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1.
Cancer Sci ; 111(1): 127-136, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31692172

RESUMO

The major cellular antioxidant glutathione (GSH) protects cancer cells from oxidative damage that can lead to the induction of ferroptosis, an iron-dependent form of cell death triggered by the aberrant accumulation of lipid peroxides. Inhibitors of the cystine-glutamate antiporter subunit xCT, which mediates the uptake of extracellular cystine and thereby promotes GSH synthesis, are thus potential anticancer agents. However, the efficacy of xCT-targeted therapy has been found to be diminished by metabolic reprogramming that affects redox status in cancer cells. Identification of drugs for combination with xCT inhibitors that are able to overcome resistance to xCT-targeted therapy might thus provide the basis for effective cancer treatment. We have now identified the vasodilator oxyfedrine (OXY) as a sensitizer of cancer cells to GSH-depleting agents including the xCT inhibitor sulfasalazine (SSZ). Oxyfedrine contains a structural motif required for covalent inhibition of aldehyde dehydrogenase (ALDH) enzymes, and combined treatment with OXY and SSZ was found to induce accumulation of the cytotoxic aldehyde 4-hydroxynonenal and cell death in SSZ-resistant cancer cells both in vitro and in vivo. Microarray analysis of tumor xenograft tissue showed cyclooxygenase-2 expression as a potential biomarker for the efficacy of such combination therapy. Furthermore, OXY-mediated ALDH inhibition was found to sensitize cancer cells to GSH depletion induced by radiation therapy in vitro. Our findings thus establish a rationale for repurposing of OXY as a sensitizing drug for cancer treatment with agents that induce GSH depletion.


Assuntos
Aldeídos/metabolismo , Sistema y+ de Transporte de Aminoácidos/metabolismo , Antineoplásicos/farmacologia , Oxifedrina/farmacologia , Vasodilatadores/farmacologia , Aldeído Desidrogenase/metabolismo , Animais , Antioxidantes/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Glutationa/metabolismo , Células HCT116 , Humanos , Camundongos , Camundongos Nus , Oxirredução/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Sulfassalazina/farmacologia
2.
Undersea Hyperb Med ; 46(5): 635-646, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31683362

RESUMO

We aimed to assess the effects of intermittent hyperbaric oxygenation (HBO2 at 2 bars for 120 minutes a day for four successive days) on acetylcholine-induced vasorelaxation (AChIR) in female Sprague-Dawley (SD) rats (N=80) that were randomized into four groups: healthy controls (CTR); diabetic rats (DM); and control and diabetic rats that underwent hyperbaric oxygenation (CTR+HBO and DM+HBO), respectively. AChIR was measured in vitro in aortic rings, with/without L-NAME, MS-PPOH, HET0016 or indomethacin. mRNA expression of eNOS, iNOS, COX-1, COX-2, thromboxane A synthase 1 (TBXAS1), CYP4A1, CYP4A3 and CYP2J3 was assessed by qPCR. Systemic oxidative stress and plasma antioxidative capacity were determined with the thiobarbituric acid-reactive substances (TBARS) and the ferric reducing ability of plasma (FRAP) assays, respectively. There was no significant difference in AChIR among experimental groups of rats. In CTR and DM group of rats, AChIR was mediated by NO and EETs pathway, while in the CTR+HBO and DM+HBO groups, NO-pathway prevailed. iNOS expression was upregulated in the DM group compared to CTR, while HBO2 upregulated eNOS in CTR group and TBXAS1 in DM group of rats. In both, CTR and DM group of rats, the sensitivity to ACh in the presence of L-NAME or in the presence of MSPPOH was significantly decreased compared to the response to ACh in the absence or presence of indomethacin or HET0016. DM and DM+HBO rats had increased TBARS compared to their respective controls. In conclusion, HBO2 presumably alters vasorelaxation in response to ACh from NO-EETs mediated pathways to solely NO-pathway, without affecting oxidative status of DM rats.


Assuntos
Acetilcolina/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Diabetes Mellitus Experimental/fisiopatologia , Oxigenação Hiperbárica , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Análise de Variância , Animais , Aorta/efeitos dos fármacos , Aorta/fisiopatologia , Glicemia/análise , Peso Corporal , Sistema Enzimático do Citocromo P-450/fisiologia , Primers do DNA , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/fisiopatologia , Feminino , Oxigenação Hiperbárica/métodos , Estresse Oxidativo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Estreptozocina , Fatores de Tempo , Vasodilatação/fisiologia
3.
Adv Clin Exp Med ; 28(10): 1409-1418, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31638745

RESUMO

BACKGROUND: Papaverine is used to induce maximal hyperemia for index of coronary microcirculatory resistance (IMR) measurement in animal experiments, although it can lead to polymorphic ventricular tachycardia and ventricular fibrillation. OBJECTIVES: This study investigated the effect of an intracoronary (IC) bolus of high adenosine triphosphate (ATP) and nicorandil doses for IMR measurement and explored the possibility of inducing maximal hyperemia with an IC alprostadil bolus. MATERIAL AND METHODS: Index of coronary microcirculatory resistance was measured in a hyperemic state induced by 7 experimental conditions in 21 pigs (IC bolus of papaverine (18 mg), ATP (40 µg, 80 µg, 160 µg, and 240 µg), and nicorandil (2 mg and 4 mg)). The 7 conditions were induced sequentially, and the average IMR was calculated. Because of the long-term hyperemic condition in the pilot experiments, the IMR was measured 1, 3, 5, 8, and 10 min after an IC bolus of alprostadil (10 µg) in another 7 pigs. RESULTS: The IMR induced by 240 µg of ATP or 4 mg of nicorandil was not significantly different from that induced by 18 mg of papaverine (both p > 0.05). A strong linear correlation was observed between IMRs with papaverine (18 mg) and nicorandil (4 mg) (R2 = 0.936, p < 0.001) and with papaverine (18 mg) and ATP (240 µg) (R2 = 0.838, p < 0.05). The IC bolus of nicorandil (4 mg) produced the smallest changes, whereas papaverine caused the most significant changes in mean blood pressure and heart rate (p < 0.05). Tachypnea and transient ST depression were more common with increasing ATP dosages (especially 240 µg). Alprostadil (5 min) yielded a significant hyperemic response but reduced baseline blood pressure by almost 40% for a long time. CONCLUSIONS: Intracoronary bolus administration of 4 mg of nicorandil was better than 18 mg of papaverine or 240 µg of ATP for induction of maximal hyperemia and IMR measurement in a pig model, whereas alprostadil was not suitable for IMR measurement.


Assuntos
Trifosfato de Adenosina/administração & dosagem , Alprostadil/administração & dosagem , Circulação Coronária/efeitos dos fármacos , Microcirculação/efeitos dos fármacos , Nicorandil/administração & dosagem , Papaverina/administração & dosagem , Vasodilatadores/administração & dosagem , Trifosfato de Adenosina/farmacologia , Alprostadil/farmacologia , Animais , Papaverina/farmacologia , Suínos , Vasodilatadores/farmacologia
4.
Fitoterapia ; 139: 104365, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31647954

RESUMO

As a folk medicine, Phlomis likiangensis is traditionally used in China to activate collaterals and protect cardiovascular system. We hypothesized that the beneficial effects of Phlomis likiangensis may be related to vasodilatation. In the present study, twelve known iridoid glucosides (1-12) were isolated from Phlomis likiangensis. The vasodilatory effects and the underlying mechanisms of the main components (iridoid glucosides) of Phlomis likiangensis on rat aortic rings were investigated. The result showed that iridoid glucosides significantly increased the vasodilatation in rat aortic rings, which was abolished by removing the endothelium of the vessels or by eliminating the generation of nitric oxide. Finally, the structure-activity relationship of compounds 1-12 was also speculated. Our findings provide the first evidence that the iridoid glucosides of Phlomis likiangensis may be the pharmacodynamic basis for its traditional efficacy.


Assuntos
Glucosídeos Iridoides/farmacologia , Phlomis/química , Vasodilatadores/farmacologia , Animais , Aorta/efeitos dos fármacos , Células Cultivadas , China , Células Endoteliais/efeitos dos fármacos , Técnicas In Vitro , Glucosídeos Iridoides/química , Masculino , Estrutura Molecular , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Plantas Medicinais/química , Ratos , Ratos Sprague-Dawley , Rizoma/química , Relação Estrutura-Atividade , Vasodilatação , Vasodilatadores/química
5.
J Vasc Res ; 56(6): 320-332, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31550717

RESUMO

BACKGROUND: Perivascular adipose tissue (PVAT) reduces vascular tone in isolated arteries in vitro, however there are no studies of PVAT effects on vascular tone in vivo. In vitro adipocyte ß3-adrenoceptors play a role in PVAT function via secretion of the vasodilator adiponectin. OBJECTIVE: We have investigated the effects of PVAT on vessel diameter in vivo, and the contributions of ß3-adrenoceptors and adiponectin. METHOD: In anaesthetised rats, sections of the intact mesenteric bed were visualised and the diameter of arteries was recorded. Arteries were stimulated with electrical field stimulation (EFS), noradrenaline (NA), arginine-vasopressin (AVP), and acetylcholine (Ach). RESULTS: We report that in vivo, stimulation of PVAT with EFS, NA, and AVP evokes a local anti-constrictive effect on the artery, whilst PVAT exerts a pro-contractile effect on arteries subjected to Ach. The anti-constrictive effect of PVAT stimulated with EFS and NA was significantly reduced using ß3-adrenoceptor inhibition, and activation of ß3-adrenoceptors potentiated the anti-constrictive effect of vessels stimulated with EFS, NA, and AVP. The ß3-adrenoceptor agonist had no effect on mesenteric arteries with PVAT removed. A blocking peptide for adiponectin receptor 1 polyclonal antibody reduced the PVAT anti-constrictive effect in arteries stimulated with EFS and NA, indicating that adiponectin may be the anti-constrictive factor released upon ß3-adrenoceptor activation. CONCLUSIONS: These results clearly demonstrate that PVAT plays a paracrine role in regulating local vascular tone in vivo, and therefore may contribute to the modulation of blood pressure. This effect is mediated via adipocyte ß3-adrenoceptors, which may trigger release of the vasodilator adiponectin.


Assuntos
Adiponectina/metabolismo , Tecido Adiposo/metabolismo , Artérias Mesentéricas/metabolismo , Comunicação Parácrina , Receptores Adrenérgicos beta 3/metabolismo , Vasoconstrição , Vasodilatação , Tecido Adiposo/efeitos dos fármacos , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Antagonistas de Receptores Adrenérgicos beta 3/farmacologia , Animais , Estimulação Elétrica , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Comunicação Parácrina/efeitos dos fármacos , Ratos Wistar , Receptores Adrenérgicos beta 3/efeitos dos fármacos , Transdução de Sinais , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia
6.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 48(3): 282-288, 2019 May 25.
Artigo em Chinês | MEDLINE | ID: mdl-31496160

RESUMO

OBJECTIVE: To determine the effect of trimetazidine on cardiac function and exercise tolerance in primary hypertension patients with type 2 diabetic. METHODS: In this randomized, double-blind, placebo-controlled prospective study, 60 primary hypertensive patients with diabetic were equally assigned into two groups, patients received trimetazidine (20 mg, 3 times a day) or placebo for 1 year. Echocardiography, cardiopulmonary exercise testing were performed; and the plasma N terminal pro B type natriuretic peptide (NT-ProBNP), hr-CRP, TNF-α, angiotensin Ⅱ and endothelin concentration were determined before and after treatment. RESULTS: In trimetazidine group, the left ventricular mass index, the mitral flow velocity E wave to A wave ratio (E/A), the peak early diastolic velocity (VE) to late diastolic velocity (VA) ratio (VE/VA) and the peak systolic velocity (Vs) were significantly improved, the plasma NT-ProBNP level was significantly decreased, and the exercise time, metabolic equivalent, maximal oxygen uptake and anaerobic threshold were significantly increased (all P<0.05); plasma concentration of hr-CRP, TNF-α, angiotensin Ⅱ and endothelin were significantly reduced after trimetazidine treatment, compared with baseline (all P<0.05) and with placebo (all P<0.05). There were no significant differences in any of above parameters after treatment in placebo group (all P>0.05). No severe adverse reaction was observed in both groups. CONCLUSIONS: For patients with both hypertension and diabetes, trimetazidine can improve cardiac function and increase exercise tolerance.


Assuntos
Complicações do Diabetes , Diabetes Mellitus , Tolerância ao Exercício , Coração , Hipertensão , Trimetazidina , Complicações do Diabetes/complicações , Diabetes Mellitus/tratamento farmacológico , Método Duplo-Cego , Tolerância ao Exercício/efeitos dos fármacos , Coração/efeitos dos fármacos , Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Peptídeo Natriurético Encefálico/sangue , Estudos Prospectivos , Resultado do Tratamento , Trimetazidina/farmacologia , Trimetazidina/uso terapêutico , Vasodilatadores/farmacologia , Vasodilatadores/uso terapêutico
7.
Life Sci ; 236: 116836, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31493479

RESUMO

AIMS: The present experiment was conceptualised to explore the therapeutic response of tetramethylpyrazine (TMP), a major active constituent of Ligusticum chuanxiong, a Chinese traditional medicinal plant, in high-fat diet (HFD)-streptozotocin (STZ)-induced diabetes in rats and to identify the possible mechanism of action. MAIN METHODS: Dose-reliant effect of oral treatment of TMP (100, 150 and 200 mg/kg/day) for 28 days was evaluated by calculating the alteration in body weight, level of fasting blood glucose (FBG), plasma insulin, homeostasis model assessment (HOMA), serum lipids, oral glucose & intraperitoneal insulin tolerance and glycosylated haemoglobin in HFD-STZ-induced type-2 diabetic (T2D) rats and underlying molecular mechanisms of TMP was also studied. KEY FINDINGS: TMP treatment prominently reduced the level of FBG, glycosylated haemoglobin and revived body weight gain and level of serum insulin dose-dependently in diabetic rats. TMP treatment considerably improved insulin resistance, as observed in oral glucose tolerance and insulin tolerance tests. Moreover, dose-dependent reduction in the level of pro-inflammatory cytokines, C-reactive protein (CRP) and interleukin-6 (IL-6) was observed and their level was found to be significantly reduced in highest dose TMP (200 mg/kg) treated diabetic rats, pointing towards TMP mediated recovery of insulin signalling and a decrease in insulin resistance. The expressions of p-PI3K-p85/p-Akt/GLUT-4 were also significantly up-regulated by TMP (200 mg/kg), suggesting the connection of the PI3K/Akt signal pathway in the anti-hyperglycemic action of TMP. SIGNIFICANCE: These findings suggest that TMP may be used as a potential agent for type-2 diabetes treatment.


Assuntos
Diabetes Mellitus Experimental/prevenção & controle , Diabetes Mellitus Tipo 2/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Transportador de Glucose Tipo 4/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirazinas/farmacologia , Animais , Glicemia , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Transportador de Glucose Tipo 4/genética , Masculino , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Ratos Wistar , Transdução de Sinais , Vasodilatadores/farmacologia
8.
Anim Reprod Sci ; 208: 106128, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31405471

RESUMO

The aim was to evaluate effects of addition of pentoxifylline to skimmed milk semen extender on uterine inflammatory response. Thirty-six estrous cycles of 15 mares were randomly divided into five groups for artificial insemination (AI): Control: mimicking the AI procedure (n = 7); Extender: deposition of skimmed milk based extender (n = 7); Extender + PTX: skimmed milk based extender plus pentoxifylline (7.18 mM; n = 8); Semen: semen diluted with extender without pentoxifylline (n = 7), and Semen + PTX: semen diluted with extender containing pentoxifylline (n = 7). Mares in estrus were examined by trans-rectal palpation and using ultrasonography, and ovulation was induced. Uterine hemodynamics were assessed immediately before ovulation induction (T-30), immediately before AI (T0), 2 (T2), 6 (T6), 12 (T12), 24 (T24) and 48 (T48) h after AI. Endometrial samples were collected 6 h after AI, and slides were stained and examined to determine percentage of PMN. Pentoxifylline had no additional effect on vascular perfusion. There was a major inflammatory response with pentoxifylline treatment that was greater than that of the control group. In the group treated with Extender + PTX, there were more PMN (57.98 ±â€¯9.42%) than in the group treated with Extender (20.20 ±â€¯6.63%) and in the Semen + PTX group more PMN (82.84 ±â€¯5.71%) than in the Semen-treated group (47.83 ±â€¯10.61%). These findings indicate the addition of pentoxifylline does not stimulate blood flow; however, it induces a greater immune defense response because more neutrophils migrate to the uterine lumen.


Assuntos
Doenças dos Cavalos/prevenção & controle , Inflamação/veterinária , Pentoxifilina/farmacologia , Sêmen/efeitos dos fármacos , Doenças Uterinas/veterinária , Animais , Estudos Cross-Over , Endométrio/irrigação sanguínea , Endométrio/efeitos dos fármacos , Feminino , Cavalos , Inflamação/prevenção & controle , Inseminação Artificial/veterinária , Masculino , Leite , Ultrassonografia/veterinária , Doenças Uterinas/prevenção & controle , Vasodilatadores/farmacologia
9.
J Agric Food Chem ; 67(35): 9805-9811, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31407895

RESUMO

Stachydrine (STA) is a constituent of citrus fruits and Leonurus heterophyllus Sweet. In the present study, we established that STA caused acute endothelium-dependent relaxation. The vascular action of STA was mediated by nitric oxide (NO) via cyclic guanosine monophosphate. Mechanistically, STA activated AMP-activated protein kinase (AMPK), protein kinase B/Akt, and endothelial NO synthase (eNOS) in vascular endothelial cells (ECs). AMPK inhibition by compound C blocked STA-induced Akt/eNOS phosphorylation, suggesting that AMPK is the upstream of Akt and eNOS. Inhibition of Akt by MK2206 blocked STA-stimulated eNOS phosphorylation without altering AMPK phosphorylation. Furthermore, we showed that STA activated AMPK via the induction of liver kinase B1 phosphorylation. These results indicated that STA can induce eNOS phosphorylation and vasorelaxation by regulating the interplay between AMPK and Akt pathways in ECs. These findings further highlighted the potential of STA as a nutritional factor in the beneficial effects of fruit intake in preventing the endothelial dysfunction-related metabolic cardiovascular diseases.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Aorta Torácica/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/metabolismo , Prolina/análogos & derivados , Proteínas Proto-Oncogênicas c-akt/metabolismo , Vasodilatadores/farmacologia , Proteínas Quinases Ativadas por AMP/genética , Animais , Aorta Torácica/metabolismo , Aorta Torácica/fisiopatologia , Bovinos , Citrus/química , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Técnicas In Vitro , Leonurus/química , Masculino , Óxido Nítrico Sintase Tipo III/genética , Fosforilação/efeitos dos fármacos , Prolina/farmacologia , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Ratos Sprague-Dawley , Vasodilatação/efeitos dos fármacos
10.
Food Chem Toxicol ; 133: 110764, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31437471

RESUMO

The present study investigated the effects of Cornus mas, Sorbus aucuparia and Viburnum opulus fruit extracts on arginase activity and arterial vasodilation. V. opulus fruit extract exerted the highest vasorelaxant activity in phenylephrine precontracted rat aortic rings (EC50 = 6.31 ±â€¯1.61 µg/mL) and a significant inhibition of arginase (IC50 = 71.02 ±â€¯3.06 µg/mL). By contrast, S. aucuparia and C. mas fruit extracts showed no important anti-arginase activity and a significantly weaker activity in the rat aortic rings relaxation assay (EC50 = 100.9 ±â€¯11.63 and 78.52 ±â€¯8.59 µg/mL, respectively). For all extracts, the main mechanism of vasodilation was proven to be endothelium-dependent. HPLC-ESI-Q-TOF-MS/MS studies revealed a very complex metabolite profiling in all three extracts with chlorogenic acid accounting for 30.89, 0.72 and 2.03 mg/g in V. opulus, C. mas and S. aucuparia fruit extracts, respectively. All extracts were declared non-toxic in the brine shrimp acute toxicity test. Our study highlights potential benefits of V. opulus fruit extract in diseases associated with endothelial dysfunction and impaired vasodilation.


Assuntos
Arginase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Frutas/química , Extratos Vegetais/farmacologia , Vasodilatadores/farmacologia , Animais , Aorta/efeitos dos fármacos , Artemia/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Cornus/química , Endotélio/efeitos dos fármacos , Inibidores Enzimáticos/toxicidade , Masculino , Metaboloma , Extratos Vegetais/toxicidade , Ratos Sprague-Dawley , Sorbus/química , Espectrometria de Massas em Tandem , Vasodilatadores/toxicidade , Viburnum/química
11.
Fitoterapia ; 138: 104299, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31404616

RESUMO

Gerbera piloselloides (L.) Cass. (Compositae) possesses various biological effects. It is used as an oriental remedy for relieving cough and resolving phlegm. The present study is to investigate the vasodilation effects of Gerbera piloselloides on isolated rat mesenteric arteries (MAs) and the potential mechanism. Different organic extracts of Gerbera piloselloides were tested, and an HPLC-UV-FD-based analytical method was established to identify the active constituents. The principal components, namely, 8-MOP (8-methoxypsoralan) and 8-MSD (8-methoxysmyrindiol), were found to be predominant in the extracts of petroleum ether and dichloroform, which showed stronger vasodilation activities. 8-MSD was isolated from Gerbera piloselloides by silica gel column chromatography coupled with a Waters 2545 high throughput autopurification system, and its vasodilation effects were explored by an assay of tension on rat MA rings. The results suggest that 8-MSD induces vascular relaxation in rat MAs via an endothelium-dependent mechanism involving the Kir channel, which enables Ca2+ entry in the cell and activates production of NO. The present research indicates that 8-MSD may be therapeutically useful as an anti-hypertension agent and to potentially treat cardiovascular and gastrointestinal diseases.


Assuntos
Asteraceae/química , Artérias Mesentéricas/efeitos dos fármacos , Extratos Vegetais/farmacologia , Vasodilatação , Vasodilatadores/farmacologia , Animais , China , Endotélio Vascular/efeitos dos fármacos , Feminino , Técnicas In Vitro , Masculino , Estrutura Molecular , Ratos , Ratos Wistar , Vasodilatadores/isolamento & purificação
12.
Molecules ; 24(15)2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31362388

RESUMO

Alkaloids derived from plants have shown great medicinal benefits, and are often reported for their use in cardiovascular disease management. Aristotelia chilensis (Molina) Stuntz (Maqui) has shown important medicinal properties in traditional useage. In this study, we evaluated the effect of the indole-alkaloid aristoteline (ARI), isolated from leaves of Maqui, on vascular reactivity of isolated aortic rings from normotensive rats. ARI induced relaxation (100%) in a concentration-dependent manner in intact or denuded-endothelium aortic rings pre-contracted with phenylephrine (PE; 1 µM). However, a specific soluble guanylyl cyclase inhibitor (ODQ; 1 µM) significantly reduced the relaxation to ARI in aortic rings pre-contracted with PE. In the presence of ARI, the contraction induced by KCl or PE was significantly (p < 0.05) decreased. Interestingly, the potassium channel blockade with 10 µM BaCl2 (Kir), 10 µM glibenclamide (KATP), 1 mM tetraethylammonium (TEA; KCa1.1), or 1 mM 4-aminopyridine (4-AP; Kv) significantly (p < 0.05) reduced the ARI-induced relaxation. ARI significantly (p < 0.05) reduced the contractile response to agonist of CaV1.2 channels (Bay K8644; 10 nM), likely reducing the influx of extracellular calcium through plasma membrane. The mechanisms associated with this process suggest an activation of the potassium channels, a calcium-induced antagonism and endothelium independent vasodilation that possibly involves the nitric oxide-independent soluble guanylate cyclase pathway.


Assuntos
Alcaloides/química , Alcaloides/farmacologia , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio/química , Canais de Potássio/química , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Cloratos/farmacologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Estrutura Molecular , Óxido Nítrico/metabolismo , Fenilefrina/farmacologia , Canais de Potássio/agonistas , Prostaglandinas/farmacologia , Ratos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/química , Vasodilatadores/farmacologia
13.
Life Sci ; 233: 116694, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31351970

RESUMO

AIMS: The hypoxia-stimulated response of the endocrine system depends on the kind and duration of hypoxia. Hypoxia has been reported to stimulate testosterone (T) production in rats, but the mechanisms remain to be investigated. MATERIALS AND METHODS: Male rats were divided into two groups. The rats exposed to chronic intermittent hypoxia (CIH) at 8 h/day were housed in a hypoxic chamber (12% O2) for 14 days. Normoxic rats were used as control animals. T was measured after challenging the rat Leydig cells (LCs) with different stimulators, including hCG (0.01 IU/ml), forskolin (10-5 M), 8-bromo-cAMP (10-4 M), A23187 (10-5 M), cyclopiazonic acid (10-4 M), and androstenedione (10-8 M). Meanwhile, the LCs were incubated with trilostane (10-5 M) and/or 25-OH-hydroxycholesterol (10-5 M); thereafter the media were collected for pregnenolone assay. KEY FINDINGS: In the CIH group, plasma T levels were increased, but the serum luteinizing hormone (LH) was decreased. Furthermore, at several time intervals after hCG injection, plasma T levels were higher in the CIH group. The evoked-release of T and pregnenolone were significantly increased in the CIH group. Compared with the normoxic group, the CIH group had higher mRNA and protein expression levels of the LH receptor and CYP11A1 but not StAR. The plasma and testicular microvasculature VEGF levels were increased in the CIH group. The testicular vessel distribution was more obvious in CIH rats. SIGNIFICANCE: CIH-induced T secretion might be partially mediated by mechanisms involving the induction of LH receptor expression, testicular angiogenesis, CYP11A1 activity, 17ß-HSD activity, and calcium-related pathway.


Assuntos
Hipóxia Celular/fisiologia , Colforsina/farmacologia , Células Intersticiais do Testículo/metabolismo , Testosterona/metabolismo , Animais , Células Cultivadas , Enzima de Clivagem da Cadeia Lateral do Colesterol/genética , Enzima de Clivagem da Cadeia Lateral do Colesterol/metabolismo , Células Intersticiais do Testículo/citologia , Células Intersticiais do Testículo/efeitos dos fármacos , Masculino , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores do LH/genética , Receptores do LH/metabolismo , Vasodilatadores/farmacologia
14.
Molecules ; 24(15)2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31349544

RESUMO

Hydroalcoholic extracts of Patagonian Calafate berry (Berberis microphylla) contain mono or disaccharide conjugated anthocyanins and flavonols. The Liquid Chromatography-Mass Spectrometry (LC-MS) chemical extract profile identified glycosylated anthocyanidins such as delphinidin-, petunidin- and malvidin-3-glucoside as the major constituents. The predominant flavonols were 3-O substituents quercetin-rutinoside or -rhamnoside. Anthocyanins doubled flavonols in mass (13.1 vs. 6 mg/g extract). Polyphenols vascular actions were examined in the rat arterial mesenteric bed bioassay; extract perfusion elicited concentration-dependent vasodilatation mimicked by conjugated anthocyanins standards. Vascular responses of main glycosylated anthocyanins were endothelium-dependent (p < 0.001) and mediated by NO production (p < 0.05). The anthocyanins antioxidant activity determined in isolated endothelial cells (CAA) showed a reduced redox potential as compared to the extract or quercetin. While in the 2,2-Diphenyl-1-picrylhydrazyl (DPPH) assay, the anthocyanins showed an equivalent quercetin potency, the extract was 15-fold less active, proposing that the anthocyanin-induced vasodilation is not due to an antioxidant mechanism. The extract shows promising commercial nutraceutical potential.


Assuntos
Antioxidantes/farmacologia , Berberis/química , Suplementos Nutricionais/análise , Frutas/química , Extratos Vegetais/farmacologia , Vasodilatadores/farmacologia , Animais , Antioxidantes/química , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Estrutura Molecular , Compostos Fitoquímicos , Extratos Vegetais/química , Ratos , Espectrometria de Massas em Tandem , Vasodilatadores/química
15.
Oncol Rep ; 42(3): 1214-1224, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31322174

RESUMO

Tetramethylpyrazine (TMP; an extract of the Chinese herbal medicine, Chuanxiong) has been shown to exert remarkable antiretinoblastoma (RB) effects. Based on our previous study, the target gene was found to be C­X­C chemokine receptor type 4 (CXCR4). CXCR4 is a prognostic marker in various types of cancer, but the exact mechanisms underlying the regulation of CXCR4 expression by TMP in WERI­Rb1 cells have yet to be fully elucidated. In the present study, it was revealed that TMP significantly downregulated CXCR4 expression and inhibited CXCR4 promoter activity in WERI­Rb1 cells, indicating that TMP inhibits CXCR4 expression in WERI­Rb1 cells through transcriptional regulatory mechanisms. Among the numerous transcription factors involved in CXCR4 function, including Yin Yang 1 (YY1), nuclear respiratory factor­1 (Nrf­1), Krüppel­like Factor 2 (KLF2), specificity protein 1 (SP1), and nuclear factor­κB subunit 1 (NF­κB1), only TMP led to a significant downregulation of Nrf­1 expression. Chromatin immunoprecipitation assays further indicated that Nrf­1 directly binds to the promoter region of CXCR4, and silencing Nrf­1 via siRNA transfection notably inhibited CXCR4 expression in WERI­Rb1 cells. In addition, the expression levels of both Nrf­1 and CXCR4 increased concomitantly with WERI­Rb1 cell density. Furthermore, the downregulation of Nrf­1 and CXCR4 expression in RB by TMP was confirmed in vivo. Taken together, the results of the present study have uncovered a novel mechanism in which CXCR4 expression is regulated by Nrf­1 in WERI­Rb1 cells, thereby identifying novel potential targets for the treatment of RB, and providing evidence for the clinical application of TMP in adjuvant retinoblastoma therapy.


Assuntos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Fator 1 Nuclear Respiratório/metabolismo , Pirazinas/farmacologia , Receptores CXCR4/genética , Neoplasias da Retina/patologia , Retinoblastoma/patologia , Transcrição Genética/efeitos dos fármacos , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Feminino , Humanos , Camundongos , Camundongos Nus , Fator 1 Nuclear Respiratório/genética , Receptores CXCR4/metabolismo , Neoplasias da Retina/tratamento farmacológico , Neoplasias da Retina/genética , Retinoblastoma/tratamento farmacológico , Retinoblastoma/genética , Células Tumorais Cultivadas , Vasodilatadores/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Phytother Res ; 33(9): 2347-2359, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31273855

RESUMO

As yet, there was no effective pharmacological therapy approved for non-alcoholic fatty liver disease (NAFLD). Here, we aimed to evaluate the therapeutic potential of puerarin against NAFLD and explored the underlying mechanisms. C57BL/6J mice were fed with a high-fat high-sucrose (HFHS) diet with or without puerarin coadministration intragastrically. The levels of hepatocellular injury, steatosis, fibrosis, and mitochondrial and metabolism alteration were detected. First, puerarin ameliorated histopathologic abnormalities due to HFHS. We observed a marked increase in hepatic lipid content, inflammation, and fibrosis level, which were attenuated by puerarin. Possible mechanisms were related to puerarin-mediated activation of PI3K/AKT pathway and further improvement in fatty acid metabolism. Puerarin restored the NAD+ content and beneficially affected the hepatic mitochondrial function, which attenuated HFHS-induced steatosis and metabolic disturbances. Finally, hepatic PARP-1 was activated due to excessive fat intake. Puerarin attenuated the PARP-1 expression in HFHS-fed mice, and PJ34, the PARP inhibitor, could mimic these protections of puerarin. However, pharmacological inhibition of PI3K disabled the protection of puerarin or PJ34 toward NAD+ refilling and mitochondrial homeostasis. In conclusion, our findings indicated that puerarin could be a promising and practical therapeutic strategy in NAFLD through modulating PARP-1/PI3K/AKT signaling pathway and further facilitating mitochondrial function.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Isoflavonas/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sacarose/efeitos adversos , Vasodilatadores/uso terapêutico , Animais , Humanos , Isoflavonas/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Vasodilatadores/farmacologia
17.
Chem Pharm Bull (Tokyo) ; 67(7): 675-689, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257323

RESUMO

An Orobanchaceae plant Cistanche tubulosa (SCHENK) WIGHT (Kanka-nikujuyou in Japanese), which is one of the authorized plant resources as Cistanches Herba in both Japanese and Chinese Pharmacopoeias, is a perennial parasitic plant growing on roots of sand-fixing plants. The stems of C. tubulosa have traditionally been used for treatment of impotence, sterility, lumbago, and body weakness as well as a promoting agent of blood circulation. In recent years, Cistanches Herba has also been widely used as a health food supplement in Japan, China, and Southeast Asian countries. Here we review our recent studies on chemical constituents from the stems of C. tubulosa as well as their bioactivities such as vasorelaxtant, hepatoprotective, and glucose tolerance improving effects.


Assuntos
Produtos Biológicos/química , Cistanche/química , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Cistanche/metabolismo , Glicosídeos/química , Glicosídeos/isolamento & purificação , Glicosídeos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Monoterpenos/química , Monoterpenos/isolamento & purificação , Monoterpenos/farmacologia , Caules de Planta/química , Caules de Planta/metabolismo , Substâncias Protetoras/química , Substâncias Protetoras/isolamento & purificação , Substâncias Protetoras/farmacologia , Vasodilatadores/química , Vasodilatadores/isolamento & purificação , Vasodilatadores/farmacologia
18.
Molecules ; 24(12)2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31208086

RESUMO

B. monnieri extract (BME) is an abundant source of bioactive compounds, including saponins and flavonoids known to produce vasodilation. However, it is unclear which components are the more effective vasodilators. The aim of this research was to investigate the vasorelaxant effects and mechanisms of action of saponins and flavonoids on rat isolated mesenteric arteries using the organ bath technique. The vasorelaxant mechanisms, including endothelial nitric oxide synthase (eNOS) pathway and calcium flux were examined. Saponins (bacoside A and bacopaside I), and flavonoids (luteolin and apigenin) at 0.1-100 µM caused vasorelaxation in a concentration-dependent manner. Luteolin and apigenin produced vasorelaxation in endothelial intact vessels with more efficacy (Emax 99.4 ± 0.7 and 95.3 ± 2.6%) and potency (EC50 4.35 ± 1.31 and 8.93 ± 3.33 µM) than bacoside A and bacopaside I (Emax 83.6 ± 2.9 and 79.9 ± 8.2%; EC50 10.8 ± 5.9 and 14.6 ± 5.4 µM). Pretreatment of endothelial intact rings, with L-NAME (100 µM); an eNOS inhibitor, or removal of the endothelium reduced the relaxant effects of all compounds. In K+-depolarised vessels suspended in Ca2+-free solution, these active compounds inhibited CaCl2-induced contraction in endothelial denuded arterial rings. Moreover, the active compounds attenuated transient contractions induced by 10 µM phenylephrine in Ca2+-free medium containing EGTA (1 mM). Thus, relaxant effects occurred in both endothelial intact and denuded vessels which signify actions through both endothelium and vascular smooth muscle cells. In conclusion, the flavonoids have about twice the potency of saponins as vasodilators. However, in the BME, there is ~20 × the amount of vaso-reactive saponins and thus are more effective.


Assuntos
Bacopa/química , Artérias Mesentéricas/efeitos dos fármacos , Extratos Vegetais/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Cálcio/metabolismo , Relação Dose-Resposta a Droga , Extratos Vegetais/química , Ratos , Vasodilatadores/química
19.
Life Sci ; 231: 116555, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31194991

RESUMO

AIMS: Caffeine is a methylxanthine with multiple actions in vascular smooth muscle cells (VSMCs), including the increase in the intracellular Ca2+ (iCa2+) concentration by the activation of ryanodine receptors (RyRs). The present study aimed at investigating the participation of Ca2+-influx through different Ca2+-channels on the transient contraction (TC) induced by caffeine in mice mesenteric arteries. MAIN METHODS: Second-order of mesenteric arteries was isolated from male Swiss mice. Vessels without functional endothelium were stimulated with caffeine (10 mM). The caffeine-induced TC was evaluated after the incubation of artery rings for 30 min with the following drugs: nifedipine (10 µM), a Cav1.2 blocker; 2-aminoethoxydiphenyl borate (2-APB; 10 µM) and ruthenium red (RuR; 10 µM), transient receptor potential (TRPs) channels blockers; capsazepine (10 µM) and HC067047 (10 µM), TRPV1 and TRPV4 antagonists, respectively; paxilline (1 µM), a selective BKCa blocker; and SKF-96365 (30 µM), an Orai blocker. Ca2+-fluorescence measurements were also performed on the investigated arteries. KEY FINDINGS: The TC induced by caffeine was partially dependent on Ca2+-influx. However, the blockage of Cav1.2 increased the TC while reduced the iCa2+ signal. Similar results were observed after the blockage of TRPs or BKCa. Therefore, caffeine promoted Ca2+-influx via TRPs and Cav1.2, and hyperpolarization through the activation of BKCa, inducing negative feedback of TC. SIGNIFICANCE: Our results indicate an alternative mechanism for the control of VSMCs contraction in resistance arteries. The evidence of the negative feedback of contraction via TRP-Cav1.2-BKCa provides a new perspective for understanding the mechanism involved in the vascular responses triggered by caffeine.


Assuntos
Cafeína/farmacologia , Canais de Cálcio Tipo L/metabolismo , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/metabolismo , Artérias Mesentéricas/efeitos dos fármacos , Animais , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Masculino , Artérias Mesentéricas/metabolismo , Camundongos , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Canais de Cátion TRPV/metabolismo , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia
20.
Einstein (Sao Paulo) ; 17(3): eAO4600, 2019 Jun 03.
Artigo em Inglês, Português | MEDLINE | ID: mdl-31166411

RESUMO

OBJECTIVE: To characterize the calcium influx pathways implicated in the sustained elevation of endothelial intracellular calcium concentration, required for the synthesis and release of relaxing factors. METHODS: We evaluated the effect of the newly synthesized pyrazole derivatives, described as selective inhibitors for ORAI (BTP2/Pyr2 and Pyr6) and TRPC3 (Pyr3 and Pyr10) channels, upon endothelium- and extracellular calcium-dependent relaxations stimulated by acetylcholine and thapsigargin, in pre-constricted rat thoracic aortic rings. RESULTS: Acetylcholine and thapsigargin responses were completely reverted by Pyr2 and Pyr6 (1 to 3µM). Pyr3 (0.3 to 3µM) caused a rapid reversal of acetylcholine (6.2±0.08mg.s-1) and thapsigargin (3.9±0.25mg.s-1) relaxations, whereas the more selective TRPC3 blocker Pyr10 (1 to 3µM) had no effect. The recently described TRPC4/5 selective blocker, ML204 (1 to 3µM), reverted completely acetylcholine relaxations, but minimally thapsigargin induced ones. Noteworthy, relaxations elicited by GSK1016790A (TRPV4 agonist) were unaffected by pyrazole compounds or ML204. After Pyr2 and Pyr6 pre-incubation, acetylcholine and thapsigargin evoked transient relaxations similar in magnitude and kinetics to those observed in the absence of extracellular calcium. Sodium nitroprusside relaxations as well as phenylephrine-induced contractions (denuded aorta) were not affected by any of pyrazole compounds (1 to 3µM). CONCLUSION: These observations revealed a previously unrecognized complexity in rat aorta endothelial calcium influx pathways, which result in production and release of nitric oxide. Pharmacologically distinguishable pathways mediate acetylcholine (ORAI/TRPC other than TRPC3/TRPC4 calcium-permeable channels) and thapsigargin (TRPC4 not required) induced calcium influx.


Assuntos
Acetilcolina/farmacologia , Cálcio/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Fatores Relaxantes Dependentes do Endotélio/metabolismo , Óxido Nítrico/metabolismo , Tapsigargina/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Canais de Cálcio Ativados pela Liberação de Cálcio/metabolismo , Masculino , Ratos Wistar , Canais de Cátion TRPC/metabolismo , Canais de Cátion TRPV/efeitos dos fármacos , Canais de Cátion TRPV/metabolismo , Fatores de Tempo , Vasodilatadores/farmacologia
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