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1.
Am J Chin Med ; 47(1): 97-117, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30776912

RESUMO

Elevated palmitic acid (PA) levels are associated with the development of inflammation, insulin resistance (IR) and endothelial dysfunction. Clinopodium chinense (Benth.) O. Kuntze has been shown to lower blood glucose and attenuate high glucose-induced vascular endothelial cells injury. In the present study we investigated the effects of ethyl acetate extract of C. chinense (CCE) on PA-induced inflammation and IR in the vascular endothelium and its molecular mechanism. We found that CCE significantly inhibited PA-induced toll-like receptor 4 (TLR4) expression in human umbilical vein endothelial cells (HUVECs). Consequently, this led to the inhibition of the following downstream adapted proteins myeloid differentiation primary response gene 88, Toll/interleukin-1 receptor domain-containing adaptor-inducing interferon- ß and TNF receptor-associated factor 6. Moreover, CCE inhibited the phosphorylation of Ikappa B kinase ß , nuclear factor kappa-B (NF- κ B), c-Jun N-terminal kinase, extracellular regulated protein kinases, p38-mitogen-activated protein kinase (MAPK) and subsequently suppressed the release of tumor necrosis factor- α , interleukin-1 ß (IL-1 ß ) and IL-6. CCE also inhibited IRS-1 serine phosphorylation and ameliorated insulin-mediated tyrosine phosphorylation of IRS-1. Moreover, CCE restored serine/threonine kinase and endothelial nitric oxide synthase (eNOS) activation and thus increased insulin-mediated nitric oxide (NO) production in PA-treated HUVECs. This led to reverse insulin mediated endothelium-dependent relaxation, eNOS phosphorylation and NO production in PA-treated rat thoracic aortas. These results suggest that CCE can significantly inhibit the inflammatory response and alleviate impaired insulin signaling in the vascular endothelium by suppressing TLR4-mediated NF- κ B and MAPK pathways. Therefore, CCE can be considered as a potential therapeutic candidate for endothelial dysfunction associated with IR and diabetes.


Assuntos
Endotélio Vascular , Resistência à Insulina/genética , Lamiaceae , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Ácido Palmítico/efeitos adversos , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Receptor 4 Toll-Like/metabolismo , Vasculite/induzido quimicamente , Vasculite/tratamento farmacológico , Animais , Glicemia/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Fosforilação/efeitos dos fármacos , Ratos Sprague-Dawley , Vasculite/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
2.
Vascul Pharmacol ; 85: 39-49, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27473516

RESUMO

Endothelial dysfunction is a key event in the progression of atherosclerosis with diabetes. Increasing cell apoptosis may lead to endothelial dysfunction. Apigenin and naringenin are two kinds of widely used flavones. In the present study, we investigated whether and how apigenin and naringenin reduced endothelial dysfunction induced by high glucose in endothelial cells. We showed that apigenin and naringenin protected against endothelial dysfunction via inhibiting phosphorylation of protein kinase C ßII (PKCßII) expression and downstream reactive oxygen species (ROS) production in endothelial cells exposed to high glucose. Furthermore, we demonstrated that apigenin and naringenin reduced high glucose-increased apoptosis, Bax expression, caspase-3 activity and phosphorylation of NF-κB in endothelial cells. Moreover, apigenin and naringenin effectively restored high glucose-reduced Bcl-2 expression and Akt phosphorylation. Importantly, apigenin and naringenin significantly increased NO production in endothelial cells subjected to high glucose challenge. Consistently, high glucose stimulation impaired acetylcholine (ACh)-mediated vasodilation in the rat aorta, apigenin and naringenin treatment restored the impaired endothelium-dependent vasodilation via dramatically increasing eNOS activity and nitric oxide (NO) level. Taken together, our results manifest that apigenin and naringenin can ameliorate endothelial dysfunction via regulating ROS/caspase-3 and NO pathway.


Assuntos
Apigenina/farmacologia , Endotélio Vascular/efeitos dos fármacos , Flavanonas/farmacologia , Glucose/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/patologia , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Endotélio Vascular/patologia , Células Endoteliais da Veia Umbilical Humana , Humanos , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Proteína Quinase C beta/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Vasodilatação/efeitos dos fármacos
3.
J Cardiovasc Pharmacol ; 67(1): 93-101, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26355761

RESUMO

Palmitic acid (PA)-induced vascular endothelial inflammation plays a pivotal role in the occurrence and development of vascular diseases. The present study was conducted to examine the effect of homoplantaginin, a main flavonoid from a traditional Chinese medicine Salvia plebeia R. Br., on PA-treated human umbilical vein endothelial cells inflammation and the underlying molecular mechanism. Firstly, we found that homoplantaginin (0.1, 1, 10 µM) dose-dependently reduced expression of toll-like receptor-4 evoked by PA (100 µM). The inhibitory effect of homoplantaginin was further confirmed under lipopolysaccharide challenge. In addition, downstream adapted proteins including myeloid differentiation primary response gene 88, toll/interleukin-1 receptor-domain containing adaptor-inducing interferon-ß and tumor necrosis factors receptor associated factor-6 were successfully inhibited by homoplantaginin under PA treatment. Also, we found that homoplantaginin tightly controlled PA-induced reactive oxygen species to prevent nucleotide-binding domain-like receptor 3 (NLRP3) inflammasome activation by suppressing reactive oxygen species-sensitive thioredoxin-interacting protein, NLRP3, and caspase-1. Meanwhile, protein and mRNA levels of inflammatory mediators (interleukin-1ß, intercellular cell adhesion molecule-1, and monocyte chemotactic protein-1) were decreased by homoplantaginin. Furthermore, homoplantaginin restored PA-impaired nitric oxide generation. Taken together, these results indicated that homoplantaginin protected endothelial cells from ameliorating PA-induced endothelial inflammation via suppressing toll-like receptor-4 and NLRP3 pathways, and restoring nitric oxide generation, suggesting it may be a potential candidate for further development in the prevention and treatment of vascular diseases.


Assuntos
Proteínas de Transporte/antagonistas & inibidores , Flavonoides/farmacologia , Glucosídeos/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Ácido Palmítico/toxicidade , Receptor 4 Toll-Like/antagonistas & inibidores , Proteínas de Transporte/metabolismo , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Flavonoides/isolamento & purificação , Flavonoides/uso terapêutico , Glucosídeos/isolamento & purificação , Glucosídeos/uso terapêutico , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamassomos/antagonistas & inibidores , Inflamassomos/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR , Salvia miltiorrhiza , Receptor 4 Toll-Like/metabolismo
4.
Molecules ; 20(8): 14879-88, 2015 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-26287144

RESUMO

A new skeleton of diterpenoid, 1,2,3,4,4α,9,10,10α-octahydro-(4α-hydroxyymethyl) -1,1-dimethyl-9-(1-methylethyl)-(2S,3S,4αR,9R,10αS)-2,3,5,7-phenanthrenetertrol, named plebeianiol A (1), along with four known diterpenoids (2-5), were isolated from Salvia plebeia R. Br. Their structures were determined on the basis of spectral analysis. In the bioactivity tests, compounds 1, 2 and 5 showed 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activities with IC50 values of 20.0-29.6 µM. In addition, these three compounds had significant inhibitory effects on reactive oxygen species (ROS) production in lipopolysaccharide (LPS)-induced macrophages. Compounds 1-3 inhibited nitric oxide (NO) production in LPS-induced macrophages with IC50 values of 18.0-23.6 µM. These results showed that compounds 1, 2 had significant antioxidant and anti-inflammatory activities and might provide basis for the treatment of diseases associated with oxidative lesions and inflammation.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Diterpenos/farmacologia , Salvia/química , Animais , Anti-Inflamatórios/química , Antioxidantes/química , Vias Biossintéticas/efeitos dos fármacos , Compostos de Bifenilo/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Sobrevivência Celular/efeitos dos fármacos , Diterpenos/química , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Óxido Nítrico/biossíntese , Picratos/química , Espectroscopia de Prótons por Ressonância Magnética , Células RAW 264.7
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