EUROPEAN JOURNAL OF PHARMACOLOGY
·
2025
·
IF 4.7
Jie Yan,Xiaowen Zhang,Lifeng Feng,Shengzheng Zhang,Han Wei,Wencong Tian,Qiwen Li,Jing Li,Liang Yang,Jie Liu,Yang Xu,Jianlin Cui,Shan Ren,Zhi Qi,Yang Gao
Hypertension is a primary risk factor for cardiovascular disease. Recently, Ertugliflozin (Ertu), a new sodium-glucose cotransporter-2 (SGLT2) inhibitor, though primarily approved by the FDA as an antidiabetic agent, has been reported to lower blood pressure. However, whether Ertu directly regulates the contractility of arteries remains unknown. Here, we examined Ertu's effects on vascular function and underlying molecular mechanisms. Isometric tension of arteries was recorded using a multi-wire myograph system. In rat mesenteric arteries, Ertu acutely relaxed vessels constricted by phenylephrine (PE) and high K + (KPSS), while pretreatment with Ertu inhibited PE- and KPSS- induced vascular constriction. Similar outcomes were observed in the mouse thoracic aorta. Notably, these vasodilatory effects of Ertu are mediated by vascular smooth muscle cells (VSMCs) rather than endothelial cells. Mechanistically, we found that Ertu activated AMP-activated protein kinase (AMPK) signaling pathway in VSMCs and rat thoracic aorta tissues by decreasing ATP levels and the ATP/ADP ratio. Using the AMPK inhibitor Compound C, we observed that Ertu-induced vasodilation was abolished. Furthermore, we found that Compound C reversed Ertu-mediated reductions in cytosolic calcium concentration ([Ca 2+ ]i) and mitochondrial fission, which were accompanied by diminished mitochondrial membrane potential in VSMCs. In conclusion, this study demonstrates for the first time that Ertu inhibits AMPK-mediated mitochondrial fission in VSMCs, leading to vasorelaxation, suggesting its potential as a therapeutic agent for hypertension.
研究领域:
药理学
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心血管生物学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF NUTRITIONAL BIOCHEMISTRY
·
2025
·
IF 4.9
Min Jia,Hao Yue,Xiuxiu Wang,Aizhen Zong,Tongcheng Xu,Yong-Jiang Xu,Yuanfa Liu
Medium-chain triacylglycerol (MCT) is a healthy lipid mainly composed of medium-chain fatty acids (MCFA), which has been proven to have physiological activities in improving metabolic disorders, reducing blood cholesterol, and controlling weight. Brown adipose tissue (BAT) has been regarded as a potential organ to fight obesity due to the function of thermogenesis and energy dissipation. Previous reports found that a diet rich in MCT contributed to the activation of BAT. However, the potential mechanism between MCT and BAT remains unknown. In the current study, MCFA was applied on C3H/10T1/2 cells differentiated brown adipocytes, and MCT was applied on high-fat diet (HFD) induced obese mice. The results showed that MCFA and MCT induced browning of adipocytes and activation of BAT, significantly increased the enrichment of mitochondria, and significantly reduced intracellular lipid accumulation and body weights in vivo and in vitro . Mechanically, MCT significantly increased the level of UCP1, AMPK, and the downstream signaling factors of Pgc1α and Ulk1 , further significantly elevated the brown differentiation factor of Pparγ . Moreover, The AMPK inhibitor dorsomorphin partially impaired the beneficial effects caused by MCT. In conclusion, this study proved that AMPK is the potential target of MCT to induce BAT activation and provided theoretical evidence for the application of MCT in the future.
研究领域:
营养学
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代谢生物学
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分子生物学
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PubMed
高影响因子
Probiotics and Antimicrobial Proteins
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2025
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IF 4.4
Zhao Yuting,Xie Weiqi,Duan Jingyi,Li Fei
Limosilactobacillus reuteri DSM 17938 ( L. reuteri DSM 17938) was one of the most widely used probiotics in humans for gastrointestinal disorders, but few studies have investigated its role in drug-induced liver injury (DILI). Here, we evaluated the efficacy of L. reuteri DSM 17938 using a mouse model of DILI induced by triptolide. Pregavage of L. reuteri DSM 17938 for 1 week remarkably lowered hepatic inflammatory cytokines level and oxidative stress, with diminished serum alanine transaminase and aspartate aminotransferase levels. Metabolomics and RT-qPCR analysis confirmed its ability in ameliorating TP-disrupted hepatic fatty acid β oxidation. Genome annotation of L. reuteri showed its ability to modulate energy metabolism. Targeted metabolomics demonstrated that L. reuteri DSM 17938 modified the short fatty acid profiles in cecum, especially enhancing propionate levels. Further experiments found that L. reuteri DSM 17938 can activate AMPK signaling by upregulating gut microbiota–derived propionate level, thus restoring impaired mitochondrial biogenesis and energy supply processes to recover energy homeostasis, which leads to diminished ROS production and oxidative stress injury in hepatocytes. Besides, AMPK inhibitor dorsomorphin abolished all the effects on propionate protecting mitochondria and energy metabolism. This study established probiotic therapy of L. reuteri DSM 17938 as a preventive intervention for DILI in clinical. We also revealed that L. reuteri DSM 17938 can activate AMPK signaling by propionate, facilitating a deeper understanding of the action mechanism of L. reuteri DSM 17938 against acute liver injury and contributing to the development of its postbiotics and wider applications. Graphical Mechanism illustration of Limosilactobacillus reuteri DSM 17938 alleviating TP-induced liver injury by enhancing AMPK signaling pathway via propionate (Created with Biorender. com).
研究领域:
医学
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微生物学
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代谢组学
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PubMed
高影响因子
Journal of Inflammation Research
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2025
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IF 4.1
Han-Xu Zhu,Jin-Ling Ren,Wen-Juan Cao,Rui Wang,Lei-Lei Chen,Qing Gao,Ye-Bo Zhou
Background Atherosclerotic cardiovascular diseases (CVD) are commonly found in obesity. Endothelial inflammation accompanied by oxidative stress is a crucial risk factor and a key initiating step for the pathogenesis of atherosclerosis (AS). In the present study, the role and mechanism of intermedin (IMD), a potent active peptide, in endothelial damage in AS in obese apolipoprotein E-deficient (apoE−/−) mice were investigated.Methods and Results In vivo, IMD1-53 was infused via Alzet mini-osmotic pump in apoE−/− mice with high-fat diet (HFD) for 4 weeks. In vitro, palmitic acid (PA) and oxidized low density lipoprotein (Ox-LDL) were used to stimulate human umbilical vein endothelial cells (HUVECs) for exploring the potential mechanism of IMD1-53 action on endothelial damage. We found that IMD1-53 application remarkably improved plasma lipid profiles, hepatic lipid accumulation and its cholesterol levels, and vascular lipid accumulation and lesion sizes. Moreover, IMD1-53 markedly increased eNOS expression and decreased the levels of vascular inflammatory factors and ROS. In vitro, the combination of PA and Ox-LDL caused more severe inflammatory and oxidative damages and lower expression of eNOS, which were significantly inhibited by IMD1-53. IMD1-53 notably induced AMPK phosphorylation, and the inhibition of AMPK activation markedly reversed the anti-inflammatory and antioxidant effects of IMD1-53 on PA and Ox-LDL-treated HUVECs.Conclusion IMD1-53 improves AS partially by reducing endothelial inflammatory and oxidative damage via AMPK signaling pathway and decreasing vascular lipid accumulation involving the improvement of lipid profiles in blood and in liver in a state of obesity.
研究领域:
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 ETHNOPHARMACOLOGY
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2025
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IF 5.4
Luoning Zhang,Tianyun Han,Rui Qian,Yao Xiao,Wen Zhu,Linshen Xie
Ethnopharmacological relevance Cadmium (Cd) can first damage the kidney, leading to renal tubular dysfunction and irreversible renal damage. Ganoderma lucidum is a traditional Chinese herb that can enhances kidney qi and is extensively used in the management of renal diseases. As a new type of high-quality Ganoderma lucidum , Ganoderma leucocontextum (GL) has been shown to have antioxidant, anti-apoptotic, and anti-inflammatory properties, demonstrating significant potential for application in the treatment of cadmium-toxic nephropathy Aim of the study This study intends to investigate the impact and mechanism of GL extract on cadmium-toxic nephropathy Materials and methods A mouse Cd-toxic nephropathy model was established by intragastric administration of cadmium chloride for 4 weeks. Serum was collected for renal function index detection, and renal tissue was collected for Cd content, histopathology, oxidative stress index, apoptosis, and autophagy index detection to evaluate the damage of renal function and the intervention effect of the extract. The chemical ingredients of the extracts were detected by ultra-high liquid chromatography coupled with mass spectrometry detection (UPLC-MS/MS), and the total antioxidant capacity was determined. The targets and pathways of interest were derived from the integration of transcriptomic and network pharmacology results. Western blot (WB) and quantitative real-time PCR (qPCR) were used for subsequent validation. Results GL extract effectively improved kidney damage caused by Cd-toxic nephropathy, especially the GL ethanol extract (GLE). Compared with the model group, the intervention group exhibited a significant reduction in serum creatinine (Scr) and blood urea nitrogen (BUN) levels, an enhancement in histopathological integrity, a notable decrease in malondialdehyde levels, a significant increase in glutathione levels and superoxide dismutase activity, as well as a marked elevation in the ratios of Bcl-2/Bax and LC3BⅡ/LC3BⅠ. Expression of Cleaved Caspase-3 and P62 protein was markedly reduced. Comprehensive network pharmacology and transcriptomic analysis showed that the AMPK signaling pathway is a crucial pathway, and PPARα is an important target and downstream regulator of the AMPK pathway. WB and qPCR analyses showed that the activation of AMPK, SIRT1, PGC-1α, and PPARα in the kidney tissue of mice in the model group was markedly diminished, whereas it was dramatically elevated following GLE intervention Conclusions GL extract can effectively ameliorate kidney damage caused by Cd accumulation, most likely through the AMPK/SIRT1/PGC-1α/PPARα signaling pathway.
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PubMed
高影响因子
LIVER INTERNATIONAL
·
2025
·Vol. 45
·期 4
·e70053
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IF 5.2
Peng Ma,Hao Ou,Junze Cai,Yuanli Zhang,Yu Ou
Background & Aims G protein-coupled receptors (GPCRs) are important potential drug targets for the treatment of metabolic disorders. The D2 dopamine receptor (DRD2), a GPCR receptor, is a member of the dopamine receptor family. However, the role of DRD2 in regulating lipid metabolism, especially in hepatic steatosis, is unclear. Methods Eight-week male mice were fed HFHC/MCD to induce the MASH model. AAV2/8 containing the TBG promoter was used to knock down and overexpress DRD2 in mouse liver. Co-immunoprecipitation, Western lotting, immunofluorescence, and immunohistochemistry were used to investigate the mechanisms and screen DRD2 antagonists. Results The study found that activation of PKC leads to the elevation and internalisation of DRD2 in a high-fat environment. Knockdown of DRD2 in mouse liver can effectively interfere with the progression of MASH, while overexpression of DRD2 significantly aggravates the process of MASH. The study on the mechanism of DRD2 regulating lipid metabolism found that the internalisation of DRD2 could lead to dephosphorylation of pAKT (T308) by binding to β-arrestin2 and pAKT, thereby inducing ubiquitin-dependent degradation of AMPK and exacerbating steatosis. L-741626, a DRD2 antagonist, was found to interfere with the internalisation of DRD2 in a high-fat environment. It has been shown that L-741626 can treat MASH by regulating the AKT-AMPK signalling axis in vitro and in vivo. Conclusions In conclusion, this study demonstrated that internalisation of DRD2 in a high-fat environment aggravated MASH progression through the AKT-AMPK signalling axis. Furthermore, L-741626, as a DRD2 antagonist, has the potential to treat MASH.
研究领域:
代谢性疾病
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肝病学
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药理学
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分子生物学
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PubMed
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Diabetes Metabolic Syndrome and Obesity-Targets and Therapy
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2021
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IF 3.168
Hongfang Zeng,Xiaoli Li,Duanfang Zhou,Ning Wang,Xiaoping Yu,Liangyuan Long,Hao Cheng,Shuyu Zhou,Zhengze Shen,Weiying Zhou
Purpose To examine the pharmacological effects of Qihu on type 2 diabetes mellitus using db/db mice. Materials and Methods Thirty-seven db/db mice were randomly divided into the following 5 groups: diabetes model control group (DM group; n = 7), administered with the adjuvant 0.3% carboxymethyl cellulose-Na; positive control group (Met group; n = 8), administered with metformin (0.13 g/kg bodyweight); Qihu-L group (n = 7), administered with a low dose of Qihu (0.75 g/kg bodyweight), Qihu-M group (n = 7), administered with a medium dose of Qihu (1.5 g/kg bodyweight); Qihu-H group (n = 8), administered with a high dose of Qihu (3.0 g/kg bodyweight). BKS mice (n = 8) were used as the negative control group. The db/db mice were administered with drugs through oral gavage for 28 days. The random blood glucose levels, glucose tolerance test, bodyweight, food intake, and blood lipid levels of the mice were measured during the experimental period. The liver and pancreas tissues were collected for pathological, quantitative real-time polymerase chain reaction, and Western blotting analyses. Results Compared with the DM group, the Qihu groups exhibited decreased bodyweight gain. The blood glucose levels in the Qihu-L, Qihu-M, and Qihu-H were 31.46%, 43.73%, and 51.83%, respectively, lower than those in the DM group. The triglyceride levels were significantly downregulated and the swelling and steatosis of the hepatocytes were significantly lower in the Qihu-M and Qihu-H groups than in the DM group. Qihu downregulated the expression of IL-1β, IL-6, and TXNIP and upregulated the AMP-activated protein kinase (AMPK) signaling pathway in the pancreas and liver tissues of db/db mice. Conclusion The anti-diabetic effects of Qihu are mediated through the activation of the AMPK/Txnip signaling and the downregulation of the secretion of inflammatory factors in db/db mice.
研究领域:
药理学
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内分泌学
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分子生物学
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PubMed
高影响因子
PHARMAZIE
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2018
·Vol. 73
·期 10
·594-597
·
IF 1.016
Wu Bo,Chen Xi,Zhou Ying,Hu Pingjun,Wu Dan,Zheng Guodong,Cai Yi
Background: Andrographolide (Andro) belongs to the main bioactive ingredients of Andrographis paniculata. Many studies have shown that andro has a variety of pharmacological activities such as anti-inflammatory, anti-bacterial, anti-virus, anti-oxidant, immune regulation
and liver protective effects. Moreover andro has been reported to have anticancer activity in multiple types of cancer, including gastric cancer, breast cancer, lung cancer and so on. However, there is no report about the effect of andro on the human NPC cell line C666-1 and the molecular
mechanisms of andro-mediated apoptosis in C666-1 cells remain to be clarified. Methods: Cell proliferation was measured by a CCK8 assay, cell apoptosis rate was evaluated by flow cytometric analysis, and the protein expression of LKB1/AMPK signaling pathways was detected by Western
blotting. Results: Treatment with andro inhibited cell proliferation and induced apoptosis of C666-1 cells. Moreover, andro could activate LKB1-AMPK signaling. We also demonstrated that Ca2+/calmodulin-dependent protein kinase kinaseβ (CaMKKβ) was not involved in
the regulation of andro on AMPK activation in C666-1 Cells. Conclusions: Andro suppressed proliferation and induced apoptosis of C666-1 cells through regulating the LKB1/AMPK/mTOR signal pathway.
研究领域:
肿瘤学
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药理学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2024
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IF 7.7
Mingjing Zheng,Huan Ouyang,Zhipeng Li,Tao Hong,Yanbing Zhu,Yuanfan Yang,Xiaoming Guo,Hui Ni,Zedong Jiang
The structure and in vitro hypolipidemic activity of Bangia fusco-purpurea polysaccharide (BFP) assisted extracted with ultra-high pressure (UHP) at 100–600 MPa were studied. Compared to native BFP, UHP assisted extracted BFP had a more loose network structure with higher total sugar and uronic acid contents while less molecular weight ( p < 0.05). Moreover, UHP assisted extraction significantly improved the in vitro hypolipidemic and antioxidant activity of BFP. Especially at 400 MPa UHP, the cholesterol adsorption and antioxidant capacities of BFP were increased by approximately 38.02 % and 11.69 %–32.29 %, respectively. BFP with UHP assisted extraction could alleviate oleic acid-induced lipid accumulation and lipid oxidation in HepG2 cells more effectively by activating the AMPK signaling pathway as well as inhibiting PPARγ expression, which was much related with its reduced molecular weight and loose network structure. The findings indicated that UHP assisted extracted BFP has better potential to develop natural hypolipidemic agent.
研究领域:
食品科学
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生物化学
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药理学
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PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Yating Cheng,Shanshan He,Zhihui Wei,Yuxuan Meng,Dun Su,Xiaomin Li,Shu Zhang,Rong-Rong He,Zifei Qin,Qi Xiang
Coix seed, a well-known traditional Chinese medicine, has been extensively used for its anti-aging properties. However, the biological mechanism of its polysaccharides remains unclear. This study systematically investigated the anti-aging effects and mechanism of purified Coix seed polysaccharide (CP1) for the first time. The structural analysis revealed that CP1 mainly consists of glucose linked by α-(1 → 4) and α-(1 → 6) glycosidic bonds and has an average molecular weight of 8.855 kDa. Further, CP1 exhibited strong scavenging activity of approximately 55.85 % against 1,1-diphenyl-2-trinitrobenzohydrazine, 71.30 % against 2,2′-bis-(3-ethylbenzothiazolin-6-sulfonic acid) diammonium salt, and 68.40 % against hydroxyl radicals. In Caenorhabditis elegans , CP1 significantly extended the lifespan by 3–5 days ( p < 0.001) and increased the survival by 78 % under oxidative stress condition ( p < 0.001). In addition, CP1 suppressed the activity of senescence-associated β-galactosidase in zebrafish ( p < 0.001) and reduced DNA damage in human skin fibroblasts ( p < 0.001). Mechanistically, CP1 mainly activates the p -AMPK/RICTOR/CREB3 pathway by interacting with PARP-1. Taken together, this study performs the structural characterization of a glucan polysaccharide from Coix seed and its anti-aging effects in different models. These findings can provide a theoretical basis and candidate molecule for anti-aging therapies.
研究领域:
天然产物化学
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药用植物学
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分子生物学
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抗衰老研究
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糖生物学
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中医药学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2024
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IF 4.8
Min Zhou,Zhen-lin Liu,Jia-yu Liu,Xiao-bo Wang
Ulcerative colitis (UC) is a subtype of inflammatory bowel disease. Previous studies have suggested a link between senescence process and the body’s inflammatory reaction, indicating that senescence may exacerbate UC, yet the relation between UC and senescence remains unclear. Tedizolid Phosphate (TED), a novel oxazolidinone antimicrobial, is indicated in acute bacterial skin infections, its impact on senescence is not known. Our research revealed that the UC inducer dextran sulfate sodium (DSS) triggers senescence in both colon epithelial NCM460 cells and colon tissues, and TED that screened from a compound library demonstrated a strong anti-senescence effect on DSS treated NCM460 cells. As an anti-senescence medication identified in this research, TED efficiently alleviated UC and colonic senescence in mice caused by DSS. By proteomic analysis and experimental validation, we found that DSS significantly inhibits the AMPK signaling pathway, while TED counteracts senescence by restoring AMPK activity. This research verified that the development of UC is accompanied with colon tissue senescence, and TED, an anti-senescence medication, can effectively treat UC caused by DSS and alleviate colon senescence. Our work suggests anti-senescence strategy is an effective approach for UC treatment.
研究领域:
药理学
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炎症性肠病
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细胞衰老
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信号转导
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PubMed
高影响因子
MOLECULAR NUTRITION & FOOD RESEARCH
·
2025
·
IF 4.2
Guoli Chang,Siyi Tian,Xinyu Luo,Yannan Xiang,Chenggang Cai,Ruiyu Zhu,Haiying Cai,Hailong Yang,Haiyan Gao
The Myrica rubra pomace polyphenols (MRPP) were used to study their hypoglycemic effects and mechanisms using Type 2 diabetes (T2D) (db/db) mice as the model. The results showed that the oral administration of MRPP (low-dose myricitrin, 50 mg/kg BW by gavage; high-dose myricitrin, 250 mg/kg BW by gavage; and Myrica rubra pomace, 500 mg/kg BW by gavage) for 4 weeks significantly reduced fasting blood glucose, glycated serum protein, serum insulin, and insulin resistance index in mice, as well as the dyslipidemia in mice was improved. MRPP was able to improve the structural morphology of hepatocytes and pancreatic β-cells in diabetic mice. Its hypoglycemic mechanism may involve the upregulation of GLUT-4 and IRS-1 genes expression in the PI3K and AMPK signaling pathways, downregulation of GSK-3β, AMPK, PI3K, and AKT genes expression, and enhancement of the activity of enzymes related to glycogen synthesis and glucose metabolism. Research findings on 16S rRNA suggest that MRPP has the ability to alter the composition of the gut microbiota, impede the growth of harmful bacteria, and foster the growth of beneficial bacteria. Therefore, MRPP was capable of reshaping the specific gut microbial community and supporting its application as a novel supplement in functional foods for the treatment of T2D.
研究领域:
营养学
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代谢生物学
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药理学
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微生物学
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产品关联
DOI
PubMed
高影响因子
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