RESUMO
The first total synthesis of juniperanol, the tricyclic sesquiterpenoid enantiomer of α-cedrol is described. The synthesis relies on stereoselective gold-catalyzed Ohloff-type propargylic ester rearrangement performed on a 10â¯g scale, and a carbocationic cascade in the presence of acetyl methanesulfonate. The ability of juniperanol to interfere in glucose processes in different cell types is described.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucose/metabolismo , Hipoglicemiantes/síntese química , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Juniperus/química , Camundongos , Estrutura Molecular , Madeira/químicaRESUMO
In the proximal tubule, angiotensin II (Ang-II) regulates HCO(-)(3) reabsorption and H+ secretion by binding the type 1 Ang-II (AT1) receptor, stimulating Na(+)/HCO(-)(3) cotransport and Na(+)/H(+) exchange. Studies were carried out to determine if long-term changes in Ang-II receptor occupation alter the abundance of the basolateral Na(+)/HCO(-)(3) cotransporter (NBC1) or the apical membrane type 3 Na(+)/H(+) exchanger (NHE3). In the first set of experiments, rats eating a low-sodium diet were infused with the AT1 blocker, candesartan, or vehicle. In the second, lisinopril-infused rats were infused with either Ang II or vehicle. Transporter abundances were determined in whole kidney homogenates (WKH) and in brush border membrane (BBM) preparations by semiquantitative immunoblotting. Tissue distribution of transporters was assessed by immunocytochemistry. Blockade of the AT1 receptor by candesartan caused decreased abundance of NBC1 in WKH (59 +/- 9% of control; P<0.05) and Ang-II infusion increased abundance (130 +/- 7% of control; P<0.05). Changes in NBC1 in response to candesartan were confirmed immunohistochemically. Neither candesartan nor Ang II infusion affected the abundance of NHE3 in WKH or cortical homogenates. Candesartan decreased type 2 sodium-phosphate cotransporter abundance in both WKH (52 +/- 7% of control; P<0.05) and BBM (32 +/- 7% of control; P<0.05). Serum bicarbonate was decreased by candesartan and increased by Ang-II. Candesartan also decreased urinary ammonium excretion (P<0.05). The long-term effects of Ang-II in the proximal tubule may be mediated in part by regulation of NBC1 abundance, modifying bicarbonate reabsorption.
Assuntos
Angiotensina II/fisiologia , Túbulos Renais Proximais/metabolismo , Simportadores de Sódio-Bicarbonato/metabolismo , Trocadores de Sódio-Hidrogênio/metabolismo , Proteínas Cotransportadoras de Sódio-Fosfato Tipo II/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Antagonistas de Receptores de Angiotensina , Animais , Benzimidazóis/farmacologia , Compostos de Bifenilo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/fisiologia , Túbulos Renais Proximais/efeitos dos fármacos , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos SHR , Simportadores de Sódio-Bicarbonato/genética , Trocadores de Sódio-Hidrogênio/genética , Proteínas Cotransportadoras de Sódio-Fosfato Tipo II/genética , ATPase Trocadora de Sódio-Potássio/genética , ATPase Trocadora de Sódio-Potássio/metabolismo , Tetrazóis/farmacologiaRESUMO
White adipose tissue is known to contain the components of the renin-angiotensin system, which gives rise to angiotensin II from angiotensinogen (AGT). Recent evidence obtained in vitro and ex vivo is in favor of angiotensin II acting as a trophic factor of adipose tissue development. To determine whether AGT plays a role in vivo in this process, comparative studies were performed in AGT-deficient (agt(-/-)) mice and control wild-type mice. The results showed that agt(-/-) mice gain less weight than wild-type mice in response to a chow or high fat diet. Adipose tissue mass from weaning to adulthood appeared altered rather specifically, as both the size and the weight of other organs were almost unchanged. Food intake was similar for both genotypes, suggesting a decreased metabolic efficiency in agt(-/-) mice. Consistent with this hypothesis, cellularity measurement indicated hypotrophy of adipocytes in agt(-/-) mice with a parallel decrease in the fatty acid synthase activity. Moreover, AGT-deficient mice exhibited a significantly increased locomotor activity, whereas metabolic rate and mRNA levels of uncoupling proteins remained similar in both genotypes. Thus, AGT appears to be involved in the regulation of fat mass through a combination of decreased lipogenesis and increased locomotor activity that may be centrally mediated.
Assuntos
Tecido Adiposo/crescimento & desenvolvimento , Angiotensinogênio/deficiência , Dieta , Atividade Motora/fisiologia , Aumento de Peso , Tecido Adiposo/patologia , Tecido Adiposo Marrom/crescimento & desenvolvimento , Tecido Adiposo Marrom/patologia , Angiotensinogênio/genética , Animais , Camundongos , Camundongos Endogâmicos ICR , Camundongos Knockout/genética , Valores de Referência , TermogêneseRESUMO
We observed recentlyl that placental leptin is markedly increased in preeclampsia. Since this disorder is associated with vascular disorders, we have tested the hypothesis that hypoxia regulates leptin expression. We show that hypoxia increased leptin mRNA and secretion in trophoblast-derived BeWo cells. This effect was mediated through leptin promoter activation. 5' deletion analysis allowed us to delineate two regions containing 1.87 kb and 1.20 kb of the promoter which conferred respectively high and low responsiveness to hypoxia. These data indicate that leptin is up-regulated by hypoxia through a transcriptional mechanism likely to involve distinct hypoxia-responsive cis-acting sequences on the promoter.