PHYTOMEDICINE
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2024
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IF 6.7
Lin Li,Shuai Xu,Wenyu Wang,Xia Li,Haotian Wang,Qi Yang,Changyuan Wang,Jiangning Gu,Haifeng Luo,Qiang Meng
Background Alcoholic liver disease (ALD), a public health challenge worldwide caused by long-term persistent drinking, is life-threatening with minimal approved therapies. Hepatic steatosis accompanied by inflammation is an initial and inevitable stage in the complex progression of simple alcoholic liver injury to more severe liver diseases such as hepatitis, liver fibrosis, cirrhosis and liver cancer. Purpose We aimed to identify the therapeutic role of Bruceine A (BA) in ALD whilst attempting to explore whether its protective effects depend specifically on the farnesoid X receptor (FXR). Methods Autodock was applied to detect the affinity between BA and FXR. Lieber-DeCarli liquid diet with 5% ethanol (v/v) was adopted to establish the mouse ALD model. The lentivirus mediating FXR (LV-FXR) was injected into mice via the tail vein to establish FXR-overexpressed mice. FXR silencing or overexpression plasmids were transfected into AML-12 cells prior to ethanol stimulation. Quantitative real-time PCR, Western blotting and immunofluorescence assays were employed to determine the expression of related genes. We subjected liver sections to H&E and Oil Red O staining to evaluate the liver histological injury and the deposition of lipid droplets. Results BA significantly reduced body weight and liver-to-body weight ratios as well as biochemical indexes in mice. Ethanol-induced liver damage and lipid accumulation could be alleviated by BA treatment. BA bound to FXR by two hydrogen bonds. There was a positive correlation between BA administration and FXR expression. BA inhibited the expression of lipid synthesis genes and enhanced the expression of lipid metabolism genes by activating FXR, thus alleviating steatosis in ALD. Moreover, BA exerted an ameliorative effect against inflammation by inhibiting the activation of absent in melanoma 2 (AIM2) inflammasome by activating FXR. FXR overexpression possessed the ability to counter the accumulation of lipid and the activation of AIM2 inflammasome caused by ethanol. FXR deficiency exacerbated ethanol-induced liver steatosis and inflammation. The hepatoprotective effect of BA could be disrupted by FXR antagonist guggulsterone (GS) in vivo and FXR siRNA in vitro . Conclusion BA alleviated alcoholic liver disease by inhibiting AIM2 inflammasome activation through an FXR-dependent mechanism. This study may potentially represent a new therapeutic approach for ALD.
研究领域:
药理学
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肝病学
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分子生物学
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免疫学
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PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2025
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IF 5.4
Wushi Chen,Yunqin Shen,Hongyun Jia,Shanshan Hou,Lingjie Li,Lixia Huang,Jiyi Cai,Yuhan Xing,Yanqiu Chen,Yan Yang
Ethnopharmacological relevance Humulus lupulus L. , an herb traditionally employed in medicinal practices across North America, Egypt, India, and China, demonstrates broad therapeutic properties, including anti-inflammatory, antioxidant, hepatoprotective, and diuretic effects. Xanthohumol (XN), a prenylated flavonoid derived from Humulus lupulus L., retains these anti-inflammatory and antioxidant activities. However, its potential efficacy in allergic asthma remains largely unexplored. Aim of the study This study aimed to investigate the protective properties of XN against allergic asthma and to elucidate the underlying mechanisms, particularly the role of Absent in Melanoma 2 (AIM2), an innate immune sensor, in allergic asthma and its modulation by XN. Materials and methods The OVA-induced murine model of allergic asthma with XN administration in different dosages was constructed to evaluate the regulatory effects of XN on allergic asthma, particularly during the period of acute attack. Pathological alterations, T-cell polarization, inflammatory cytokine profiles, and oxidative stress markers were systematically assessed. Bioinformatic analysis, clinical case-control, and molecular docking combined with cellular thermal shift assay (CETSA) were applied to identify the specific target of XN to execute its effects. Human bronchial epithelial (16HBE) cell models with various stimulations and treatments were used in this study to verify the mechanistic exploration. Results In allergic asthmatic mice, the results demonstrated that XN dose-dependently attenuated airway inflammation and immune balance, characterized by reduced inflammatory cell infiltration, cytokine production, IgE secretion, and Th2 immune response. AIM2 was recognized as a critical binding target of xanthohumol through database analysis, molecular docking, and CETSA. Clinically, elevated serum AIM2 levels in asthma patients correlated positively with eosinophil percentage, IgE levels, and systemic immune inflammation index (SII). Mechanistically, both in vivo and in vitro studies revealed that XN mitigated oxidative stress and mitochondrial dysfunction, thereby reducing double-stranded DNA release, a key activator of the AIM2 inflammasome. Moreover, XN dose-dependently suppressed AIM2 inflammasome activation, an effect further validated in Poly (dA:dT)-stimulated and AIM2-silenced 16HBE cells. Conclusion This study provides the first evidence implicating XN can improve OVA-induced allergic asthma by suppressing AIM2 inflammasome activation, highlighting XN as a promising therapeutic candidate for allergic asthma.
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Hepatology International
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2024
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IF 5.9
Li Lin,Kong Lina,Xu Shuai,Wang Changyuan,Gu Jiangning,Luo Haifeng,Meng Qiang
Background and purpose Alcoholic liver disease (ALD), a metabolic liver disease caused by excessive alcohol consumption, has attracted increasing attention due to its high prevalence and mortality. Up to date, there is no effective and feasible treatment method for ALD. This study was to investigate whether Farnesoid X receptor (FXR, NR1H4) can alleviate ALD and whether this effect is mediated by inhibiting absent in melanoma 2 (AIM2) inflammasome activation. Methods The difference in FXR expression between normal subjects and ALD patients was analyzed using the Gene Expression Omnibus (GEO) database. Lieber–DeCarli liquid diet with 5% ethanol (v/v) (EtOH) was adopted to establish the mouse ALD model. Liver histopathological changes and the accumulation of lipid droplets were assessed by H&E and Oil Red O staining. Quantitative real-time PCR, Western blotting analysis and immunofluorescence staining were utilized to evaluate the expression levels of related genes and proteins. DCFH–DA staining was adopted to visualize reactive oxidative species (ROS). Results FXR was distinctly downregulated in liver tissues of patients with steatosis compared to normal livers using the GEO database, and in ethanol-induced AML-12 cellular steatosis model. FXR overexpression ameliorated hepatic lipid metabolism disorder and steatosis induced by ethanol by inhibiting the expression of genes involved in lipid synthesis and inducing the expression of genes responsible for lipid metabolism. Besides, FXR overexpression inhibited ethanol-induced AIM2 inflammasome activation and alleviated oxidative stress and ROS production during ethanol-induced hepatic steatosis. However, when FXR was knocked down, the results were completely opposite. Conclusions FXR attenuated lipid metabolism disorders and lipid degeneration in alcohol-caused liver injury and alleviated oxidative stress and inflammation by inhibiting AIM2 inflammasome activation. Graphical abstract
研究领域:
肝病学
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分子生物学
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炎症
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代谢紊乱
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高影响因子
Frontiers in Pharmacology
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2022
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IF 5.988
Chuyu Shen,Meilin Xu,Siqi Xu,Shuoyang Zhang,Wei Lin,Hao Li,Shan Zeng,Qian Qiu,Liuqin Liang,Youjun Xiao,Hanshi Xu
Objective: To explore the effect and underlying mechanism of Myricitrin (Myr) in regulating fibroblast-like synoviocyte (FLS)-mediated synovitis and joint destruction in RA. Methods: FLSs were isolated from synovial tissues from patients with RA. Gene expression was measured using quantitative RT-qPCR. Protein expression was detected by immunohistochemistry or Western blot. Cell apoptosis was performed by an Annexin-PI staining assay. EdU incorporation was used to assess the proliferation of RA FLS. Transwell assay was used to characterize the cell migration and invasion ability of RA FLS. The potential target of Myr was identified by RNA sequencing analysis. The in vivo effect of Myr was assessed in a collagen-induced arthritis (CIA) model. Results: Myr treatment inhibited the lamellipodia formation, migration, and invasion, but not the apoptosis and proliferation, of RA FLSs. Myr also reduced the expression of CCL2, IL-6, IL-8, MMP-1, MMP-3, and MMP-13 induced by TNF-α. The RNA-seq results indicated that AIM2 may be a target gene of Myr in RA FLSs. Furthermore, compared to healthy controls, AIM2 expression showed higher levels in synovial tissues and FLSs from RA patients. AIM2 knockdown also inhibited RA FLS migration, invasion, cytokine, and MMP expression. In addition, either Myr treatment or AIM2 knockdown reduced the phosphorylation of AKT induced by TNF-α stimulation. Importantly, Myr administration relieved arthritis symptoms and inhibited AIM2 expression in the synovium of CIA mice. Conclusion: Our results indicate that Myr exerts an anti-inflammatory and anti-invasion effect in RA FLSs and provide evidence of the therapeutic potential of Myr for RA.
研究领域:
风湿病学
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免疫学
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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
JOURNAL OF ETHNOPHARMACOLOGY
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2024
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IF 4.8
Liangliang Kong,Yan Liu,Jingwei Li,Yanyan Wang,Pengmin Ji,Qifeng Shi,Min Han,Hanyang Xu,Weiping Li,Weizu Li
Ethnopharmacological relevance Ginseng is a valuable herb in traditional Chinese medicine. Modern research has shown that it has various benefits, including tonifying vital energy, nourishing and strengthening the body, calming the mind, improving cognitive function, regulating fluids, and returning blood pressure, etc. Rg1 is a primary active component of ginseng. It protects hippocampal neurons, improves synaptic plasticity, enhances cognitive function, and boosts immunity. Furthermore, it exhibits anti-aging and anti-fatigue properties and holds great potential for preventing and managing neurodegenerative diseases (NDDs). Aim of the study The objective of this study was to examine the role of Rg1 in treating chronic inflammatory NDDs and its molecular mechanisms. Materials and methods In vivo , we investigated the protective effects of Rg1 against chronic neuroinflammation and cognitive deficits in mice induced by 200 μg/kg lipopolysaccharide (LPS) for 21 days using behavioral tests, pathological sections, Western blot, qPCR and immunostaining. In vitro experiments involved the stimulation of HT22 cells with 10 μg/ml of LPS, verification of the therapeutic effect of Rg1, and elucidation of its potential mechanism of action using H2DCFDA staining, BODIPY™ 581/591 C11, JC-1 staining, Western blot, and immunostaining. Results Firstly, it was found that Rg1 significantly improved chronic LPS-induced behavioral and cognitive dysfunction in mice. Further studies showed that Rg1 significantly attenuated LPS-induced neuronal damage by reducing levels of IL-6, IL-1β and ROS, and inhibiting AIM2 inflammasome. Furthermore, chronic LPS exposure induced the onset of neuronal ferroptosis by increasing the lipid peroxidation product MDA and regulating the ferroptosis-associated proteins Gpx4, xCT, FSP1, DMT1 and TfR, which were reversed by Rg1 treatment. Additionally, Rg1 was found to activate Nrf2 and its downstream antioxidant enzymes, such as HO1 and NQO1, both in vivo and in vitro . In vitro studies also showed that the Nrf2 inhibitor ML385 could inhibit the anti-inflammatory, antioxidant, and anti-ferroptosis effects of Rg1. Conclusions This study demonstrated that Rg1 administration ameliorated chronic LPS-induced cognitive deficits and neuronal ferroptosis in mice by inhibiting neuroinflammation and oxidative stress. The underlying mechanisms may be related to the inhibition of AIM2 inflammasome and activation of Nrf2 signaling. These findings provide valuable insights into the treatment of chronic neuroinflammation and associated NDDs.
研究领域:
神经药理学
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药理学
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神经科学
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免疫学
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分子生物学
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PubMed
高影响因子
Cell Communication and Signaling
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2024
·Vol. 22
·期 1
·1-17
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IF 8.2
Zhang Yu,Wu Rong,Zhan Xi,Wang Xuan-Yi,Xiang Lin-Wei,Duan Ya-Qian,You Yan,Zhang Jian-Bo,Wu Rui,Zhang Yun-Yuan,Duan Liang
Background Absent in melanoma 2 (AIM2) inflammasome-dependent pyroptosis and neutrophil extracellular traps (NETs) have been implicated in chronic liver disease (CLD). However, the specific intrahepatic cell type that undergoes AIM2 inflammasome-dependent pyroptosis and how their interaction augments hepatic inflammation/fibrosis remains unclear.Methods The expression and correlation of AIM2 inflammasome-dependent pyroptosis-related indicators and NETs were analyzed in biopsy tissue and blood specimens from chronic hepatitis patients (CHs). Cell-based experiments were conducted to investigate their interaction. In vitro and in vivo experiments were used to analyze their effects on the progression of hepatic inflammation/fibrosis as well as their clinical importance.Results Elevated levels of AIM2 inflammasome-dependent pyroptosis indicators and NETs were detected in biopsy tissue and blood specimens. Circulating NETs were positively correlated with pyroptosis-related indicators, and both were related with disease severity. Confocal imaging revealed that AIM2 was mainly localized to hepatic macrophages, indicating that hepatic macrophages were the major cell type that underwent pyroptosis. NETs were directly engulfed by macrophages and then stimulated AIM2 inflammasome-dependent macrophage pyroptosis in vitro, which amplified the activation of hepatic stellate cells (HSCs) and increased collagen deposition. Administration of the NETs degradation agent DNase I or the AIM2 inflammasome activation inhibitor ODN A151 effectively alleviated chronic liver inflammation/fibrosis progression in vivo.Conclusion sNETs-induced AIM2 inflammasome-dependent pyroptosis in macrophages facilitates liver inflammation/fibrosis progression. The identified NET–AIM2 inflammasome cascade could serve as a novel therapeutic target for hepatic inflammation/fibrosis progression.
研究领域:
免疫学
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肝病学
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细胞生物学
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分子生物学
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PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
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2025
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IF 7.7
Hui Ma,Yue Chen,Yi-Mo Zhang,Yue Zhang,Xiao-Juan Hou,Hai-Long Li,Yi-Xin Yang,Qian Long,Xin Qiao,Yun-Feng Li
Background and Purpose Ischaemic stroke is one of the most critical causes of death and disability worldwide, but its pharmacotherapies are currently lacking. This study aimed to investigate the effects of the sigma non-opioid intracellular receptor 1 agonist hypidone hydrochloride (YL-0919) on ischaemic stroke as well as the underlying mechanisms. Experimental Approach Male mice were subjected to a middle cerebral artery occlusion (MCAO)/reperfusion (R) model to mimic ischaemic stroke injury. Neurological and cognitive functions were evaluated, and neuroinflammatory pathways in the medial prefrontal cortex and hippocampus were detected. Key Results Mice subjected to MCAO exhibited obvious neurological and motor deficits, increased infarct volume and neuronal death in the acute phase, and severe cognitive impairment in the chronic phase. Administration of YL-0919 for seven consecutive days beginning within 7 h after MCAO significantly ameliorated the pathological changes described above. Further studies demonstrated that YL-0919 exerted its effect by suppressing absent in melanoma 2 (AIM2)-related inflammatory signals in MCAO mice and alleviated the neuronal deficits in the medial prefrontal cortex and hippocampus, thereby ameliorating chronic post-stroke cognitive impairment. This effect was eliminated by AIM2 overexpression in the medial prefrontal cortex and hippocampus. Conclusions and Implications This study highlights the extended therapeutic window for sigma non-opioid intracellular receptor 1 agonist administration during the acute phase of ischaemic stroke and further demonstrates that targeted inhibition of AIM2-mediated neuroinflammatory pathways may promote sustained cognitive rehabilitation in post-stroke survivors. Graphical
研究领域:
神经药理学
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卒中研究
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炎症生物学
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认知神经科学
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药物研发
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高影响因子
Journal of the American Heart Association
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2026
·Vol. 15
·期 3
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IF 5.3
Zhu‐chen Zhou,Meng‐ting Liu,Yi‐jia Fangma,Bing‐jie Wan,Jing Zhou,Xiao‐lan Zhang,Yu‐ting Yan,Shu‐hui Deng,Yan Zhang,Yuan‐jie Zhang,Wen‐lu Li,Zhong Chen,Yan‐rong Zheng
BackgroundInflammasome hyperactivation drives neuroinflammation following cerebral ischemia, yet pharmacological strategies inducing their selective clearance remain largely unexplored. Selective autophagy holds particular promise as a therapeutic strategy by eliminating detrimental substrates while avoiding the side effects of excessive autophagy. However, few compounds are currently available to achieve this selective regulation.MethodsTransient middle cerebral artery occlusion was used to screen the active compounds from Fritillaria, combined with TTC staining and neurological scores. Postischemic apoptosis, inflammation, and autophagy were evaluated via immunofluorescence and immunoblotting. RNA sequencing of the ischemic penumbra revealed transcriptomic changes. Cell‐specific effects were confirmed using cell coculture and glial‐deficient transgenic mice. Compound‐inflammasome interactions were studied by biolayer interferometry and molecular dynamics.ResultsPeiminine demonstrates robust neuroprotection after cerebral ischemia. RNA sequencing and immunoblotting analyses revealed that peiminine markedly suppresses postischemic inflammation. Correspondingly, peiminine exerts its neuroprotective effect primarily through actions on microglia but not astrocytes, indicated by neuron–glia cocultures and transgenic mice models with targeted cell‐type depletion. Biolayer interferometry and molecular dynamics simulations indicated that peiminine selectively binds to AIM2, showing no interaction with NLRP1 (NLR family pyrin domain containing 1) and approximately 100‐fold higher affinity compared with NLRP3. Notably, peiminine specifically activates the selective autophagic clearance of AIM2 inflammasomes within microglia without increasing overall autophagic flux or affecting other inflammasomes. Selective blockage of autophagy in microglia abolished the neuroprotective effect of peiminine.ConclusionsPeiminine exhibited robust neuroprotection against cerebral ischemia by selectively promoting the autophagic clearance of AIM2 inflammasomes to mitigate neuroinflammation.
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BIOCHEMICAL PHARMACOLOGY
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2026
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IF 6.5
Hao Wang,Chunliu Li,Xiao Wang,Feng Yan,Bihan Li,Jiahui Gao,Kuo Zhang,Jiahong Wang
Diabetic kidney disease (DKD), a predominant microvascular complication of diabetes mellitus, still lacks curative therapies to completely halt its progressive deterioration. Our study investigated the renoprotective mechanisms of dapagliflozin (dapa) in DKD. Through bioinformatic analysis of clinical DKD datasets, preclinical in vivo and in vitro assays, we identified absent in melanoma 2 (AIM2) as a critical pyroptosis-associated gene upregulated in DKD. In silico structure-based validation revealed that dapa stably binds to the catalytic domain of silent information regulator 1 (SIRT1) via key residues GLN-361 and SER-365, suggesting its potential to modulate SIRT1 deacetylase function. Gain- and loss-of-function assays confirmed that SIRT1 is the core functional target of dapa: dapa upregulated SIRT1 protein expression to inhibit nuclear factor-κB (NF-κB) signaling, thereby blocking AIM2 inflammasome-mediated renal tubular pyroptosis and oxidative damage. These findings reveal a previously unreported mechanism by which dapa regulates SIRT1/NF-κB/AIM2 signaling to exert renoprotection, and provide promising therapeutic targets for the clinical management of DKD.
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Thoracic Cancer
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2026
·Vol. 17
·期 17
·e70383
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IF 2.6
Kairui Zhu,Yulong Mu,Zhenguo Su,Zhen Yue,Dongyang Wu,Guiwu Qu,Chenyang Jiang,Qing Li,Youjie Li,Ning Xie
Background Pyroptosis-related signaling contributes to lung adenocarcinoma (LUAD) progression and prognosis. Apigenin (AP) has anti-inflammatory and cytoprotective properties, but its effects on pyroptosis-associated signaling in injured LUAD cells remain unclear. Methods A549 cells were treated with carbonyl cyanide m -chlorophenyl hydrazone (CCCP) and ferrous sulfate (FeSO 4 ) to establish a cellular injury model. Cell morphology, Cell Counting Kit-8 signals, and pyroptosis-associated proteins were assessed after AP treatment. Network pharmacology, molecular docking, molecular dynamics simulations, and analyses of The Cancer Genome Atlas and Gene Expression Omnibus datasets were used to prioritize candidate targets, characterize pyroptosis-related genes, and develop a prognostic signature. Results CCCP/FeSO 4 reduced CCK-8 signals and induced morphological injury, whereas AP partially reversed these changes. AP also reduced alterations in GSDMD-N, caspase-1, IL-1β, TNF-α/NF-κB pathway proteins, AIM2, and ASC. TNF was prioritized as a candidate target, and computational analyses predicted a potentially stable AP–TNF interaction without demonstrating direct binding. Bioinformatic analyses identified distinct pyroptosis-related LUAD subgroups and generated a prognostic signature that stratified survival in training and external validation cohorts. AIM2 was additionally prioritized as a LUAD- and stress-associated candidate. Conclusion AP attenuated CCCP/FeSO 4 -induced injury and pyroptosis-associated molecular changes in A549 cells, potentially through TNF-α/NF-κB and AIM2-related signaling. Further mechanistic validation is required.
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Cell Reports
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2025
·Vol. 44
·期 12
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IF 6.9
Min Chen,Zhiwei Liang,Mengyuan Sun,Zhen Chen,Chun Peng,Suliman Khan,Mubbashar Abbas,Dongmei Chen,Shuyu Xie
Understanding how mitochondrial dysfunction (MD) triggers damage-associated molecular pattern (DAMP) signaling could advance therapies for inflammatory diseases. While aryl hydrocarbon receptor (AHR) is implicated in MD-related inflammation, its mechanistic role remains unclear. 8:2 fluorotelomer alcohol (8:2 FTOH), a per- and polyfluoroalkyl substance compound, was identified as an exogenous ligand for AHR. We demonstrate that AHR ligands drive mitochondrial outer membrane permeabilization (MOMP) and mitochondrial permeability transition (MPT) via transcriptional and non-transcriptional activation of AHR, promoting mitochondrial DNA (mtDNA) leakage and AIM2 inflammasome activation—the key mechanism of 8:2 FTOH-induced inflammation. Mechanistically, the F 1 F 0 ATP synthase/ATPase activity inhibition and B-cell lymphoma-2 (BCL-2)-associated X and BCL-2 antagonist/killer expression increase, with crosstalk between MOMP and MPT amplifying the mtDNA release. Inhibition of AHR/AIM2 alleviates the 8:2 FTOH-caused inflammation. Our findings establish AHR as a central regulator of mitochondrial DAMP signaling, and we propose therapeutic strategies for inflammatory diseases linked to environmental AHR activation.
研究领域:
免疫学
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毒理学
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分子生物学
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环境健康
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炎症研究
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高影响因子
Advanced Science
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2025
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IF 14.1
Wei Duan,Rendy Hosea,Lingxian Wang,Cao Ruan,Fuqiang Zhao,Jingyi Liu,Hezhao Zhao,Makoto Miyagishi,Shourong Wu,Vivi Kasim
Immune checkpoint inhibitor (ICI) therapy is a promising anti-tumor therapeutic strategy; however, its efficacy in solid tumors is limited. Chromosome missegregation is common in various solid tumors; however, its role in tumor progression remains poorly understood, and its correlation with ICI is yet to be explored. Here, it is found that increased chromosome missegregation promotes tumor immune microenvironment, and eventually immunotherapeutic efficacy, by triggering pyroptosis. yin yang 2 (YY2) is identified as a mitotic checkpoint regulator, which promotes chromosome missegregation by upregulating BUB1B transcription. Increased chromosome missegregation promoted the formation of micronuclei and release of double-stranded DNA (dsDNA) into the cytosol, triggering an AIM2-mediated cytosolic dsDNA response. The subsequent pyroptosis strengthened the tumor immune microenvironment, thereby enhancing immunoinfiltration and cytotoxicity of CD8 + T cells, while preventing their exhaustion. Finally, through in vitro and in vivo experiments, it is demonstrated that combining YY2 overexpression-induced chromosome missegregation/cytosolic dsDNA response and PD-1 inhibitor significantly enhanced the efficacy of ICI immunotherapy in microsatellite instable and microsatellite stable colorectal cancer cells. Together, these findings provide new insights on the role of chromosome missegregation in triggering cytosolic dsDNA response-mediated pyroptosis and modulating the tumor immune microenvironment, suggesting a novel strategy for improving ICI therapeutic efficacy in colorectal cancer.
研究领域:
肿瘤学
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免疫学
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分子生物学
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癌症治疗
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PubMed
高影响因子
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