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OBJECTIVE: To analyze changes in height, weight, and body mass index (BMI = kg/m2 ) from 1986 to 2022 in 3-11 year old children from Dzeal, a rural Maya community in Yucatan, Mexico. MATERIALS AND METHODS: From October-2022 to February-2023 (third-wave survey), we obtained anthropometric measurements of children (n = 80) and family socioeconomic data and compared them with data obtained in 1986 (n = 38) and 2000 (n = 76). Comparisons of anthropometric parameters by sex between years of measurement were performed graphically and through one-way ANOVA, splitting children into two age groups: 3-7 and 8-11. Bonferroni adjustments for multiple comparisons were used when ANOVAs were statistically significant (p < .05). RESULTS: In girls, significant increases in height and weight between surveys were found in 3-7 and 8-11 age groups; in boys, significant increases were only found in the 8-11 age group. Regarding BMI, there were increases in 2022 compared with 1986/2000 in both sexes from 8 years onwards. Differences indicate increases of 3.9 and 4.4 cm per decade in girls aged 3-7 and 8-11, respectively, and increases in weight of 1.1 and 3.3 kg per decade, respectively. Increases in boys 8-11 years were 2.3 cm and 2.4 kg per decade. CONCLUSION: Significant increases in growth parameters were observed in specific-age children in the community studied in the context of changes in livelihoods and improvements in household material conditions.
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Estatura , População Rural , Criança , Masculino , Feminino , Humanos , Pré-Escolar , México , Antropometria , Índice de Massa Corporal , Peso CorporalRESUMO
BACKGROUND: Knowledge about the influence of early developmental factors on cardiometabolic health in the Maya is limited. AIM: To analyse the relationship between birthweight (BW) and cardiometabolic parameters in a sample of rural Maya children from Yucatan, Mexico. SUBJECTS AND METHODS: We took anthropometric measurements and obtained data on BW and fasting blood samples in a sample of 75 children aged 5-14 years. Dependent variables were: fat mass index (FMI), body mass index (BMI), glucose (G), triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), LDL/HDL and TC/HDL ratios and metabolic index (TGxG/HDL2). Outcomes were transformed to y = 100 log(e)x and the resulting estimates are interpreted as symmetrical percentage differences. The main independent variable was BW z-score. Multiple linear regression analyses were used to assess the relationship between BW and outcomes. RESULTS: An increase of one standard deviation in BW predicted 6.6% (95% CI [-11.6, -1.6]) decrease in HDL and 11% (95% CI [3.7, 18.4]), 7.8% (95% CI [2.3, 13.2]) and 19.6% (95% CI [3.1, 36]) increases in LDL/HDL, TC/HDL and metabolic index, respectively. CONCLUSION: Higher birthweights were associated with adverse levels of biochemical parameters in this sample of rural Maya children.
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Glicemia , Doenças Cardiovasculares , Criança , Humanos , Peso ao Nascer , México/epidemiologia , Glicemia/análise , Triglicerídeos , Índice de Massa Corporal , HDL-Colesterol , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Fatores de RiscoRESUMO
Despite the overwhelming advances in the understanding of the pathogenesis of stroke, a devastating disease affecting millions of people worldwide, currently there are only a limited number of effective treatments available. Preclinical and clinical studies show that stroke is a sexually dimorphic disorder, affecting males and females differently. Strong experimental evidence indicates that estrogen may play a role in this difference and that exogenous 17ß-estradiol (E2) is neuroprotective against stroke in both male and female rodents. However, the molecular mechanisms by which E2 intervenes in ischemia-induced cell death, revealing these sex differences, remain unclear. The present study was aimed to determine, in female rats, the molecular mechanisms of two well-known pro-survival signaling pathways, MAPK/ERK1/2 and PI3K/Akt, that mediate E2 neuroprotection in response to acute ischemic stroke. E2 pretreatment reduced brain damage and attenuated apoptotic cell death in ovariectomized female rats after an ischemic insult. Moreover, E2 decreased phosphorylation of ERK1/2 and prevented ischemia/reperfusion-induced dephosphorylation of both Akt and the pro-apoptotic protein, BAD. However, MAPK/ERK1/2 inhibitor PD98059, but not the PI3K inhibitor LY294002, attenuated E2 neuroprotection. Thus, these results suggested that E2 pretreatment in ovariectomized female rats modulates MAPK/ERK1/2 and activates Akt independently of PI3K to promote cerebroprotection in ischemic stroke. A better understanding of the mechanisms and the influence of E2 in the female sex paves the way for the design of future successful hormone replacement therapies.
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Prolinamides are well-known organocatalysts for the HSiCl3 reduction of imines; however, custom design of catalysts is based on trial-and-error experiments. In this work, we have used a combination of computational calculations and experimental work, including kinetic analyses, to properly understand this process and to design optimized catalysts for the benchmark (E)-N-(1-phenylethylidene)aniline. The best results have been obtained with the amide derived from 4-methoxyaniline and the N-pivaloyl protected proline, for which the catalyzed process is almost 600 times faster than the uncatalyzed one. Mechanistic studies reveal that the formation of the component supramolecular complex catalyst-HSiCl3-substrate, involving hydrogen bonding breaking and costly conformational changes in the prolinamide, is an important step in the overall process.
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Chiral imidazolium l-prolinate salts, providing a complex network of supramolecular interaction in a chiral environment, have been studied as synzymatic catalytic systems. They are demonstrated to be green and efficient chiral organocatalysts for direct asymmetric aldol reactions at room temperature. The corresponding aldol products were obtained with moderate to good enantioselectivities. The influence of the presence of chirality in both the imidazolium cation and the prolinate anion on the transfer of chirality from the organocatalyst to the aldol product has been studied. Moreover, interesting match/mismatch situations have been observed regarding configuration of chirality of the two components through the analysis of results for organocatalysts derived from both enantiomers of prolinate (R/S) and the trans/cis isomers for the chiral fragment of the cation. This is associated with differences in the corresponding reaction rates but also to the different tendencies for the formation of aggregates, as evidenced by nonlinear effects studies (NLE). Excellent activities, selectivities, and enantioselectivities could be achieved by an appropriate selection of the structural elements at the cation and anion.
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Including sex is of paramount importance in preclinical and clinical stroke researches, and molecular studies dealing in depth with sex differences in stroke pathophysiology are needed. To gain insight into the molecular sex dimorphism of ischaemic stroke in rat cerebral cortex, male and female adult rats were subjected to transient middle cerebral artery occlusion. The expression of neuroglobin (Ngb) and other functionally related molecules involved in sex steroid signalling (oestrogen and androgen receptors), steroidogenesis (StAR, TSPO and aromatase) and autophagic activity (LC3B-II/LC3B-I ratio, UCP2 and HIF-1α) was assessed in the ipsilateral ischaemic and contralateral non-ischaemic hemispheres. An increased expression of Ngb was detected in the injured female cerebral cortex. In contrast, increased expression of oestrogen receptor α, GPER, StAR, TSPO and UCP2, and decreased androgen receptor expression were detected in the injured male cortex. In both sexes, the ischaemic insult induced an upregulation of LC3B-II/-I ratio, indicative of increased autophagy. Therefore, the cerebral cortex activates both sex-specific and common molecular responses with neuroprotective potential after ischaemia-reperfusion, which globally results in similar stroke outcome in both sexes. Nonetheless, these different potential molecular targets should be taken into account when neuroprotective drugs aiming to reduce brain damage in ischaemic stroke are investigated.
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Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Animais , Autofagia , Córtex Cerebral , Modelos Animais de Doenças , Feminino , Infarto da Artéria Cerebral Média , Masculino , Neuroglobina , Ratos , Ratos Sprague-Dawley , Caracteres Sexuais , EsteroidesRESUMO
We have previously shown that the selective estrogen receptor modulator, bazedoxifene, improves the consequences of ischemic stroke. Now we aimed to characterize the effects and mechanisms of action of bazedoxifene in cerebral arteries. Male rabbit isolated basilar arteries were used for isometric tension recording and quantitative polymerase chain reaction. Bazedoxifene relaxed cerebral arteries, as 17-ß-estradiol, 4,4',4â³-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol [estrogen receptor (ER) α agonist], and G1 [G protein-coupled ER (GPER) agonist] did it (4,4',4â³-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol > bazedoxifene = G1 > 17-ß-estradiol). 2,3-Bis(4-hydroxyphenyl)-propionitrile (ERß agonist) had no effect. Expression profile of genes encoding for ERα (ESR1), ERß (ESR2), and GPER was GPER > ESR1 > ESR2. As to the endothelial mechanisms, endothelium removal, N-nitro-L-arginine methyl ester, and indomethacin, did not modify the relaxant responses to bazedoxifene. As to the K channels, both a high-K medium and the Kv blocker, 4-aminopyridine, inhibited the bazedoxifene-induced relaxations, whereas tetraethylammonium (nonselective K channel blocker), glibenclamide (selective KATP blocker) or iberiotoxin (selective KCa blocker) were without effect. Bazedoxifene also inhibited both Ca- and Bay K8644-elicited contractions. Therefore, bazedoxifene induces endothelium-independent relaxations of cerebral arteries through (1) activation of GPER and ERα receptors; (2) increase of K conductance through Kv channels; and (3) inhibition of Ca entry through L-type Ca channels. Such a profile is compatible with the beneficial effects of estrogenic compounds (eg, SERMs) on vascular function and, specifically, that concerning the brain. Therefore, bazedoxifene could be useful in the treatment of cerebral disorders in which the cerebrovascular function is compromised (eg, stroke).
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Artéria Basilar/efeitos dos fármacos , Estrogênios/farmacologia , Indóis/farmacologia , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Vasodilatação/efeitos dos fármacos , Animais , Artéria Basilar/fisiologia , Relação Dose-Resposta a Droga , Masculino , Técnicas de Cultura de Órgãos , Coelhos , Vasodilatação/fisiologiaRESUMO
Resveratrol (RSV) holds promise as cerebroprotective treatment in cerebral ischemia. This systematic review aims to assess the effects and mechanisms of RSV in animal models of ischemic stroke. We searched Medline, Embase and Web of Science to identify 75 and 57 eligible rodent studies for qualitative and quantitative syntheses, respectively. Range of evidence met 10 of 13 STAIR criteria. Median (Q1, Q3) quality score was 7 (5, 8) on the CAMARADES 15-item checklist. Bayesian meta-analysis showed SMD estimates (95% CI) favoring RSV: infarct size (-1.72 [-2.03; -1.41]), edema size (-1.61 [-2.24; -0.98]), BBB impairment (-1.85 [-2.54; -1.19]), neurofunctional impairment (-1.60 [-1.92; -1.29]), and motor performance (1.39 [0.64; 2.08]); and less probably neuronal survival (0.63 [-1.40; 2.48]) and apoptosis (-0.96 [-2.87; 1.02]). Species (rat vs mouse) was associated to a larger benefit. Sensitivity analyses confirmed robustness of the estimates. Reduction of oxidative stress, inflammation, and apoptosis underlie these effects. Our results quantitatively state the beneficial effects of RSV on structural and functional outcomes in rodent stroke models, update the evidence on the mechanisms of action, and provide an exhaustive list of targeted signaling pathways. Current evidence highlights the need for conducting further high-quality preclinical research to better inform clinical research.
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AVC Isquêmico , Acidente Vascular Cerebral , Animais , Ratos , Camundongos , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Teorema de Bayes , Acidente Vascular Cerebral/tratamento farmacológico , AVC Isquêmico/tratamento farmacológico , Modelos Animais de DoençasRESUMO
BACKGROUND AND PURPOSE: Ischemic stroke continues to be one of the main causes of death worldwide. Inflammation accounts for a large part of damage in this pathology. The cannabinoid type 2 receptor (CB2R) has been proposed to have neuroprotective properties in neurological diseases. Therefore, our aim was to determine the effects of the activation of CB2R on infarct outcome and on ischemia-induced brain expression of classic and alternative markers of macrophage/microglial activation. METHODS: Swiss wild-type and CB2R knockout male mice were subjected to a permanent middle cerebral artery occlusion. Mice were treated with either a CB2R agonist (JWH-133), with or without a CB2R antagonist (SR144528) or vehicle. Infarct outcome was determined by measuring infarct volume and neurological outcome. An additional group of animals was used to assess mRNA and protein expression of CB2R, interleukin (IL)-1ß, IL-6, tumor necrosis factor α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory peptide (MIP) -1α, RANTES, inducible nitric oxide synthase (iNOS), cyclooxygenase-2, IL-4, IL-10, transforming growth factor ß (TGF-ß), arginase I, and Ym1. RESULTS: Administration of JWH-133 significantly improved infarct outcome, as shown by a reduction in brain infarction and neurological impairment. This effect was reversed by the CB2R antagonist and was absent in CB2R knockout mice. Concomitantly, administration of JWH-133 led to a lower intensity of Iba1+ microglia/macrophages and a decrease in middle cerebral artery occlusion-induced gene expression of both classic (IL-6, TNF-α, MCP-1, MIP-1α, RANTES, and iNOS) and alternative mediators/markers (IL-10, TGF-ß, and Ym1) of microglial/macrophage activation after permanent middle cerebral artery occlusion. CONCLUSIONS: The inhibitory effect of CB2R on the activation of different subpopulations of microglia/macrophages may account for the protective effect of the selective CB2R agonist JWH-133 after stroke.
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Encéfalo/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Macrófagos/metabolismo , Microglia/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Canfanos/farmacologia , Canabinoides/farmacologia , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Infarto da Artéria Cerebral Média/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Masculino , Camundongos , Camundongos Knockout , Microglia/efeitos dos fármacos , Microglia/patologia , Óxido Nítrico Sintase Tipo II/metabolismo , Pirazóis/farmacologia , Receptor CB2 de Canabinoide/genéticaRESUMO
Diabetes is associated with increased prevalence of hypertension, cardiovascular and renal disease. Atrial natriuretic peptide (ANP) plays an important role in cardiovascular pathophysiology and is claimed to have cardioprotective and renoprotective effect in diabetic patients. The working hypothesis was that alloxan-induced diabetes might modify the vascular effects of ANP in isolated rabbit renal arteries and the mechanisms involved in such actions. Plasma ANP levels were higher in diabetic rabbits than in control rabbits. ANP (10(-12)-10(-7)M) induced a relaxation of precontracted renal arteries, which was lower in diabetic than in control rabbits. In arteries from both groups of animals, endothelium removal decreased the ANP-induced relaxation but inhibition of NO-synthesis did not modify ANP-induced relaxations. In KCl-depolarised arteries, relaxation to ANP was almost abolished both in control and diabetic rabbits. Tetraethylammonium (TEA) partly inhibited the relaxation to ANP in control rabbits but did not modify it in diabetic rabbits. Glibenclamide and 4-aminopyridine inhibited the relaxation to ANP, and these inhibitions were lower in diabetic than in control rabbits. Indomethacin potentiated the relaxation to ANP, more in control than in diabetic rabbits. In the presence of ANP the renal artery released thromboxane A(2) and prostacyclin, and the release of prostacyclin resulted decreased in diabetic rabbits. The present results suggest that diabetes produces hyporeactivity of the rabbit renal artery to ANP by mechanisms that at least include the reduced modulation by prostacyclin and a lower participation of ATP-sensitive K(+) channel (K(ATP)), voltage-sensitive K(+) channels (K(V)) and TEA-sensitive K(+) channels (K(Ca)).
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Fator Natriurético Atrial/farmacologia , Diabetes Mellitus Experimental/fisiopatologia , Epoprostenol/fisiologia , Artéria Renal/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Animais , Fator Natriurético Atrial/sangue , Endotélio Vascular/fisiologia , Técnicas In Vitro , Masculino , Canais de Potássio/fisiologia , Coelhos , Artéria Renal/fisiologia , Tetraetilamônio/farmacologia , Tromboxano A2/fisiologia , Vasodilatação/fisiologiaRESUMO
BACKGROUND: Socioeconomic factors influence diet quality during pregnancy. However, a dearth of evidence about the influence on energy and macronutrients adequacy calls for research. OBJECTIVE: To analyze the association between socioeconomic factors and adequacy rates of energy and macronutrient intakes in pregnant women from Merida, Yucatan, Mexico. METHODS: During September to December 2019, we applied a socioeconomic questionnaire and three 24-hour dietary recalls to 83 pregnant females resident in Merida, Yucatan. Energy and macronutrient intakes were compared with the estimated trimester-specific energy and macronutrient requirements to calculate adequacies (%). Outcome variables were average adequacy of energy, carbohydrates, total fat, and protein intakes and the main predictors were maternal education, monthly family income, working status, and marital status. Descriptive statistics of adequacy were calculated for each category of predictors. The association between socioeconomic factors and outcome variables was analyzed through simple and multiple linear regression models. RESULTS: Adequacy rates of energy and macronutrients decreased as education and familial income levels increased, as well as among unemployed women. Consistently with these results, simple linear regressions showed that years of education, family income, and working status (i.e., women working to earn money), were negatively associated with adequacy rates of energy and macronutrients intakes. When all predictors and covariates were included in a multiple linear regression model, only having a job was significantly associated with adequacy rates. Marital status was not associated with outcomes. CONCLUSIONS: Women in disadvantaged socioeconomic conditions (unemployed and low levels of education and familial income) show greater energy and macronutrient intakes.
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Dieta , Gestantes , Ingestão de Alimentos , Ingestão de Energia , Feminino , Humanos , México , Gravidez , Fatores SocioeconômicosRESUMO
Aging is a major risk factor for cerebral infarction. Since cellular senescence is intrinsic to aging, we postulated that stroke-induced cellular senescence might contribute to neural dysfunction. Adult male Wistar rats underwent 60-minute middle cerebral artery occlusion and were grouped according to 3 reperfusion times: 24 hours, 3, and 7 days. The major biomarkers of senescence: 1) accumulation of the lysosomal pigment, lipofuscin; 2) expression of the cell cycle arrest markers p21, p53, and p16INK4a; and 3) expression of the senescence-associated secretory phenotype cytokines interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and interleukin-1ß (IL-1ß) were investigated in brain samples. Lipofuscin accumulation was scarce at the initial stage of brain damage (24 hours), but progressively increased until it reached massive distribution at 7 days post-ischemia. Lipofuscin granules (aggresomes) were mainly confined to the infarcted areas, that is parietal cortex and adjacent caudate-putamen, which were equally affected. The expression of p21, p53, and p16INK4a, and that of IL-6, TNF-α, and IL-1ß, was significantly higher in the ischemic hemisphere than in the non-ischemic hemisphere. These data indicate that brain cell senescence develops during acute ischemic infarction and suggest that the acute treatment of ischemic stroke might be enhanced using senolytic drugs.
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Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Animais , Encéfalo/patologia , Isquemia Encefálica/metabolismo , Senescência Celular , Infarto da Artéria Cerebral Média/metabolismo , Interleucina-6 , Lipofuscina/metabolismo , Masculino , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa , Proteína Supressora de Tumor p53/metabolismoRESUMO
Atrial natriuretic peptide (ANP) plays an important role in the pathophysiology of the vascular complications in diabetes. The working hypothesis was that diabetes might modify the vascular actions of ANP in isolated rabbit carotid arteries and the mechanisms involved in these actions. ANP (10(-12)-10(-7)M) induced a relaxation of precontracted carotid arteries, which was lower in diabetic than in control rabbits. In arteries from both groups of animals, endothelium removal increased the ANP-induced relaxation. Isatin inhibited the relaxation to ANP both in arteries with and without endothelium. Carotid arteries from diabetic rabbits showed a decreased natriuretic peptide receptor (NPR)-A expression and an enhanced NPR-C expression. Inhibition of NO-synthesis did not modify ANP-induced relaxation in control rabbits but inhibited it in diabetic rabbits. In arteries with endothelium indomethacin enhanced the relaxation to ANP in control rabbits but did not modify it in diabetic rabbits. In endothelium-denuded arteries indomethacin inhibited the relaxation to ANP in both groups of animals. In KCl-depolarised arteries, relaxation to ANP was almost abolished both in control and diabetic rabbits. Tetraethylammonium inhibited the relaxation to ANP, and this inhibition was higher in diabetic than in control rabbits. These results suggest that diabetes produces hyporeactivity of the rabbit carotid artery to ANP by a mechanism that at least includes a reduced expression of NPR-A, an enhanced expression of NPR-C and a reduced participation of K(+)-channels. Furthermore, diabetes enhances endothelial NO release and diminishes the ratio thromboxane A(2)/prostacyclin. This increase of vasodilators could result from compensatory mechanisms counteracting the arterial hyporeactivity to ANP.
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Fator Natriurético Atrial/fisiologia , Artérias Carótidas/metabolismo , Diabetes Mellitus Experimental/metabolismo , Regulação para Baixo/fisiologia , Vasodilatação/fisiologia , Animais , Diabetes Mellitus Experimental/fisiopatologia , Masculino , Coelhos , Distribuição AleatóriaRESUMO
Cerebral ischemia is a devastating disease that affects many people worldwide every year. The neurodegenerative damage as a consequence of oxygen and energy deprivation, to date, has no known effective treatment. The ischemic insult is followed by an inflammatory response that involves a complex interaction between inflammatory cells and molecules which play a role in the progression towards cell death. However, there is presently a matter of controversy over whether inflammation could either be involved in brain damage or be a necessary part of brain repair. The inflammatory response is triggered by inflammasomes, key multiprotein complexes that promote secretion of pro-inflammatory cytokines. An early event in post-ischemic brain tissue is the release of certain molecules and reactive oxygen species (ROS) from injured neurons which induce the expression of the nuclear factor-kappaB (NF-κB), a transcription factor involved in the activation of the inflammasome. There are conflicting observations related to the role of NF-κB. While some observe that NF-κB plays a damaging role, others suggest it to be neuroprotective in the context of cerebral ischemia, indicating the need for additional investigation. Here we discuss the dual role of the major inflammatory signaling pathways and provide a review of the latest research aiming to clarify the relationship between NF-κB mediated inflammation and neuronal death in cerebral ischemia.
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The involvement of plasma membrane glutamate transporters (EAATs - excitatory aminoacid transporters) in the pathophysiology of ischemia has been widely studied, but little is known about the role of vesicular glutamate transporters (VGLUTs) in the ischemic process. We analyzed the expression of VGLUT1-3 in the cortex and caudate-putamen of rats subjected to transient middle cerebral artery occlusion. Western blot and immunohistochemistry revealed an increase of VGLUT1 signal in cortex and caudate-putamen until 3 days of reperfusion followed by a reduction 7 days after the ischemic insult. By contrast, VGLUT2 and 3 were drastically reduced. Confocal microscopy revealed an increase in VGLUT2 and 3 immunolabelling in the reactive astrocytes of the ischemic corpus callosum and cortex. Changes in VGLUTs and EAATs expression were differently correlated to neurological deficits. Interestingly, changes in VGLUT1 and EAAT2 expression showed a significant positive correlation in caudate-putamen. Taken together, these results suggest a contribution of VGLUTs to glutamate release in these structures, which could promote neuroblast migration and neurogenesis during ischemic recovery, and a possible interplay with EAATs in the regulation of glutamate levels, at least in the first stages of ischemic recovery.
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Astrócitos/metabolismo , Proteínas de Transporte de Glutamato da Membrana Plasmática/metabolismo , Ataque Isquêmico Transitório/metabolismo , Proteínas Vesiculares de Transporte de Glutamato/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Western Blotting , Núcleo Caudado/efeitos dos fármacos , Núcleo Caudado/metabolismo , Morte Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Imunofluorescência , Ácido Glutâmico/metabolismo , Imuno-Histoquímica , Infarto da Artéria Cerebral Média/metabolismo , Ataque Isquêmico Transitório/patologia , Microscopia Confocal , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Putamen/efeitos dos fármacos , Putamen/metabolismo , Ratos , Traumatismo por ReperfusãoRESUMO
Kidney disease is a frequent complication in diabetes, and significant differences have been reported between male and female patients. Our working hypothesis was that diabetes might modify the vascular actions of testosterone in isolated rabbit renal arteries and the mechanisms involved in these actions. Testosterone (10(-8) to 10(-4)M) induced relaxation of precontracted arteries, without significant differences between control and diabetic rabbits. Both in control and diabetic rabbits endothelium removal inhibited testosterone relaxant action. In arteries with endothelium, incubation with indomethacin (10(-5)M), N(G)-nitro-l-arginine (10(-5)M) or tetraethylammonium (10(-5)M) did not modify relaxations to testosterone neither in control nor in diabetic rabbits. In endothelium-denuded arteries indomethacin enhanced the relaxant action of testosterone, both in control and diabetic rabbits. In arteries from diabetic rabbits, eNOS, iNOS and COX-1 expression and testosterone-induced release of thromboxane A(2) and prostacyclin were not significantly different from those observed in control rabbits. However, COX-2 expression was significantly lower in diabetic rabbits that in control rabbits. In nominally Ca(2+)-free medium, cumulative addition of CaCl2 (10(-5) to 3x10(-2)M) contracted previously depolarized arteries. Testosterone (10(-4)M) inhibited CaCl2 contractions of the renal artery both in control and diabetic rabbits. These results show that testosterone relaxes the renal artery both in control and diabetic rabbits. This relaxation is modulated by muscular thromboxane A(2), it is partially mediated by endothelial prostacyclin, and it involves the blocking of extracellular Ca2+ entry. Diabetes does not modify the mechanisms involved in the relaxant action of testosterone in the rabbit renal artery.
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Diabetes Mellitus Experimental/metabolismo , Artéria Renal/metabolismo , Testosterona/metabolismo , Vasodilatação , Animais , Glicemia/metabolismo , Western Blotting , Cálcio/metabolismo , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Diabetes Mellitus Experimental/fisiopatologia , Relação Dose-Resposta a Droga , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Técnicas Imunoenzimáticas , Indometacina/farmacologia , Masculino , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiopatologia , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/metabolismo , Nitroarginina/farmacologia , Potássio/metabolismo , Bloqueadores dos Canais de Potássio/farmacologia , Prostaglandinas I/metabolismo , Coelhos , Artéria Renal/fisiopatologia , Transdução de Sinais , Testosterona/sangue , Tetraetilamônio/farmacologia , Tromboxano A2/metabolismoRESUMO
Two individual catalytic platforms (metal- and organo-catalyzed) based on the use of an ionic liquid phase were successfully integrated for the synthesis of α-cyano-amine and cyanohydrin trimethylsilyl ethers from allylic alcohol. The right combination of continuous flow processes enabled access to the divergent preparation of two alternative and interesting intermediate compounds from the same starting material.
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Because neuroprotection in stroke should be revisited in the era of recanalisation, the present study analysed the potential neuroprotective effect of the selective oestrogen receptor modulator, bazedoxifene acetate (BZA), in an animal model of diabetic ischaemic stroke that mimics thrombectomy combined with adjuvant administration of a putative neuroprotectant. Four weeks after induction of diabetes (40 mg kg-1 streptozotocin, i.p.), male Wistar rats were subjected to transient middle cerebral artery occlusion (intraluminal thread technique, 60 minutes) and assigned to one of three groups treated with either: vehicle, BZA (3 mg kg-1 day-1 , i.p.) or 17ß-oestradiol (E2 ) (100 µg kg-1 day-1 , i.p.). At 24 hours post-ischaemia-reperfusion, brain damage (neurofunctional score, infarct size and apoptosis), expression of oestrogen receptors (ER)α, ERß and G protein-coupled oestrogen receptor), and activity of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK)1/2 and phosphoinositide 3-kinase/Akt pathways were analysed. At 24 hours after the ischaemic insult, both BZA- and E2 -treated animals showed lower brain damage in terms of improved neurofunctional condition, decreased infarct size and decreased apoptotic cell death. Ischaemia-reperfusion induced a significant decrease in ERα and ERß expression without affecting that of G protein-coupled oestrogen receptor, whereas BZA and E2 reversed such a decrease. The ischaemic insult up-regulated the activity of both the MAPK/ERK1/2 and phosphoinositide 3-kinase/Akt pathways; BZA and E2 attenuated the increased activity of the ERK1/2 pathway, without affecting that of the Akt pathway. The results of the present study lend further support to the consideration of BZA as an effective and safer alternative overcoming the drawbacks of E2 with respect to improving diabetic ischaemic stroke outcome after successful reperfusion.
Assuntos
Isquemia Encefálica/prevenção & controle , Angiopatias Diabéticas/prevenção & controle , Estradiol/farmacologia , Indóis/farmacologia , Receptores de Estrogênio/genética , Acidente Vascular Cerebral/prevenção & controle , Animais , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Angiopatias Diabéticas/genética , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Wistar , Receptores de Estrogênio/metabolismo , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Estreptozocina , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologiaRESUMO
Hydrogen sulfide (H2S) is a potential endothelium-derived hyperpolarizing factor (EDHF) and adventitium- or adipocyte-derived relaxing factor (ADRF) which vasorelaxant action is mediated by potassium channels. H2S could also play an important role in the pathophysiology of diabetic cardiovascular complications. The present study has investigated the influence of alloxan-induced diabetes on the role of potassium channels mediating the relaxant response of the rabbit carotid artery to NaHS, a donor of H2S. NaHS (10-8-3â¯×â¯10-5 M) relaxed phenylephrine-precontracted carotid arteries, with higher potency in diabetic than in control rabbits. The selective blockers of potassium channels charybdotoxin, 4-amynopiridine and glibenclamide significantly inhibited the relaxant action of NaHS in diabetic rabbits, but not in control rabbits. When compared to control rabbits, carotid arteries from diabetic rabbits showed significantly reduced expression of big conductance Ca+2-activated potassium channels (BKCa), significantly enhanced expression of intermediate conductance Ca+2-activated potassium channels (IKCa) and not significant different expression of voltage-sensitive potassium channels (KV) and ATP-sensitive potassium channels (KATP). These results suggest that an enhanced role of IKCa, KV and KATP potassium channels could be involved in the increased sensitivity of the rabbit carotid artery to H2S in diabetes.