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Luteolin alleviated calcium oxalate crystal induced kidney injury by inhibiting Nr4a1-mediated ferroptosis.
IF 6.7 1区 医学
Phytomedicine Pub Date : 2024-11-28 DOI: 10.1016/j.phymed.2024.156302
Zehua Ye, Songyuan Yang, Lijia Chen, Weimin Yu, Yuqi Xia, Bojun Li, Xiangjun Zhou, Fan Cheng
{"title":"Luteolin alleviated calcium oxalate crystal induced kidney injury by inhibiting Nr4a1-mediated ferroptosis.","authors":"Zehua Ye, Songyuan Yang, Lijia Chen, Weimin Yu, Yuqi Xia, Bojun Li, Xiangjun Zhou, Fan Cheng","doi":"10.1016/j.phymed.2024.156302","DOIUrl":"https://doi.org/10.1016/j.phymed.2024.156302","url":null,"abstract":"<p><strong>Background: </strong>The global incidence of calcium oxalate (CaOx) kidney stones is rising, and effective treatments remain limited. Luteolin (Lut), a naturally flavonoid present in several plants, is recognized for its anti-inflammatory, anti-injury, and neuroprotective effects. However, its effects on CaOx kidney stone formation and the associated kidney damage are still unknown.</p><p><strong>Objective: </strong>Our study seeks to explore the therapeutic impact of Lut on kidney injury and renal fibrosis caused by CaOx crystal and to elucidate the underlying mechanisms.</p><p><strong>Methods: </strong>CaOx stone models were established in mice via intraperitoneal injection of glyoxylate (Gly, 100 mg/kg) for 12 days. Lut (50 mg/kg or 100 mg/kg) was administered intraperitoneally 7 days before and with the period of Gly treatment. Kidney function and histopathology changes in renal tissues were assessed. RNA sequencing was used to explore potential mechanisms between the model and Lut treatment groups. Molecular docking simulations evaluated the interaction between Lut and the downstream target Nr4a1. Moreover, Nr4a1 knockout mice and knockdown plasmids were used to validate the mechanism of Lut in the treatment of CaOx crystal-induced kidney injury.</p><p><strong>Results: </strong>Lut significantly mitigated kidney injury and renal fibrosis induced by CaOx crystal, as evidenced by improved kidney function, histopathology staining and Western blot analysis. Lut treatment also significantly inhibited lipid peroxidation and mitochondrial injury. In vitro experiments further demonstrated that Lut treatment alleviated injury and fibrosis in HK-2 cells. Mechanistically, RNA sequencing and molecular docking simulations indicated that Lut binds to Nr4a1 to regulate ferroptosis, thereby alleviating kidney injury induced by CaOx crystal. Overexpression of Nr4a1 negated Lut's beneficial effects, whereas Nr4a1 knockout exhibited a protective effect against kidney injury.</p><p><strong>Conclusion: </strong>Lut exerts its protective effects by inhibiting ferroptosis via targeting Nr4a1-Slc7a11-GPX4 pathway, alleviating kidney injury and renal fibrosis caused by CaOx crystal deposition.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"136 ","pages":"156302"},"PeriodicalIF":6.7,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142814034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Corrigendum to " Baicalin and N-acetylcysteine regulate choline metabolism via TFAM to attenuate cadmium-induced liver fibrosis" [Phytomedicine. 2024 Mar;125:155337.
IF 6.7 1区 医学
Phytomedicine Pub Date : 2024-11-28 DOI: 10.1016/j.phymed.2024.156285
Jian Sun, Yan Chen, Tao Wang, Waseem Ali, Yonggang Ma, Yan Yuan, Jianhong Gu, Jianchun Bian, Zongping Liu, Hui Zou
{"title":"Corrigendum to \" Baicalin and N-acetylcysteine regulate choline metabolism via TFAM to attenuate cadmium-induced liver fibrosis\" [Phytomedicine. 2024 Mar;125:155337.","authors":"Jian Sun, Yan Chen, Tao Wang, Waseem Ali, Yonggang Ma, Yan Yuan, Jianhong Gu, Jianchun Bian, Zongping Liu, Hui Zou","doi":"10.1016/j.phymed.2024.156285","DOIUrl":"https://doi.org/10.1016/j.phymed.2024.156285","url":null,"abstract":"","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":" ","pages":"156285"},"PeriodicalIF":6.7,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142755042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Plumbagin alleviates muscle atrophy in female mice through inhibiting the DANCR/NF-κB axis
IF 6.7 1区 医学
Phytomedicine Pub Date : 2024-11-28 DOI: 10.1016/j.phymed.2024.156282
Yu Liu , Honglin Chen , You Zhang , Qi Shang , Wenhua Zhao , Yuzhuo Zhang , Weiyu Qiu , Weicheng Qin , Feng Lin , Jiahui He , Huiwen Liu , Xingda Chen , Yan Gong , Lingjuan Liu , Yixuan Jiang , Hui Ren , Xiaobing Jiang , Gengyang Shen
{"title":"Plumbagin alleviates muscle atrophy in female mice through inhibiting the DANCR/NF-κB axis","authors":"Yu Liu ,&nbsp;Honglin Chen ,&nbsp;You Zhang ,&nbsp;Qi Shang ,&nbsp;Wenhua Zhao ,&nbsp;Yuzhuo Zhang ,&nbsp;Weiyu Qiu ,&nbsp;Weicheng Qin ,&nbsp;Feng Lin ,&nbsp;Jiahui He ,&nbsp;Huiwen Liu ,&nbsp;Xingda Chen ,&nbsp;Yan Gong ,&nbsp;Lingjuan Liu ,&nbsp;Yixuan Jiang ,&nbsp;Hui Ren ,&nbsp;Xiaobing Jiang ,&nbsp;Gengyang Shen","doi":"10.1016/j.phymed.2024.156282","DOIUrl":"10.1016/j.phymed.2024.156282","url":null,"abstract":"<div><h3>Background</h3><div>Muscle atrophy is a condition of the skeletal muscular system closely related to inflammation and significantly affects a person's quality of life and physical activity. It is characterized primarily by the progressive loss of muscle mass, strength, and function. Plumbagin (PB), the main bioactive component of the traditional Chinese medicine Plumbago zeylanica L., has bFeen shown to treat various inflammatory diseases, such as osteoporosis, osteoarthritis, and sepsis. Furthermore, many biological processes, including inflammation, involve differentiation antagonistic nonprotein-coding RNA (DANCR). However, their role and clinical importance in myogenesis and amyotrophy are not well understood.</div></div><div><h3>Purpose</h3><div>This study aimed to explore the role of DANCR and the inflammatory response in the anti-muscle atrophy effects of PB.</div></div><div><h3>Methods</h3><div>The expression of DANCR in muscle atrophic mice and during myogenic differentiation was examined using quantitative reverse transcription PCR (RT‒qPCR). The mechanism of DANCR in muscle atrophy was confirmed through gene knockdown, RNA sequencing (RNA-seq), RNA pull-down, RNA immunoprecipitation (RIP), immunofluorescence (IF), and luciferase reporter gene assays. Bioinformatics was utilized to investigate the mechanism by which PB treatment affects muscle atrophy. The relationship between PB and DANCR was verified by surface plasmon resonance (SPR) and RT‒qPCR. Additionally, the role of PB in muscle atrophy was explored through its control of DANCR-mediated regulation of the NF-κB pathway. Finally, the effect of PB on the myogenic differentiation of human skeletal muscle cells (HsKMCs) was investigated.</div></div><div><h3>Results</h3><div>DANCR expression was upregulated in the muscle tissues of mice with muscle atrophy and downregulated during myogenic differentiation. Knockout of DANCR promoted myogenic differentiation and significantly alleviated the loss of muscle mass, strength, and function in mice with muscle atrophy. The primary mechanism involved DANCR directly binding to the p65 protein to regulate NF-κB pathway activity. Experiments revealed that PB could target the degradation of DANCR, reduce the nuclear entry of p65, and inhibit the activation of the NF-κB pathway. Consequently, PB significantly inhibited myotube atrophy and the inflammatory response in HsKMCs and promoted their myogenic differentiation by regulating the NF-κB pathway.</div></div><div><h3>Conclusions</h3><div>Our results suggest that PB regulates myogenesis and prevents amyotrophy by targeting the degradation of DANCR and inhibiting the activation of the NF-κB pathway. This study reveals the crucial role of DANCR in maintaining muscle physiology during muscle atrophy and identifies PB as an effective drug that can target DANCR degradation to alleviate muscle atrophy.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"136 ","pages":"Article 156282"},"PeriodicalIF":6.7,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142747490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Quercetin inhibits hydrogen peroxide-induced cleavage of heat shock protein 90 to prevent glutathione peroxidase 4 degradation via chaperone-mediated autophagy.
IF 6.7 1区 医学
Phytomedicine Pub Date : 2024-11-26 DOI: 10.1016/j.phymed.2024.156286
Caiwang Peng, Hengli Li, Qingling Mao, Keyan Tang, Mu Sun, Qidi Ai, Yantao Yang, Fang Liu
{"title":"Quercetin inhibits hydrogen peroxide-induced cleavage of heat shock protein 90 to prevent glutathione peroxidase 4 degradation via chaperone-mediated autophagy.","authors":"Caiwang Peng, Hengli Li, Qingling Mao, Keyan Tang, Mu Sun, Qidi Ai, Yantao Yang, Fang Liu","doi":"10.1016/j.phymed.2024.156286","DOIUrl":"https://doi.org/10.1016/j.phymed.2024.156286","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Oxidative stress is caused by the accumulation of reactive oxygen species (ROS) and the depletion of free radical scavengers, which is closely related to ferroptosis in diseases. Quercetin, as a natural flavonoid compound, has been reported to have multiple pharmacological effects on the basis of its anti-oxidative and anti-ferroptotic activities. This study was designed to explore the specific mechanism of quercetin against ferroptosis induced by hydrogen peroxide (H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt;).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;The HT22 cells (mouse hippocampal neuronal cells) treated with 40 μg·ml&lt;sup&gt;-1&lt;/sup&gt; H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; were used to investigate the role of ferroptosis in oxidative stress damage and the regulation of quercetin (7.5, 15, 30 μmol·l&lt;sup&gt;-1&lt;/sup&gt;), as evidenced by assessments of cell viability, morphological damage, Fe&lt;sup&gt;2+&lt;/sup&gt; accumulation, and the expressions of ferroptotic-related proteins. The changes in the expression levels of glutathione peroxidase 4 (GPX4), heat shock cognate protein 70 (HSC70), lysosomal-associated membrane protein 2a (LAMP-2a), and heat shock protein (HSP90) were assessed by qPCR, western blotting (WB) and immunofluorescence (IF) assays. Additionally, the interactions of GPX4, HSC70, LAMP-2a, and HSP90 were examined by co-immunoprecipitation (Co-IP) assay to elucidate the impact of quercetin on the degradation pathway of GPX4 and the CMA pathway. To further explore the regulatory mechanism of quercetin, the si-LAMP-2a and HSP90 mutant cells were conducted.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Pretreatment with 30 μmol·l&lt;sup&gt;-1&lt;/sup&gt; quercetin for 6 h significantly enhanced the survival rate (p &lt; 0.05), maintained cell morphology, and inhibited Fe&lt;sup&gt;2+&lt;/sup&gt; levels in HT22 cells exposed to H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; (40 μg·ml&lt;sup&gt;-1&lt;/sup&gt;). HT22 cells under oxidative stress showed lower expressions of GPX4 and ferritin heavy chain 1 (FTH1), and a higher level of Acyl-CoA synthetase long-chain family member 4 (ACSL4) (p &lt; 0.05). And quercetin significantly reversed the expressions of these ferroptotic proteins (p &lt; 0.05). Moreover, the autophagic lysosomal pathway inhibitor CQ effectively increased the expression of GPX4 in oxidative stress cell model. Further study showed that H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; increased the activity of macroautophagy and chaperone-mediated autophagy (CMA), while quercetin notably suppressed the levels of microtubule-associated protein light chain 3 Ⅱ (LC3 Ⅱ), LAMP-2a, and the activity of lysosomes (p &lt; 0.01). Additionally, quercetin disrupted the interactions of GPX4, HSC70, and LAMP-2a, reduced cellular levels of CMA by decreasing the cleaved HSP90 (c-HSP90), and these effects were reversed in the R347 mutant HT22 cells.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Quercetin has a significantly protective effect on oxidative stress cell model through the inhibition on ferroptosis, which is related to the degradation of GPX4 via CMA. And querc","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"136 ","pages":"156286"},"PeriodicalIF":6.7,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Wolfberry (Lycium barbarum) glycopeptide attenuates dopaminergic neurons loss by inhibiting lipid peroxidation in Parkinson's disease.
IF 6.7 1区 医学
Phytomedicine Pub Date : 2024-11-26 DOI: 10.1016/j.phymed.2024.156275
Xiao-Min Lin, Meng Wang, Xin Xiao, Ya-Li Shi, Ya-Si Zheng, Zi-Han Huang, Ya-Ting Cheng, Rui-Ting Huang, Feng Huang, Kun Li, Jie Sun, Wan-Yang Sun, Hiroshi Kurihara, Yi-Fang Li, Wen-Jun Duan, Rong-Rong He
{"title":"Wolfberry (Lycium barbarum) glycopeptide attenuates dopaminergic neurons loss by inhibiting lipid peroxidation in Parkinson's disease.","authors":"Xiao-Min Lin, Meng Wang, Xin Xiao, Ya-Li Shi, Ya-Si Zheng, Zi-Han Huang, Ya-Ting Cheng, Rui-Ting Huang, Feng Huang, Kun Li, Jie Sun, Wan-Yang Sun, Hiroshi Kurihara, Yi-Fang Li, Wen-Jun Duan, Rong-Rong He","doi":"10.1016/j.phymed.2024.156275","DOIUrl":"https://doi.org/10.1016/j.phymed.2024.156275","url":null,"abstract":"<p><strong>Background: </strong>Parkinson's disease (PD) is a common neurodegenerative disorder characterized clinically by motor dysfunction due to gradual loss of dopaminergic neurons in the nigrostriatal system. Currently, medications such as levodopa preparations, offer only temporary symptomatic relief without preventing neuronal loss or halting disease progression. In traditional Chinese medicine (TCM), a particular type of wolfberry or goji berry, the fruit of Lycium barbarum L., has been historically regarded for its neuroprotective properties, potentially offering therapeutic benefits for PD. However, scientific validation of these effects remains limited.</p><p><strong>Purpose: </strong>This study aims to investigate the neuroprotective effects of wolfberry glycopeptide (WGP) on PD progression in various animal models, and to elucidate the underlying mechanisms responsible for its therapeutic action.</p><p><strong>Study design: </strong>Diverse canonical animal models, including 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, 6-hydroxydopamine (6-OHDA)-treated rats, and α-synuclein overexpressed hSNCA<sup>A53T</sup> mice, were used to evaluate WGP's anti-PD efficacy. Behavioral deficits and pathological damage to dopaminergic neurons were assessed to determine WGP's neuroprotective potential.</p><p><strong>Methods: </strong>After establishing the animal models and administering WGP treatment, PD-like behaviors were assessed using pole test, rotarod test and gait analysis. Dopaminergic neurons loss in the midbrain and striatum was detected by means of immunohistochemistry, immunofluorescence and Western blot analysis. Inflammatory markers in these brain regions were measured by ELISA.</p><p><strong>Results: </strong>WGP treatment significantly alleviated motor deficits as well as progressive dopaminergic neurons loss. Mechanistically, WGP exerted its neuroprotective effects by regulating iron homeostasis, specifically through the modulation of key proteins such as TFRC, FTH1, and FPN. This function contributed to reducing the accumulation of lipid peroxidation in nigrostriatal system, thereby mitigating neuroinflammation and neuronal degeneration.</p><p><strong>Conclusion: </strong>Our findings underscore the innovative potential of WGP as a neuroprotective agent in PD, with a unique mechanism of action targeting iron homeostasis and lipid peroxidation-driven neurodegeneration. This study advances the understanding of TCM's therapeutic contributions to neurodegeneration and positions WGP as a strong candidate for further clinical development in PD treatment.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"136 ","pages":"156275"},"PeriodicalIF":6.7,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142792383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Long term Coptidis Rhizoma intake induce gastrointestinal emptying inhibition and colon barrier weaken via bitter taste receptors activation in mice.
IF 6.7 1区 医学
Phytomedicine Pub Date : 2024-11-26 DOI: 10.1016/j.phymed.2024.156292
Zhizhongbin Wu, Wei Yang, Tianyue Wu, Yulin Liu, Yu Pu, Weiqing Hu, Yunbin Jiang, Jifen Zhang, Huifeng Zhu, Xuegang Li, Shan Feng
{"title":"Long term Coptidis Rhizoma intake induce gastrointestinal emptying inhibition and colon barrier weaken via bitter taste receptors activation in mice.","authors":"Zhizhongbin Wu, Wei Yang, Tianyue Wu, Yulin Liu, Yu Pu, Weiqing Hu, Yunbin Jiang, Jifen Zhang, Huifeng Zhu, Xuegang Li, Shan Feng","doi":"10.1016/j.phymed.2024.156292","DOIUrl":"https://doi.org/10.1016/j.phymed.2024.156292","url":null,"abstract":"<p><strong>Background: </strong>Coptidis Rhizoma, a classic bitter traditional Chinese medicine, can lead to digestive dysfunction when long-term use according to traditional experience. Bitter taste receptors have been found to regulate gastrointestinal smooth muscle contraction. Coptidis Rhizoma alkaloids are potential agonists for bitter taste receptors, but whether they can induce gastrointestinal dysfunction via bitter taste receptors is not clear.</p><p><strong>Purpose: </strong>The purpose of this study is to elucidate whether long-term Coptidis Rhizoma decoction/berberine intake can affect gastrointestinal function via bitter taste receptors.</p><p><strong>Methods: </strong>Firstly, mice were orally administered Coptidis Rhizoma decoction (or berberine) for 8 weeks, then their appetite, gastrointestinal emptying function, colon barrier function, and gut microbiota homeostasis were evaluated. Subsequently, isolated intestine, molecular docking, calcium release, and immunofluorescence co-localization experiments were applied to explore the mechanism of Coptidis Rhizoma decoction (or berberine) inhibition effects on gastrointestinal motility. Finally, transmembrane resistance, scratch assay, tight junction and cytoskeletal protein immunofluorescence staining were conducted to verify that the bitter taste receptor is the target for Coptidis Rhizoma decoction (or berberine) to damage the colon barrier function.</p><p><strong>Result: </strong>Long-term Coptidis Rhizoma decoction (or berberine) intake can reduce appetite, inhibit gastrointestinal contractions, disrupt bacterial balance and colon barrier function in mice. Further mechanistic studies have shown that the alkaloids of Coptidis Rhizoma are agonists for bitter taste receptors, which can promote α-gustducin binding to CHRM3 by activating bitter taste receptors, finally inhibiting gastrointestinal smooth muscle contraction. In addition, Coptidis Rhizoma decoction (or berberine) can activate bitter taste receptors and its downstream pathways PKCβ/RhoA/ROCK1/MLC-2, reshape skeletal proteins, downregulate tight junction protein expression, and ultimately disrupt colon barrier function.</p><p><strong>Conclusions: </strong>Long term Coptidis Rhizoma intake induce gastrointestinal emptying inhibition and colon barrier weaken via bitter taste receptor activation in mice.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"136 ","pages":"156292"},"PeriodicalIF":6.7,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Cyclovirobuxine D inhibits triple-negative breast cancer via YAP/TAZ suppression and activation of the FOXO3a/PINK1-Parkin pathway-induced mitophagy
IF 6.7 1区 医学
Phytomedicine Pub Date : 2024-11-26 DOI: 10.1016/j.phymed.2024.156287
Zi-qiong Wang , Zhi-xuan Wu , Jia-wei Chen , Hong-feng Li , Hao-dong Wu , Jing-xia Bao , Yao Cheng , Yin-wei Dai , Ou-chen Wang , Xuan-xuan Dai
{"title":"Cyclovirobuxine D inhibits triple-negative breast cancer via YAP/TAZ suppression and activation of the FOXO3a/PINK1-Parkin pathway-induced mitophagy","authors":"Zi-qiong Wang ,&nbsp;Zhi-xuan Wu ,&nbsp;Jia-wei Chen ,&nbsp;Hong-feng Li ,&nbsp;Hao-dong Wu ,&nbsp;Jing-xia Bao ,&nbsp;Yao Cheng ,&nbsp;Yin-wei Dai ,&nbsp;Ou-chen Wang ,&nbsp;Xuan-xuan Dai","doi":"10.1016/j.phymed.2024.156287","DOIUrl":"10.1016/j.phymed.2024.156287","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Triple-negative breast cancer (TNBC) is characterized by its rapid progression and aggressive nature, with limited effective therapeutic interventions currently available. &lt;em&gt;Cyclovirobuxine D&lt;/em&gt; (&lt;em&gt;CVB-D&lt;/em&gt;), a natural alkaloid extracted from the traditional Chinese herb &lt;em&gt;Buxus sinica&lt;/em&gt;, is renowned for its cardioprotective and anti-ischemic effects, demonstrating notable anti-cancer properties. Nevertheless, the anti-tumor effects of &lt;em&gt;CVB-D&lt;/em&gt; on TNBC remain unverified.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Purpose&lt;/h3&gt;&lt;div&gt;This study seeks to investigate the effects of &lt;em&gt;CVB-D&lt;/em&gt; on TNBC and to uncover the underlying mechanisms.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Study Design&lt;/h3&gt;&lt;div&gt;Network pharmacology, SPR, DSF, and cell-based functional assays were conducted on TNBC cells to assess the impact of &lt;em&gt;CVB-D&lt;/em&gt;. Findings were further corroborated using xenograft mouse models.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Cell Counting Kit-8, 5-Ethynyl-2′-deoxyuridine, transwell assays, flow cytometry, wound healing assays, immunofluorescence, and immunoblotting were employed to evaluate &lt;em&gt;CVB-D&lt;/em&gt;'s influence on TNBC cell lines. SPR, DSF and molecular docking techniques were utilized to assess the binding affinity of &lt;em&gt;CVB-D&lt;/em&gt; to Yes-associated protein (YAP). The interaction between &lt;em&gt;CVB-D&lt;/em&gt; and autophagy/mitophagy was further analyzed through plasmid transient transfection, JC-1 assay, TUNEL assay, and the use of autophagy inhibitors. The anti-TNBC mechanism of &lt;em&gt;CVB-D&lt;/em&gt; was elucidated by overexpressing YAP in MDA-MB-231 cells. Additionally, the &lt;em&gt;in vivo&lt;/em&gt; efficacy and safety of &lt;em&gt;CVB-D&lt;/em&gt; were assessed in a xenograft mouse model.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;&lt;em&gt;In vitro&lt;/em&gt; analyses revealed that &lt;em&gt;CVB-D&lt;/em&gt; effectively suppressed G1 phase arrest and inhibited TNBC cell proliferation. Moreover, &lt;em&gt;CVB-D&lt;/em&gt; induced mitochondrial-dependent apoptosis and reduced cell migration by antagonizing epithelial-mesenchymal transition. Mechanistically, &lt;em&gt;CVB-D&lt;/em&gt; exerted its anti-cancer effects by directly binding to YAP, thereby inhibiting the nuclear translocation of YAP/TAZ and suppressing the transcription of downstream oncogenic target genes. Furthermore, &lt;em&gt;CVB-D&lt;/em&gt; triggered excessive mitophagy by activating the FOXO3a/PINK1-Parkin axis, promoting apoptosis and leading to mitochondrial dysfunction in TNBC cells. Elevated YAP expression counteracted the effects of &lt;em&gt;CVB-D&lt;/em&gt; on TNBC, including the suppression of mitophagy-related protein expression induced by &lt;em&gt;CVB-D&lt;/em&gt;, suggesting that YAP modulates mitophagy through the FOXO3a/PINK1-Parkin axis. The anti-tumor efficacy of &lt;em&gt;CVB-D&lt;/em&gt; and its underlying mechanisms were further substantiated using a subcutaneous xenograft model.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;This study is the first to demonstrate that &lt;em&gt;CVB-D&lt;/em&gt; can directly bind to the YAP target, proposing a novel therapeutic strategy for TNBC. &lt;em&gt;CVB-D&lt;","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"136 ","pages":"Article 156287"},"PeriodicalIF":6.7,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142747377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Isoquercitrin promotes hair growth through induction of autophagy and angiogenesis by targeting AMPK and IGF-1R
IF 6.7 1区 医学
Phytomedicine Pub Date : 2024-11-26 DOI: 10.1016/j.phymed.2024.156289
Majid Manzoor , Danni Chen , Jiahui Lin, Ying Wang, Lan Xiang, Jianhua Qi
{"title":"Isoquercitrin promotes hair growth through induction of autophagy and angiogenesis by targeting AMPK and IGF-1R","authors":"Majid Manzoor ,&nbsp;Danni Chen ,&nbsp;Jiahui Lin,&nbsp;Ying Wang,&nbsp;Lan Xiang,&nbsp;Jianhua Qi","doi":"10.1016/j.phymed.2024.156289","DOIUrl":"10.1016/j.phymed.2024.156289","url":null,"abstract":"<div><h3>Background</h3><div>Hair follicles play a crucial role in hair growth, wound healing, thermoregulation, and sebum production. Hair loss affects millions of people worldwide, yet therapeutic options for managing hair loss and pattern baldness are limited. Isoquercitrin (IQ), a natural small molecule from drinkable Chinese tea, is famous for anti-aging properties.</div></div><div><h3>Purpose</h3><div>This study aimed to explore the potential of IQ in treating and preventing hair loss, along with its underlying mechanisms.</div></div><div><h3>Methods</h3><div>The adult male and female, as well as middle-aged female sprague dawley (SD) rats were used to conduct hair growth experiments <em>in vivo</em>. Signaling pathways and target protein identification were analyzed through western blotting, drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA) and surface plasmon resonance (SPR) analyses. Further, the targets were confirmed through <em>in vivo</em> inhibition experiments.</div></div><div><h3>Results</h3><div>IQ is reported here to stimulate anagen phase initiation and hair regrowth by directly interacting with adenosine 5′-monophosphate-activated protein kinase (AMPK) and insulin-like growth factor 1 receptor (IGF-1R). This process involves the AMPK/mammalian target of rapamycin (mTOR)/ unc-51-like autophagy-activating kinase 1 (ULK1) signalling pathway to trigger autophagy and the IGF-1R/phosphatidylinositol 3-kinase (PI3 K)/protein Kinase B (AKT), vascular endothelial growth factor (VEGF)/ vascular endothelial growth factor receptor (VEGFR)/ angiotensin (ANG) pathways to promote angiogenesis in female rats. Furthermore, the hair regrowth efficacy of IQ in adult male rats and middle-aged female rats was verified and shown. Similarly, our findings indicate that IQ promotes hair regrowth in middle-aged rats through autophagy and angiogenesis, akin to its effects in adult rats.</div></div><div><h3>Conclusion</h3><div>AMPK and IGF-1R proteins are identified as the target proteins of IQ and the AMPK/mTOR/ULK1, IGF-1R/PI3K/AKT and VEGF/VEGFR/ANG signalling pathways take important roles in hair growth effect of IQ. Thus, these signaling pathways are crucial for developing future treatments and clinical strategies for hair regeneration.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"136 ","pages":"Article 156289"},"PeriodicalIF":6.7,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142747562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Bioinformatics and molecular docking reveal Cryptotanshinone as the active anti-inflammation component of Qu-Shi-Xie-Zhuo decoction by inhibiting S100A8/A9-NLRP3-IL-1β signaling.
IF 6.7 1区 医学
Phytomedicine Pub Date : 2024-11-26 DOI: 10.1016/j.phymed.2024.156257
Xiao-Zhong Liao, Rui-Xia Xie, Song-Yuan Zheng, Cui-Ling Fan, Meng-Yue Zuo, Shi-Xian Chen, Jun-Qing Zhu, Juan Li
{"title":"Bioinformatics and molecular docking reveal Cryptotanshinone as the active anti-inflammation component of Qu-Shi-Xie-Zhuo decoction by inhibiting S100A8/A9-NLRP3-IL-1β signaling.","authors":"Xiao-Zhong Liao, Rui-Xia Xie, Song-Yuan Zheng, Cui-Ling Fan, Meng-Yue Zuo, Shi-Xian Chen, Jun-Qing Zhu, Juan Li","doi":"10.1016/j.phymed.2024.156257","DOIUrl":"https://doi.org/10.1016/j.phymed.2024.156257","url":null,"abstract":"<p><strong>Background: </strong>Gout is a common type of arthritis marked by monosodium urate (MSU) crystal deposition in joints, triggering an inflammatory response. Qu-Shi-Xie-Zhuo (QSXZ), a traditional Chinese medicine (TCM) formula, has been clinically used for the treatment of gouty arthritis (GA).</p><p><strong>Purpose: </strong>The study sought to examine the impact of QSXZ on GA and to delve into the pharmacological mechanisms that underlie its effects.</p><p><strong>Methods: </strong>The chemical constituents of QSXZ were analyzed through UPLC-MS. MSU-induced acute gouty arthritis (AGA) and subcutaneous (SC) air pouch models in mice were employed to evaluate the anti-inflammatory properties of QSXZ and its primary active compound, Cryptotanshinone (CTS). To investigate the therapeutic mechanisms of QSXZ, we used MS-based network pharmacology, transcriptomic analysis, molecular docking and multiscale bioassays.</p><p><strong>Results: </strong>Treatment of QSXZ revealed a significant reduction of inflammatory cell infiltration and the expression of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin -1β (IL-1β). Based on UPLC/MS/MS results, 49 components were considered the active ingredients of QSXZ. Network pharmacology analysis indicated that QSXZ regulates multiple inflammation-related pathways. Subsequent transcriptomic analysis showed that QSXZ regulates gene expression of S100A8 and S100A9. Our investigation observed an increased expression of S100A8 and S100A9 in monocytes derived from gout patients. Molecular docking and molecular dynamics simulation analysis revealed the binding pattern and interaction between QSXZ active compound CTS and S100A8/A9, and subsequent surface plasmon resonance (SPR) and cell thermal shift assay (CETSA) experiments verified the direct interaction between them. To investigate the mechanisms of action, we conducted RT-PCR, Western blotting, immunohistochemistry, flow cytometry, and measured the inflammatory response. Our findings highlight the pathogenic role of S100A8/A9 mediated TLR4-NLRP3 axis in gout and review outstanding therapeutic effects of QSXZ and its primary active compound CTS on MSU-induced experimental models.</p><p><strong>Conclusions: </strong>In summary, this study substantiates the therapeutic potential of QSXZ and its primary active compound CTS, as promising alternative treatments for GA. Our findings provide valuable insight into the critical pharmacological mechanism of QSXZ in regulating inflammation, highlighting its potential therapeutic effects in GA management.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"136 ","pages":"156257"},"PeriodicalIF":6.7,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Effusol ameliorates ischemic stroke by targeting NLRP3 protein to regulate NLRP3 inflammasome-mediated pyroptosis
IF 6.7 1区 医学
Phytomedicine Pub Date : 2024-11-25 DOI: 10.1016/j.phymed.2024.156253
Libin Xu , Siyu Li , Jiaxin Qi , Yan Mi , Ying Zhang , Yuxin Yang , Yingjie Wang , Di Zhou , Ning Li , Yue Hou
{"title":"Effusol ameliorates ischemic stroke by targeting NLRP3 protein to regulate NLRP3 inflammasome-mediated pyroptosis","authors":"Libin Xu ,&nbsp;Siyu Li ,&nbsp;Jiaxin Qi ,&nbsp;Yan Mi ,&nbsp;Ying Zhang ,&nbsp;Yuxin Yang ,&nbsp;Yingjie Wang ,&nbsp;Di Zhou ,&nbsp;Ning Li ,&nbsp;Yue Hou","doi":"10.1016/j.phymed.2024.156253","DOIUrl":"10.1016/j.phymed.2024.156253","url":null,"abstract":"<div><h3>Background</h3><div>The significance of pyroptosis as an inflammatory mode of death in ischemic stroke (IS) has attracted much attention in recent years. Effusol is a dihydrophenanthrene component extracted from <em>Juncus effusus</em> L.. Previous studies have found that <em>Juncus effusus</em> L. has a good inhibitory effect against microglia activation. However, it is not clear whether effusol inhibits microglia over-activation and attenuates its mediated microglia pyroptosis in the treatment of IS.</div></div><div><h3>Purpose</h3><div>The aim is to examine how effusol influences the initiation and activation stages of pyroptosis, as well as the NLRP3 inflammasome, resulting from microglial over-activation triggered post-IS.</div></div><div><h3>Methods</h3><div>This study investigated the impact of effusol on neurological severity and edema to assess its neuroprotective effects in IS. Mechanistically, immunofluorescence and western blotting were applied to explore the initiation and activation of the NLRP3 inflammasome. Finally, we employed the NLRP3 specific inhibitor, molecular docking, drug affinity responsive target stability (DARTS), and cellular thermal shift assay (CETSA) to further explore the underlying targets of effusol.</div></div><div><h3>Results</h3><div>Effusol mitigated IS-induced damage and downregulated the expression of inflammatory factors at the mRNA level, the protein levels of toll-like receptor 4 (TLR4), nuclear transcription factor NF-κB p65, and key components of the NLRP3 inflammasome. Effusol also mitigated mitochondrial damage by increasing ATP levels and decreasing mitochondrial membrane potential. Importantly, effusol targets NLRP3 protein to inhibit pyroptosis, thereby suppressing the hyperactivation of NLRP3 inflammasome.</div></div><div><h3>Conclusions</h3><div>Effusol may be protective against IS by targeting NLRP3 proteins to inhibit NLRP3 inflammasome activation-mediated pyroptosis. This finding provides a theoretical basis and a prospective drug candidate for the treatment of effusol in IS.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"136 ","pages":"Article 156253"},"PeriodicalIF":6.7,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142747556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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