ARCHIVES OF PHYSIOLOGY AND BIOCHEMISTRY
·
2021
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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
Drug Design Development and Therapy
·
2023
·
IF 4.8
Ning Zhang,Tong Liu,Jianan Wang,Yingying Xiao,Ying Zhang,Jun Dai,Zhihong Ma,Donglai Ma
Background Metabolic associated fatty liver disease (MAFLD) is a chronic disease characterized by excessive lipid deposition in the liver without alcohol or other clear liver-damaging factors. AMP-activated protein kinase (AMPK)/silencing information regulator (SIRT)1 signaling pathway plays an important role in MAFLD development. Si-Ni-San (SNS), a traditional Chinese medicine, has shown reducing hepatic lipid deposition in MAFLD rats, however, the underlying mechanisms of SNS are barely understood.Purpose The aim of this research was to investigate the mechanisms of SNS in reducing hepatic lipid deposition in MAFLD rats by regulating AMPK/SIRT1 signaling pathways.Methods The components of SNS were determined by high performance liquid chromatography with mass spectrometry (HPLC-MS) analysis. MAFLD rats were induced by high-fat and high-cholesterol diet (HFHCD), and treated by SNS. SNS-containing serum and Compound C (AMPK inhibitor) were used to treat palmitic acid (PA)-induced HepG2 cells. To elucidate the potential mechanism, lipid synthesis-related proteins (SREBP-1c and FAS), fatty acid oxidation (PPARα and CPT-1), and AMPK/SIRT1 signaling pathway (p-AMPK and SIRT1) were assessed by Western blot.Results SNS improved serum lipid levels, liver function and reduced hepatic lipid deposition in MAFLD rats. SNS-containing serum reduced lipid deposition in PA-induced HepG2 cells. SNS could up-regulate protein expressions of PPARα, CPT-1, p-AMPK and SIRT1, and down-regulate protein expressions of SREBP-1c and FAS. Similar effects of SNS-containing serum were observed in PA-induced HepG2 cells. Meanwhile, Compound C weakened the therapeutic effects of SNS-containing serum on lipid deposition.Conclusion SNS could reduce hepatic lipid deposition by inhibiting lipid synthesis and promoting fatty acid oxidation, which might be related with activating the AMPK/SIRT1 signaling pathway. This study could provide a theoretical basis for the clinical use of SNS to treat MAFLD.
研究领域:
药理学
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肝病学
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中医药
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分子生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
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IF 4.7
Dake Huang,Ke Shen,Li Gui,Qiongqiong Cao,Fangmei Yu,Yunxia Lu
Given resveratrol's (RES) potential as an anti-aging agent, this study explored its ability to inhibit the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome through the miR-217/SIRT1 axis in senescent endothelial cells. Male C57BL/6 mice were administered a customized regular diet supplemented with 0.04 % RES for 64 consecutive weeks. Subsequently, the effects of RES on senescent human umbilical vein endothelial cells (HUVECs) induced by H 2 O 2 were evaluated. Gene expression analyses were conducted following SIRT1 knockdown in HUVECs treated with H 2 O 2 and RES, or transfected with miR-217 mimics and inhibitors. The study found that RES reduced body weight, improved endothelial function, enhanced SIRT1 expression, and suppressed the expression of miR-217, NADPH oxidase 4 (NOX4), and NLRP3 in the senescent thoracic aorta. Additionally, RES significantly reduced the expression of NOX4, X-box binding protein 1 spliced (XBP1s), and reactive oxygen species (ROS) production in a dose-dependent manner in senescent HUVECs. SIRT1 knockdown resulted in the activation of the NLRP3 inflammasome by upregulating NOX4 and XBP1s expression, an effect that was partially attenuated by RES pretreatment. RES also suppressed the expression of miR-217 induced by H 2 O 2 . The miR-217 mimic facilitated cellular senescence; however, RES mitigated this effect, which was further amplified by the miR-217 inhibitor.
研究领域:
分子生物学
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老年医学
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心血管病学
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细胞衰老
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信号转导
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氧化应激
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RNA干扰
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Aging-US
·
2019
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IF 5.515
Yin Ying,Cheng Jiang,Meiling Zhang,Jiye Jin,Shuyu Ge,Xiaodong Wang
Diabetic cardiomyopathy increases the risk of heart failure independent of coronary artery disease and hypertension. Phloretin (PHL) shows anti-inflammatory effects in macrophages. In this study, we explored the protective effects of PHL on high glucose (HG)-induced injury in diabetic cardiomyopathy in vivo and in vitro . Using streptozotocin-induced diabetic mouse model and incubating cardiac cells line under a HG environment, PHL were evaluated of the activities of anti-inflammation and anti-fibrosis. In the study, PHL treatment ameliorated cardiomyocyte inflammation injury, and reduced fibrosis in vivo and in vitro . PHL also improved cardiac biochemical criterions after 8 weeks of induction of diabetes in C57BL/6 mice. Molecular docking results indicated that silent information regulator 2 homolog 1 (SIRT1) bound to PHL directly and that SIRT1 expression was upregulated in the PHL-treated group in HG-induced H9C2 cells. Protective effect of PHL was been eliminated in silence SIRT1 H9C2 cells. Taken together, these results suggested that PHL suppressed HG-induced cardiomyocyte injury via restoring SIRT1 expression.
研究领域:
药理学
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心脏病学
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糖尿病研究
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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
·
2021
·
IF 4.932
Xinrui Li,Peiquan Yu,Yinghua Yu,Ting Xu,Jiao Liu,Yuan Cheng,Xia Yang,Xiaoying Cui,Cui Yin,Yi Liu
Hyperglycemia-induced neuroinflammation promotes the progression of diabetic encephalopathy. Hydrogen sulfide (H 2 S) exerts anti-inflammatory and neuroprotective activities against neurodegenerative diseases. However, the effects of H 2 S on hyperglycemia-induced neuroinflammation has not been investigated in neurons. Herein, by using HT-22 neuronal cells, we found that high glucose decreased the levels of endogenous H 2 S and its catalytic enzyme, cystathionine-β-synthase (CBS). The administration of sodium hydrosulfide (NaHS, a H 2 S donor) or S-adenosylmethionine (SAMe, an allosteric activator of CBS) restored high glucose-induced downregulation of CBS and H 2 S levels. Importantly, H 2 S ameliorated high glucose-induced inflammation in HT-22 cells, evidenced by NaHS or SAMe inhibited the pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) expression in HT-22 cells exposed to high glucose. Furthermore, NaHS or SAMe restored the SIRT1 level and the phosphorylation of mTOR and NF-κB p65 disturbed by high glucose in HT-22 cells, suggesting H 2 S reversed high glucose-induced alteration of SIRT1-mTOR/NF-κB signaling pathway. Our results demonstrated that exogenous H 2 S treatment or enhancing endogenous H 2 S synthesis prevents the inflammatory processes in the neurons with the exposure of high glucose. Therefore, increasing the H 2 S level using NaHS or SAMe might shed light on the prophylactic treatment of diabetic encephalopathy.
研究领域:
神经科学
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药理学
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糖尿病
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炎症
✓ 已验证
DOI
PubMed
高影响因子
Oxidative Medicine and Cellular Longevity
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2022
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IF 7.31
Zhihui Yin,Demin Gao,Ke Du,Chen Han,Yuhan Liu,Ying Wang,Xiaoyan Gao
Mitochondrial oxidative stress plays an important role in the pathogenesis of Alzheimer’s disease (AD). Recently, antioxidant therapy has been considered an effective strategy for the treatment of AD. Our previous work discovered that rhein relieved mitochondrial oxidative stress in β-amyloid (Aβ) oligomer-induced primary neurons by improving the sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha- (PGC-1α-) regulated mitochondrial biogenesis. While encouraging results have been provided, mechanisms underlying the beneficial effect of rhein on AD are yet to be elucidated in vivo. In this study, we evaluated the therapeutic effect of rhein on an APP/PS1 transgenic (APP/PS1) mouse model of AD and explored its antioxidant mechanisms. As a result, rhein significantly reduced Aβ burden and neuroinflammation and eventually ameliorated cognitive impairment in APP/PS1 mice. Moreover, rhein reversed oxidative stress in the brain of APP/PS1 mice and protected neurons from oxidative stress-associated apoptosis. Further study revealed that rhein promoted mitochondrial biogenesis against oxidative stress by upregulating SIRT1 and its downstream PGC-1α as well as nuclear respiratory factor 1. Improved mitochondrial biogenesis not only increased the activity of superoxide dismutase to scavenge excess reactive oxygen species (ROS) but also repaired mitochondria by mitochondrial fusion to inhibit the production of ROS from the electron transport chain. Notably, the exposure of rhein in the brain analyzed by tissue distribution study indicated that rhein could permeate into the brain to exert its therapeutic effects. In conclusion, these findings drive rhein to serve as a promising therapeutic antioxidant for the treatment of AD. Our research highlights the therapeutic efficacy for AD through regulating mitochondrial biogenesis via the SIRT1/PGC-1α pathway.
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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老年医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food & Nutrition Research
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2022
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IF 3.221
Tian Su,Zhen Wang,Zhengyi Zhang,Zhanwu Hou,Xiao Han,Fei Yang,Huadong Liu
Background Resveratrol, a well-known natural compound and nutrient, activates the deacetylation ability of SIRT1, demonstrating p53-dependent apoptosis functions in many diseases. However, the nascent proteomic fluctuation caused by resveratrol is still unclear. Objective In this study, we investigated the effect of resveratrol on the nascent proteome and transcriptome initiated by SIRT1 activation, and we explored the mechanism of resveratrol in HEK 293T cells. Methods Bioorthogonal noncanonical amino acid tagging (BONCAT) is a method used to metabolically label nascent proteins. In this strategy, L-azidohomoalanine (AHA) was used to replace methionine (Met) under different conditions. Taking advantage of the click reaction between AHA and terminal alkyne- and disulfide-functionalized agarose resin (TAD resin), we were able to efficiently separate stimulation responsive proteins from the pre-existing proteome. Resveratrol responsive proteins were identified by Liquid Chromatograph-Mass Spectrometer/Mass Spectrometer (LC-MS/MS). Furthermore, changes in mRNA levels were analyzed by transcriptome sequencing. Results Integrational analysis revealed a resveratrol response in HEK 293T cells and showed that Hsp60 was downregulated at both the nascent protein and mRNA levels. Knockdown of SIRT1 and Hsp60 provides evidence that resveratrol downregulated Hsp60 through SIRT1 and that Hsp60 decreased p53 through the Akt pathway. Conclusions This study revealed dynamic changes in the nascent proteome and transcriptome in response to resveratrol in HEK 293T cells and demonstrated that resveratrol downregulates Hsp60 by activating SIRT1, which may be a possible mechanism by which resveratrol prevents p53-dependent apoptosis by regulating Hsp60.
研究领域:
分子生物学
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细胞生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
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
Frontiers in Microbiology
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2022
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IF 6.064
Jiang Hui,Mao Tangyou,Sun Zhongmei,Shi Lei,Han Xiao,Zhang Yang,Zhang Xiaosi,Wang Jiali,Hu Juncong,Zhang Liming,Li Junxiang,Han Haixiao
Yinchen Linggui Zhugan decoction (YLZD) is an effective and classical traditional herbal prescription for treating the nonalcoholic fatty liver disease (NAFLD) and has been proven to be effective in the regulation of lipid metabolism disorder and attenuate inflammation for a NAFLD rat model. However, the exact underlying mechanism has not been elucidated. In the current study, a NAFLD rat model was established using a high-fat diet (HFD) for 10 weeks, followed by YLZD treatment with 1.92 g/kg/day for 4 weeks to explore the mechanisms of YLZD. Our results showed that YLZD decreased the hepatic lipid deposition, restored the liver tissue pathological lesions, inhibited the expression of oxidative stress, and decreased the inflammatory cytokines levels. Meanwhile, the genes and proteins expressions of SIRT1/Nrf2 signaling pathway together with downstream factors including HO-1 and NQO1 were elevated in the YLZD treated NAFLD rats. For further elaborating the upstream mechanism, short-chain fatty acids (SCFAs) in serum and feces were measured by liquid chromatograph mass spectrometer and gas chromatograph mass spectrometer, and the differences in gut microbiota of rats in each group were analyzed through high-throughput sequencing of 16S rRNA. The results demonstrated that the contents of butyric acid (BA) and total SCFAs in YLZD-treated NAFLD rats were significantly increased in serum and feces. 16S rRNA sequencing analysis illustrated that YLZD intervention led to a modification of the gut microbiota composition, with a decrease of Oribacterium, Lactobacillus and the ratio of Firmicutes/Bacteroides, as well as the increase in SCFAs-producing bacteria such as Christensenellaceae, Clostridia, Muribaculaceae, and Prevotellaceae. Spearman rank correlation analysis indicated that BA and total SCFAs were negatively co-related with oxidative stress-related factors and inflammatory cytokines, while they were positively co-related with SIRT1/Nrf2 pathway related genes and proteins. Furthermore, in vitro study confirmed that BA effectively reduced oxidative stress by activating SIRT1/Nrf2 signaling pathway in L02 cells. Together, the present data revealed YLZD could ameliorate HFD-induced NAFLD in rats by the modulation of SIRT1/Nrf2 signaling pathway and gut microbiota.
研究领域:
药理学
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肝病学
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微生物学
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分子生物学
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营养学
✓ 已验证
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
·
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
TOXICOLOGY
·
2025
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IF 4.6
Mei-Ling Le,Jia-Yu Xue,Li-Hai Wu,Xin-Yuan Zhao,Jing Ding,Yang-Yang Yuan,Yi-Qi Wan,Da-Lei Zhang
Hexafluoropropylene oxide (HFPO) homologues (HFPOs), specifically HFPO-dimeric acid (DA), HFPO-trimeric acid (TA) and HFPO-tetrameric acid (TeA), have emerged as industrial replacements for phased-out perfluorooctanoic acid (PFOA), garnering considerable attention due to their environmental ubiquity and bioaccumulation potential. Nevertheless, the reproductive toxicity of HFPOs remains incompletely characterized, particularly regarding their endocrine-disrupting effect and the underlying mechanisms involving Leydig cell dysfunction. In this study, we investigated the cytotoxic influences of HFPOs on TM3 Leydig cells, focusing on mitochondrial function and dynamics, oxidative stress, and apoptosis. Our findings demonstrated that exposure to HFPOs significantly compromised mitochondrial function and fusion-fission dynamics by disrupting the SIRT1/PGC1α signaling pathway. The mitochondrial dysfunction further triggered excessive ROS production and apoptosis, ultimately impairing TM3 Leydig cell viability and testosterone secretion. However, supplementation with the SIRT1 agonist SRT1720 relieved the inhibitory effect of HFPOs on SIRT1/PGC1α signaling pathway and reversed the expression of apoptosis-associated proteins (BAX/BCL2), oxidative stress-associated proteins (SOD1/SOD2), as well as proteins associated with mitochondrial fusion (MFN2/OPA1) and fission (DRP1/FIS1). These results elucidated the involvement of the SIRT1/PGC1α pathway in mediating the cytotoxicity of HFPOs. Notably, the activation of SIRT1 mitigated HFPO-induced toxicity in the TM3 cells, uncovering its potential in safeguarding testicular cells from the damage caused by HFPOs exposure.
研究领域:
毒理学
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环境健康
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内分泌学
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生殖生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
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2019
·
IF 3.585
Wu Luo,Yiyi Jin,Gaojun Wu,Weiwei Zhu,Yuanyuan Qian,Yali Zhang,Jieli Li,Aisong Zhu,Guang Liang
Diabetic cardiomyopathy (DCM) is a common and severe complication of diabetes. A multitude of factors are involved in the pathogenesis of DCM including chronic inflammation and oxidative stress . We have recently shown that compound LF10 prevents inflammatory responses in an animal model of lung injury. In the present study, we explored the protective effects and mechanism of LF10 against DCM using a mouse model of streptozotocin-induced diabetes and high glucose (HG)-challenged cultured cardiomyocytes. We show that LF10 suppressed diabetes-induced cardiomyocyte hypertrophy and fibrosis , which was accompanied by preservation of cardiac function in mice. Mechanistically, LF10 prevented increases in the levels of pro-inflammatory molecules and oxidative stress under in vitro and in vivo diabetic conditions. Moreover, LF10 restored HG-downregulated sirtuin 1 (SIRT1) in cardiomyocytes and prevented HG-induced activation of MAPKs. Using specific small-molecule regulators, we found that SIRT1 was an upstream signal of MAPKs. In conclusion, LF10 inhibited ROS and MAPKs-mediated inflammation by restoring SIRT1, and prevented development of DCM. LF10 targeted both oxidative stress and inflammation, two tightly interconnected pathogenic pathways, which makes LF10 a highly advantageous therapeutic drug potential.
研究领域:
心脏病学
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药理学
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糖尿病
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炎症
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氧化应激
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）