TOXICOLOGY MECHANISMS AND METHODS
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2025
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IF 2.7
Dan Wang,Hui Sun,Kerong Hai,Ningkang Li,Yang Gu,Zengrui Ma
Traumatic brain injury (TBI), a prevalent neurological disorder in clinical practice, is primarily induced by external trauma. Propofol has been reported to alleviate the symptoms associated with TBI. In this study, a TBI model was established in mice using the controlled cortical impact (CCI) method. After treatment with propofol and BML-275, neuronal damage in the TBI model was assessed through the modified Neurological Severity Score (mNSS), Hematoxylin and Eosin (HE) staining, and Nissl staining. To investigate the role of the AMPK/SIRT1 pathway in propofol-regulated TBI, AMPKα-silenced vectors and overexpressed SIRT1 vectors were transfected. Western blot was performed to evaluate the expression of proteins involved in the AMPK/SIRT1 pathway and pyroptosis markers. The regulatory impact of Th17/Treg balance was examined by detecting the key transcription factors RORγt and FOXP3 through immunofluorescent staining and RT-qPCR. Enzyme-linked immunosorbent assay (ELISA) was used to measure IL-17 and IL-10 concentrations. Results showed that propofol significantly reduced neuronal injury in the TBI model, an effect that was reversed by BML-275. Moreover, propofol mitigated pyroptosis by downregulating Caspase-1 and GSDMD-N expression post-TBI. Propofol inhibited Th17 differentiation while promoting Treg differentiation by modulating RORγt/FOXP3 and IL-17/IL-10 levels. Silencing AMPKα markedly diminished propofol’s effects on Th17 and Treg differentiation, with these effects being reversed upon SIRT1 overexpression. Propofol suppressed neuronal pyroptosis through the regulation of Th17/Treg balance via activation of the AMPK/SIRT1 pathway. These findings suggest propofol exerts a protective effect against neuronal damage following TBI, potentially through the modulation of the Th17/Treg balance and AMPK/SIRT1 signaling pathway.
研究领域:
神经科学
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免疫学
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药理学
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DOI
PubMed
高影响因子
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY
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2020
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IF 2.598
Kaijie Wang,Jinping Zhao,Wenwen Zhang,Minglin Zhu,Ming Xu,Dan Li,Hongjie Shi,Ming Zhang,Jiajun Shi,Zhe Dong
Aortic dissection (AD) is a serious condition and a health issue on a global scale. β-Aminopropionitrile–induced AD in mice is similar to the pathogenesis of AD in humans. Resveratrol (RSV) is a natural polyphenolic substance that provides anti-inflammatory and cardiovascular effects, but the role of RSV in AD is unclear. In this study, we investigated the effects and mechanisms of RSV on β-aminopropionitrile–induced AD in mice. Our results indicate that RSV can prevent the occurrence of AD. More meaningfully, we found that the protective effect comprises an increase in sirtuin 1 (SIRT1) expression in endothelial cells for the reconstruction of their structure, reducing the recruitment of inflammatory cells by endothelial cells and inhibiting the inflammation response, thereby suppressing the occurrence of AD.
研究领域:
心血管疾病
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药理学
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分子生物学
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DOI
PubMed
高影响因子
Cell Death & Disease
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2025
·Vol. 16
·期 1
·1-16
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IF 9.6
Yang Mengxue,Wang Ting,Shao Jingrong,Ran Xinna,Xiao Rui,Zhao Rui,Wu Chunyan,Ji Ming,Tian Weiping,Sun Huabing,Liu Jiao,Zuo Shengkai
Myocardial infarction (MI) remains one of the leading causes of mortality worldwide, and cardiomyocyte death plays a critical role in cardiac remodeling after MI. Ferroptosis is a recently identified form of iron-dependent programmed cell death that has been shown to be involved in the progression of various cardiovascular diseases, including MI. Bromodomain-containing protein 4 (BRD4) is an epigenetic reader and a key regulator of cell survival. In this study, we screened an epigenetic target library containing 773 small-molecule compounds and found that (+)-JQ-1(hereafter abbreviated as JQ-1), a BRD4-specific inhibitor, markedly attenuated ferroptosis induced by erastin (a ferroptosis inducer) in cardiomyocytes. Both prophylactic and therapeutic JQ-1 administration significantly improved cardiac remodeling and reduced cardiomyocyte ferroptosis in mice with MI. Mechanistically, JQ-1 protected cardiomyocytes from erastin-induced ferroptosis by downregulating the expression of nicotinate phosphoribosyltransferase (NAPRT) and upregulating the expression of nicotinamide phosphoribosyltransferase (NAMPT) and sirtuin1 (SIRT1). Inhibition of NAMPT or SIRT1 abrogated the protection conferred by JQ-1 in erastin-treated H9C2 cardiomyocytes. The combination of proteolysis-targeting chimeras (PROTACs) with JQ-1 (JQ-1-PROTAC) promoted BRD4 protein degradation and rescued erastin-induced ferroptosis in H9C2 cardiomyocytes, and prevented erastin-induced ferroptosis in human cardiomyocytes. Thus, JQ-1 can protect cardiomyocytes from ferroptosis through the NAMPT-SIRT1 pathway, and JQ-1-based therapy may serve as a novel promising strategy to improve cardiac remodeling after MI.
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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细胞死亡
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表观遗传学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NUTRITIONAL BIOCHEMISTRY
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2025
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IF 4.9
Jie Li,Bingyong Mao,Botao Wang,Xin Tang,Qiuxiang Zhang,Tianmeng Zhang,Jianxin Zhao,Hao Zhang,Shumao Cui
Luteolin (LUT) is a natural dietary ingredient with a wide range of biological functions and has been used in skin improvement. Skin lipid oversecreting is an exceedingly common disorder of the pilosebaceous glands and popular in adolescents. This study evaluated the effect of LUT on ameliorating oleic acid (OA) induced skin lipid accumulation in C57BL/6 mice and SZ95 cells. The level of major lipids and some key lipid metabolism markers were assessed, including triglyceride (TG), non-esterified fatty acid (NEFA), cholesterol, sterol regulatory-binding protein 1 and peroxisome proliferator-activated receptors. In vivo data showed decreasing significantly cholesterol levels and in vitro data demonstrated the remarkable influence in the reduction of TG and NEFA levels. Besides, LUT affected the diversity and structure of gut bacteria, an increase in the relative abundance of Akkermansia, Bacteroides and Alistipes , which were associated with the anti-oxidative and anti-inflammatory process. Additionally, our study presented that LUT significantly reduced the level of malondialdehyde (MDA, a lipid peroxidation marker), inhibited the expression of pro-inflammatory factor (TNF-α, IL-6) as well as up-regulated the mRNA expression level of SIRT1, indicating LUT alleviating inflammation and enhancing antioxidation may be associate with the activation of SIRT1 pathway.
研究领域:
皮肤病学
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药理学
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生物化学
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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
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
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2022
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IF 5.011
Xijie Yu,Xiaoxiao Xu,Wei Dong,Chang Yang,Yao Luo,Ying He,Chenxi Jiang,Yanru Wu,Jiawei Wang
Endoplasmic reticulum (ER) stress is an evolutionarily conserved cellular stress response related to multiple diseases, including temporomandibular joint (TMJ) cartilage-related diseases. Recent studies have indicated that DDIT3/CHOP (a downstream transcription factor of ER stress) is an important effector in mediating ER stress to inhibit chondrogenesis . However, the underlying mechanism by which DDIT3 regulates chondrogenesis remains unclear. In this study, tunicamycin (an ER stress agonist)-induced ER stress inhibited chondrocyte differentiation and matrix synthesis in vitro and led to an osteoarthritis-like phenotype in mouse TMJ cartilage. Meanwhile, DDIT3 expression in chondrocytes was robustly upregulated. Loss-of-function experiments validated the inhibiting effect of DDIT3 on chondrocyte differentiation and matrix synthesis. Mechanistically, the inhibiting effect was attributed to the direct and indirect regulatory effect of DDIT3 on SIRT1 (sirtuin1, silent mating type information regulation protein type 1, a member of NAD+ dependent class III histone deacetylases). On one hand, DDIT3 directly promoted the transcription of SIRT1. On the other hand, DDIT3 indirectly increased the expression of SIRT1 by promoting AMPKα phosphorylation and activation. Furthermore, activation of AMPKα or SIRT1 with the corresponding agonist AICAR or resveratrol in the DDIT3-knockdown cells partially restored the inhibiting effect of DDIT3 on chondrocyte differentiation and matrix synthesis. Collectively, these novel findings indicate that DDIT3 regulates the inhibitory effect of ER stress on chondrocyte differentiation and matrix synthesis partially via the AMPKα-SIRT1 pathway. A thorough understanding of ER stress in regulating chondrocyte homeostasis and its role in the onset of osteoarthritis may be promising to develop therapeutic targets and prevent condyle cartilage destruction.
研究领域:
细胞生物学
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分子生物学
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骨科
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病理学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
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2023
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IF 7.9
Anni Zhu,Zhiguang Duan,Yanru Chen,Chenhui Zhu,Daidi Fan
Background The aging of skeletal muscle is the leading cause of physical disability in older adults, currently effective treatment methods are lacking. Ginsenoside Rh4, an active component extracted from ginseng , possesses beneficial anti-inflammatory and anti-oxidative effects. Purpose The aim of this study was to elucidate the antioxidant effect of ginsenoside Rh4 on aging skeletal muscle and its molecular mechanism of anti-aging of skeletal muscle. Study design In this study, we employed a D-galactose-induced model of skeletal muscle aging to investigate whether ginsenoside Rh4 can delay the process of skeletal muscle senescence. Methods The effects of ginsenoside Rh4 on oxidative damage and inflammation in aging skeletal muscle were analyzed using immunofluorescence, immunohistochemistry , ELISA kits, H&E staining, flow cytometry, and protein immunoblotting . The changes of ginsenoside Rh4 on mitochondrial morphology were observed by transmission electron microscopy , and ELISA kits and protein immunoblotting analyzed the effects of ginsenoside Rh4 on mitochondrial homeostasis in skeletal muscle cells . The influence of ginsenoside Rh4 on the SIRT1 signaling pathway in aging skeletal muscle were investigated by protein immunoblotting, immunofluorescence, and β-galactosidase staining. Results Our results showed that Rh4 improved the morphology of muscle fibers and produced an anti-inflammatory response. Furthermore, in vitro experiments indicated that ginsenosides reduced the production of senescent cells, while Rh4 effectively alleviated oxidative damage in skeletal muscle and restored mitochondrial balance. Transcriptome analysis and molecular docking showed that Rh4 improved mitochondrial homeostasis and delayed skeletal muscle aging by regulating the PGC-1α-TFAM and HIF-1α-c-Myc pathways via targeting SIRT1. Conclusion Ginsenoside Rh4 improves oxidative stress and inflammation in skeletal muscle by activating SIRT1, deacetylating Nrf2, regulating PGC-1α-TFAM and HIF-1α-c-Myc pathways, and enhancing mitochondrial homeostasis, thus achieving the effect of delaying skeletal muscle aging.
研究领域:
药理学
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老年学
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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
FOOD AND CHEMICAL TOXICOLOGY
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2020
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IF 4.679
Rili Hao,Xinyu Song,Feng Li,Xintong Tan,Dongxiao Sun-Waterhouse,Dapeng Li
Exposure to nonbiodegradable cadmium (Cd) causes many health problems including the damage to the nervous system. This study aimed to increase knowledge about its neurotoxic effects and the neuroprotective potential of caffeic acid phenethyl ester (CAPE, a polyphenol abundant in honeybee propolis). In mice, CAPE (10 μmol/kg/day body weight) attenuated significantly learning and memory deficits induced by CdCl 2 (1.5 mg/kg/day body weight). For the CdCl 2 -treated mice, CAPE increased crossing number in open field test, decreased the alternation in Y-maze test, and increased the latency time and error number in step down test. CAPE also inhibited CdCl 2 -initiated Aβ accumulation and activation of pro-inflammatory factors and microglia in the brains. Therefore, CAPE could be a food-derived neuroprotective agent against Cd-induced neurotoxicity and neurodegenerative disorders, through attenuating neuronal apoptosis and neuroinflammation via the AMPK/SIRT1 pathway and amyloid-tau-neuroinflammation axis.
研究领域:
神经科学
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毒理学
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药理学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
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2015
·Vol. 36
·期 3
·873-880
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IF 2.088
Yu Lou,Zhen Wang,Yi Xu,Ping Zhou,Junxian Cao,Yuanshi Li,Yeping Chen,Junfeng Sun,Lu Fu
Treatment with doxorubicin (DOX) is one of the major causes of chemotherapy-induced cardiotoxicity and is therefore, the principal limiting factor in the effectiveness of chemotherapy for cancer patients. DOX‑induced heart failure is thought to result from endoplasmic reticulum (ER) stress and cardiomyocyte apoptosis. Resveratrol (RV), a polyphenol antioxidant found in red wine, has been shown to play a cardioprotective role. The aim of the present study was to examine the effects of RV on DOX‑induced cardiotoxicity in H9c2 cells. We hypothesized that RV would protect H9c2 cells against DOX‑induced ER stress and subsequent cell death through the activation of the Sirt1 pathway. Our results demonstrated that the decrease observed in the viability of the H9c2 cells following exposure to DOX was accompanied by a significant increase in the expression of the ER stress‑related proteins, glucose‑regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP). However, we found that RV downregulated the expression of ER stress marker protein in the presence of DOX and restored the viability of the H9c2 cells. Exposure to RV or DOX alone only slightly increased the protein expression of Sirt1, whereas a significant increase in Sirt1 protein levels was observed in the cells treated with both RV and DOX. The Sirt1 inhibitor, nicotinamide (NIC), partially neutralized the effects of RV on the expression of Sirt1 in the DOX‑treated cells and completely abolished the effects of RV on the expression of GRP78 and CHOP. The findings of our study suggest that RV protects H9c2 cells against DOX‑induced ER stress through ER stabilization, and more specifically through the activation of the Sirt1 pathway, thereby leading to cardiac cell survival.
研究领域:
药理学
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心脏病学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2023
·
IF 5.6
Qi Liang,Rongjie Guo,Jia-Ruei Tsao,Yun He,Chenchen Wang,Jiaxuan Jiang,Di Zhang,Taige Chen,Tingting Yue,Kai Hu
Dry eye disease (DED) is a multifactorial disease, and oxidative stress plays a crucial role in its pathogenesis. Recently, multiple studies have shown that upregulation of autophagy can protect the cornea from oxidative stress damage. The present study investigated the therapeutic effects of salidroside, the main component of Rhodiola crenulata , in both in vivo and in vitro dry eye models. The results showed that topical eye drop treatment with salidroside restored corneal epithelium damage, increased tear secretion, and reduced cornea inflammation in the DED mice. Salidroside activated autophagy through AMP-activated protein kinase (AMPK)-sirtuin-1 (Sirt1) signaling pathway, which promoted the nuclear translocation of nuclear factor erythroid-2-related factor 2 (Nrf2) and increased the expression of downstream antioxidant factors heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1). This process restored antioxidant enzyme activity, reduced reactive oxygen species (ROS) accumulation, and alleviated oxidative stress. The application of autophagy inhibitor chloroquine and AMPK inhibitor Compound C reversed the therapeutic efficacy of salidroside, validating the above findings. In conclusion, our data suggest that salidroside is a promising candidate for DED treatment.
研究领域:
药理学
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眼科
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ARCHIVES OF PHYSIOLOGY AND BIOCHEMISTRY
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2021
·
IF 4.076
Lihua Li,Jun Chen,Yun Zhou,Jiahua Zhang,Lei Chen
Context Artesunate (ART), an antimalarial drug, possesses the ability to induce autophagy and exhibits a protective effect on diabetes.Objective This study aimed to evaluate the effects of ART on diabetic retinopathy (DR) and to explore the underlying mechanisms.Methods Rats with streptozotocin-induced DR were given intravitreal injection of ART.Results ART administration inhibited the increase in retinal thickness and prevented blood–retinal barrier in diabetic rats. Further, vascular leukocyte adherence, microglial activation, inflammatory cytokine, and ROS production in the retinas of diabetic rats were also inhibited by ART. Additionally, ART enhanced autophagy in the retinas of diabetic rats as demonstrated by up-regulated Beclin-1 expression and LC3II/I ratio and down-regulated p62. ART also activated AMP-activated protein kinase (AMPK)/sensor class III histone deacetylase sirtuin 1 (SIRT1) pathway.Conclusions ART, as an autophagy activator, has therapeutic potential in DR treatment.
研究领域:
药理学
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眼科学
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糖尿病
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2022
·
IF 3.322
Hengte Xing,Chuancai Liang,Chenyu Wang,Xiongfeng Xu,Yong Hu,Bo Qiu
In this study, we aim to investigate the effect of metformin on cholesterol synthesis and efflux-related genes in chondrocytes during osteoarthritis (OA) and explore the underlying mechanisms. Primary chondrocytes were harvested from Wistar rat cartilage and divided into control and treatment groups. Chondrocytes in the treatment group were treated with interleukin-1β (IL-1β) mimicking the inflammatory environment of osteoarthritis. Subsequently, RT-qPCR, Western blotting, immunofluorescence staining, and Cell Counting Kit-8 (CCK-8) were conducted. Significant reductions in phosphorylated AMP-activated protein kinase (p-AMPK) and silent information regulator 1 (SIRT1) protein expression were observed in both human OA chondrocytes and cultured primary murine chondrocytes treated with IL-1β, while AMP-activated protein kinase (AMPK) was not inhibited. Moreover, in the presence of IL-1β, metformin significantly increased the expression of p-AMPK and SIRT1 at the protein and mRNA level. Meanwhile, metformin could reverse IL-1β-induced cartilage extracellular matrix degradation in chondrocytes from the rat model of OA (treated by IL-β) by activating the AMPK/SIRT1 pathway. Moreover, metformin activated AMPK and SIRT1, mediated by the activation of SREBP-2 and HMGCR in OA chondrocytes. Inhibiting AMPK/SIRT1 activity by its specific inhibitor could suppress IL-1β-induced expression of LXRα, ABCA1 and ApoA1 and cholesterol efflux. Thus, metformin inhibits cholesterol synthesis and promotes cholesterol efflux by activating the AMPK/SIRT1 pathway in OA chondrocytes. This study improves our understanding of the effect of metformin on cholesterol accumulation in OA chondrocytes.
研究领域:
药理学
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风湿病学
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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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