INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
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IF 4.8
Yongping Chen,Haotian Yang,Xueyuan Hu,Tianyuan Yang,Yuan Zhao,Huanqi Liu,Honggang Fan
Increasing evidence has demonstrated that coenzyme Q10 (CoQ10) exhibits a range of biological properties. Herein, we explored the protective effect and potential molecular mechanism of CoQ10 on lipopolysaccharide (LPS)-induced acute lung injury (ALI). We found that medium (10 mg/kg) and high (50 mg/kg) doses of CoQ10 ameliorated LPS (50 µg/µL)-induced ALI to varying degrees, as demonstrated by reduced lung coefficient, lower wet/dry weight lung tissue ratio, decreased bronchoalveolar lavage fluid protein concentration, less anatomical and histopathological damage to the lung, and increased expression of proteins related to lung epithelial barrier structure. CoQ10 also alleviated LPS-induced oxidative stress and inflammation mediated by NOD-like receptor protein 3 (NLRP3) by reducing the reactive oxygen species (ROS), malondialdehyde, and mitochondrial ROS concentrations, increasing superoxide dismutase, glutathione, and catalase activity, and decreasing NLRP3 expression at the protein and mRNA levels. Moreover, CoQ10 alleviated structural and functional damage to the mitochondria, inhibited mitochondrial fission, and promoted mitochondrial fusion, mainly by inhibiting phosphorylation of dynamin-related protein 1 (Drp1) at Ser616 and Ser637. Correlation analysis revealed that mitochondrial fission (especially Drp1) was positively correlated with oxidative stress, NLRP3-mediated inflammation, and structural damage to the lung epithelial barrier. Molecular docking analysis showed that CoQ10 binds stably to Drp1, with a binding energy of −5.9 kcal/mol. Furthermore, the use of schaftoside (a Drp1 inhibitor) has further elucidated the mechanism of action of CoQ10. Together, these results suggest that CoQ10 alleviates LPS-induced ALI by regulating mitochondrial dynamics, attenuating oxidative stress, and decreasing NLRP3-medated inflammation, thereby promoting lung epithelial barrier structural remodeling.
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CARDIOVASCULAR DRUGS AND THERAPY
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2025
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IF 3.1
Ba Lina,Wu Nan,Feng Xiang,Wang Ruixuan,Zhao Zhichao,Wang Rui,Liu Renling,Shi Pilong,Sun Hongli,Qi Hanping
Purpose The purpose of this study was to investigate the protective effects of biochanin A (BCA) on cardiac hypertrophy and to elucidate the underlying molecular mechanisms. The research question was whether BCA can reverse heart dysfunction and attenuate cardiomyocyte hypertrophy induced by pressure overload and AngII, respectively, and how it interacts with the NLRP3 pyroptosis pathway to achieve these effects. Methods We employed an animal model of pressure overload-induced cardiac hypertrophy and an in vitro model of AngII-induced cardiomyocyte hypertrophy to assess the effects of BCA. The expression of NLRP3 and its related signaling molecules was analyzed by western blotting, and the activity of the NLRP3 pathway was measured using pyroptosis assays. The role of Cbl-b, an E3 ubiquitin ligase, in BCA-mediated NLRP3 inhibition was also investigated. Results BCA was found to reverse heart dysfunction and attenuate cardiomyocyte hypertrophy induced by pressure overload and AngII. Mechanistically, BCA mitigated cardiac hypertrophy by targeting the NLRP3 pyroptosis pathway. The reduction in NLRP3 expression by BCA was predominantly mediated through the upregulation of Cbl-b, which enhanced the ubiquitination and subsequent degradation of NLRP3. Additionally, BCA facilitated the upregulation of Cbl-b expression by interacting with NF-κB, preventing NF-κB binding to the promoter region of Cbl-b and reversing its suppressive action on Cbl-b expression. Conclusion This study provides initial evidence that BCA can protect against cardiac hypertrophy. Its mechanism of action involves interacting with NF-κB to promote the expression of Cbl-b, which facilitates the ubiquitination and degradation of NLRP3, ultimately inhibiting pyroptosis. This finding suggests that BCA may be a potential therapeutic agent for the treatment of cardiac hypertrophy.
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2024
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IF 6.2
Yu Ma,Wei Yang,Peiyao Liang,Ruzhen Feng,Tianming Qiu,Jingyuan Zhang,Xiance Sun,Qiujuan Li,Guang Yang,Xiaofeng Yao
As a persistent organic pollutant, perfluorooctane sulfonate (PFOS) has a serious detrimental impact on human health. It has been suggested that PFOS is associated with liver inflammation. However, the underlying mechanisms are still unclear. Here, PFOS was found to elevate the oligomerization tendency of voltage-dependent anion channel 1 (VDAC1) in the mice liver and human normal liver cells L-02. Inhibition of VDAC1 oligomerization alleviated PFOS-induced nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasome activation. Cytoplasmic membrane VDAC1 translocated to mitochondria was also observed in response to PFOS. Therefore, the oligomerization of VDAC1 occurred mainly in the mitochondria. VDAC1 was found to interact with the ATP synthase beta subunit (ATP5B) under PFOS treatment. Knockdown of ATP5B or immobilization of ATP5B to the cytoplasmic membrane alleviated the increased VDAC1 oligomerization and NLRP3 inflammasome activation. Therefore, our results suggested that PFOS induced NLRP3 inflammasome activation through VDAC1 oligomerization, a process dependent on ATP5B to transfer VDAC1 from the plasma membrane to the mitochondria. The findings offer novel perspectives on the activation of the NLRP3 inflammasome, the regulatory mode on VDAC1 oligomerization, and the mechanism of PFOS toxicity.
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Journal of Inflammation Research
·
2025
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IF 4.1
Zhongzhu Ai,Dongfeng Yuan,Yun Li,Jingyi Cai,Daonian Zhou,Wei Liu
Background Hemorrhoidal disease (HD) is characterized by the pathological dilation of anal vascular cushions, causing pain, itching and bleeding. Recent evidence links HD onset and progression to rectal inflammation. Medical Hemorrhoid Gel (MHG), a multi-component botanical preparation, has gained empirical validation for HD management. This study aims to systematically evaluate the safety, efficacy, and mechanism of action of MHG in treating HD.Methods The phytochemical composition of MHG was characterized using UPLC-QTOF-MS/MS and GC-MS/MS analyses. In vivo, the efficacy was assessed in a croton oil preparation (COP)‑induced HD rat model (n=10 per group) via anorectal coefficient (ARC) measurement, macroscopic severity score, Evans blue extravasation quantification, and H&E/PAS staining. Transcriptomic sequencing of anorectal tissues was integrated with experimental validation using ELISA, immunohistochemistry (IHC), and Western blotting to delineate molecular mechanism. Data were analyzed by one-way analysis of variance (ANOVA) followed by Dunnett’s multiple comparison post hoc test (significance at p<0.05).Results MHG significantly reduced ARC, macroscopic severity score, and Evans blue extravasation, restored intestinal villus structure and goblet cell numbers, and alleviated inflammation. Acute toxicity tests showed that MHG did not cause anorectal abnormalities or systemic toxicity in rats. Transcriptomic analysis integrated with experimental validation suggested the therapeutic mechanism of MHG involves inflammation response and NF-κB pathway. Specifically, MHG suppressed the levels of the pro-inflammatory mediator TNF-α, while it enhanced the levels of the anti-inflammatory mediator IL-10. Mechanistic studies revealed that MHG inhibited NLRP3 inflammasome activation, reduced the phosphorylation level of p65 and enhanced IκBα expression. Phytochemical analysis identified 20 constituents that contribute to the bioactivity of MHG.Conclusion Our study substantiated that MHG exerts anti-hemorrhoidal effects through NLRP3 inflammasome suppression via NF-κB pathway regulation. This mechanistic insight provides scientific validation for clinical application of MHG in HD management.
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Scientific Reports
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2024
·Vol. 14
·期 1
·1-16
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IF 3.8
Wei Wei,Heng Yan-Yan,Wu Fei-Fei,Dong Hao-Yu,Zhang Peng-Fei,Li Jing-Xia,Liu Chun-Yan,Yang Bing-Jie,Fu Jia-Ning,Liang Xin-Yue
Diabetes accelerates vascular senescence, which is the basis for atherosclerosis and stiffness. The activation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and oxidative stress are closely associated with the deteriorative senescence in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). For decades, Sodium Tanshinone IIA Sulfonate (STS) has been utilized as a cardiovascular medicine with acknowledged anti-inflammatory and anti-oxidative properties. Nevertheless, the impact of STS on vascular senescence remains unexplored in diabetes. Diabetic mice, primary ECs and VSMCs were transfected with the NLRP3 overexpression/knockout plasmid, the tumor necrosis factor alpha-induced protein 3 (TNFAIP3/A20) overexpression/knockout plasmid, and treated with STS to detect senescence-associated markers. In diabetic mice, STS treatment maintained catalase (CAT) level and vascular relaxation, reduced hydrogen peroxide probe (ROSgreen) fluorescence, p21 immunofluorescence, Senescence β-Galactosidase Staining (SA-β-gal) staining area, and collagen deposition in aortas. Mechanistically, STS inhibited NLRP3 phosphorylation (serine 194), NLRP3 dimer formation, NLRP3 expression, and NLRP3-PYCARD (ASC) colocalization. It also suppressed the phosphorylation of IkappaB alpha (IκBα) and NFκB, preserved A20 and CAT levels, reduced ROSgreen density, and decreased the expression of p21 and SA-β-gal staining in ECs and VSMCs under HG culture. Our findings indicate that STS mitigates vascular senescence by modulating the A20-NFκB-NLRP3 inflammasome-CAT pathway in hyperglycemia conditions, offering novel insights into NLRP3 inflammasome activation and ECs and VSMCs senescence under HG culture. This study highlights the potential mechanism of STS in alleviating senescence in diabetic blood vessels, and provides essential evidence for its future clinical application.
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PHYTOTHERAPY RESEARCH
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2025
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IF 6.3
Anpei Wang,Yi Li,Fei Zhao,Hai Fang,Chengxue Pan,Bo Wei
Cardioprotective formulations in traditional Chinese medicine often combine cold and hot herbs, with licorice frequently included to balance their properties and reduce adverse effects. However, the independent cardioprotective mechanisms of licorice in ischemic heart disease remain unclear. This study aimed to investigate the effects of licorice extract (GC) on myocardial ischemia (MI) and ischemia/reperfusion (MI/R) injury. Myocardial injury models were established using H 2 O 2 -induced H9c2 cardiomyocytes and left anterior descending coronary artery ligation in rats. Cardioprotective effects were evaluated through electrocardiography, echocardiography, and pharmacodynamic assessments. Network pharmacology and PCR were used to explore the anti-inflammatory mechanism, followed by investigation of the upstream inflammatory pathways using Western blotting, co-immunoprecipitation, immunofluorescence, and molecular docking. Metabolomics confirmed GC's impact on terminal metabolic disturbances. Pharmacodynamic evaluations demonstrated that GC exerted significant cardioprotective effects both in vitro and in vivo. Network pharmacology suggested anti-inflammatory potential, which was confirmed by PCR showing reduced levels of IL-1β, IL-6, and TNF-α. Expression analysis of seven Sirtuin and four NOD-like receptor family members revealed that GC's anti-inflammatory effect was mediated by upregulation of Sirt3, leading to inhibition of NLRP3 inflammasome activation, decreased Caspase-1 activity, and reduced secretion of IL-1β and IL-18. Additionally, GC modulated ischemia-induced metabolic disturbances, notably restoring disrupted amino acid and unsaturated fatty acid metabolism. In conclusion, GC exerted cardioprotective effects by suppressing inflammation through the Sirt3/NLRP3 axis and restoring metabolic homeostasis. These findings supported its traditional use and suggested its potential application in cardiovascular health.
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FOOD RESEARCH INTERNATIONAL
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2025
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IF 8
Han Li,Shuzhen Cheng,Kai Zhou,Jiachen Zang,Zhenyu Wang,Ming Du
Ferritin is expected to alleviate lead-induced oxidative damage. Despite being a relatively stable macromolecular protein that can withstand high temperatures and extreme pH conditions without its structure and activity being compromised, oral administration of ferritin may still result in its degradation within the gastrointestinal tract, reducing its bioavailability. In recent years, microcapsules have emerged as an effective approach in oral protein delivery to enhance bioavailability. In this study, carboxymethyl-β-cyclodextrin grafted chitosan embedded oyster ( Crassostrea gigas ) ferritin (CMCD-CS@GF1) was fabricated with favorable encapsulation efficiency (57.73 ± 4.84 %) and loading capacity (5.78 ± 0.48 %), as well as a certain degree of resistance to digestion in the gastric environment. In the simulated gastric fluid with an acidic pH, the cumulative release of GF1 over 4 h was 24.18 %. In the simulated intestinal fluid with a neutral pH, the cumulative release of GF1 over 8 h was 70.56 %. Animal experiments showed that oyster ferritin could reduce the accumulation of lead in the body, enhance the activity of antioxidant enzymes, activate the Nrf2 signaling pathway, and down-regulate the NLRP3 signaling pathway to reduce oxidative stress and inflammation levels. The findings demonstrate that oyster ferritin may mitigate the toxic effects of lead in the body, providing a significant theoretical foundation for its application in functional foods.
研究领域:
食品科学
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分子生物学
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毒理学
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2024
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IF 5.7
Yanan Zhao,Bin Li,Hongting Deng,Chang Zhang,Yitong Wang,Lei Chen,Hui Teng
Prolonged and excessive intake of alcohol results in the onset of alcoholic liver disease, which is marked by oxidative stress, intestinal barrier dysfunction, and disturbance in the intestinal microbiome. Galangin, a potent flavonoid from Alpinia officinarum Hance, has been recognized for its diverse biological properties; however, its ability for protecting against alcohol-stimulated hepatotoxicity remains unexplored in prior research. In the current study, a Gao-Binge mouse model was established to assess the positive role and mechanisms of galangin upon alcohol-induced liver injury. The administration of galangin relieved liver pathological damage, oxidative stress, and NLRP3-mediated inflammation induced by alcohol. In addition, galangin significantly reversed abnormal intestinal histopathological manifestations and damaged the intestinal barrier function. Furthermore, microbiota composition revealed that galangin improved intestinal imbalance by improving the gut microbiota dysbiosis and short-chain fatty acid level. Collectively, this study explored the interactions between phytochemical factors and virulence factors and discovered that galangin powerfully improved alcohol-induced liver disease by repressing the inflammatory cascade via the gut microbiota-mediated gut–liver axis. These results suggested that alcohol-targeted natural products could have potential applications in promoting food safety and human health and offer valuable insights into the possible use of these substances in these important areas.
研究领域:
药理学
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肝病学
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微生物学
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免疫学
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营养学
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Journal of Neuroinflammation
·
2026
·Vol. 23
·期 1
·71
·
IF 11.5
Geng Fan,Zhao Na,Zhou Lv,Liu Xue-ting,Chen Xiu,Wang Zhi-Tian,Zhang Zhi-Jun,Ren Qing-Guo
Background Alzheimer’s disease (AD) is characterized by extracellular Aβ deposition and tau hyperphosphorylation, leading to synaptic dysfunction and cognitive decline. Mounting evidence indicates that circadian rhythm disorders are associated with increased AD risks. Growing evidence implicates the microbiota-gut-brain axis and its metabolites as critical modulators of both circadian physiology and AD pathology. However, the molecular mechanism through which circadian disturbance modulates gut-brain communication to influence AD pathogenesis remains poorly understood. Methods Core circadian clock gene expression was assessed across four AD human brain datasets, and found Cry2 to be the only gene consistently downregulated. To investigate its functional role in vivo, we established a mouse model with hippocampal-specific Cry2 knockdown. Cognitive performance, gut microbiota composition, and metabolic alterations were evaluated using the Morris water maze, 16 S rRNA sequencing, and untargeted metabolomics, respectively. Intestinal barrier integrity, blood-brain barrier function, and neuroinflammatory signaling were examined through immunohistochemistry, immunofluorescence, and Western blotting. The contribution of microbiota disturbance was tested using fecal microbiota transplantation (FMT). The involvement of sphingolipid signaling was further assessed through FMT, pharmacological modulation with the S1PR agonist FTY720, NLRP3 knockout mice, and microglial assays. Results We found that the expression of Cry2 consistently decreased in the AD group in four AD-related datasets. Then, knockdown of Cry2 in the hippocampus ( shCry2 ) caused dysbiosis of gut microbiota, intestinal barrier impairment, cognitive dysfunction and tau pathology in mice. Intriguingly, along with the disturbance in intestinal sphingolipid metabolism pathways, activation of the S1P/NLRP3/IL-1β pathway was found in the brain of shCry2 mice. Transplantation of “ shCry2 microbiota” mimicked the pathological and behavioral changes induced by hippocampal Cry2 deficiency. Administration of S1PR agonist FTY720 significantly improved cognitive impairment and decreased the expression of NLRP3 in shCry2 mice, and knockdown of Cry2 in NLRP3 −/− mice alleviated tau pathology and cognitive impairment. FTY720 and S1PR1 antagonist W146 dose-dependently modulated the expression of NLRP3 in BV2 cells. Overexpressing Cry2 in the hippocampus significantly alleviated the tau pathology and cognitive decline in APP/PS1 mice. Conclusion Hippocampal Cry2 deficiency leads to cognitive impairment through the gut-brain axis mediated S1P/NLRP3/IL-1β pathway and might provide a potential therapeutic target for AD.
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JOURNAL OF ETHNOPHARMACOLOGY
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2025
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IF 5.4
HuiNa Yang,Qiao Peng,Ruonan Shuang,Zihang Guo,Hao Yang,Chang Chen,Weiwei Tao,Li Liu
Ethnopharmacological relevance Depression in traditional Chinese medicine is mechanistically linked to neuroinflammation–a key pathogenesis driving depressive disorders. Baixian Houpo Decoction (BXHPD), originating from the classical TCM text Jinkui Yaolue, is prescribed for depression attributable to “phlegm-qi stagnation”. While modern pharmacological studies confirm its potent anti-inflammatory properties, the molecular pathways underpinning BXHPD’s therapeutic effects against neuroinflammation remain undefined. Objective We aimed to evaluate the antidepressant effect of BXHPD in a cortical corticosterone (CORT)-induced mouse model of depression and its potential molecular mechanisms. Materials and Methods Male C57BL/6 wild-type and Aldh1l1-Cre/ERT2 mice received CORT injections to induce depression. Behavioral tests included sucrose preference (SPT), tail suspension (TST), forced swim (FST), and open field (OFT) tests. Hippocampal neuropathology was assessed via Nissl staining for neuronal damage and ELISA for pro-inflammatory (IL-1β, IL-6, TNF-α) and anti-inflammatory (IL-10, IL-4) cytokines. Molecular analyses involved CO-IP for O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT)-Cathepsin B (CTSB) interaction, O-GlcNAcylation, and NLRP3 inflammasome activation; western blotting for protein expression; immunofluorescence for OGT/GFAP and CTSB/LAMP1 colocalization; and DHE staining for ROS detection. Results BXHPD alleviated depressive-like behaviors, reduced neuronal damage, and inhibited pro-inflammatory cytokine release in depressed mice. Mechanistically, BXHPD downregulated OGT, thereby reducing CTSB O-GlcNAcylation to promote its maturation. This decrease in O-GlcNAcylation lowered ROS levels, attenuated lysosomal membrane permeabilization (LMP), limited cytoplasmic CTSB leakage, and ultimately suppressed NLRP3 inflammasome activation. Conclusion BXHPD targets astrocytes in the medial prefrontal cortex via the OGT /CTSB/NLRP3 pathway to alleviate neuroinflammation and improve depressive-like behaviors.
研究领域:
民族药理学
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神经科学
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分子生物学
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中医中药
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炎症研究
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2025
·
IF 8.5
Wen-Jing Xiao,Su Dong,Yue Xuan,Xiao-Jie Huang,Jing-Rui Feng,Hong-Jing You,Yang Chen
Existing studies lack systematic investigation of the polysaccharide components in Citri Reticulatae Pericarpium (CRP), despite established anti-inflammatory and cardioprotective effects of its bioactive constituents. This study isolated and characterized CRP-derived polysaccharides, focusing on CP-0's protective role against Lactobacillus casei cell wall extract (LCWE)-induced endothelial barrier dysfunction. Structural characterization identified CP-0 and CP-1 as novel triple-helical heteropolysaccharides (MW 81,404 and 83,540 Da; glucose, ribose, mannose). Following isolation and physicochemical screening, CP-0 exhibited low cytotoxicity and high anti-inflammatory activity. Mechanistic analyses revealed that CP-0 attenuated LCWE-induced endothelial injury by reducing inflammatory infiltration, IL-1β levels, and adhesion molecules (VCAM-1/ICAM-1) while upregulating tight junction proteins ZO-1/2 in mouse microvascular endothelial cells (MVECs). CP-0 suppressed NLRP3 inflammasome activation via decreased colocalization of NLRP3/Caspase-1/ASC, and competitive binding assays confirmed its interaction with TLR2, which blocked NF-κB nuclear translocation. By targeting TLR2-mediated signaling pathways, CP-0 effectively mitigated LCWE-induced coronary arteritis in vitro, demonstrating potential as a therapeutic candidate for cardiovascular diseases through early-stage anti-inflammatory intervention.
研究领域:
生药学
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免疫药理学
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血管生物学
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天然产物化学
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炎症研究
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IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL
·
2023
·Vol. 59
·期 3
·204-213
·
IF 2.1
Liu Xu-Ying,Li Qiu-Shi,Yang Wen-Hai,Qiu Yue,Zhang Fei-Fei,Mei Xiu-Hui,Yuan Qi-Wen,Sui Ru-Bo
Cerebral ischemia/reperfusion (CI/R) usually causes neuroinflammation within the central nervous system, further prompting irreversible cerebral dysfunction. Perilipin 2 (Plin2), a lipid droplet protein, has been reported to exacerbate the pathological process in different diseases, including inflammatory responses. However, the role and mechanism of Plin2 in CI/R injury are unclear. In this study, the rat models of transient middle cerebral artery occlusion followed by reperfusion (tMCAO/R) were established to mimic I/R injury, and we found that Plin2 was highly expressed in the ischemic penumbra of tMCAO/R rats. The siRNA-mediated knockdown of Plin2 significantly decreased neurological deficit scores and reduced infarct areas in rats induced by I/R. Detailed investigation showed that Plin2 deficiency alleviated inflammation of tMCAO/R rats as evidenced by reduced secretion of proinflammatory factors and the blockade of NLR family pyrin domain containing 3 (NLRP3) inflammasome activation. In vitro experiments showed that Plin2 expression was upregulated in mouse microglia subjected to oxygen–glucose deprivation/reoxygenation (OGD/R). Plin2 knockdown inhibited OGD/R-induced microglia activation and the accumulation of inflammation-related factors. Taken together, this study demonstrates that lipid droplet protein Plin2 contributes to the pathologic process of CI/R damage by impacting inflammatory response and NLRP3 inflammasome activation. Thus, Plin2 may provide a new therapeutic direction for CI/R injury.
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