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1.
Phytother Res ; 37(7): 3025-3041, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36879478

RESUMO

Vascular endothelial cell (VEC) injury is a key factor in the development of diabetic vascular complications. Homoplantaginin (Hom), one of the main flavonoids from Salvia plebeia R. Br. has been reported to protect VEC. However, its effects and mechanisms against diabetic vascular endothelium remain unclear. Here, the effect of Hom on VEC was assessed using high glucose (HG)-treated human umbilical vein endothelial cells and db/db mice. In vitro, Hom significantly inhibited apoptosis and promoted autophagosome formation and lysosomal function such as lysosomal membrane permeability and the expression of LAMP1 and cathepsin B. The antiapoptosis effect of Hom was reversed by autophagy inhibitor chloroquine phosphate or bafilomycin A1. Furthermore, Hom promoted gene expression and nuclear translocation of transcription factor EB (TFEB). TFEB gene knockdown attenuated the effect of Hom on upregulating lysosomal function and autophagy. Moreover, Hom activated adenosine monophosphate-dependent protein kinase (AMPK) and inhibited the phosphorylation of mTOR, p70S6K, and TFEB. These effects were attenuated by AMPK inhibitor Compound C. Molecular docking showed a good interaction between Hom and AMPK protein. Animal studies indicated that Hom effectively upregulated the protein expression of p-AMPK and TFEB, enhanced autophagy, reduced apoptosis, and alleviated vascular injury. These findings revealed that Hom ameliorated HG-mediated VEC apoptosis by enhancing autophagy via the AMPK/mTORC1/TFEB pathway.


Assuntos
Proteínas Quinases Ativadas por AMP , Autofagia , Camundongos , Animais , Humanos , Proteínas Quinases Ativadas por AMP/metabolismo , Simulação de Acoplamento Molecular , Flavonoides/farmacologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Glucose/efeitos adversos , Apoptose , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/farmacologia
2.
Food Funct ; 13(4): 1890-1905, 2022 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-35084418

RESUMO

Vascular endothelial cell injury induced by high glucose (HG) plays an important role in the occurrence and development of diabetic vascular complications. Yellow tea has a protective effect on vascular endothelial cells. However, the molecular mechanisms underlying this effect are unclear. In this study, the effects of the n-butanol fraction of Huoshan large-leaf yellow tea extract (HLYTBE) on vascular endothelial injury were investigated using human umbilical vein endothelial cells (HUVECs) and diabetic mice. In HUVECs, HLYTBE significantly reduced the production of reactive oxygen species, increased the activity of anti-oxidases (superoxide dismutase and glutathione peroxidase), enhanced the production of reduced glutathione, and decreased the level of oxidized glutathione, thereby improving cell viability. HLYTBE also promoted autophagosome formation, increased the LC3-II/LC3-I ratio, increased the expressions of Beclin1 and Atg 5, and decreased the expression of p62. HLYTBE up-regulated p-AMPK and down regulated p-mTOR, and these effects were reversed by compound C, an AMPK inhibitor. HLYTBE reduced apoptosis and cytochrome C expression, and these effects were attenuated by the autophagy inhibitor 3-methyladenine. In vivo studies showed that HLYTBE improved the impaired pyruvate tolerance, glucose tolerance, and insulin resistance; reduced the concentrations of blood glucose, glycated serum protein, lipids, and 8-isomeric prostaglandin 2α; increased the anti-oxidase activity in serum; and alleviated pathological damage in the thoracic aorta of diabetic mice induced by high sucrose-high fat diet along with streptozotocin. The results suggest that HLYTBE protects the vascular endothelium by up-regulating autophagy via the AMPK/mTOR pathway and inhibiting oxidative stress.


Assuntos
Autofagia/efeitos dos fármacos , Endotélio Vascular , Glucose/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Chá , Animais , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Células Endoteliais da Veia Umbilical Humana/citologia , Humanos , Camundongos , Preparações de Plantas/química , Preparações de Plantas/farmacologia , Regulação para Cima/efeitos dos fármacos
3.
Phytother Res ; 36(1): 433-447, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34859513

RESUMO

Nonalcoholic fatty liver disease is the most prevalent liver disease characterized by excessive lipid accumulation in hepatocytes. Endoplasmic reticulum (ER) stress and autophagy play an important role in lipid accumulation. In this study, scutellarin (Scu) was examined in palmitic acid-treated HepG2 cells and C57/BL6 mice fed a high-fat diet (HFD). Scu reduced intracellular lipid content and inhibited sterol regulatory element binding protein-1c (SREBP-1c)-mediated lipid synthesis and fatty acid translocase-mediated lipid uptake in HepG2 cells. Additionally, Scu restored impaired autophagy and inhibited excessive activation of ER stress in vivo and in vitro. Moreover, Scu upregulated forkhead box O transcription factor 1-mediated autophagy by inhibiting inositol-requiring enzyme 1α (IRE1α)/X-box-binding protein 1 (XBP1) branch activation, while XBP1s overexpression exacerbated the lipid accumulation and impaired autophagy in HepG2 cells and also weakened the positive effects of Scu. Furthermore, Scu attenuated ER stress by activating autophagy, ultimately downregulating SREBP-1c-mediated lipid synthesis, and autophagy inhibitors offset these beneficial effects. Scu inhibited the crosstalk between autophagy and ER stress and downregulated saturated fatty acid-induced lipid accumulation in hepatocytes. These findings demonstrate that Scu ameliorates hepatic lipid accumulation by enhancing autophagy and suppressing ER stress via the IRE1α/XBP1 pathway.


Assuntos
Endorribonucleases , Hepatopatia Gordurosa não Alcoólica , Animais , Apigenina , Autofagia , Ácidos Graxos , Glucuronatos , Inositol , Metabolismo dos Lipídeos , Camundongos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Proteínas Serina-Treonina Quinases , Proteína 1 de Ligação a X-Box/genética
4.
J Ethnopharmacol ; 271: 113855, 2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-33485979

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Scutellarin (Scu) is one of the main active ingredients of Erigeron breviscapus (Vant.) Hand.-Mazz which has been used to treat cardiovascular disease including vascular dysfunction caused by diabetes. Scu also has a protective effect on vascular endothelial cells against hyperglycemia. However, molecular mechanisms underlying this effect are not clear. AIM OF THE STUDY: This aim of this study was to investigate the effect of Scu on human umbilical vein endothelial cells (HUVECs) injury induced by high glucose (HG), especially the regulation of PTEN-induced kinase 1 (PINK1)/Parkin-mediated mitophagy. MATERIALS AND METHODS: HUVECs were exposed to HG to induce vascular endothelial cells injury in vitro. Cell viability was assessed by MTT assay. The extent of cell apoptosis was measured by Hoechst staining and flow cytometry. Mitophagy was assayed by fluorescent immunostaining, transmission electron microscope and immunoblot. Besides, virtual docking was conducted to validate the interaction of PINK1 protein and Scu. RESULTS: We found that Scu significantly increased cell viability in HG-treated HUVECs. Scu reduces the expression of Bcl-2, Bax and cytochrome C (Cyt.c) to inhibit apoptosis through a mitochondria-dependent pathway. Meanwhile, Scu improved the overload of reactive oxygen species (ROS), superoxide dismutase (SOD) activity and SOD2 protein expression, and reversed the collapse of mitochondrial membrane potential. Besides, Scu increased autophagic flux, improved the expression of microtubule-associated protein 1 light chain 3 Ⅱ (LC3 II), Beclin 1 and autophagy-related gene 5 (Atg 5) and decreased the expression of Sequestosome1/P62 in HG-treated HUVECs. Furthermore, Scu improved the expressions of PINK1, Parkin, and Mitofusin2, which revealed the enhancement of mitophagy. Moreover, the beneficial effects of Scu on HG-induced low expression of Parkin, overproduction of ROS, and over expressions of P62, Cyt.c and Cleaved caspase-3 were weakened by PINK1 gene knockdown. Molecular docking suggested good interaction of Scu and PINK1 protein. CONCLUSION: These results suggest that Scu may protect vascular endothelial cells against hyperglycemia-induced injury by up-regulating mitophagy via PINK1/Parkin signal pathway.


Assuntos
Apigenina/farmacologia , Glucuronatos/farmacologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Mitofagia/efeitos dos fármacos , Proteínas Quinases/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Apigenina/química , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Angiopatias Diabéticas/tratamento farmacológico , Angiopatias Diabéticas/metabolismo , Inativação Gênica , Glucose/toxicidade , Glucuronatos/química , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Hiperglicemia/induzido quimicamente , Hiperglicemia/complicações , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitofagia/genética , Simulação de Acoplamento Molecular , Estresse Oxidativo/efeitos dos fármacos , Proteínas Quinases/química , Proteínas Quinases/genética , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
5.
Phytother Res ; 34(6): 1455-1466, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31828866

RESUMO

High levels of consumption of saturated lipids have been largely associated with the increasing prevalence of metabolic diseases. In particular, saturated fatty acids such as palmitic acid (PA) have been implicated in the development of insulin resistance (IR). Scutellarin (Scu) is one of the effective traditional Chinese medicines considered beneficial for liver diseases and diabetes. In this study, we investigated the effect of Scu on IR and lipid metabolism disorders in vitro and in high fat diet (HFD)-fed mice. In vitro, we found that Scu decreased insulin-dependent lipid accumulation and the mRNA expression of CD36, Fasn, and ACC in PA-treated HepG2 cells. Additionally, Scu upregulated Akt phosphorylation and improved the insulin signalling pathway. Moreover, Scu downregulated mammalian target of rapamycin (mTOR) phosphorylation and the n-SREBP-1c protein level and also reduced lipid accumulation via the mTOR-dependent pathway, as confirmed by the molecular docking of Scu to mTOR. In HFD-fed C57BL/6 mice, Scu improved oral glucose tolerance, pyruvate tolerance and the IR index and also increased the Akt phosphorylation level. Moreover, Scu reduced hepatocyte steatosis, decreased lipid accumulation and triglyceride levels, inhibited mTOR phosphorylation, and decreased the SREBP-1c level in the liver. Taken together, these findings suggest that Scu ameliorates hepatic IR by regulating hepatocyte lipid metabolism via the mTOR-dependent pathway through SREBP-1c suppression.


Assuntos
Apigenina/uso terapêutico , Glucuronatos/uso terapêutico , Hepatócitos/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Simulação de Acoplamento Molecular/métodos , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Serina-Treonina Quinases TOR/efeitos dos fármacos , Animais , Apigenina/farmacologia , Técnicas de Cultura de Células , Glucuronatos/farmacologia , Humanos , Masculino , Camundongos
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