FASEB JOURNAL
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2025
·Vol. 39
·期 5
·e70420
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IF 4.2
Min Zhu,Xiaofang Fan,Nan Zhang,Hui Wang,Jianshe Ma,Xianghong Yin,Junyan Cai,Linjing Cong,Ran Chen,Junming Fan,Xiaoxia Kong,Bin Geng,Yongsheng Gong,Congkuo Du
Endothelial pyroptosis, a pro-inflammatory programmed cell death, promotes endothelial inflammation and is a pivotal process in the initial stage of acute lung injury (ALI). Hydrogen sulfide (H 2 S), a gasotransmitter primarily dependent on cystathionine γ-lyase (CSE) in the cardiovascular and respiratory systems, plays a protective role during ALI. Nonetheless, the modulatory role and precise molecular mechanism of endothelial endogenous CSE/H 2 S in the pathogenesis of ALI remain elusive. Herein, we prepared an ALI mouse model using intratracheal administration of LPS (5 mg/kg), and lung injury was assessed by evaluating pulmonary edema, inflammatory response, and endothelial pyroptosis. In this model, H 2 S production from pulmonary tissues declined in a time-dependent manner, accompanied by a compensatory elevation of CSE protein levels. Treatment with the H 2 S donor (NaHS) attenuated pulmonary edema, inflammatory cell infiltration, endothelial pyroptosis, and reduced serum levels of tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Meanwhile, the inducible deletion of CSE in endothelial cells exacerbated these changes. The blocking effect of CSE/H 2 S on endothelial pyroptosis (evidenced by caspase-11 activation and GSDMD-NT formation) was also confirmed in cultured pulmonary microvascular endothelial cells (PMECs). Mechanistically, H 2 S-mediated regulation of sirtuin-1 (SIRT1) expression and activation (via sulfhydration) contributed to the modulatory process. Collectively, we uncovered that endothelial endogenous CSE/H 2 S alleviates endothelial pyroptosis by activating SIRT1, thereby preventing LPS-induced acute lung injury. Graphical In the LPS-induced ALI model, caspase-1-independent pyroptosis was activated. The expression of activated caspase-11 and GSDMD-NT was increased, accompanied by pulmonary edema and inflammatory infiltration. Endothelial CSE/H 2 S deficiency aggravated endothelial pyroptosis and acute lung injury. Mechanistically, endothelial endogenous CSE/H 2 S mediated the expression and activation of sirtuin-1 (SIRT1) via sulfhydration, one of the post-translational modifications. Activated SIRT1 inhibited the activation of caspase-11 and GSDMD-NT to inhibit endothelial pyroptosis, thereby alleviating acute lung injury.
研究领域:
医学
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分子生物学
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PubMed
高影响因子
Food Bioscience
·
2025
·
IF 5.9
Yahong Cheng,Yi Ding,Ziyan Tang,Xiaoyi Lei,Yufang Ma,Mengxin Xia,Jiaying Li,Gaoge Hu,Jiahui Zhang,Jing Rao
This study investigated the antiepileptic effects of polydatin (PD) and its potential mechanisms. Racine scoring and EEG were used to assess seizure severity in a PTZ-induced mouse epilepsy model. The results demonstrated that PD significantly reduced the intensity of seizures. Behavioral tests revealed that PD improved learning, memory, and motor coordination. Histological analysis using HE and Nissl staining showed that PD alleviated hippocampal neuronal damage. TUNEL staining further confirmed that PD effectively prevented neuronal apoptosis. Network pharmacology predicted SIRT1 as a potential target of PD, and GO and KEGG pathway enrichment analyses indicated that PD regulated mitochondrial function. Therefore, PD may reduce neuronal damage by protecting mitochondrial function through SIRT1. This process was tested both in vitro and in vivo . In a Mg 2+ -free neuronal excitability model, CCK-8, LDH, and Hoechst staining results demonstrated that PD significantly increased cell survival and reduced apoptosis. Reduced mitosox staining, along with increased activity of Complexes IV and V and ATP production, indicated that PD mitigated mitochondrial function. Gene expression studies revealed that PD activated the SIRT1-PGC-1α signaling pathway via AMPK. In conclusion, PD exerted neuroprotective effects by regulating mitochondrial function, suggesting a potential therapeutic target for epilepsy.
研究领域:
药理学
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神经科学
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生物信息学
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高影响因子
PHYTOTHERAPY RESEARCH
·
2024
·Vol. 38
·期 6
·3218-3239
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IF 6.1
MinFeng Zhou,HuiFang Niu,DanDan Cui,GuoQuan Huang,JinXiao Li,HaoRan Tian,XiaoJuan Xu,FengXia Liang,Rui Chen
Colorectal cancer (CRC) is a significant health problem with elevated mortality rates, prompting intense exploration of its complex molecular mechanisms and innovative therapeutic avenues. Resveratrol (RSV), recognised for its anticancer effects through SIRT1 activation, is a promising candidate for CRC treatment. This study focuses on elucidating RSV's role in CRC progression, particularly its effect on autophagy-related apoptosis. Using bioinformatics, protein imprinting and immunohistochemistry, we established a direct correlation between FOXQ1 and adverse CRC prognosis. Comprehensive in vitro experiments confirmed RSV's ability to promote autophagy-related apoptosis in CRC cells. Plasmids for SIRT1 modulation were used to investigate underlying mechanisms. Molecular docking, glutathione-S-transferase pull-down experiments and immunoprecipitation highlighted RSV's direct activation of SIRT1, resulting in the inhibition of FOXQ1 expression. Downstream interventions identified ATG16L as a crucial autophagic target. In vivo and in vitro studies validated RSV's potential for CRC therapy through the SIRT1/FOXQ1/ATG16L pathway. This study establishes RSV's capacity to enhance autophagy-related cell apoptosis in CRC, positioning RSV as a prospective therapeutic agent for CRC within the SIRT1/FOXQ1/ATG16L pathway.
研究领域:
肿瘤学
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分子生物学
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药理学
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PubMed
高影响因子
Phytochemistry Letters
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2015
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IF 1.45
Chunmei Zhang,Jianbo Ji,Mei Ji,Peihong Fan
Curcuma xanthorrhiza is a well-known traditional medicine with anti-inflammatory and anticancer activities, as well as protective effects against neurodegenerative disorders. A previous study revealed the acetylcholinesterase (AChE) inhibitory activity of some sesquiterpenoids from C. xanthorrhiza . In this study, further bioassay-guided isolation led to the identification of nine compounds for the first time from C. xanthorrhiza , including a new Guaiane-type sesquiterpene, zedoaraldehyde ( 1 ). Their structures were elucidated using NMR and MS techniques. The AChE inhibitory activities of compounds 1 , 3 , 4 and 7 were detected as minimum inhibitory quantities of 3, 4, 6 and 1 μg, respectively, using a TLC bioautography assay. Meanwhile, compounds 1 , 3 , 4 and 8 could promote SIRT1 expression by 1.37-, 1.71-, 1.73- and 1.27-fold, respectively, in HEK293 cell lines exposed to compounds at a concentration of 20 μM for 24 h. SIRT1 is becoming an important drug target for new therapies in the treatment of neurodegenerative diseases. This study indicates the potential of sesquiterpenoids from C. xanthorrhiza for use against Alzheimer's disease.
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Journal of Translational Medicine
·
2023
·Vol. 21
·期 1
·1-15
·
IF 7.4
Wan Can,Liu Xiao-Qi,Chen Mei,Ma Hui-Han,Wu Guang-Liang,Qiao Li-Jun,Cai Ye-Feng,Zhang Shi-Jie
Background The disruption of blood-brain barrier (BBB), predominantly made up by brain microvascular endothelial cells (BMECs), is one of the characteristics of Alzheimer’s disease (AD). Thus, improving BMEC function may be beneficial for AD treatment. Tanshinone IIA (Tan IIA) has been proved to ameliorate the cognitive dysfunction of AD. Herein, we explored how Tan IIA affected the function of BMECs in AD.Methods Aβ1–42-treated brain-derived endothelium cells.3 (bEnd.3 cells) was employed for in vitro experiments. And we performed molecular docking and qPCR to determine the targeting molecule of Tan IIA on Sirtuins family. The APPswe/PSdE9 (APP/PS1) mice were applied to perform the in vivo experiments. Following the behavioral tests, protein expression was determined through western blot and immunofluorescence. The activities of oxidative stress-related enzymes were analyzed by biochemically kits. Nissl staining and thioflavin T staining were conducted to reflect the neurodegeneration and Aβ deposition respectively.Results Molecular docking and qPCR results showed that Tan IIA mainly acted on Sirtuin1 (SIRT1) in Sirtuins family. The inhibitor of SIRT1 (EX527) was employed to further substantiate that Tan IIA could attenuate SIRT1-mediated endoplasmic reticulum stress (ER stress) in BMECs. Behavioral tests suggested that Tan IIA could improve the cognitive deficits in APP/PS1 mice. Tan IIA administration increased SIRT1 expression and alleviated ER stress in APP/PS1 mice. In addition, LRP1 expression was increased and RAGE expression was decreased after Tan IIA administration in both animals and cells.Conclusion Tan IIA could promote Aβ transportation by alleviating SIRT1-mediated ER stress in BMECs, which ameliorated cognitive deficits in APP/PS1 mice.
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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细胞生物学
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PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2026
·
IF 5.7
Shuoning Wu,Ting Wang,Zhijie Mao,Zhentong Yang,Zhuoqun Wang,Zhuyin Jia,Zhouqing Huang,Yonghua Wang
Purpose Doxorubicin (DOX), a widely used chemotherapeutic agent for malignancies, exhibits dose-dependent cardiotoxicity, which restricts its clinical utility. While artesunate (ART) demonstrates potentially cardioprotective effects against acute DOX-induced cardiac damage, its role in chronic cardiotoxicity and its underlying mechanisms remain unclear. This study aimed to elucidate the mechanism underlying artesunate-mediated protection against doxorubicin (DOX)-induced cardiotoxicity. Methods Mice were treated with 5 mg/kg DOX (intraperitoneal injection) once weekly for 4 weeks to induce myocardial damage and with 25 mg/kg ART (intragastric administration) for 28 days. Echocardiography and histological staining were used to evaluate cardiac function and structural changes. We also assessed mRNA and protein levels using real-time polymerase chain reaction and Western blotting, respectively, and evaluated HuR-Sirt1 mRNA interaction via RNA immunoprecipitation (RIP). Results ART treatment significantly ameliorated DOX-induced cardiac dysfunction, fibrosis, hypertrophy, and apoptosis both in vivo and in vitro . Furthermore, ART restored cardiac sirtuin-1 (Sirt1) expression, which was suppressed by DOX. Critically, cardiac-specific Sirt1 knockout exacerbated DOX-induced cardiac damage and abolished the protective effects of ART. Mechanistically, we observed that siRNA-mediated HuR knockdown reduced Sirt1 expression, whereas Sirt1 knockdown did not affect HuR expression, indicating that HuR positively regulates Sirt1 expression. ART promotes the nuclear-to-cytoplasmic translocation of HuR, thereby enhancing its binding to Sirt1 mRNA and stabilizing Sirt1 transcripts. Conclusion Collectively, these findings demonstrate that ART attenuates DOX cardiotoxicity by activating the HuR-Sirt1 axis through the stabilization of Sirt1 mRNA.
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COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY C-TOXICOLOGY & PHARMACOLOGY
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2021
·
IF 3.228
Hui Li,Guilan Di,Yi Zhang,Junping Liang,Xianfeng Wang,Zhenshan Xu,Xianghui Kong
MicroRNAs (miRNAs) play a critical role in regulating the response of animals exposed to heavy metal stress. As a globally dispersed heavy metal in aquatic ecosystems , cadmium (Cd) is highly toxic to many aquatic species . However, little is known about the miRNA response to Cd stress in fish. To investigate the regulatory effect of miRNAs in response to Cd, common carp ( Cyprinus carpio ) were exposed to Cd 2+ -containing water (0.005 mg/L, 0.05 mg/L, 0.5 mg/L) for 30 days. After exposure, Cd 2+ contents were significantly higher in the kidneys of C. carpio compared to other tissues, when exposed to 0.5 mg/L Cd 2+ . Hematoxylin and eosin staining images revealed that elevated Cd induced inflammatory damage in the kidneys of C.carpio . Further, miRNA sequencing revealed nine differentially expressed miRNAs (miR-217, miR-205 and seven novel miRNAs) in the kidneys, between 0.5 mg/L Cd 2+ exposure and control groups. Potential target mRNAs of miRNAs suggest that miR-217 is involved in immunotoxicity . miR-217 agomir was intraperitoneally administered to C. carpio and RT-PCR revealed that the expression of IL-8 and SIRT1 decreased, while TLR-4, TRAF6 , NF-kB, TNF-α, IL-1β, and TGF-β increased in the kidneys of C.carpio . Additionally, the expression of SIRT1 decreased, while the expression of other mRNAs increased in kidneys of C. carpio exposed to Cd. According to mRNAs expression in the agomir and Cd treatment, miRNAs inhibit the expressions of target mRNAs. These results demonstrate that miR-217 via SIRT1 plays a regulatory role in the immunotoxicity of Cd to C. carpio .
研究领域:
环境毒理学
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分子生物学
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水生生态学
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高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2025
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IF 5.6
Heng Tang,Ke Ning,Boji Wu,Xuhong Wang,Jingyu He,Pingping Li,Lina Pan,Jiawen Zhang,Yi He,Shizhu Bian,Xingyu Ma,Jihang Zhang,Chuan Liu,Zhexue Qin,Houyuan Hu
Scutellarein (Sc), a natural flavonoid, holds potential for treating pulmonary arterial hypertension (PAH), yet its mechanisms remain unexplored. This study investigated Sc’s therapeutic effects and underlying pathways in PAH. In vivo experiments demonstrated that Sc significantly attenuated right ventricular hypertension, pulmonary arterial remodeling, αSMA expression, and vascular inflammation in PAH models. In vitro, Sc suppressed hypoxia-induced proliferation, migration, inflammation, and pyroptosis in human pulmonary artery smooth muscle cells (HPASMCs). Mechanistically, Sc activated the SIRT1/NAD + axis to restore mitochondrial homeostasis: it upregulated SIRT1 expression and elevated NAD + levels by promoting SIRT1-mediated deacetylation of nicotinamide nucleotide transhydrogenase (NNT), thereby enhancing NNT activity. Elevated NAD + further activated SIRT1, forming a self-reinforcing SIRT1/NNT/NAD + feedback loop that mitigated hypoxia-induced mitochondrial dysfunction. This study identifies Sc as a novel regulator of the SIRT1-dependent NNT deacetylation pathway, which stabilizes NAD + homeostasis to counteract HPASMCs dysregulation in PAH. These findings highlight Sc’s potential as a therapeutic candidate for PAH, offering insights into targeting mitochondrial-metabolic pathways for vascular remodeling diseases.
研究领域:
药理学
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心血管疾病
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分子生物学
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PubMed
高影响因子
Journal of Ovarian Research
·
2026
·Vol. 19
·期 1
·157
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IF 5.3
Wang Mei,Chen Hongling,Lin Shaozi,Meng Zuyu,Zhang Yiyao,Liu Fang,Li Menghan,Sun Chengjin,Guan Minxi,Song Lingliang,Zhao Guoping,Zhang Di,Qin Jiajia
Background Premature ovarian insufficiency (POI) is characterized by complex etiologies and currently lacks effective treatments, posing significant threats to women’s physical and psychological health. Quercetin (QUE), a bioactive flavonoid inherent in traditional herbs such as Flos Sophorae and Cuscuta chinensis, demonstrates potent redox-modulating and anti-senescence capacities. This investigation validates its therapeutic efficacy against POI, specifically elucidating granulosa cell-centric mechanisms. Methods POI mouse models and injury models of the KGN (human ovarian granulosa cell line) were induced through the administration of cyclophosphamide (CTX). Subsequently, these models were treated with drugs such as QUE. Morphological changes in the ovaries of the mice were observed, and vaginal smears were conducted to monitor the estrus cycles and patterns of the mice. ELISA was employed to detect sex hormone levels in various mouse groups, while Hematoxylin-eosin (H&E) staining was utilized to assess the status of ovarian follicles at different stages. Moving forward, immunohistochemical analysis and Western blot were conducted to detect the expression levels of Sirtuin 1 (SIRT1), Hypoxia-Inducible Factor 1 Alpha (HIF-1α), and other apoptosis-related proteins. Ultimately, methods such as Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL) assay, β -galactosidase staining, flow cytometry for apoptosis detection, and 5-Ethynyl-2′-deoxyuridine (EdU) assay were utilized to evaluate the apoptosis, senescence, and proliferation of mouse ovarian tissues and human ovarian granulosa cells KGN. Results QUE alleviated CTX-induced ovarian atrophy and follicular atresia by upregulating SIRT1 expression. Furthermore, QUE partially restored estrous cyclicity, normalized sex hormone levels, and improved follicular counts through SIRT1/HIF-1α modulation. Concurrently, QUE suppressed apoptosis in both murine and human granulosa cells via the SIRT1/HIF-1α pathway. Conclusion Our findings demonstrate that QUE enhances ovarian reserve by inhibiting granulosa cells apoptosis via SIRT1/HIF-1α signaling, highlighting its therapeutic potential for POI management. Graphical The alternative text for this image may have been generated using AI.
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高影响因子
Frontiers in Pharmacology
·
2026
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IF 5.4
Yihuang Liu,Xiaofeng Li,Xia Zhang,Hua Cao,Nailin Zhang,Jianhui Sun,Pingping Chen
Introduction This research sought to investigate the therapeutic efficacy and underlying mechanisms of Shengjiang Powder (SJP) in the context of chronic gastritis. Methods A rat model of gastric mucosal injury was induced by 1-methyl-3-nitroso-1-nitrosoguanidine (MNNG) and a 10% NaCl solution, followed by treatment with either Vitacoenzyme or SJP. Histopathological changes in gastric tissues were evaluated using hematoxylin-eosin staining. Serum IL-6 levels were measured by enzyme-linked immunosorbent assay. Western blot (WB) analysis was performed to detect COX-2 expression. Immunohistochemistry was used to assess TFF1 and TFF2 expression. Serum metabolomics was conducted to identify differential metabolites and enriched pathways, while proteins related to the FOXO signaling pathway were further examined in vivo . WB analysis was used to detect SIRT1, FOXO1, and STAT3. CAT and SOD2 activities were measured using biochemical assays. Multiplex immunohistochemistry was used to examine SIRT1-FOXO1 co-localization and FOXO1 nuclear localization. For the in vitro experiments, normal human gastric epithelial cells were treated with MNNG to induce inflammatory injury, followed by SJP administration in the presence or absence of the SIRT1 inhibitor EX-527. Results SJP alleviated gastric mucosal injury, reduced serum IL-6 levels and COX-2 expression, and significantly increased TFF1 and TFF2 expression. Metabolomics analysis identified 13 differential metabolites. The targets of these metabolites were intersected with gastritis-related targets, yielding 522 overlapping targets that were significantly enriched in the FOXO signaling pathway. In vivo and in vitro experiments showed that SJP upregulated SIRT1 and FOXO1 expression, increased CAT and SOD2 activities, inhibited STAT3 expression, and promoted FOXO1 nuclear localization. EX-527 blocked the restorative effects of SJP on FOXO1 expression and antioxidant enzyme activities. Conclusion SJP ameliorates gastric mucosal injury and inflammation, potentially through modulation of the SIRT1/FOXO1 axis.
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npj Science of Food
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2026
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IF 9.7
Wang Xiaoran,Song Yagang,Zhao Wenyu,Liu Yuting,Fu Yiping,Zhang Yu,Zhao Quanyou,Miao Mingsan,Zhao Wenxia,Wang Xianbo,Li Zhanzhan
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global health burden with limited therapeutic options. Cinnamomum cassia , a medicinal-food homologous plant, contains principal bioactive cinnamaldehyde (CA), whose anti-MASLD mechanisms require clarification. This study employed both a high-fat diet (HFD)-induced MASLD model and a free fatty acid (FFA)-stimulated cell model. CA administration attenuated intracellular lipid accumulation in vitro and ameliorated both hepatic steatosis and systemic hyperlipidemia in vivo, while inhibiting hepatic lipid peroxidation. Mechanistically, integrated RNA-seq, network pharmacology, siRNA, immunofluorescence, and transmission electron microscopy analyses identified the SIRT1/FOXO1–autophagy axis as CA’s key regulatory pathway. Gut microbiome profiling revealed CA’s capacity to ameliorate HFD-induced dysbiosis, particularly enriching Lachnospiraceae_NK4A136 . Fecal microbiota transplantation (FMT) and Spearman correlations link serum lipids and hepatic injury factors to gut microbiota, indicating partially microbiota-mediated metabolic modulation by CA. Collectively, CA ameliorates MASLD through coordinated autophagy enhancement and microbial homeostasis restoration, holding promise as a functional food ingredient for metabolic liver disease prevention.
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高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2025
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IF 5.6
Huimin Kong,Yao Wang,Dandan Song,Haohui Zhao,Zhihong Zhuo
Epilepsy is a chronic brain disorder characterized by recurrent epileptic seizures, which are caused by abnormal discharges of neurons in the brain. The Vav guanine nucleotide exchange factor (Vav1) has been reported to modulate inflammation and neuronal apoptosis; however, its role in epilepsy remains elusive. This study aimed to investigate the specific function of Vav1 in epileptogenesis and its underlying molecular mechanisms. Rats were challenged with lithium chloride-pilocarpine (LiCl-Pilo) treatment to induce epilepsy model. It was found a high expression of Vav1 in hippocampal tissue of epileptic rats. Vav1 knockdown reduced seizure frequency and mortality in epileptic rats. Besides, LiCl-Pilo treatment-induced spontaneous recurrent seizures was inhibited by Vav1 downregulation, as well as epileptic activity and abnormal sprouting of mossy fibers. We also showed that interfering with the expression of Vav1 alleviates seizure-induced cognitive impairment. Vav1 knockdown restrained neuronal damage and degeneration. Moreover, Sirtuin 1 (Sirt1) was found to regulate the histone acetylation of Vav1 promotor. Sirt1 activation increased the neuronal activity and decreased the neuronal apoptosis, while Vav1 overexpression reversed it. Additionally, the results of mRNA-seq indicated that Vav1 is related to neuronal function and apoptosis regulation. Our study demonstrated that Vav1 accelerates the development of epilepsy, and neuronal damage might be the critical event. These findings could provide a novel direction for epilepsy therapy.
研究领域:
神经科学
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分子生物学
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癫痫研究
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细胞信号传导
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高影响因子
危险品化学品经营许可证（带存储）