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1.
Curr Vasc Pharmacol ; 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38847159

RESUMO

BACKGROUND: Hypertension is associated with endothelial dysfunction. An imbalance in the production of Nitric Oxide (NO) and Reactive Oxygen Species (ROS), leading to impaired NO-cyclic Guanosine Monophosphate (cGMP) pathway, contributes to this disorder. Red Yeast Rice (RYR), produced from the fermentation of rice with Monascus purpureus, is a traditional functional food originating from China. Although recognized for its anti-dyslipidemia properties, there has been growing evidence regarding the anti-hypertensive effects of RYR. However, these studies only focused on its direct and short-term effects. AIM: This study aims to investigate the vasoprotective effects of chronic oral RYR administration using Spontaneously Hypertensive Rats (SHR). MATERIALS AND METHODS: SHR were randomly divided into 3 groups: SHR - Control; SHR - RYR extract (100 mg/kg/day); SHR - lovastatin (10 mg/kg/day). Wistar-Kyoto Rats (WKY) were used as normotensive controls. All animals were treated for 12 weeks by oral gavage. Systolic Blood Pressure (SBP) was measured weekly (tail-cuff method). Vascular reactivity was determined using isolated rat aortic rings in an organ bath. Aortic ROS, NO, tetrahydrobiopterin (BH4 ), and cGMP levels were evaluated. RESULTS: Administration of RYR attenuated SBP elevation and enhanced endothelium-dependent vasodilation in aortic rings. In addition, RYR decreased ROS production and significantly improved the level of vascular NO, BH4, and cGMP. CONCLUSION: In an SHR model, treatment with RYR for 12 weeks exerts an SBP lowering effect that can be attributed to improved vascular function via reduction of oxidative stress, decreased endothelial NO Synthase (eNOS) uncoupling and enhanced NO-cGMP pathway.

3.
Front Pharmacol ; 14: 1254470, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37869747

RESUMO

Objective: The field of targeting cellular senescence with drug candidates to address age-related comorbidities has witnessed a notable surge of interest and research and development. This study aimed to gather valuable insights from pharmaceutical experts and healthcare practitioners regarding the potential and challenges of translating senolytic drugs for treatment of vascular aging-related disorders. Methods: This study employed a qualitative approach by conducting in-depth interviews with healthcare practitioners and pharmaceutical experts. Participants were selected through purposeful sampling. Thematic analysis was used to identify themes from the interview transcripts. Results: A total of six individuals were interviewed, with three being pharmaceutical experts and the remaining three healthcare practitioners. The significant global burden of cardiovascular diseases presents a potentially large market size that offer an opportunity for the development and marketability of novel senolytic drugs. The pharmaceutical sector demonstrates a positive inclination towards the commercialization of new senolytic drugs targeting vascular aging-related disorders. However potential important concerns have been raised, and these include increasing specificity toward senescent cells to prevent off-site targeting, thus ensuring the safety and efficacy of these drugs. In addition, novel senolytic therapy for vascular aging-related disorders may encounter competition from existing drugs that treat or manage risk factors of cardiovascular diseases. Healthcare practitioners are also in favor of recommending the novel senolytic drugs for vascular aging-related disorders but cautioned that its high cost may hinder its acceptance among patients. Besides sharing the same outcome-related concerns as with the pharmaceutical experts, healthcare practitioners anticipated a lack of awareness among the general public regarding the concept of targeting cellular senescence to delay vascular aging-related disorders, and this knowledge gap extends to healthcare practitioner themselves as well. Conclusion: Senolytic therapy for vascular aging-related disorders holds great promise, provided that crucial concerns surrounding its outcomes and commercial hurdles are effectively addressed.

4.
Molecules ; 28(3)2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36770715

RESUMO

Cardiovascular disease (CVD) is the leading cause of death worldwide, in both developed and developing countries. According to the WHO report, the morbidity and mortality caused by CVD will continue to rise with the estimation of death going up to 22.2 million in 2030. NADPH oxidase (NOX)-derived reactive oxygen species (ROS) production induces endothelial nitric oxide synthase (eNOS) uncoupling and mitochondrial dysfunction, resulting in sustained oxidative stress and the development of cardiovascular diseases. Seven distinct members of the family have been identified of which four (namely, NOX1, 2, 4 and 5) may have cardiovascular functions. Currently, the treatment and management plan for patients with CVDs mainly depends on the drugs. However, prolonged use of prescribed drugs may cause adverse drug reactions. Therefore, it is crucial to find alternative treatment options with lesser adverse effects. Natural products have been gaining interest as complementary therapy for CVDs over the past decade due to their wide range of medicinal properties, including antioxidants. These might be due to their potent active ingredients, such as flavonoid and phenolic compounds. Numerous natural compounds have been demonstrated to have advantageous effects on cardiovascular disease via NADPH cascade. This review highlights the potential of natural products targeting NOX-derived ROS generation in treating CVDs. Emphasis is put on the activation of the oxidases, including upstream or downstream signalling events.


Assuntos
Doenças Cardiovasculares , NADPH Oxidases , Humanos , NADPH Oxidases/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Oxirredutases/metabolismo , Estresse Oxidativo , NADPH Oxidase 4/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo
5.
Sci Rep ; 12(1): 17633, 2022 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-36271015

RESUMO

Epigallocatechin gallate (EGCG) has been shown to have antihypertensive activity. However, the role of epigallocatechin gallate (EGCG) in improving vascular function via modulation of endothelial nitric oxide synthase (eNOS) in hypertensive subjects is not well researched. Angiotensin II-infused hypertensive mice (8-10 weeks old) received EGCG (50 mg/kg/day) for 14 days via oral gavage. The arterial systolic blood pressure (SBP) was measured using the tail-cuff method every three days. At the end of the treatment, the vascular reactivity of the isolated aortae was studied using wire myographs. The level of nitric oxide (NO), cyclic guanosine monophosphate (cGMP) and tetrahydrobiopterine (BH4) were determined using assay kits while the presence of proteins (NOS, p-eNOS and NOx-2) were determined using by Western blotting. In vivo treatment with EGCG for 14 days significantly attenuated the increase in SBP, alleviated the vascular dysfunction, increased the vascular cGMP and BH4 level as well as the expression of p-eNOS and decreased elevated ROS level and NOx-2 protein in angiotensin II-infused hypertensive mice. Collectively, treatment with EGCG in hypertensive mice exerts a blood pressure lowering effect which is partly attributed to the improvement in the vascular function due to its ability to reduce vascular oxidative stress in the aortic tissue leading to a decrease in eNOS uncoupling thus increasing NO bioavailability.


Assuntos
Hipertensão , Óxido Nítrico Sintase Tipo III , Animais , Camundongos , Óxido Nítrico Sintase Tipo III/metabolismo , Angiotensina II/metabolismo , Anti-Hipertensivos/farmacologia , Óxido Nítrico/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Guanosina Monofosfato/metabolismo , Guanosina Monofosfato/farmacologia , Endotélio Vascular/metabolismo , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Estresse Oxidativo , GMP Cíclico/metabolismo
6.
J Control Release ; 343: 237-254, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35085695

RESUMO

Acute kidney injury (AKI) causes considerable morbidity and mortality, particularly in the case of post-cardiac infarction or kidney transplantation; however, the site-specific accumulation of small molecule reno-protective agents for AKI has often proved ineffective due to dynamic fluid and solute excretion and non-selectivity, which impedes therapeutic efficacy. This article reviews the current status and future trajectories of renal nanomedicine research for AKI management from pharmacological and clinical perspectives, with a particular focus on appraising nanosized drug carrier (NDC) use for the delivery of reno-protective agents of different pharmacological classes and the effectiveness of NDCs in improving renal tissue targeting selectivity and efficacy of said agents. This review reveals the critical shift in the role of the small molecule reno-protective agents in AKI pharmacotherapy - from prophylaxis to treatment - when using NDCs for delivery to the kidney. We also highlight the need to identify the accumulation sites of NDCs carrying reno-protective agents in renal tissues during in vivo assessments and detail the less-explored pharmacological classes of reno-protective agents whose efficacies may be improved via NDC-based delivery. We conclude the paper by outlining the challenges and future perspectives of NDC-based reno-protective agent delivery for better clinical management of AKI.


Assuntos
Injúria Renal Aguda , Nanopartículas , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/etiologia , Portadores de Fármacos/uso terapêutico , Sistemas de Liberação de Medicamentos/efeitos adversos , Humanos , Rim , Nanomedicina , Nanopartículas/uso terapêutico
7.
Antioxidants (Basel) ; 10(8)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34439415

RESUMO

In different pathological states that cause endoplasmic reticulum (ER) calcium depletion, altered glycosylation, nutrient deprivation, oxidative stress, DNA damage or energy perturbation/fluctuations, the protein folding process is disrupted and the ER becomes stressed. Studies in the past decade have demonstrated that ER stress is closely associated with pathogenesis of obesity, insulin resistance and type 2 diabetes. Excess nutrients and inflammatory cytokines associated with metabolic diseases can trigger or worsen ER stress. ER stress plays a critical role in the induction of endothelial dysfunction and atherosclerosis. Signaling pathways including AMP-activated protein kinase and peroxisome proliferator-activated receptor have been identified to regulate ER stress, whilst ER stress contributes to the imbalanced production between nitric oxide (NO) and reactive oxygen species (ROS) causing oxidative stress. Several drugs or herbs have been proved to protect against cardiovascular diseases (CVD) through inhibition of ER stress and oxidative stress. The present article reviews the involvement of ER stress and oxidative stress in cardiovascular dysfunction and the potential therapeutic implications.

8.
Phytother Res ; 35(11): 5936-5960, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34219306

RESUMO

Obesity is one of the most serious public health problems in both developed and developing countries in recent years. While lifestyle and diet modifications are the most important management strategies of obesity, these may be insufficient to ensure long-term weight reduction in certain individuals and alternative strategies including pharmacotherapy need to be considered. However, drugs option remains limited due to low efficacy and adverse effects associated with their use. Hence, identification of safe and effective alternative therapeutic agents remains warranted to combat obesity. In recent years, bioactive phytochemicals are considered as valuable sources for the discovery of new pharmacological agents for the treatment of obesity. Adipocyte hypertrophy and hyperplasia increases with obesity and undergo molecular and cellular alterations that can affect systemic metabolism giving rise to metabolic syndrome and comorbidities such as type 2 diabetes and cardiovascular diseases. Many phytochemicals have been reported to target adipocytes by inhibiting adipogenesis, inducing lipolysis, suppressing the differentiation of preadipocytes to mature adipocytes, reducing energy intake, and boosting energy expenditure mainly in vitro and in animal studies. Nevertheless, further high-quality studies are needed to firmly establish the clinical efficacy of these phytochemicals. This review outlines common pathways involved in adipogenesis and phytochemicals targeting effector molecules of these pathways, the challenges faced and the way forward for the development of phytochemicals as antiobesity agents.


Assuntos
Fármacos Antiobesidade , Diabetes Mellitus Tipo 2 , Adipócitos , Adipogenia , Animais , Fármacos Antiobesidade/farmacologia , Humanos , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico
9.
Front Pharmacol ; 12: 632169, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33986669

RESUMO

Type 2 diabetes mellitus is characterized by both resistance to the action of insulin and defects in insulin secretion. Bird's nest, which is derived from the saliva of swiftlets are well known to possess multiple health benefits dating back to Imperial China. However, it's effect on diabetes mellitus and influence on the actions of insulin action remains to be investigated. In the present study, the effect of standardized aqueous extract of hydrolyzed edible bird nest (HBN) on metabolic characteristics and insulin signaling pathway in pancreas, liver and skeletal muscle of db/db, a type 2 diabetic mice model was investigated. Male db/db diabetic and its euglycemic control, C57BL/6J mice were administered HBN (75 and 150 mg/kg) or glibenclamide (1 mg/kg) orally for 28 days. Metabolic parameters were evaluated by measuring fasting blood glucose, serum insulin and oral glucose tolerance test (OGTT). Insulin signaling and activation of inflammatory pathways in liver, adipose, pancreas and muscle tissue were evaluated by Western blotting and immunohistochemistry. Pro-inflammatory cytokines were measured in the serum at the end of the treatment. The results showed that db/db mice treated with HBN significantly reversed the elevated fasting blood glucose, serum insulin, serum pro-inflammatory cytokines levels and the impaired OGTT without affecting the body weight of the mice in all groups. Furthermore, HBN treatment significantly ameliorated pathological changes and increased the protein expression of insulin, and glucose transporters in the pancreatic islets (GLUT-2), liver and skeletal muscle (GLUT-4). Likewise, the Western blots analysis denotes improved insulin signaling and antioxidant enzyme, decreased reactive oxygen species producing enzymes and inflammatory molecules in the liver and adipose tissues of HBN treated diabetic mice. These results suggest that HBN improves ß-cell function and insulin signaling by attenuation of oxidative stress mediated chronic inflammation in the type 2 diabetic mice.

10.
J Cardiovasc Pharmacol ; 75(2): 123-134, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31651673

RESUMO

Nitrite, an anion produced from the oxidative breakdown of nitric oxide (NO), has traditionally been viewed as an inert molecule. However, this dogma has been challenged with the findings that nitrite can be readily reduced to NO under pathological conditions, hence representing a physiologically relevant storage reservoir of NO either in the blood or tissues. Nitrite administration has been demonstrated to improve myocardial function in subjects with heart failure and to lower the blood pressure in hypertensive subjects. Thus, extensive amount of work has since been carried out to investigate the therapeutic potential of nitrite in treating cardiovascular diseases, especially hypertension. Studies done on several animal models of hypertension have demonstrated the efficacy of nitrite in preventing and ameliorating the pathological changes associated with the disease. This brief review of the current findings aims to re-evaluate the use of nitrite for the treatment of hypertension and in particular to highlight its role in improving endothelial function.


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Óxido Nítrico/metabolismo , Nitritos/uso terapêutico , Animais , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Humanos , Hipertensão/diagnóstico , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Resultado do Tratamento
11.
Metab Brain Dis ; 34(6): 1713-1722, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31396844

RESUMO

In the current study, the effect of methanolic extract of Mitragyna speciosa leaf (MMS) against the rewarding and reinforcing properties of ethanol using a mouse model of conditioned place preference (CPP) and runway model of drug self-administration was studied. Subsequently, the effect of MMS on dopamine level in the nucleus accumbens (NAc) of the mouse brain was further investigated. From the data obtained, MMS (50 and 75 mg/kg, p.o.) significantly reversed the ethanol-place preference in mice, which is similar to the effect observed in the reference drugs acamprosate (300 mg/kg, p.o.) and clozapine (1 mg/kg, p.o.) treatment groups in CPP test. Likewise, the escalating doses of ethanol-conditioned mice reduced the runtime to reach goal box, infers the positive reinforcing effects of alcohol. Interestingly, MMS (50, 75 and 100 mg/kg, p.o.) significantly prolonged the runtime in ethanol-conditioned mice. Besides, MMS (50 and 75 mg/kg, p.o.) and reference drugs; acamprosate (300 mg/kg, p.o.) and clozapine (1 mg/kg, p.o.) treated mice significantly decreased the alcohol-induced elevated dopamine level in the NAc region of the brain. Overall, this study provides first evidence that MMS inhibits ethanol seeking behaviour in mice. Based on these findings, we suggest that Mitragyna speciosa may well be utilized for novel drug development to combat alcohol dependence.


Assuntos
Dopamina/metabolismo , Comportamento de Procura de Droga/efeitos dos fármacos , Etanol/administração & dosagem , Núcleo Accumbens/efeitos dos fármacos , Extratos Vegetais/farmacologia , Recompensa , Animais , Condicionamento Operante/efeitos dos fármacos , Masculino , Camundongos , Mitragyna , Núcleo Accumbens/metabolismo , Folhas de Planta , Autoadministração
12.
Eur J Nutr ; 58(1): 5-25, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29541908

RESUMO

PROPOSE: Obesity is a fast growing epidemic worldwide. During obesity, the increase in adipose tissue mass arise from two different mechanisms, namely, hyperplasia and hypertrophy. Hyperplasia which is the increase in adipocyte number is characteristic of severe obese patients. Recently, there has been much interest in targeting adipogenesis as therapeutic strategy against obesity. Flavonoids have been shown to regulate several pathways and affect a number of molecular targets during specific stages of adipocyte development. METHODS: Presently, we provide a review of key studies evaluating the effects of dietary flavonoids in different stages of adipocyte development with a particular emphasis on the investigations that explore the underlying mechanisms of action of these compounds in human or animal cell lines as well as animal models. RESULTS: Flavonoids have been shown to regulate several pathways and affect a number of molecular targets during specific stages of adipocyte development. Although most of the studies reveal anti-adipogenic effect of flavonoids, some flavonoids demonstrated proadipogenic effect in mesenchymal stem cells or preadipocytes. CONCLUSION: The anti-adipogenic effect of flavonoids is mainly via their effect on regulation of several pathways such as induction of apoptosis, suppression of key adipogenic transcription factors, activation of AMPK and Wnt pathways, inhibition of clonal expansion, and cell-cycle arrest.


Assuntos
Adipogenia/efeitos dos fármacos , Flavonoides/farmacologia , Humanos
13.
Front Pharmacol ; 10: 1624, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32116666

RESUMO

Increased oxidative stress by hyperglycemia is a major cause of vascular complications in diabetes. Bird's nest, which is made from the saliva of swiftlets has both medicinal and nutritional values dated back to ancient China. However, its role in improving endothelial dysfunction due to diabetes is yet to be elucidated. The present study examined the protective effect and mechanism of action of the aqueous extract of hydrolyzed edible bird nest (HBN) on endothelium in models of diabetes, in vitro and in vivo. Male db/m+ and db/db mice were orally administered with or without HBN and glibenclamide for 28 days, followed by vascular reactivity studies in mouse aortas. Human umbilical vein endothelial cells (HUVECs) and isolated mouse aorta from C57BL/6J were treated with high glucose (HG), HBN, sialic acid (SA), glibenclamide, and apocynin, respectively. The effects of HBN on reactive oxygen species (ROS) production and nitric oxide (NO) bioavailability were assessed by Western blot, 2',7'-dichlorofluorescin-diacetate (DCF-DA), and 4-amino-5-methylamino-2',7' difluorofluorescein (DAF-FM DA) in HUVECs, isolated mouse aorta, and db/db diabetic mice. HBN significantly reversed the endothelial dysfunction in diabetic mice and isolated mouse aorta. HBN normalized ROS over-production of NOX2 and nitrotyrosine, reversed the reduction of anti-oxidant marker, SOD-1 as well as restored NO bioavailability in both HUVECs challenged with HG and in db/db diabetic mice. Similarly, HG-induced elevation of oxidative stress in HUVECs were reversed by SA, glibenclamide, and apocynin. This attests that HBN restores endothelial function and protects endothelial cells against oxidative damage induced by HG in HUVECs, isolated mouse aorta, and db/db diabetic mice via modulating ROS mechanism, which subsequently increases NO bioavailability. This result demonstrates the potential role of HBN in preserving endothelial function and management of micro- or macrovascular complications in diabetes.

14.
Vascul Pharmacol ; 102: 11-20, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28552746

RESUMO

AIM: Endothelial dysfunction accompanied by an increase in oxidative stress is a key event leading to hypertension. As dietary nitrite has been reported to exert antihypertensive effect, the present study investigated whether chronic oral administration of sodium nitrite improves vascular function in conduit and resistance arteries of hypertensive animals with elevated oxidative stress. METHODS: Sodium nitrite (50mg/L) was given to angiotensin II-infused hypertensive C57BL/6J (eight to ten weeks old) mice for two weeks in the drinking water. Arterial systolic blood pressure was measured using the tail-cuff method. Vascular responsiveness of isolated aortae and renal arteries was studied in wire myographs. The level of nitrite in the plasma and the cyclic guanosine monophosphate (cGMP) content in the arterial wall were determined using commercially available kits. The production of reactive oxygen species (ROS) and the presence of proteins (nitrotyrosine, NOx-2 and NOx-4) involved in ROS generation were evaluated with dihydroethidium (DHE) fluorescence and by Western blotting, respectively. RESULTS: Chronic administration of sodium nitrite for two weeks to mice with angiotensin II-induced hypertension decreased systolic arterial blood pressure, reversed endothelial dysfunction, increased plasma nitrite level as well as vascular cGMP content. In addition, sodium nitrite treatment also decreased the elevated nitrotyrosine and NOx-4 protein level in angiotensin II-infused hypertensive mice. CONCLUSIONS: The present study demonstrates that chronic treatment of hypertensive mice with sodium nitrite improves impaired endothelium function in conduit and resistance vessels in addition to its antihypertensive effect, partly through inhibition of ROS production.


Assuntos
Angiotensina II , Anti-Hipertensivos/administração & dosagem , Antioxidantes/administração & dosagem , Aorta Torácica/efeitos dos fármacos , Pressão Arterial/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Hipertensão/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Artéria Renal/efeitos dos fármacos , Nitrito de Sódio/administração & dosagem , Administração Oral , Animais , Aorta Torácica/metabolismo , Aorta Torácica/fisiopatologia , GMP Cíclico/metabolismo , Modelos Animais de Doenças , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , NADPH Oxidase 2/metabolismo , NADPH Oxidase 4/metabolismo , Óxido Nítrico/metabolismo , Artéria Renal/metabolismo , Artéria Renal/fisiopatologia , Tirosina/análogos & derivados , Tirosina/metabolismo , Vasodilatação/efeitos dos fármacos
15.
Biochem Pharmacol ; 136: 76-85, 2017 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-28396195

RESUMO

Salvianolic acid B (Sal B) is one of the most abundant phenolic acids derived from the root of Danshen with potent anti-oxidative properties. The present study examined the vasoprotective effect of Sal B in hypertensive mice induced by angiotensin II (Ang II). Sal B (25mg/kg/day) was administered via oral gavage for 11days to Ang II (1.2mg/kg/day)-infused C57BL/6J mice (8-10weeks old). The vascular reactivity (both endothelium-dependent relaxations and contractions) in mouse arteries was examined by wire myography. The production of reactive oxygen species (ROS), protein level and localization of angiotensin AT1 receptors and the proteins involved in ROS formation were evaluated using dihydroethidium (DHE) fluorescence, lucigenin-enhanced chemiluminescence, immunohistochemistry and Western blotting, respectively. The changes of ROS generating proteins were also assessed in vitro in human umbilical vein endothelial cells (HUVECs) exposed to Ang II with and without co-treatment with Sal B (0.1-10nM). Oral administration of Sal B reversed the Ang II-induced elevation of arterial systolic blood pressure in mice, augmented the impaired endothelium-dependent relaxations and attenuated the exaggerated endothelium-dependent contractions in both aortas and renal arteries of Ang II-infused mice. In addition, Sal B treatment normalized the elevated levels of AT1 receptors, NADPH oxidase subunits (NOx-2 and NOx-4) and nitrotyrosine in arteries of Ang II-infused mice or in Ang II-treated HUVECs. In summary, the present study provided additional evidence demonstrating that Sal B treatment for 11days reverses the impaired endothelial function and with a marked inhibition of AT1 receptor-dependent vascular oxidative stress. This vasoprotective and anti-oxidative action of Sal B most likely contributes to the anti-hypertensive action of the plant-derived compound.


Assuntos
Angiotensina II/toxicidade , Benzofuranos/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Endotélio Vascular/fisiologia , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Animais , Benzofuranos/farmacologia , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/farmacologia , Endotélio Vascular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Hipertensão/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Cultura de Órgãos , Resultado do Tratamento
16.
Eur J Pharmacol ; 799: 160-170, 2017 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-28213289

RESUMO

Pioglitazone is an anti-diabetic drug with potential to cause adverse effects following prolonged use. This study, therefore, investigated the effects of combination treatment of a subliminal concentration of pioglitazone and quercetin, a potent antioxidant, on vascular reactivity of aorta isolated from fructose-streptozotocin (F-STZ)-induced diabetic rats. Relaxation to acetylcholine and sodium nitroprusside, and contraction to phenylephrine were tested in organ bath chambers following pre-incubation with vehicle (DMSO; 0.05%), quercetin (10-7 M), pioglitazone (10-7 M), or their combination (P+Q; 10-7 M each drug). Subliminal concentration of quercetin or pioglitazone did not alter the acetylcholine- induced relaxation nor the phenylephrine-induced contraction in both normal rat and diabetic F-STZ induced tissues. However, P+Q combination synergistically improved the impaired acetylcholine-induced relaxation and decreased the elevated phenylephrine-induced contraction in aortic rings from diabetic, but not in the normal rats. Neither mono nor combination treatment altered sodium nitroprusside-induced relaxation. The combination also synergistically decreased superoxide anion and increased nitric oxide production compared to the individual treatments in aorta from diabetic rats. Overall, these data demonstrated a synergistic effect, in which, a combination (P+Q; 10-7 M each drug) caused a significantly greater effect than 10-6 M of either agent in improving endothelial function of isolated diabetic aorta. In conclusion, a combination of subliminal concentrations of pioglitazone and quercetin is able to decrease oxidative stress and provide synergistic vascular protection in type 2 diabetes mellitus and thus the possibility of using quercetin as a supplement to pioglitazone in the treatment of diabetes with the goal of reducing pioglitazone toxicity.


Assuntos
Aorta/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Endotélio Vascular/efeitos dos fármacos , Frutose/efeitos adversos , Quercetina/farmacologia , Tiazolidinedionas/farmacologia , Animais , Aorta/metabolismo , Aorta/patologia , Aorta/fisiopatologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Sinergismo Farmacológico , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Masculino , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pioglitazona , Quercetina/uso terapêutico , Ratos , Ratos Sprague-Dawley , Tiazolidinedionas/uso terapêutico , Vasodilatação/efeitos dos fármacos
17.
Sci Rep ; 6: 33048, 2016 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-27616322

RESUMO

Sodium nitrite (NaNO2) induces relaxation in isolated arteries partly through an endothelium-dependent mechanism involving NO-eNOS-sGC-cGMP pathway. The present study was designed to investigate the effect of chronic NaNO2 administration on arterial systolic blood pressure (SBP) and vascular function in hypertensive rats. NaNO2 (150 mg L-1) was given in drinking water for four weeks to spontaneously (SHR) and Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) treated hypertensive SD rats. Arterial SBP and vascular function in isolated aortae were studied. Total plasma nitrate/nitrite and vascular cyclic guanosine monophosphate (cGMP) levels were measured using commercially available assay kits. Vascular nitric oxide (NO) levels were evaluated by DAF-FM fluorescence while the proteins involved in endothelial nitric oxide synthase (eNOS) activation was determined by Western blotting. NaNO2 treatment reduced SBP, improved the impaired endothelium-dependent relaxation, increased plasma total nitrate/nitrite level and vascular tissue NO and cGMP levels in SHR. Furthermore, increased presence of phosphorylated eNOS and Hsp-90 was observed in NaNO2-treated SHR. The beneficial effect of nitrite treatment was not observed in L-NAME treated hypertensive SD rats. The present study provides evidence that chronic treatment of genetically hypertensive rats with NaNO2 improves endothelium-dependent relaxation in addition to its antihypertensive effect, partly through mechanisms involving activation of eNOS.


Assuntos
Anti-Hipertensivos/administração & dosagem , Aorta/efeitos dos fármacos , Aorta/metabolismo , Hipertensão/fisiopatologia , Óxido Nítrico Sintase Tipo III/metabolismo , Nitrito de Sódio/administração & dosagem , Acetilcolina/administração & dosagem , Animais , Pressão Arterial , GMP Cíclico/metabolismo , Endotélio Vascular , Ativação Enzimática/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/metabolismo , Hipertensão/prevenção & controle , Masculino , Nitratos/metabolismo , Óxido Nítrico/metabolismo , Nitritos/metabolismo , Fosforilação , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Ratos Sprague-Dawley
18.
Sci Rep ; 6: 27236, 2016 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-27250532

RESUMO

Activation of inflammatory pathways via reactive oxygen species (ROS) by free fatty acids (FFA) in obesity gives rise to insulin resistance and endothelial dysfunction. Withaferin A (WA), possesses both antioxidant and anti-inflammatory properties and therefore would be a good strategy to suppress palmitic acid (PA)-induced oxidative stress and inflammation and hence, insulin resistance and dysfunction in the endothelium. Effect of WA on PA-induced insulin resistance in human umbilical vein endothelial cells (HUVECs) was determined by evaluating insulin signaling mechanisms whilst effect of this drug on PA-induced endothelial dysfunction was determined in acetylcholine-mediated relaxation in isolated rat aortic preparations. WA significantly inhibited ROS production and inflammation induced by PA. Furthermore, WA significantly decreased TNF-α and IL-6 production in endothelial cells by specifically suppressing IKKß/NF-κß phosphorylation. WA inhibited inflammation-stimulated IRS-1 serine phosphorylation and improved the impaired insulin PI3-K signaling, and restored the decreased nitric oxide (NO) production triggered by PA. WA also decreased endothelin-1 and plasminogen activator inhibitor type-1 levels, and restored the impaired endothelium-mediated vasodilation in isolated aortic preparations. These findings suggest that WA inhibited both ROS production and inflammation to restore impaired insulin resistance in cultured endothelial cells and improve endothelial dysfunction in rat aortic rings.


Assuntos
Anti-Inflamatórios/administração & dosagem , Endotélio/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ácido Palmítico/efeitos adversos , Vitanolídeos/administração & dosagem , Animais , Anti-Inflamatórios/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Endotélio/imunologia , Endotélio/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Quinase I-kappa B/metabolismo , Resistência à Insulina , Interleucina-6/metabolismo , NF-kappa B/metabolismo , Fosforilação/efeitos dos fármacos , Ratos , Fator de Necrose Tumoral alfa/metabolismo , Vitanolídeos/farmacologia
19.
Biochimie ; 125: 131-9, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27012965

RESUMO

This study investigated the effects of combined minimal concentrations of quercetin and pioglitazone on angiotensin II-induced contraction of the aorta from fructose-streptozotocin (F-STZ)-induced type 2 diabetic rats and the possible role of superoxide anions (O2(-)) and nitric oxide (NO) in their potential therapeutic interaction. Contractile responses to Ang II of aortic rings from Sprague-Dawley (SD) and F-STZ rats were tested following pre-incubation of the tissues in the vehicle (DMSO; 0.05%), quercetin (Q, 0.1 µM), pioglitazone (P, 0.1 µM) or their combination (P + Q; 0.1 µM each). The amount of superoxide anion was evaluated by lucigenin-enhanced chemiluminescence and dihydroethidium fluorescence, and NO by assay of total nitrate/nitrite, and 4-Amino-5-Methylamino-2',7'-Difluorofluorescein (DAF-FM) diacetate. The synergistic reduction of Ang II-induced contraction of diabetic but not normal aorta with minimally effective concentrations of P + Q occurs through inhibiting O2(-) and increasing NO bioavailability. This finding opens the possibility of maximal vascular protective/antidiabetic effects with low dose pioglitazone combined with quercetin, thus minimizing the risk of adverse effects.


Assuntos
Angiotensina II/farmacologia , Aorta/fisiopatologia , Diabetes Mellitus Experimental/fisiopatologia , Contração Muscular/efeitos dos fármacos , PPAR gama/antagonistas & inibidores , Quercetina/farmacocinética , Tiazolidinedionas/farmacologia , Animais , Aorta/metabolismo , Diabetes Mellitus Experimental/metabolismo , Frutose/toxicidade , Masculino , Pioglitazona , Ratos , Ratos Sprague-Dawley
20.
Vascul Pharmacol ; 74: 87-92, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26044183

RESUMO

Ingestion of dietary nitrites lowers arterial blood pressure in experimental animals and in humans. However, the exact mechanism underlying the hypotensive effect of nitrite remains unclear. The present study compared nitrite-induced responses in rings (with or without endothelium) of aortae of 18-20weeks old Wistar-Kyoto Rats (WKY) and spontaneously hypertensive (SHR) rats and investigated the underlying mechanism. Relaxations of aortae from WKY and SHR to increasing concentrations (1nM-100µM) of sodium nitrite (NaNO2) were determined during sustained contractions to phenylephrine, in the absence and presence of pharmacological agents. The nitrite-induced relaxations were concentration-dependent and larger in SHR than in WKY aortic rings. Inhibition of endothelial nitric oxide synthase (eNOS) and the absence of endothelium decreased nitrite-induced relaxations in both WKY and SHR aortae, indicating the role of endothelium-derived nitric oxide (NO) in the response. The involvement of eNOS was further confirmed by increases in phosphorylation of eNOS at ser1177 in HUVEC cells following treatment with sodium nitrite. The presence of NO scavengers decreased the relaxation to nitrite in both WKY and SHR preparations while inhibition of soluble guanylyl cyclase (sGC) abolished the response, indicating that besides producing NO, nitrite also induces relaxation by directly activating the enzyme. Thus, the present study demonstrates that the sensitivity to exogenous nitrite is increased in the aorta of the SHR compared to that of the WKY. The endothelium-dependent component of the relaxation to nitrite involves activation of eNOS with production of endothelium-derived NO, while the endothelium-independent component is due to stimulation of sGC.


Assuntos
Aorta/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Guanilato Ciclase/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Nitrito de Sódio/farmacologia , Vasodilatadores/farmacologia , Animais , Aorta/metabolismo , Células Cultivadas , Endotélio Vascular/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Masculino , Músculo Liso Vascular/metabolismo , Óxido Nítrico/metabolismo , Fenilefrina/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Guanilil Ciclase Solúvel , Vasodilatação/efeitos dos fármacos
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