RESUMO
Microvascular damage is a key pathological change in myocardial ischemia/reperfusion (I/R) injury. Using a rat model of myocardial I/R, our current study has provided the first evidence that nicotinamide adenine dinucleotide (NAD+) administration can significantly attenuate myocardial I/R-induced microvascular damage, including reduced regional blood perfusion, decreased microvessel density and integrity, and coronary microvascular endothelial cells (CMECs) injury. In studies with primary cultured CMECs under hypoxia/reoxygenation (HR) and a rat model of I/R, our results suggested that the protective effect of NAD+ on CMECs exposed to HR or I/R is at least partially mediated by the NAD+-induced restoration of autophagic flux, especially lysosomal autophagy: NAD+ treatment markedly induced transcription factor EB (TFEB) activation and attenuated lysosomal dysfunction in the I/R or HR-exposed cells. Collectively, our study has provided the first in vivo and in vitro evidence that NAD+ significantly rescued the impaired autophagic flux and cell apoptosis that was induced by I/R in rat CMECs, which is mediated in part through the action of TFEB-mediated lysosomal autophagy.
Assuntos
Autofagia/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/prevenção & controle , NAD/uso terapêutico , Animais , Separação Celular , Avaliação Pré-Clínica de Medicamentos , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Masculino , Microvasos/efeitos dos fármacos , NAD/farmacologia , Ratos Sprague-DawleyRESUMO
To investigate the effect of hyperhomocysteinaemia (HHCy) on penile erectile function in a rat model, a methionine-rich diet was used in which erectile function, the reproductive system, and nitric oxide synthase were characterized. The intracavernous pressure, apomorphine experiments, measurement of oxidative stress, hematoxylin and eosin staining, immunohistochemistry analysis, reverse transcription-polymerase chain reactions and measurement of endothelial nitric oxide synthase activity were utilized. Our results showed that erections in the middle-dose, high-dose, and interference (INF) groups were significantly lower than the control (P < 0.05). INF group, being fed with vitamins B and folic acid, demonstrated markedly improved penile erections compared with the middle-dose group (P < 0.05). HHCy-induced eNOS and phospho-eNOS protein expression was reduced and the antioxidant effect was markedly impaired. The data of the present data provide evidence that HHCy is a vascular risk factor for erectile dysfunction by impairing cavernosa endothelial nitric oxide synthase activity. Intake of vitamins B can alleviate this abnormality.
Assuntos
Disfunção Erétil/enzimologia , Hiper-Homocisteinemia/enzimologia , Óxido Nítrico Sintase Tipo III/biossíntese , Animais , Disfunção Erétil/induzido quimicamente , Hiper-Homocisteinemia/induzido quimicamente , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Current research on the progression of diabetic nephropathy (DN) suggests many important factors; metabolic disturbance, haemodynamic abnormity, chronic inflammation, oxidative stress, innate immune system activation and podocyte lesion. Triptolide, which is active diterpene purified from the traditional Chinese medicine Tripterygium wilfordii Hook F (TwHF), has anti-inflammatory, anti-oxidative, immunosuppressive and podocyte-protective effects. Herein, we investigated the therapeutic effects of triptolide on DN in db/db diabetic mice and studied the potential mechanisms. METHODS: db/db mice with DN were administrated with triptolide or valsartan. After 4, 8 and 12 weeks of treatment, 24-h urine albumin level, blood biochemical parameters and body weight were measured. Glomerulus area, glomerulus volume to Bowman's capsule volume ratio, podocyte changes and inflammatory and oxidative stress markers were quantitatively determined to evaluate renal lesions. RESULTS: The albuminuria in db/db diabetic mice was markedly attenuated after triptolide treatment, accompanied with alleviated glomerular hypertrophy and podocyte injury. In addition, the inflammation and oxidative stress in the kidneys were also attenuated, accompanied with improved hyperlipidaemia and obesity. The efficacy increased with the prolonging of triptolide treatment, and the efficacy in high-dose triptolide group was superior to that in the low-dose group. The effect of triptolide on glomerular hypertrophy was similar to valsartan, but the effects of triptolide on renal inflammation and oxidative stress were more profound than those of valsartan. CONCLUSIONS: Triptolide can dramatically attenuate albuminuria and renal lesion accompanied with dyslipidaemia and obesity in db/db diabetic mice. It is a new drug that exerts comprehensive protective effects on preventing DN progression.