TISSUE & CELL
·
2021
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IF 2.466
Yujie Jia,Yu Tong,Lianqiu Min,Yanrong Li,Yan Cheng
NOD-like receptor protein 3 (NLRP3) inflammasome is tightly related to the pathogenesis of cerebral ischemia/reperfusion (I/R) injury, and oridonin (Ori) has shown the potential to alleviate ischemia/reperfusion injury with underlying mechanisms. Our study aims to figure out whether Ori protects against the cerebral ischemia/reperfusion injury by the NLRP3 inflammasome signaling. In this study, a temporary middle cerebral artery occlusion (MCAO) and reperfusion surgery was conducted on male C57BL/6 mice to mimic cerebral I/R injury in vivo. Cellular model of cerebral I/R in vitro was achieved by oxygen-glucose deprivation and reintroduction (OGD/R) in BV2 microglia cells. We found that Ori treatment significantly relieved the neurological deficits, neuronal injury and microglia activation in I/R mice according to morphological and histological analyses. Meanwhile, the inactivation of NLRP3 inflammasome was determined in Ori-treated mice with significantly down-regulated expressions of inflammasome-related genes. Western-blot analysis further demonstrated the negative effect of Ori on NF-κB signaling with diminished phosphorylation and degradation of IκBα as well as suppressed translocation of p65. Furthermore, we indicated that Ori suppressed the activation of NLRP3 inflammasome in OGD/R induced BV2 microglia cells by inhibiting NF-κB signaling. In summary, our findings make Ori a potential candidate for therapy of cerebral I/R injury in the future.
研究领域:
神经科学
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药理学
·
炎症研究
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产品关联
DOI
PubMed
高影响因子
Biochemistry and Biophysics Reports
·
2024
·
IF 2.3
Youyang Liu,Yunlu Zhao,Qi Guo,Pengfei Wang,Peixuan Li,Qingqing Du,Huazhou Xu,Qingyin Yu,Xiaoyi Zhao,Weiya Zhang,Shengjun An,Shuhui Wu
Immune responses, especially NLRP3 signaling in macrophages, play critical roles in rheumatoid arthritis (RA), an autoimmune and inflammatory disease. In this study, we aimed to identify novel therapies for RA. We focused on sophoricoside (SOP), an isoflavone glycoside isolated from Sophora japonica . We predicted the targets of SOP and performed a Gene Ontology analysis to assess its effects. The results suggested that SOP is related to inflammation regulation. We verified these findings by performing in vitro experiments with M1 macrophages differentiated from human peripheral blood monocytes (THP-1 cells). Sophoricoside administration reduced inflammatory activity and NLRP3, Caspase-1, and IL-1β protein levels in macrophages. In addition, SOP and triptolide (TP) was administered intragastrically to male SD rats (n = 40) in a collagen-induced arthritis model. We observed that SOP and TP reduced the inflammatory responses and symptoms of RA. Moreover, unlike TP, SOP showed no liver or kidney toxicity in rats. In conclusion, SOP reduces inflammation in type II collagen-induced arthritis by downregulating NLRP3 signaling and has potential for future clinical applications as an ideal therapy for RA.
研究领域:
免疫学
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药理学
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风湿病学
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炎症
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DOI
PubMed
高影响因子
Frontiers in Bioengineering and Biotechnology
·
2022
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IF 6.064
Zhiwei Zha,Qiumeng Chen,Decheng Xiao,Chengjie Pan,Wei Xu,Liangliang Shen,Jianliang Shen,Wei Chen
The inflammatory response mediated by oxidative stress is the main pathogenesis of dry eye, but clinical observations have shown that scavenging oxygen-free radicals alone has limited therapeutic effect. Moreover, the unique anatomy and physiology of the ocular surface result in low bioavailability of drugs, and higher concentration is required to achieve the desired efficacy, which, however, may bring systemic side effects. These problems pose a challenge, but the revelation of the ROS-NLRP3-IL-1β signaling axis opens up new possibilities. In this investigation, an NLRP3 inhibitor was successfully encapsulated in polydopamine-based microgels and used for dry eye treatment. It was demonstrated that the well-designed microgels exhibited good biocompatibility, prolonged drug retention time on the ocular surface, and effective inhibition of corneal epithelial damage and cell apoptosis. In addition, due to the synergistic effect, the NLRP3 inhibitor–loaded microgels could exert enhanced oxygen radical scavenging and inflammation-inhibiting effects at a lower dose than monotherapy. These findings suggest that polydopamine-based microgels have advantages as ocular surface drug delivery platforms and have promising applications in oxidative damage–related inflammatory diseases in synergy with anti-inflammatory drugs.
研究领域:
药学
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眼科
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材料科学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2023
·
IF 7.2
Shanshan Wei,Wanjun Ma,Chuanhao Jiang,Jiaqin Liu,Jian Liu,Bikui Zhang,Wenqun Li
Clinical application of doxorubicin (Dox) in cancer chemotherapy is limited by its cardiotoxicity. Present study aimed to demonstrate the effect and mechanism of hyperoside in Dox-induced cardiotoxicity. C57BL/6 mice were injected with 12 mg/kg of Dox, and 1 μM Dox was exposed to primary cardiomyocytes. Cardiac function was evaluated by echocardiographic and myocardial enzyme levels. Cardiomyocyts apoptosis was analyzed by TUNEL staining and flow cytometry. Network pharmacology and molecular docking were utilized to explore potential targets of hyperoside. Protein expressions were detected by western blot and enzyme activities were determined by colorimetry. Cardiac dysfunction and cardiomyocyte apoptosis induced by Dox were attenuated by hyperoside. Mechanism of hyperoside was mainly related to “oxidative stress” pathway. Hyperoside exhibited strong binding activities with nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs, the main source of ROS in cardiomyocytes) and cyclooxygenases (COXs). Experiments proved that hyperoside suppressed the ROS generation and the elevated activities of NOXs and COXs induced by Dox. Dox also triggered the activation of NLRP3 inflammasome, which was reversed by hyperoside. Hyperoside bound to NOXs and COXs, which prevents Dox-induced cardiotoxicity by inhibiting NOXs/ROS/NLRP3 inflammasome signaling pathway. Hyperoside holds promise as a therapeutic strategy for Dox-induced cardiotoxicity.
研究领域:
药理学
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心脏病学
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肿瘤学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
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.
研究领域:
心脏病学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2025
·
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.
研究领域:
心血管药理学
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分子生物学
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炎症免疫学
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代谢组学
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中药药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Oxidative Medicine and Cellular Longevity
·
2021
·
IF 6.543
Jin-jin Zhu,Bin-yuan Yu,Xiao-kai Huang,Min-zhi He,Bin-wen Chen,Ting-ting Chen,Huang-yi Fang,Shang-qin Chen,Xiao-qin Fu,Pei-jun Li,Zhen-lang Lin,Jiang-hu Zhu
Hypoxic-ischemic encephalopathy (HIE) is recognized as the main cause of neonatal death, and efficient treatment strategies remain limited. Given the prevalence of HIE and the associated fatality, further studies on its pathogenesis are warranted. Oxidative stress and neuroinflammatory injury are two important factors leading to brain tissue injury and nerve cell loss in HIE. Neferine, an alkaloid extracted from lotus seed embryo, exerts considerable effects against several diseases such as cancers and myocardial injury. In this study, we demonstrated the neuroprotective effect of neferine on HIE and hypothesized that it involves the inhibition of neuronal pyroptosis, thereby ameliorating neurological inflammation and oxidative stress. We demonstrated that the mRNA levels of proteins associated with pyroptosis including caspase-1, the caspase adaptor ASC, gasdermin D, interleukin- (IL-) 18, IL-1β, and some inflammatory factors were significantly increased in neonatal HIBD model rats compared to those in the control group. The increase in these factors was significantly suppressed by treatment with neferine. We stimulated PC12 cells with CoCl2 to induce neuronal HIBD in vitro and investigated the relationship between neferine and pyroptosis by altering the expression of the NLRP3 inflammasome. The overexpression of NLRP3 partially reversed the neuroprotective effect of neferine on HIBD, whereas NLRP3 knockdown further inhibited caspase-1 activation and IL-1β and IL18 expression. In addition, simultaneous alteration of NLRP3 expression induced changes in intracellular oxidative stress levels after HIBD. These findings indicate that neferine ameliorates neuroinflammation and oxidative stress injury by inhibiting pyroptosis after HIBD. Our study provides valuable information for future studies on neferine with respect to neuroinflammation and pyroptosis.
研究领域:
神经科学
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药理学
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分子生物学
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儿科
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DOI
PubMed
高影响因子
Experimental and Therapeutic Medicine
·
2024
·Vol. 27
·期 4
·1-13
·
IF 2.4
Linfeng Zheng,Wenjuan Mei,Jing Zhou,Xin Wei,Zhijuan Huang,Xiaozhen Lin,Li Zhang,Wei Liu,Qian Wu,Jinhong Li,Yan Yan
Currently, no antifibrotic drug in clinical use can effectively treat renal fibrosis. Fluorofenidone (AKFPD), a novel pyridone agent, significantly reduces renal fibrosis by inhibiting the activation of the NOD‑like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome; however, the underlying mechanism of this inhibition is not fully understood. The present study aimed to reveal the molecular mechanism underlying the suppression of NLRP3 inflammasome activation by AKFPD. It investigated the effect of AKFPD on NLRP3 activation and lysosomal cathepsins in a unilateral ureteral obstruction (UUO) rat model, and hypoxia/reoxygenation (H/R)‑treated HK‑2 cells and murine peritoneal‑derived macrophages (PDMs) stimulated with lipopolysaccharide (LPS) and ATP. The results confirmed that AKFPD suppressed renal interstitial fibrosis and inflammation by inhibiting NLRP3 inflammasome activation in UUO rat kidney tissues. In addition, AKFPD reduced the production of activated caspase‑1 and maturation of IL‑1β by suppressing NLRP3 inflammasome activation in H/R‑treated HK‑2 cells and murine PDMs stimulated with LPS and ATP. AKFPD also decreased the activities of cathepsins B, L and S both in vivo and in vitro. Notably, AKFPD downregulated cathepsin B expression and NLRP3 colocalization in the cytoplasm after lysosomal disruptions. Overall, the results suggested that AKFPD attenuates renal fibrosis by inhibiting lysosomal cathepsin‑mediated activation of the NLRP3 inflammasome.
研究领域:
药理学
·
肾脏生理学
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炎症
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
Autophagy
·
2019
·
IF 11.059
Xiaojuan Han,Sifan Sun,Yiming Sun,Qiqi Song,Jialei Zhu,Nanshan Song,Miaomiao Chen,Ting Sun,Meiling Xia,Jianhua Ding,Ming Lu,Honghong Yao,Gang Hu
Aging-related, nonresolving inflammation in both the central nervous system (CNS) and periphery predisposes individuals to the development of neurodegenerative disorders (NDDs). Inflammasomes are thought to be especially relevant to immune homeostasis, and their dysregulation contributes to inflammation and NDDs. However, few agents have been clinically shown to reduce NDD incidence by targeting inflammasomes. Our study indicated that NLRP3 (NLR family, pyrin domain containing 3) inflammasome is involved in Parkinson disease (PD) progression in patients and various murine models. In addition, the small molecule kaempferol (Ka) protected mice against LPS- and SNCA-induced neurodegeneration by inhibiting NLRP3 inflammasome activation as evidenced by the fact that Ka reduced cleaved CASP1 expression and disrupted NLRP3-PYCARD-CASP1 complex assembly with concomitant decreased IL1B secretion. Mechanically, Ka promoted macroautophagy/autophagy in microglia, leading to reduced NLRP3 protein expression, which in turn deactivated the NLRP3 inflammasome. Intriguingly, ubiquitination was involved in Ka-induced autophagic NLRP3 degradation. These findings were further confirmed in vivo as knockdown of Atg5 expression or autophagy inhibitor treatment significantly inhibited the Ka-mediated NLRP3 inflammasome inhibition and neurodegeneration amelioration. Thus, we demonstrated that Ka promotes neuroinflammatory inhibition via the cooperation of ubiquitination and autophagy, suggesting that Ka is a promising therapeutic strategy for the treatment of NDDs.Abbreviations: 3-MA: 3-methyladenine; AAV: adeno-associated virus; ACTB: actin, beta; AIF1/IBA1: allograft inflammatory factor 1; ATG5: autophagy related 5; ATG7: autophagy related 7; BafA1: bafilomycin A1; BECN1: beclin 1, autophagy related; CASP1: caspase 1; CNS: central nervous system; CQ: chloroquine; DA neurons: dopaminergic neurons; DAMPS: damage-associated molecular patterns; DAPI: 4’,6-diamidino-2-phenylindole; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; GFAP: glial fibrillary acidic protein; IP: immunoprecipitation; i.p.: intraperitoneally; Ka: kaempferol; KD: knockdown; KO: knockout; LPS: lipopolysaccharide; IL1B: interleukin 1 beta; IL6: interleukin 6; Ly: lysate; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NC: negative control; NDD: neurodegenerative diseases; NLRP3: NLR family, pyrin domain containing 3; OE: overexpression; PD: Parkinson disease; poly-Ub: poly-ubiquitin; PTM: post-translational modification; PYCARD/ASC: PYD and CARD domain containing; Rapa: rapamycin; RFP: red fluorescent protein; SN: supernatant; SNCA: synuclein alpha; SNpc: substantia nigra pars compacta; SQSTM1: sequestosome 1; TH: tyrosine hydroxylase; TNF/TNF-alpha: tumor necrosis factor; Ub: ubiquitin; WT: wild type
研究领域:
神经科学
·
药理学
·
免疫学
·
神经退行性疾病
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产品关联
DOI
PubMed
高影响因子
Microbiome
·
2019
·Vol. 7
·期 1
·1-16
·
IF 10.465
Zhang Yuan,Huang Rongrong,Cheng Mengjing,Wang Lirui,Chao Jie,Li Junxu,Zheng Peng,Xie Peng,Zhang Zhijun,Yao Honghong
Background Inflammasomes have been found to interact with the gut microbiota, and this effect is associated with depression, but the mechanisms underlying this interaction have not been elucidated in detail.Results The locomotor activity of NLRP3 KO mice was significantly greater than that of their WT littermates, while cohousing and transplantation of the NLRP3 KO gut microbiota avoid the effects of NLRP3 KO on the general locomotor activity at baseline. Meanwhile, transplantation of the NLRP3 KO microbiota alleviated the CUS-induced depressive-like behaviors. The compositions of the gut microbiota in NLRP3 KO mice and WT mice were significantly different in terms of the relative abundance of Firmicutes, Proteobacteria, and Bacteroidetes. Fecal microbiota transplantation (FMT) from NLRP3 KO mice significantly ameliorated the depressive-like behavior induced by chronic unpredictable stress (CUS) in recipient mice. Given the correlation between circular RNA HIPK2 (circHIPK2) and depression and the observation that the level of circHIPK2 expression was significantly increased in CUS-treated mice compared with that in the control group, further experiments were performed. FMT significantly ameliorated astrocyte dysfunction in recipient mice treated with CUS via inhibition of circHIPK2 expression.Conclusion sOur study illustrates the involvement of the gut microbiota-circHIPK2-astrocyte axis in depression, providing translational evidence that transplantation of the gut microbiota from NLRP3 KO mice may serve as a novel therapeutic strategy for depression.
研究领域:
神经科学
·
微生物学
·
分子生物学
·
行为科学
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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2024
·
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.
研究领域:
毒理学
·
细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Journal of Functional Foods
·
2023
·
IF 5.6
Wenjing Xu,Yufeng Chen,Fenfen Li,Xiaoxi Zhang,Cantao Li,Chenxi Wu,Yan Huang,Daozong Xia
Gout is a metabolic disease that seriously affects people's health. Polydatin, a stilbene compound isolated from Polygonum cuspidatum , has attracted much attention because of its rich biological activity and high safety. This study aimed to investigate the therapeutic effect and mechanism of polydatin on hyperuricemia (HUA) combined with gouty arthritis (GA). The results showed that polydatin reduced the levels of uric acid and inflammatory cytokines, indicating that polydatin had the effect of reducing uric acid and anti-GA. Then the inhibitors of ABCG2, NLRP3 inflammasome and NF-κB pathway (Ko143, MCC950 and QNZ) were used to demonstrate that polydatin played a role in reducing uric acid and anti-GA via regulating urate transporters, NLRP3 inflammasome and NF-κB pathway. Taken together, these results provided evidence that polydatin might be used as a potential functional ingredient for the synchronous treatment of HUA and GA.
研究领域:
药理学
·
代谢性疾病
·
炎症
·
分子生物学
✓ 已验证
DOI
高影响因子
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