PHYTOMEDICINE
·
2025
·
IF 8.3
Mengxin Li,Jun Wang,Zihan Xu,Yue Lin,Jingquan Dong
Background Obstructive sleep apnea syndrome (OSAS), a chronic disorder affecting approximately 10% of adults worldwide with heightened prevalence in males and obese populations, induces irreversible neurocognitive impairment. Atraric Acid (AA), a natural depside compound derived from lichens, exhibits dual functional properties through its molecular groups capable of free radical scavenging and metal chelation. However, its therapeutic potential in OSAS-related pathologies remains unexplored. Objective This study aims to investigate the neuroprotective effects and molecular mechanisms of AA against CIH-induced neuronal damage. Methods CIH mouse models and hypoxic injury models in HT22 neurons were established. AA was administered to mice at doses of 5, 10, and 20 mg/kg (selected based on literature references and preliminary experiments), and to cells at an optimal concentration of 20 μM (determined by CCK-8 assays). Therapeutic efficacy was evaluated through behavioral tests including the Morris Water Maze, Elevated Plus Maze, and Open Field Test. Neuroprotective effects were assessed via histopathological examination (e.g., neuronal survival in hippocampal CA3 and DG sub-regions) and detection of oxidative stress/ferroptosis markers (e.g., MDA levels, GPX4 expression, and related biomarkers). Transcriptomic sequencing and molecular docking analyses were employed to investigate differentially expressed genes, pathway enrichment, and underlying mechanisms. Results In vivo and in vitro experiments demonstrated that AA significantly alleviated neuronal damage in CIH mice and enhanced HT22 cell viability. AA down-regulated oxidative stress- and ferroptosis-related gene expression. Transcriptomic sequencing identified AMPK signaling as a key target. Combined AMPK inhibitor (Compound C) and nuclear-cytoplasmic fractionation experiments confirmed that AA synergistically regulates dual antioxidant pathways (Nrf2/HO-1 and FoxO3a/SOD2) via AMPK activation. Conclusion AA mitigates CIH-induced neurocognitive impairment by AMPK-dependent activation of the Nrf2/HO-1 and FoxO3a/SOD2 axes, establishing a dual antioxidant-ferroptosis defense barrier. This study is the first to systematically elucidate AA's molecular mechanisms using transcriptomics data integrated with computational simulations, providing novel therapeutic targets and a translational paradigm for developing natural compound-based therapies for OSAS.
研究领域:
神经生物学
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睡眠医学
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分子药理学
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氧化应激
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信号转导
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转化医学
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天然产物药理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION
·
2025
·
IF 3.5
Liang Yongchao,Huo Hongjin,Wei Wei,Wang Dongxuan,Lu Jingjing,Yi Wenjie,Jiang Fei
Purpose Perfluorooctane sulfonic acid (PFOS) is a representative persistent organic pollutant that has been shown to impair male reproductive function. Epidemiological studies and animal models suggest that vitamin D may modify male reproductive function. However, whether 1α,25(OH) 2 D 3 could mitigate the PFOS-induced damage of Sertoli cells, and the underlying mechanisms remain poorly defined. Methods Mouse Sertoli cell line TM4 were pretreated with or without 10 nM or 100 nM 1α,25(OH) 2 D 3 for 6 h, followed by 100 µM or 200 µM PFOS for 24 h. Cell viability was assessed using the CCK8 assay. Reactive oxygen species (ROS) were detected by fluorescent staining, while malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) levels were measured using commercial kits. siRNA transfection, quantitative real-time PCR (qRT‒PCR), and Western blotting were performed to elucidate the underlying mechanisms. Molecular docking studies were conducted to explore the potential binding of PFOS to Keap1. Results PFOS increased MDA contents, decreased GSH levels, and induced cytotoxicity in mouse Sertoli cells. Mechanistically, PFOS might directly bind to Keap1, facilitating its degradation, leading to persistent activation of the Nrf2-ARE pathway. Conversely, 1α,25(OH) 2 D 3 attenuated PFOS-induced cytotoxicity by alleviating the Nrf2-ARE pathway, a protective effect which was abolished by vitamin D receptor (VDR) knockdown. Conclusion PFOS induces cytotoxicity in Sertoli cells by binding to Keap1 and persistently activating the Nrf2-ARE pathway. 1α,25(OH) 2 D 3 emerges as a promising candidate for mitigating PFOS-induced testicular dysfunction. Graphical abstract
研究领域:
毒理学
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分子生物学
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内分泌学
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生殖生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICAL RESEARCH
·
2024
·
IF 2.8
Yang Chen,Shujun Bao,Zhongzhao Wang,Zheng Fang,Hao Tang
Background Cisplatin (DDP) chemotherapy is commonly used in therapy for non-small cell lung cancer (NSCLC), but increased drug resistance has become a huge obstacle. Baicalin (BA) contributed to the sensitivity of NSCLC to DDP. Here, we aimed to further probe the pathophysiological mechanisms of BA in NSCLC. Methods A549 and A549/DDP cells and xenograft mice were treated with BA and DDP. Xenograft mice were treated additionally with the NRF2 inducer (Bardoxolone methyl, BM) and KEAP1 knockdown. The levels of ferritinophagy-related proteins and biomarkers were determined. The autophagosomes were observed. M1 macrophage polarization and the contents of related indicators were analyzed. The involvement of KEAP1/NRF2/HO-1 was determined. Results BA inhibited cell development, and the effect of BA and DDP on cell development was additive. The abundance of ferritinophagy-related proteins and the number of autophagosomes were induced by BA. BA also promoted the transition of GSH to GSSH. BA favored M1 macrophage polarization and affected the expression of related proteins. When BA and DDP combined, these molecular phenomena were further exacerbated. BA induced accumulation of KEAP1 and reduction of NRF2 and HO-1. However, BM and KEAP1 knockdown disrupted the synergistic effects of BA and DDP on inhibiting NSCLC growth. BM and KEAP1 knockdown reversed DDP and BA-promoted protein expression activity and M1 macrophage polarization. Conclusion Our findings suggest that BA is involved in ferritinophagy and macrophage immunity through the KEAP1-NRF2/HO-1 axis, thereby improving the DDP sensitivity in NSCLC, which could provide new candidates for treatment strategies.
研究领域:
肿瘤学
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药理学
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免疫学
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分子生物学
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2023
·
IF 5.8
Xinyu Guo,Mengqing Liu,Bing Han,Yeqing Zheng,Kaina Zhang,Gaowa Bao,Chenying Gao,Hongwen Shi,Qiang Sun,Zhenghang Zhao
The clinic application of doxorubicin (DOX) is severely limited by its severe cardiotoxicity. Tripartite motif-containing protein 16 (TRIM16) has E3 ubiquitin ligase activity and is upregulated in cardiomyocytes under pathological stress, yet its role in DOX-induced cardiotoxicity remains elusive. This study aims to investigate the role and mechanism of TRIM16 in DOX cardiotoxicity. Following TRIM16 overexpression in hearts with AAV9-TRIM16, mice were intravenously administered DOX at a dose of 4 mg/kg/week for 4 weeks to assess the impact of TRIM16 on doxorubicin-induced cardiotoxicity. Transfection of OE-TRIM16 plasmids and siRNA-TRIM16 was performed in neonatal rat cardiomyocytes (NRCMs). Our results revealed that DOX challenge elicited a significant upregulation of TRIM16 proteins in cardiomyocytes. TRIM16 overexpression efficiently ameliorated cardiac function while suppressing inflammation, ROS generation, apoptosis and fibrosis provoked by DOX in the myocardium. TRIM16 knockdown exacerbated these alterations caused by DOX in NRCMs. Mechanistically, OE-TRIM16 augmented the ubiquitination and degradation of p-TAK1, thereby arresting JNK and p38MAPK activation evoked by DOX in cardiomyocytes. Furthermore, DOX enhanced the interaction between p-TAK1 and YAP1 proteins, resulting in a reduction in YAP and Nrf2 proteins in cardiomyocytes. OE-TRIM16 elevated YAP levels and facilitated its nuclear translocation, thereby promoting Nrf2 expression and mitigating oxidative stress and inflammation. This effect was nullified by siTRIM16 or TAK1 inhibitor Takinib. Collectively, the current study elaborates that upregulating TRIM16 mitigates DOX-induced cardiotoxicity through anti-inflammation and anti-oxidative stress by modulating TAK1-mediated p38 and JNK as well as YAP/Nrf2 pathways, and targeting TRIM16 may provide a novel strategy to treat DOX-induced cardiotoxicity.
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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细胞生物学
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DOI
PubMed
高影响因子
ENVIRONMENTAL TOXICOLOGY
·
2022
·Vol. 37
·期 12
·2910-2923
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IF 4.109
Yuting Wu,Jiwen Liu,Shuhui Liu,Wentao Fan,Chenchen Ding,Zhangshan Gao,Zhihui Tang,Yan Luo,Xizhi Shi,Lei Tan,Suquan Song
Since the outbreak of COVID-19, widespread utilization of disinfectants has led to a tremendous increase in the generation of disinfection byproducts worldwide. Bromoacetic acid (BAA), one of the common disinfection byproducts in the environment, has triggered public concern because of its adverse effects on urinary system in mammals. Nevertheless, the BAA-induced nephrotoxicity and potential mechanism in birds still remains obscure. According to the detected content in the Taihu Lake Basin, the model of BAA exposure in chicken was established at doses of 0, 3, 300, 3000 μg/L for 4 weeks. Our results indicated that BAA exposure caused kidney swelling and structural disarrangement. BAA led to disorder in renal function (CRE, BUN, UA) and increased apoptosis (Bax, Bcl-2, caspase3). BAA suppressed the expression of mitochondrial biogenesis genes (PGC-1α, Nrf1, TFAM) and OXPHOS complex I genes (ND1, ND2, ND3, ND4, ND4L, ND5, ND6). Subsequently, BAA destroyed the expression of Nrf2 antioxidant reaction genes (Nrf2, Keap1, HO-1, NQO1, GCLM, GCLC). Furthermore, renal oxidative damage led to disorder in uric acid metabolism genes (Mrp2, Mrp4, Bcrp, OAT1, OAT2, OAT3) and exacerbated destruction in renal function. Overall, our study provided insights into the potential mechanism of BAA-induced nephrotoxicity, which were important for the clinical monitoring and prevention of BAA.
研究领域:
环境科学
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毒理学
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动物生理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Food Science & Nutrition
·
2025
·Vol. 13
·期 3
·e70105
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IF 3.8
Heting Zhou,Xinyue Zheng,Shaolin Huang,Xiaomeng Wang,Ting Zhou,Shuwen Zhang,Yihan Ling,Wenxi Wang,Xingjie Li,Shouqian Li,Yongmei Xie,Wenya Yin
Pulmonary fibrosis (PF) is a chronic and progressive lung disease, and oxidative stress plays a critical role in its pathogenesis. Rosa roxburghii Tratt, known for its anti-inflammatory and antioxidant properties, has been shown to alleviate fibrosis. This study aimed to explore whether two Rosa roxburghii fermentation broths (RRFBs) (with different proportions) could attenuate bleomycin (BLM)-induced PF in mice and to elucidate the molecular mechanisms. The results revealed that RRFBs reduced structural lung damage, collagen deposition, and lung inflammation. RRFBs also suppressed fibrotic markers (Collagen I, Vimentin, and α-SMA) while enhancing epithelial marker E-cadherin expression. Additionally, RRFBs alleviated BLM-induced oxidative stress and apoptosis by activating the Nrf2/HO-1/NQO1 signaling pathway and facilitating Nrf2 nuclear translocation. Furthermore, RRFBs attenuated the BLM-induced changes in the gut microbiota; in particular, they decreased the abundance of the pathogenic bacterium Proteus and increased the abundance of the probiotics Ileibacterium and Dubosiella . Spearman correlation analysis revealed a strong association between oxidative stress inhibition and gut microbiota composition. These results indicated that RRFBs could exert lung-protective effects by inhibiting oxidative stress and alleviating intestinal disturbances.
研究领域:
药理学
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分子生物学
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微生物学
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产品关联
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2023
·
IF 5.1
Tianyang Wang,Jian Zhang,Haokai Wei,Xi Wang,Minjuan Xie,Yinjie Jiang,Jie Zhou
Introduction Matrine (MT), an ingredient extracted from the Chinese herb Sophora flavescens , can result in nephrotoxicity because of long-term exposure. However, the underlying mechanism by which MT leads to kidney injury remains unclear. This study aimed to investigate the roles of oxidative stress and mitochondria in MT-induced kidney toxicity both in vitro and in vivo . Methods Mice were exposed to MT for 20 days, and NRK-52E cells were exposed to MT with or without LiCl (a GSK-3β inhibitor), tert-Butylhydroquinone (t-BHQ, an Nrf2 activator), or small interfering RNA . Results The results showed that MT caused nephrotoxicity accompanied by an increase in reactive oxygen species (ROS) accumulation and mitochondrial dysfunction. Meanwhile, MT significantly upregulated glycogen synthase kinase-3β (GSK-3β) activity, released cytochrome c (Cyt C) and cleaved caspase-3, decreased the activity of nuclear factor-erythroid 2-related Factor 2 (Nrf2), and reduced the expression of heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO-1), which led to the inactivation of antioxidant enzymes and the activation of apoptosis . In addition, GSK-3β inhibition by LiCl or small interfering RNA pretreatment or Nrf2 activation by t-BHQ pretreatment attenuated the toxic effects of MT in NRK-52E cells. Conclusions Taken together, these results revealed that MT-induced apoptosis triggered kidney toxicity and that GSK-3β or Nrf2 might serve as a promising nephroprotective target for MT-induced kidney injury.
研究领域:
药理学
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毒理学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Kunfeng Zhang,Hao Chen,Yunbo Hao,Wensen Li,Yong Li,Wenna Zhang,Yan Chen
We identified Armillariella tabescens polysaccharide (PAT-W), a compound isolated from a Chinese medicinal mushroom , as a potential novel oral ulcer (OU) drug. In treating OU rats with PAT-W, especially in the high-dose group, oral mucous tissue TNF- α , IL-1 β , and IL-6 levels were markedly reduced, and pathological morphology and oxidative stress were effectively improved. Western blot analysis showed that the PAT-W channel ameliorated OU mucous tissue damage, which depends on the activation of the Nrf2/HO-1 antioxidant signaling pathway . Furthermore, high-throughput sequencing results showed that PAT-W regulated the maladjustment of the oral microbiota caused by OU. Therefore, based on the new viewpoint of activating the Nrf2/HO-1 pathway and regulating oral microbiota, PAT-W is expected to become a new natural drug for treating oral ulcers and improving patients' quality of life.
研究领域:
药理学
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免疫学
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微生物学
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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 AGRICULTURAL AND FOOD CHEMISTRY
·
2019
·
IF 3.571
Dongwen Hu,Tao Bao,Yang Lu,Hongming Su,Huihui Ke,Wei Chen
This study was aimed to investigate the protective effects of three different mulberry fruit polysaccharide fractions (MFP-I, MFP-II, and MFP-III) against palmitic acid (PA)-induced hepatocyte lipotoxicity and characterize the functional polysaccharide fraction using gel permeation chromatography, high-performance liquid chromatography, Fourier transform infrared spectroscopy, and nuclear magnetic resonance analyses. MFP-I, MFP-II, and MFP-III were isolated from mulberry fruit by stepwise precipitation with 30, 60, and 90% ethanol, respectively. MFP-II at 0.1 and 0.2 mg/mL dramatically attenuated PA-induced hepatic lipotoxicity, while MFP-I and MFP-III showed weak protection. It was demonstrated that MFP-II not only increased nuclear factor erythroid-2-related factor 2 (Nrf2) phosphorylation and its nuclear translocation, thereby activating the Nrf2/ARE signaling pathway, but also enhanced heme oxygenase 1, NAD(P)H:quinone oxidoreductase 1, and γ-glutamate cysteine ligase gene expressions and promoted catalase and glutathione peroxidase activities, which protected hepatocytes against PA-induced oxidative stress and lipotoxicity. Further investigation indicated that the molecular weight of MFP-II was 115.0 kDa, and MFP-II mainly consisted of galactose (30.5%), arabinose (26.2%), and rhamnose (23.1%). Overall, our research might provide in-depth insight into mulberry fruit polysaccharide in ameliorating lipid metabolic disorders.
研究领域:
药理学
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生物化学
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细胞生物学
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营养学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL RESEARCH IN TOXICOLOGY
·
2018
·
IF 3.432
Zixuan Liu,Wenjing Dong,Bingwei Yang,Lu Peng,Xiaomin Xia,Lanxiang Pu,Na Zhang,Erqun Song,Yang Song
Our previous studies demonstrated that tetrachlorobenzoquinone (TCBQ) is toxic to neuron-like cells, which is related to endoplasmic reticulum (ER) stress-induced apoptosis. However, it remains unclear whether TCBQ causes the opening of cellular defense responses. Here we found that activation of nuclear factor erythroid-derived 2-like 2 (Nrf2) triggered an adaptive response against the neurotoxicity induced by TCBQ through the upregulation of intracellular glutathione (GSH) levels in rat pheochromocytoma PC12 cells. TCBQ upregulated the levels of GSH mainly by the following two ways: (i) Nrf2 activation induced the expression of cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11, also called xCT); (ii) Nrf2 activation resulted in increased the expression of glutamylcysteine ligase. GSH is involved in cell antioxidant ability and protein thiol homeostasis, especially in the ER. Therefore, GSH has the ability to inhibit ER stress and promote cell survival. Our data showed that decreasing GSH levels exacerbated TCBQ-induced depletion of protein-SH, particularly in the ER. Conversely, increasing GSH levels attenuated TCBQ-induced protein damage, degree of ER stress, and cell death. These findings demonstrated that GSH-inhibited cells were vulnerable to TCBQ-induced ER stress and apoptosis. Overall, our results analyzed the relationships between Nrf2 and ER stress in response to TCBQ and showed that activation of Nrf2-GSH played a protective role against TCBQ-induced ER stress-associated neurotoxicity via regulating GSH synthesis and protein thiol homeostasis.
研究领域:
神经科学
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细胞生物学
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毒理学
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产品关联
DOI
PubMed
高影响因子
CHINESE JOURNAL OF PHYSIOLOGY
·
2023
·Vol. 66
·期 6
·437
·
IF 1.8
Fan Wenbo,Zhou Jianwu
Parkinson's disease (PD) is recognized as a degenerative and debilitating neurodegenerative disorder. The novel protective role of icariside II (ICS II) as a plant-derived flavonoid compound in neurodegenerative diseases has aroused much attention. Herein, the definite impacts of ICS II on the process of PD and the relevant action mechanism were studied. Human neuroblastoma SK-N-SH cells were challenged with 1-methyl-4-phenylpyridinium ion (MPP + ) to construct the PD cell model. MTT assay and flow cytometry analysis, respectively, appraised cell viability and apoptosis. Caspase 3 Activity Assay examined caspase 3 activity. Corresponding kits examined oxidative stress levels. BODIPY 581/591 C11 assay evaluated lipid reactive oxygen species. Iron Assay Kit assessed iron content. Western blot tested the expression of apoptosis-, ferroptosis- and Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) signaling-associated proteins. Molecular docking verified the binding of ICS II with Keap1. The existing experimental results unveiled that ICS II elevated the viability whereas reduced the apoptosis, oxidative stress, and ferroptosis in MPP + -treated SK-N-SH cells in a concentration-dependent manner. Furthermore, ICS II declined Keap1 expression while raised Nrf2, heme oxygenase 1, and GPX4 expression. In addition, ICS II had a strong binding with Keap1 and Nrf2 inhibitor ML385 partially abolished the suppressive role of ICS II in MPP + -triggered apoptosis, oxidative stress, and ferroptosis in SK-N-SH cells. To summarize, ICS II might inhibit apoptosis, oxidative stress, and ferroptosis in the MPP + -stimulated PD cell model, which might be due to the activation of Keap1/Nrf2/GPX4 signaling.
研究领域:
神经科学
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药理学
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细胞生物学
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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
Yilin Pi,Huaiwen Zuo,Yuxin Wang,Weiping Zheng,Huiyuan Zhou,Lamei Deng,Hongli Song
Severe steatosis in donor livers is contraindicated for transplantation due to the high risk of ischemia–reperfusion injury (IRI). Although Ho-1 gene-modified bone marrow mesenchymal stem cells (HO-1/BMMSCs) can mitigate IRI, the role of gut microbiota and metabolites in this protection remains unclear. This study aimed to explore how gut microbiota and metabolites contribute to HO-1/BMMSCs-mediated protection against IRI in severe steatotic livers. Using rat models and cellular models (IAR20 and THLE-2 cells) of steatotic liver IRI, this study revealed that ischemia–reperfusion led to significant liver and intestinal damage, heightened immune responses, impaired liver function, and altered gut microbiota and metabolite profiles in rats with severe steatosis, which were partially reversed by HO-1/BMMSCs transplantation. Integrated microbiome and metabolome analyses identified gut microbial metabolite oleanolic acid as a potential protective agent against IRI. Experimental validation showed that oleanolic acid administration alone alleviated IRI and inhibited ferroptosis in both rat and cellular models. Network pharmacology and molecular docking implicated KEAP1/NRF2 pathway as a potential target of oleanolic acid. Indeed, OA experimentally upregulated NRF2 activity, which underlies its inhibition of ferroptosis and protection against IRI. The gut microbial metabolite OA protects against IRI in severe steatotic liver by promoting NRF2 expression and activity, thereby inhibiting ferroptosis.
研究领域:
肝病学
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移植学
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药理学
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微生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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