Vitamin D3 protects against prednisolone-induced liver injury associated with the impairment of the hepatic NF-κB/iNOS/NO pathway.

The study was carried out to define whether prednisolone-induced damage to hepatic cells is accompanied by excessive nitric oxide (NO) levels associated with nuclear factor kappa B (NF-κB)/inducible NO synthase (iNOS) activation and evaluate the efficacy of the treatment with vitamin D3. Histopathological examination, activities of liver transaminases (alanine aminotransferase and aspartate aminotransferase), and cell death assays consistently showed that prednisolone (5 mg/kg body weight, 30 days) induces chronic liver injury in female Wistar rats. Specifically, increased hepatocellular necrosis and caspase-3-dependent apoptosis were observed. Prednisolone enhanced iNOS protein expression, NO generation, and tyrosine nitration in liver cells. Despite unchanged hepatic level of the NF-κB/p65 protein, prednisolone increased inhibitory κB-α (IκB-α) degradation, nuclear translocation, and phosphorylation of NF-κB/p65 at Ser311, indicating that NF-κB activation can be involved in the induction of iNOS/NO. All changes were associated with a 2.9-fold decrease in the serum content of 25-hydroxyvitamin D3 and significant reduction of hepatic vitamin D3 receptor (VDR) expression that points reliably to vitamin D3 deficiency and failures in VDR signaling. Vitamin D3 co-administration (100 IU/rat, 30 days) prevented glucocorticoid-evoked abnormalities in hepatic tissue. In conclusion, prednisolone-induced liver disturbances were associated with the impairment of NF-κB/iNOS/NO responses that can be ameliorated by vitamin D3 treatment through VDR-mediated mechanisms.

1-methylnicotinamide (MNA) in prevention of diabetes-associated brain disorders.

The present study has been designed to establish the potential benefits from 1-methylnicotinamide (MNA) treatment on brain disorders associated with type 1 diabetes. All experiments were carried out after 6 weeks of streptozotocin-induced diabetes (60 mg/kg of body weight, i.p.) in male Wistar rats treated for 5 weeks with or without MNA (100 mg/kg of body weight, per os in drinking water) after 1 week of diabetes induction. Diabetes was shown to reduce monoamine neurotransmitter serotonin transporters activity, as assessed by significant inhibition of [2-(14)C]serotonin uptake, that was accompanied by elevation of spontaneous mediator release in rat brain synaptosomes. Treatment with MNA slightly attenuated diabetes-induced changes in brain serotoninergic system. The precise mechanism underlying MNA action on central serotonin neurotransmission is not known, but appears to be linked to metabolic and signalling pathways involved in controlling synaptic function rather than being associated with direct modulation of serotonin transporters. In particular, MNA action was associated with its partial normalizing effects on such biochemical indices of neuropathy development as decrease in synaptosomal Na(+),K(+)-ATPase activity and plasma membrane depolarization of synaptic endings. Elevated sorbitol formation in brain and NAD(+) deficits resulted from diabetes as major metabolic imbalances were remarkably countered by MNA treatment. However, diabetes-induced decrease in cytosolic NAD(+) to NADH ratio in brain remained unchanged. Notably, MNA supplementation to diabetic rats caused a slight lowering effect on blood glucose level. Accordingly, our findings indicate that neuroprotective properties of MNA are linked to modulation of synaptic activity through multiple mechanisms. In conclusion, we suggest that 1-methylnicotinamide might be a useful agent for treating brain failures related to diabetes.

Poly(ADP-ribosyl)ation enhancement in brain cell nuclei is associated with diabetic neuropathy.

UNLABELLED: The study has been undertaken to evaluate the effect of streptozotocin (STZ)-induced diabetes on rat brain poly(ADP-ribose)polymerase (Parp) activity and assess whether and how a Parp inhibitor, nicotinamide (NAm), may potentially regulate the diabetes-induced changes. Experiments were carried out after 4 weeks of diabetes duration in rats treated with or without NAm (100 or 200 mg kg(-1) day(-1), injected intraperitonally for 2 weeks). Assays were performed in purified brain cell nuclei to determine Parp activity by incorporation of radiolabeled ADP-ribose moieties from nicotinamide adenine dinucleotide (NAD+) into nuclear proteins. NAD+ and ATP levels were measured by enzymatic procedures. DNA damage was detected spectrophotometrically. RESULTS: Parp activity but not NAD-glycohydrolase (NADase) was stimulated by 21% in diabetes vs. control while lowering effects of diabetes on NAD+ and ATP levels were observed. Increase in Parp activity was accompanied by accumulation of malondialdehyde (MDA) and increase in DNA breakage. Treatment with either 100 or 200 mg/kg NAm dose diminished both DNA damage and Parp activity and partially restored the NAD+ and ATP contents, which is probably associated with direct competitive inhibition of Parp as well as with NAm's ability to block diabetes induced oxidative stress. CONCLUSION: Poly(ADP-ribosyl)polymerase overactivation is involved in the development of brain dysfunction in diabetic neuropathy. The mechanism of brain disorders seems to be at least partially connected with a decrease in cellular content and altered subcellular distribution of Parp substrate, NAD+, which, in turn, results in a reduction of ATP level that leads to a total failure of oxidative metabolism. NAm in both doses is effective for the inhibition of poly(ADP-ribosyl)ation.