The renin-angiotensin system plays a critical role in the pathogenesis of obesity, obesity-associated hypertension, and insulin resistance. However, the biological actions of angiotensin II (AII) on insulin sensitivity remain controversial. Because angiotensinogen and AII receptors are expressed on adipose tissue, we investigated the effect of AII on the insulin sensitivity of isolated rat adipocytes. The results of a receptor binding assay showed the maximal AII binding capacity of adipocytes to be 8.3 +/- 0.9 fmol/7 x 10(6) cells and the dissociation constant to be 2.72 +/- 0.11 nM. Substantial expression of both type 1 and 2 AII (AT1 and AT2) receptors was detected by RT-PCR. AII had no effect on basal glucose uptake, but significantly potentiated insulin-stimulated glucose uptake; this effect was abolished by the AT1 antagonist, losartan. In addition, AII did not alter the insulin binding capacity of adipocytes, but increased insulin-stimulated tyrosine phosphorylation of the insulin receptor beta-subunit, Akt phosphorylation, and translocation of glucose transporter 4 to the plasma membrane. AII potentiated insulin-stimulated glucose uptake through the AT1 receptor and by alteration of the intracellular signaling of insulin. Intraperitoneal injection of Sprague Dawley rats with AII increased insulin sensitivity in vivo. In conclusion, we have shown that AII enhances insulin sensitivity both in vitro and in vivo, suggesting that dysregulation of the insulin-sensitizing effect of AII may be involved in the development of insulin resistance.
Recent evidence strongly suggests that oxidative stress due to redox imbalance is highly associated with metabolic syndrome. The objective of this study was to evaluate the effect of the supplementation of longan flower water extract (LFWE), which showed powerful antioxidative activity in vitro, on markers of metabolic syndrome in a fructose-fed rat model. Male Sprague-Dawley rats were randomly divided into four groups: group C, fed with standard Purina chow; group F, fed with high-fructose diet (HF) alone; group L, fed with HF plus LFWE 125 mg/kg bw per day by gavage; and group H, fed HF plus LFWE 250 mg/kg bw per day by gavage. The dietary manipulation lasted for 14 weeks. Results of our study showed that rats fed with HF resulted in oxidative stress and affected the antioxidant status including plasma thiobarbituric acid and liver antioxidant enzyme activity. Treatment with LFWE significantly augmented the antioxidant system. HF was able to cause insulin resistance and elevation of the blood pressure. The supplementation of LFWE ameliorated insulin resistance by enhancing the expression of insulin signaling pathway related proteins, including insulin receptor substrate-1 and glucose transporter 4. LFWE supplementation was also found to decrease systolic blood pressure. These findings indicate that longan flower water extract may improve the symptoms of metabolic syndrome in fructose-fed rats.
Nitric oxide (NO) is an endogenous gasotransmitter regulating alternative physiological processes in the cardiovascular system. To achieve translational application of NO, continued efforts are made on the development of orally active NO prodrugs for long-term treatment of chronic cardiovascular diseases. Herein, immobilization of NO-delivery [Fe 2 (μ-SCH 2 CH 2 COOH) 2 (NO) 4 ] (DNIC-2) onto MIL-88B, a metal−organic framework (MOF) consisting of biocompatible Fe 3+ and 1,4-benzenedicarboxylate (BDC), was performed to prepare a DNIC@MOF microrod for enhanced oral delivery of NO. In simulated gastric fluid, protonation of the BDC linker in DNIC@MOF initiates its transformation into a DNIC@tMOF microrod, which consisted of DNIC-2 well dispersed and confined within the BDC-based framework. Moreover, subsequent deprotonation of the BDC-based framework in DNIC@tMOF under simulated intestinal conditions promotes the release of DNIC-2 and NO. Of importance, this discovery of transformer-like DNIC@MOF provides a parallel insight into its stepwise transformation into DNIC@ tMOF in the stomach followed by subsequent conversion into molecular DNIC-2 in the small intestine and release of NO in the bloodstream of mice. In comparison with acid-sensitive DNIC-2, oral administration of DNIC@MOF results in a 2.2-fold increase in the oral bioavailability of NO to 65.7% in mice and an effective reduction of systolic blood pressure (SBP) to a ΔSBP of 60.9 ± 4.7 mmHg in spontaneously hypertensive rats for 12 h.
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