Obesity and associated diabetes (diabesity) impair kidney mitochondrial dynamics by augmenting fission and diminishing fusion, which results in mitochondrial and renal dysfunction. Based on available evidence, the antioxidant activities of melatonin may improve impaired renal mitochondrial function in obese diabetic animals by restoring the imbalanced dynamics through inhibiting fission and promoting fusion. Male Zücker diabetic fatty (ZDF) rats and lean littermates (ZL) were orally treated either with melatonin (10 mg/kg BW/day) (M-ZDF and M-ZL) or vehicle (C-ZDF and C-ZL) for 17 weeks. Kidney function was evaluated by measurement of total urine volume, proteinuria, creatinine clearance, and assessment of kidney mitochondrial dynamics and function. C-ZDF exhibited impaired dynamics and function of kidney mitochondria in comparison to C-ZL. Melatonin improved nephropathy of ZDF rats and modulated their mitochondrial dynamics by reducing expression of Drp1 fission marker and increasing that of fusion markers, Mfn2 and Opa1. Furthermore, melatonin ameliorated mitochondrial dysfunction by increasing respiratory control index and electron transfer chain complex IV activity. In addition, it lowered mitochondrial oxidative status. Our findings show that melatonin supplementation improves nephropathy likely via modulation of the mitochondrial fission/fusion balance and function in ZDF rats.
Time-restricted feeding (TRF) showed a potent effect in preventing obesity and improving metabolicoutcomes in several animal models of obesity. However, there is, as of yet, scarce evidence concerning its effectiveness against obesogenic challenges that more accurately mimic human Western diets, such as the cafeteria diet. Moreover, the mechanism for its efficacy is poorly understood. White adipose browning has been linked to body weight loss. Herein, we tested whether TRF has the potential to induce browning of inguinal white adipose tissue (iWAT) and to attenuate obesity and associated dyslipidemia in a cafeteria-diet-induced obesity model. Male Wistar rats were fed normal laboratory chow (NC) or cafeteria diet (CAF) for 16 weeks and were subdivided into two groups that were subjected to either ad libitum (ad lib, A) or TRF (R) for 8 h per day. Rats under the TRF regimen had a lower body weight gain and adiposity than the diet-matchedad lib rats, despite equivalent levels of food intake and locomotor activity. In addition, TRF improved the deranged lipid profile (total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL-c), low-density lipoprotein (LDL-c)) and atherogenic indices (atherogenic index of plasma (AIP), atherogenic coefficient (AC), coronary risk index (CRI) in CAF-fed rats. Remarkably, TRF resulted in decreased size of adipocytes and induced emergence of multilocular brown-like adipocytes in iWAT of NC- and CAF-fed rats. Protein expression of browning markers, such as uncoupling protein-1 (UCP1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), were also up-regulated in the iWAToftime-restricted NC- or CAF-fed rats. These findings suggest that a TRF regimen is an effective strategy to improve CAF diet-induced obesity, probably via a mechanismthe involving WAT browning process.
Two new families of pyrazoline and thiadiazoline heterocycles have been developed. Their inhibitory activities against two different isoforms of nitric oxide synthase (inducible and neuronal NOS) are reported. The novel derivatives were synthesized combining the arylthiadiazoline or arylpyrazoline skeleton and a carboxamide or carbothioamide moiety, used as starting material ethyl 2-nitrobenzoates or substituted nitrobenzaldehydes, respectively. The structure-activity relationships of final molecules are discussed in terms of the R1 radical effects in the aromatic ring, the Y atom in the heterocyclic system, the X heteroatom in the main chain, and the R2 substituent in the carboxamide or carbothioamide rest. In general, thiadiazolines (5a–e) inhibit preferentially the neuronal isoform; among them, 5a is the best nNOS inhibitor (74.11% at 1 mM, IC50 = 420 μM). In contrast, pyrazolines (6a–r) behave better as iNOS than nNOS inhibitors, 6m being the best molecule of this series (76.86% at 1 mM of iNOS inhibition, IC50 = 130 μM) and the most potent of all tested compounds.
The role of melatonin in obesity control is extensively accepted, but its mechanism of action is still unclear. Previously we demonstrated that chronic oral melatonin acts as a brown-fat inducer,...
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