Melatonin attenuates diabetic cardiomyopathy and reduces myocardial vulnerability to ischemia-reperfusion injury by improving mitochondrial quality control: Role of SIRT6.

Targeting mitochondrial quality control with melatonin has been found promising for attenuating diabetic cardiomyopathy (DCM), although the underlying mechanisms remain largely undefined. Activation of SIRT6 and melatonin membrane receptors exerts cardioprotective effects while little is known about their roles during DCM. Using high-fat diet-streptozotocin-induced diabetic rat model, we found that prolonged diabetes significantly decreased nocturnal circulatory melatonin and heart melatonin levels, reduced the expressions of cardiac melatonin membrane receptors, and decreased myocardial SIRT6 and AMPK-PGC-1α-AKT signaling. 16 weeks of melatonin treatment inhibited the progression of DCM and the following myocardial ischemia-reperfusion (MI/R) injury by reducing mitochondrial fission, enhancing mitochondrial biogenesis and mitophagy via re-activating SIRT6 and AMPK-PGC-1α-AKT signaling. After the induction of diabetes, adeno-associated virus carrying SIRT6-specific small hairpin RNA or luzindole was delivered to the animals. We showed that SIRT6 knockdown or antagonizing melatonin receptors abolished the protective effects of melatonin against mitochondrial dysfunction as evidenced by aggravated mitochondrial fission and reduced mitochondrial biogenesis and mitophagy. Additionally, SIRT6 shRNA or luzindole inhibited melatonin-induced AMPK-PGC-1α-AKT activation as well as its cardioprotective actions. Collectively, we demonstrated that long-term melatonin treatment attenuated the progression of DCM and reduced myocardial vulnerability to MI/R injury through preserving mitochondrial quality control. Melatonin membrane receptor-mediated SIRT6-AMPK-PGC-1α-AKT axis played a key role in this process. Targeting SIRT6 with melatonin treatment may be a promising strategy for attenuating DCM and reducing myocardial vulnerability to ischemia-reperfusion injury in diabetic patients.

ALK-TPM3 rearrangement in adult renal cell carcinoma: a case report and literature review.

BACKGROUND: Translocation-associated renal cell carcinoma involving ALK (ALK-tRCC) is a rare subtype of adult renal cell carcinoma (RCC) reported in recent years. It was recognized as a group of emerging /provisional RCC in the latest World Health Organization's classification (2016). CASE PRESENTATION: A new Chinese case of ALK-tRCC was reported. The patient was a 58-year-old man with a tumor in kidney. The tumor was composed of sheets of large cells with abundant eosinophilic cytoplasm and indistinct cell borders but conspicuous intracytoplasmic vacuoles. The nuclei were enlarged with a nucleolar of grade 4. Immunohistochemically, tumor cells were diffusely positive for PAX8, keratin (AE1/AE3), epithelial membrane antigen (EMA) and CK7. Fluorescent in situ hybridization (FISH) showed a rearrangement of ALK in tumor cells. CONCLUSION: ALK-tRCC is a rare subtype of adult RCC. Its diagnosis is very difficult because the histological spectrum is very wide. We suggested that RCCs should be screened for ALK expression by immunohistochemistry (IHC) for the patient might benefit from ALK inhibitors therapy.

[Nephrotoxicity of tacrolimus and preventive effect of diltiazem: experiment with rats].

OBJECTIVE: To study the nephrotoxicity tacrolimus (FK506) at the therapeutic dose the preventive effect of diltiazem (Dil), a calcium antagonist against the FK506-induced pathological changes. METHODS: 24 Sprague-Dawley male rats were randomly divided into 4 equal groups: cyclosporine A (CsA) group, undergoing treatment of CsA at the therapeutic dose after kidney transplantation (25 mg x kg(-1) x d(-1)) for 4 weeks, FK506 group treated with FK506 (0.8 mg x kg(-1) x d(-1)), FK506 + Dil group treated with FK506 (0.8 mg x kg(-1) x d(-1)) and Dil at the dose of 8 mg x kg(-1) x d(-1), and control group. Four weeks later body weight was measured and 24 h urine sample was collected. Then the rats were killed. Their kidneys underwent light and transmission electron microscopy. RESULTS: The body weight ad weight gain, and the weights of both kidney of the CsA group were all significantly lower than those of the other 3 groups (all P < 0.05), and there were not significant differences in there parameters among the other 3 groups. The serum creatinine levels of the FK506 and CsA groups were (36.0 +/- 2.6) and (34.2 +/- 4.5) micromol/L respectively, both significantly higher than those of the FK506 + Dil and control groups [(28.5 +/- 2.1) and (29.2 +/- 3.428) micromol/L respectively, all P < 0.05], however, there was no significant difference between the FK506 + Dil and control groups. The creatinine clearance rate of the FK506 and CsA groups were (0.63 +/- 0.45) and (0.58 +/- 0.39) ml x min(-1) x 100 g(-1) respectively, significantly lower than those of the FK506 + Dil and control groups [(1.55 +/- 0.91) and (1.02 +/- 0.62) mlxmin(-1) x 100 g(-1) respectively, all P < 0.05]. Pathological examination showed epithelial cell cloudy swelling and vacuolization and interstitial fibrosis in the renal tubules, mitochondria swelling and vacuolization in renal tubular epithelial cells, renal arteriole hyalinization, and foot cell conjugation glomerulus, mitochondria swelling and vacuolization in the FK506 and CsA groups, and such changes were relatively mild in the FK506 + Dil group. CONCLUSION: FK506 at renal transplantation therapeutic dose, as well as CsA, induces pathological changes in renal tissues and ultrastructural organization. Dil is able to prevent FK506-induced these pathological changes.

[Prevention of diltiazem in tacrolimus-induced nephrotoxicity: experiment with rats].

OBJECTIVE: To study the nephrotoxicity induced by first oral administration of tacrolimus (FK506) and the prevention of diltiazem (Dil). METHODS: 24 Sprague-Dawley male rats were randomly divided into 4 equal groups: control (n = 6), cyclosporine A (CsA) group (receiving CsA 25 mg.kg(-1).d(-1) so as to develop CsA-induced nephropathy model), FK506 group (receiving FK506 0.8 mg.kg(-1).d(-1), the common renal transplantation therapeutic dose, so as to develop FK506-induced nephropathy model), FK506 + Dil group (receiving CsA 0.8 mg.kg(-1).d(-1) and Dil 8 mg.kg(-1).d(-1)), and control group. Four weeks later body weight was measured, blood samples were collected to examine the creatinine, urea nitrogen, and uric acid, and urine samples were collected to examine the 24 h urine protein, uric acid, and creatinine. Then the rats were killed with their kidneys taken out to undergo histopathological examination. RESULTS: The urine creatinine levels of the CsA and FK506 groups were significantly lower than that of the control group (both P < 0.05), however, there was no significant difference in urine creatinine between the FK506 + Dil group and control group. The blood creatinine levels of both CsA and FK506 groups were significantly higher than those of the FK506 + Dil group and control group (all P < 0.05), however, there was no significant difference in blood creatinine between the FK506 + Dil group and control group. The urea nitrogen level of the CsA group was significantly higher than those of the other 3 groups (all P < 0.05). The creatinine clearance rates of the CsA and FK506 groups were both significantly lower than that of the control group (both P < 0.05), and the creatinine clearance rate of the FK506 + Dil group was between those of the FK506 group and control group, however, with significant differences with both of them. Histopathology examination showed cloudy swelling and vacuolization of the renal tubular epithelial cells in the CsA and FK506 groups. However, the pathological changes of the FK506 + Dil group were remarkably milder in comparison with these 2 groups. CONCLUSION: FK506 and CsA at the renal transplantation therapeutic dose induce nephrotoxicity. Diltiazem prevents FK506-induced nephrotoxicity.