings demonstrated that chronic SD in mice not only led to cognitive decline but also induced gut microbiota dysbiosis, elevated NLRP3 inflammasome expression, GSK-3β activation, autophagy dysfunction, and tau hyperphosphorylation in the hippocampus. Colonization with the “SD microbiota” replicated the pathological and behavioral abnormalities observed in chronic sleep-deprived mice. Remarkably, both the deletion of NLRP3 in NLRP3 -/- mice and specific knockdown of NLRP3 in the hippocampus restored autophagic flux, suppressed tau hyperphosphorylation, and ameliorated cognitive deficits induced by chronic SD, while GSK-3β activity was not regulated by the NLRP3 inflammasome in chronic SD. Notably, deletion of NLRP3 reversed NLRP3 inflammasome activation, autophagy deficits, and tau hyperphosphorylation induced by GSK-3β activation in primary hippocampal neurons, suggesting that GSK-3β, as a regulator of NLRP3-mediated autophagy dysfunction, plays a significant role in promoting tau hyperphosphorylation. Thus, gut microbiota dysbiosis was identified as a contributor to chronic SD-induced tau pathology via NLRP3-mediated autophagy dysfunction, ultimately leading to cognitive deficits. Overall, these findings highlight GSK-3β as a regulator of NLRP3-mediated autophagy dysfunction, playing a critical role in promoting tau hyperphosphorylation.
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INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
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IF 4.7
Ziyi Song,Yucheng Gao,Jiangkai Yu,Yang Zhang,Wenbin Xuan,Yijun Rong,Youheng Zhang,Zengxin Gao
This study investigates the role of calreticulin (CRT) in intervertebral disc degeneration (IVDD) and elucidates its underlying mechanisms. CRT expression was markedly reduced in degenerated disc tissues, implicating its involvement in IVDD pathogenesis. Both in vitro and in vivo experiments were conducted to assess the effects of CRT on nucleus pulposus cell (NPC) pyroptosis, apoptosis, and mitochondrial function. Functional analyses demonstrated that CRT overexpression alleviated disc degeneration, inhibited pyroptotic cell death, and preserved mitochondrial integrity. Mechanistically, CRT promoted the clearance of damaged mitochondria through PINK1/Parkin-mediated mitophagy, restoring mitochondrial homeostasis and suppressing ROS accumulation and NLRP3 inflammasome activation. In vivo studies using an IVDD animal model further validated these protective effects, showing reduced disc degeneration and maintenance of extracellular matrix integrity. Recent studies have demonstrated the protective effect of CRT in IVDD. This study builds on these findings and investigates a novel mechanism through which CRT mediates its protective effects in IVDD. Specifically, our study identifies the involvement of PINK1/Parkin-mediated mitophagy in CRT's ability to preserve mitochondrial function and mitigate inflammation in NPCs, offering new insights into the molecular pathways underlying CRT's protective role in IVDD.
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