TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2025
·
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.
研究领域:
皮肤病学
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药理学
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免疫学
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放射生物学
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产品关联
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2024
·
IF 4.5
Yi Chen,Shasha Song,Yongfang Wang,Lili Wu,Jianbing Wu,Zhengmeng Jiang,Xinyu Li
Psoriasis (PSO) is a common inflammatory skin disease caused by multiple factors. Magnolia officinalis is an important medicinal plant in China, with various values such as ecology, medicine, food, and daily chemicals. However, its diverse application potential has not been fully explored. Magnolol (MGO) is the main active compound of Magnolia officinalis with significant anti-inflammatory effect. To investigate the application potential of MGO in inflammatory skin disease, the effects and underlying mechanisms of topical MGO treating psoriasis were explored in this study. Network pharmacology and molecular docking firstly predicted that topical MGO may treat psoriasis by regulating pyroptosis pathway and acting on caspase-1 (CASP1). In vitro experiments then demonstrated that MGO could inhibit the level of inflammatory cytokines and the key protein expression of NOD-like receptor protein 3 (NLRP3)/Caspase-1 pathway in lipopolysaccharide (LPS)-stimulated phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 cells. Meanwhile, MGO could inhibit CuSO 4 -induced neutrophils migration in Tg (mpx:EGFP) zebrafish by suppressing inflammation and pyroptosis. This study further indicated that topical application of MGO ameliorated imiquimod (IMQ)-induced psoriasis-like dermatitis by reducing the release of inflammatory factors and decreasing the key protein expression of pyroptosis-related NLRP3/Caspase-1 pathway. Metabolomics analysis revealed that topical application of MGO could significantly regulate tryptophan metabolism and affect the level of tryptophan in skin lesions. Tryptophan could also regulate inflammation-related genes and inhibit pyroptosis-related NLRP3/Caspase-1 pathway in LPS-stimulated PMA-differentiated THP-1 cells. In conclusion, this study suggested that topical MGO may ameliorate psoriasis-like dermatitis by inhibiting NLRP3/Caspase-1 pathway and regulating tryptophan metabolism.
研究领域:
药理学
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皮肤科
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分子生物学
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代谢组学
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产品关联
DOI
PubMed
高影响因子
Food & Function
·
2018
·Vol. 9
·期 12
·6155-6164
·
IF 3.289
Lang Zhang,Ya Fan,Hanwen Su,Li Wu,Yuying Huang,Lei Zhao,Bing Han,Guangwen Shu,Meixian Xiang,Jin-Ming Yang
The objective of this study was to investigate the anti-inflammatory effect of chlorogenic acid methyl ester (CME) and the molecular mechanism involved, through using non-infectious inflammation and infectious inflammation animal models as well as lipopolysaccharide (LPS)-stimulated mouse macrophage RAW264.7 cell models. Our results demonstrated that CME markedly inhibited ear swelling, paw swelling and granuloma swelling, and decreased intraperitoneal capillary permeability in non-infectious inflammation. Moreover, CME significantly alleviated the pathological damage of the lung tissue, reduced the levels of PGE2 and IL-1β in the serum and the protein expression levels of related-inflammatory factors in the lung tissue of LPS-induced mice with acute lung injury (ALI). In addition, CME affected the RAW264.7 cell cycle and inhibited the protein expressions of COX-2 and NLRP3 and prevented the phosphorylation of NF-κB p65 in RAW264.7 cells treated with LPS. These observations not only validated the anti-inflammatory effects of CME, but also revealed the underlying molecular basis, which involves the down-regulation of the expression of inflammatory factors and blockade of the COX-2/NLRP3/NF-κB signaling pathway.
研究领域:
药理学
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免疫学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2023
·
IF 15.1
Dongju Zhao,Chao Tian,Meng Cheng,Fan Yang,Chunxiao Tian,Yining Liu,Ziyao Chen,Gaoju Pang,Hui Shen,Jin Chang,Yan Dou
NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome is a key drug target for Parkinson’s disease (PD) therapeutics. Identifying the underlying upstream mechanisms of assembly formation is crucial for clarifying the exact pharmacological effects, but currently remains elusive for most drugs. Here, we develop a carrier-free nanomedicine (NanoQC) derived from natural phytochemical quercetin (QC) to mitigate neuroinflammation and neurodegeneration for PD treatment and demonstrate that it attenuates aberrant inflammasome assembly and activation through inhibiting the deubiquitination of NLRP3 and blocking its interaction with thioredoxin-interacting protein (TXNIP). Intranasal NanoQC administration alleviates nigral dopaminergic neuronal loss and striatal dopamine depletion, while improving nigral dopaminergic neuronal excitability and hippocampal synaptic plasticity, relieving olfactory dysfunction, ultimately ameliorating motor and memory impairments in PD mice. This work demonstrates the great promise of NanoQC inhibiting the upstream mechanisms of NLRP3 inflammasome assembly to combat PD, providing novel insight for precise target identification of nanomedicines.
研究领域:
神经科学
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药理学
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纳米技术
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分子生物学
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产品关联
DOI
高影响因子
CHEMICAL RESEARCH IN TOXICOLOGY
·
2016
·
IF 3.025
Xiaomin Xia,Qiong Shi,Xiufang Song,Juanli Fu,Zixuan Liu,Yawen Wang,Yuxin Wang,Chuanyang Su,Erqun Song,Yang Song
Our previous studies suggested that tetrachlorobenzoquinone (TCBQ) elicits pro-inflammatory activities; however, the mechanism of its toxicity toward vascular endothelial cell has not been characterized. Although TCBQ has been shown to stimulate interleukin-1 beta (IL-1β) expression, it is unknown whether TCBQ regulates post-translational IL-1β activation. Using human umbilical vein endothelial cells, we discovered that TCBQ not only promotes the expression of NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) components [composed of NLRP3, adaptor molecule apoptosis-associated speck like protein containing a caspase activation and recruitment domain (ASC), and pro-caspase 1] but also participates in priming the NLRP3 inflammasome. Activation of the NLRP3 inflammasome results in the maturation and release of IL-1β. Further experiments showed that K+ efflux, reactive oxygen species (ROS) production, and mitochondrial DNA damage may be involved in NLRP3 inflammasome activation mediated by TCBQ. Moreover, TCBQ downregulates the ubiquitination of NLRP3, further facilitating the activation of the NLRP3 inflammasome. These results suggest that the NLRP3/IL-1β signaling pathway plays an important role in TCBQ-induced endothelial cell pro-inflammatory responses, which may point to potential therapeutic approaches against TCBQ-mediated toxicity.
研究领域:
毒理学
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免疫学
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细胞生物学
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血管生物学
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产品关联
DOI
PubMed
高影响因子
AQUACULTURE
·
2023
·
IF 4.5
Enzhuang Pan,Huimiao Feng,Zuwang Yang,Yue Xin,Xiaomeng Ji,Kaixin Ping,Yong Sun,Jingquan Dong
As a widely used fungicide at present, difenoconazole can enter the aquatic ecosystem and cause adverse effects on freshwater carp culture. The spleen, an important immune organ of carp, is vulnerable to damage by environmental toxins. Studies have shown that the inflammatory response is an important mechanism of immunotoxicity of difenoconazole. Whereas quercetin has anti-inflammatory pharmacological activity, the role and mechanism of quercetin in difenoconazole-induced inflammatory damage in the spleen of carp is unknown. In this study, we developed a model for carp with quercetin added to the diet and exposed to environmentally relevant concentrations of difenoconazole. We found that quercetin protects against inflammatory damage in the splenic tissue of carp through histopathological observations. We found that quercetin alleviated ROS enrichment and disruption of redox homeostasis (dynamic balance of GSH, T-AOC, CAT, and MDA) in the spleen tissue of carp by fluorescence assay and biochemical assay. We found that quercetin was able to inhibit the activation of the NF-κB signaling pathway (elevated p-NF-κB p65 expression level) and NLRP3 inflammasome pathway (NLRP3/ASC/caspase-1) in carp spleen tissue induced by difenoconazole by immunohistochemistry and qPCR analysis. In conclusion, this study confirms that the addition of quercetin as a supplement to the diets of freshwater cultured carp is effective against the spleen toxicity induced by difenoconazole. Mechanistically, quercetin may alleviate the difenoconazole-induced splenic inflammatory injury in carp by suppressing the excessive activation of ROS/NF-κB/NLRP3 inflammasome axis, providing new insights into the mechanism of quercetin alleviation of splenic inflammatory injury in carp.
研究领域:
水产养殖
·
毒理学
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免疫学
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药理学
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环境科学
✓ 已验证
产品关联
DOI
高影响因子
Pharmaceuticals
·
2025
·Vol. 18
·期 8
·1109
·
IF 4.8
Lingxin Zhuo,Mingxuan Ma,Jiayi Zhang,Jiayu Zhou,Yuqi Zheng,Aiyin Liang,Qingqing Sun,Jia Liu,Wenting Liao
Background/Objectives: Sepsis-induced cardiomyopathy (SIC) is a serious clinical disorder with a high death rate. Qifu decoction (QFD) is a renowned traditional Chinese medicine with documented pharmacological actions, such as anti-inflammatory, anti-oxidant and anti-apoptosis activities, and it has good therapeutic effects on cardiovascular diseases. This study aimed to reveal the cardioprotective effects and underlying mechanisms of QFD against SIC.Methods: Electrocardiography, histopathological examination, and biochemical indicator determination were carried out to investigate the cardioprotective effects of QFD in the treatment of LPS-induced SIC mice. Metabolomics and network pharmacology strategies were employed to preliminarily analyze and predict the mechanisms of QFD against SIC. Molecular docking and Western blot were further applied to validate the core targets and potential pathways for the treatment of SIC in in vitro and in vivo models.Results: It was found that QFD considerably enhanced cardiac function; attenuated myocardial injury; and reduced the serum levels of LDH, CK-MB, IL-1β, and TNF-α by 28.7%, 32.3%, 38.6%, and 36.7%, respectively. Metabolomic analysis showed that QFD could regulate seven metabolic pathways, namely, glutathione metabolism; alanine, aspartate, and glutamate metabolism; arachidonic acid metabolism; glycerophospholipid metabolism; purine metabolism; sphingolipid metabolism; and fatty acid metabolism. Network pharmacology suggested that the anti-SIC effect of QFD may be mediated through the TNF, toll-like receptor, NOD-like receptor, NF-κB, and PPAR signaling pathways. Additionally, 26 core targets were obtained. Molecular docking revealed that active ingredients such as formononetin, kaempferol, quercetin, and (R)-norcoclaurine in QFD had a high affinity for binding to PPARα and TLR4. Further Western blot validation indicated that QFD could regulate the protein levels of NLRP3, TLR4, NF-κB, IL-6, TNF-α, COX2, sPLA2, PPARα, CPT1B, and CPT2.Conclusions: This study demonstrates that QFD can alleviate SIC by suppressing the TLR4/NF-κB/NLRP3 inflammatory pathway and modulating impaired FAO through the activation of the PPARα/CPT pathway, highlighting QFD as a promising candidate drug for SIC treatment.
研究领域:
心脏病学
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药理学
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中医学
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分子生物学
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免疫学
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代谢组学
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网络药理学
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产品关联
DOI
PubMed
高影响因子
EXPERIMENTAL GERONTOLOGY
·
2024
·
IF 3.3
Baoying Wang,Lei Tian,Mengdi Wu,Duo Zhang,Xiangli Yan,Ming Bai,Yucheng Li,Pan Su,Erping Xu
The NLRP3 inflammasome is critically involved in the development of depression. The E3 ubiquitin ligase TRIM31 negatively regulates this process by promoting the degradation of NLRP3 through the ubiquitin-proteasome pathway. Modified Danzhi Xiaoyaosan (MDZXYS) has shown good therapeutic effect in both preclinical and clinical depression treatments, yet the underlying mechanisms of its antidepressant effects are not fully understood. In the present study, we aimed to explore the antidepressant mechanisms of MDZXYS, focusing on NLRP3 activation and ubiquitin-mediated degradation. We employed rats with depression induced by chronic unpredictable mild stress (CUMS) and conducted various behavioral tests, including the sucrose preference, forced swimming, and open field tests. Neuronal damage in CUMS-treated rats was assessed using Nissl staining. We measured proinflammatory cytokine levels using ELISA kits and analyzed NLRP3/TRIM31 protein expression via Western blotting and immunofluorescence staining. Our results disclosed that MDZXYS reversed CUMS-induced depression-like behaviors in rats, reduced proinflammatory cytokine levels (IL-1β), and ameliorated neuronal damage in the prefrontal cortex. Additionally, CUMS activated the NLRP3 inflammasome in the prefrontal cortex and upregulated the protein expression of TRIM31. After MDZXYS administration, the expression of NLRP3 inflammasome-associated proteins was reduced, while the expression level of TRIM31 was further increased. Through co-localized immunofluorescence staining, we observed a significant elevation in the co-localization expression of NLRP3 and TRIM31 in the prefrontal cortex of the MDZXYS group. These findings suggest that inhibiting NLRP3 inflammasome-mediated neuroinflammation by modulating the TRIM31signaling pathway may underlie the antidepressant effects of MDZXYS, and further support targeting NLRP3 as a novel approach for the prevention and treatment of depression.
研究领域:
神经科学
·
药理学
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精神病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Neural Regeneration Research
·
2024
·Vol. 19
·期 10
·2270
·
IF 5.9
Qi Yize,Zhou Yao,Li Jiyang,Zhu Fangyuan,Guo Gengni,Wang Can,Yu Man,Wang Yijie,Ma Tengfei,Feng Shanwu,Zhou Li
Methamphetamine addiction is a brain disorder characterized by persistent drug-seeking behavior, which has been linked with aberrant synaptic plasticity. An increasing body of evidence suggests that aberrant synaptic plasticity is associated with the activation of the NOD-like receptor family pyrin domain containing-3 (NLRP3) inflammasome. 3′-Deoxyadenosin, an active component of the Chinese fungus Cordyceps militaris, has strong anti-inflammatory effects. However, whether 3′-deoxyadenosin attenuates methamphetamine-induced aberrant synaptic plasticity via an NLRP3-mediated inflammatory mechanism remains unclear. We first observed that 3′-deoxyadenosin attenuated conditioned place preference scores in methamphetamine-treated mice and decreased the expression of c-fos in hippocampal neurons. Furthermore, we found that 3′-deoxyadenosin reduced the aberrant potentiation of glutamatergic transmission and restored the methamphetamine-induced impairment of synaptic plasticity. We also found that 3′-deoxyadenosin decreased the expression of NLRP3 and neuronal injury. Importantly, a direct NLRP3 deficiency reduced methamphetamine-induced seeking behavior, attenuated the impaired synaptic plasticity, and prevented neuronal damage. Finally, NLRP3 activation reversed the effect of 3′-deoxyadenosin on behavior and synaptic plasticity, suggesting that the anti-neuroinflammatory mechanism of 3′-deoxyadenosin on aberrant synaptic plasticity reduces methamphetamine-induced seeking behavior. Taken together, 3′-deoxyadenosin alleviates methamphetamine-induced aberrant synaptic plasticity and seeking behavior by inhibiting the NLRP3 inflammasome.
研究领域:
神经科学
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药理学
·
炎症
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成瘾
·
行为神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Gut Microbes
·
2024
·
IF 12.2
Zhenhui Chen,Huijuan Chen,Wanwen Huang,Xiaotong Guo,Lu Yu,Jiamin Shan,Xiaoshi Deng,Jiaxin Liu,Wendan Li,Wei Shen,Hongying Fan
Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in premature infants with no specific treatments available. We aimed to identify the molecular mechanisms underlying NEC and investigate the therapeutic effects of Bacteroides fragilis on NEC. Clinical samples of infant feces, bile acid-targeted metabolomics, pathological staining, bioinformatics analysis, NEC rat model, and co-immunoprecipitation were used to explore the pathogenesis of NEC. Taxonomic characterization of the bile salt hydrolase (bsh) gene, enzyme activity assays, 16S rRNA sequencing, and organoids were used to explore the therapeutic effects of B. fragilis on NEC-related intestinal damage. Clinical samples, NEC rat models, and in vitro experiments revealed that total bile acid increased in the blood but decreased in feces. Moreover, the levels of FXR and other bile acid metabolism-related genes were abnormal, resulting in disordered bile acid metabolism in NEC. Taurochenodeoxycholic acid accelerated NEC pathogenesis and taurodeoxycholate alleviated NEC. B. fragilis displayed bsh genes and enzyme activity and alleviated intestinal damage by restoring gut microbiota dysbiosis and bile acid metabolism abnormalities by inhibiting the FXR-NLRP3 signaling pathway. Our results provide valuable insights into the therapeutic role of B. fragilis in NEC. Administering B. fragilis may substantially alleviate intestinal damage in NEC.
研究领域:
微生物学
·
胃肠病学
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儿科
·
代谢组学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Pan Su,Liming Liu,Yuhang Gong,Shuaijun Peng,Xiangli Yan,Ming Bai,Erping Xu,Yucheng Li
Background The pathogenesis of depression is largely influenced by dyshomeostasis of neuroinflammation regulated by microglia M1/M2 polarization, and NLRP3 inflammasome acts critical roles in shifting microglia polarization. Kaempferol (Kae), a major flavonoid in edible plants, possesses anti-inflammation and anti-depression capacity, but its underlying cellular and molecular mechanisms of antidepressive effect have not yet fully explored. Methods In vivo studies with lipopolysaccharide (LPS)-induced depressive mice were carried out to evaluate antidepressant effect of Kae. In vitro, BV2 microglia cell line stimulated by LPS along with IFN-γ to detect pharmacological effects of Kae on microglia polarization and NLRP3. Based on two depression-related GEO datasets (GSE54570 and GSE54568) and the potential targets of Kae obtained from GeneCards database, enrichment analysis and protein–protein interaction (PPI) network construction reveal potential therapeutic targets of Kae for depression. Then the precise antidepressant mechanisms of Kae were verified by western blot and immunofluorescent staining in vivo and vitro . Results Our results showed that Kae significantly improves LPS-induced depressive behaviors and alleviates neuroinflammation in prefrontal cortex. Moreover, Kae obviously shifted microglia polarization to M2 phenotype, and also suppressed NLRP3 in prefrontal cortex and BV2. Enrichment analysis and PPI network construction suggested PPARγ and STAT1 signaling are related to regulation of NLRP3 in depression. Furtherly, Kae remarkably enhanced PPARγ activation and inhibited nuclear translocation of p-STAT1 in microglia of prefrontal cortex and BV2. Importantly, pre-incubation with PPARγ antagonist T0070907 or overexpression with CA STAT1 (constitutively active STAT1) both prevented pharmacologic effects of Kae on shifting microglia polarization and suppressing NLRP3 in BV2. Noteworthily, T0070907 significantly blocked the inhibitory effect of Kae on STAT1 while overexpression with CA STAT1 abolished the effect of Kae on PPARγ activation in BV2. Above results suggested that pharmacologic effects of Kae on microglia polarization and NLRP3 are dependent on the balance of counter-regulatory PPARγ and STAT1 signaling. Conclusion Our results indicated that the shifting microglia polarization and suppression of NLRP3 via tilting the balance of PPARγ and STAT1 signaling may be the antidepressant mechanism of Kae, which provides a novel perspective for elucidating antidepressive effect of Kae.
研究领域:
药理学
·
神经科学
·
免疫学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FASEB JOURNAL
·
2023
·Vol. 37
·期 6
·e22964
·
IF 4.8
Fei Sun,Cheng An,Can Liu,Ying Hu,Yue Su,Zhixiang Guo,Hong Che,Shenglin Ge
Cardiac ischemia/reperfusion (I/R) injury is a complicated pathological event, which has close association with pyroptosis. This study uncovered the regulatory mechanisms of fat mass and obesity-associated protein (FTO) in NLRP3-mediated pyroptosis during cardiac I/R injury. H9c2 cells were stimulated with oxygen–glucose deprivation/reoxygenation (OGD/R). Cell viability and pyroptosis were detected by CCK-8 and flow cytometry. Western blotting or RT-qPCR was performed to analyze target molecule expression. NLRP3 and Caspase-1 expression was observed by immunofluorescence staining. IL-18 and IL-1β production was detected by ELISA. The total m6A and m6A level of CBL was determined by dot blot assay and methylated RNA immunoprecipitation-qPCR, respectively. The interaction between IGF2BP3 and CBL mRNA was confirmed by RNA pull-down and RIP assays. The protein interaction between CBL and β-catenin and β-catenin ubiquitination were evaluated by Co-IP. Myocardial I/R model was established in rats. We determined infarct size by TTC staining and pathological changes by H&E staining. LDH, CK-MB, LVFS, and LVEF were also assessed. FTO and β-catenin were down-regulated, while CBL was up-regulated by OGD/R stimulation. FTO/β-catenin overexpression or CBL silencing restrained OGD/R-induced NLRP3 inflammasome-mediated pyroptosis. CBL repressed β-catenin expression via ubiquitination and degradation. FTO reduced the mRNA stability of CBL by inhibiting m6A modification. CBL-mediated ubiquitination and degradation of β-catenin were involved in FTO-induced pyroptosis inhibition during myocardial I/R injury. FTO inhibits NLRP3-mediated pyroptosis to attenuate myocardial I/R injury via repressing CBL-induced ubiquitination degradation of β-catenin.
研究领域:
心脏病学
·
分子生物学
·
细胞生物学
·
病理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）