Genetic variations in the PSMA6 and PSMC6 proteasome genes are associated with multiple sclerosis and response to interferon-ß therapy in Latvians.

Several polymorphisms in genes related to the ubiquitin-proteasome system exhibit an association with pathogenesis and prognosis of various human autoimmune diseases. Our previous study reported the association between multiple sclerosis (MS) and the PSMA3-rs2348071 polymorphism in the Latvian population. The current study aimed to evaluate the PSMA6 and PSMC6 genetic variations, their interaction between each other and with the rs2348071, on the susceptibility to MS risk and response to therapy in the Latvian population. PSMA6-rs2277460, -rs1048990 and PSMC6-rs2295826, -rs2295827 were genotyped in the MS case/control study and analysed in terms of genotype-protein correlation network. The possible association with the disease and alleles, single- and multi-locus genotypes and haplotypes of the studied loci was assessed. Response to therapy was evaluated in terms of 'no evidence of disease activity'. To the best of our knowledge, the present study was the first to report that single- and multi-loci variations in the PSMA6, PSMC6 and PSMA3 proteasome genes may have contributed to the risk of MS in the Latvian population. The results of the current study suggested a potential for the PSMA6-rs1048990 to be an independent marker for the prognosis of interferon-ß therapy response. The genotype-phenotype network presented in the current study provided a new insight into the pathogenesis of MS and perspectives for future pharmaceutical interventions.

1,4-dihydropyridine derivatives increase mRNA expression of Psma3, Psmb5, and Psmc6 in rats.

The ubiquitin-proteasome system modifies different cellular and protein functions. Its dysregulation may lead to disrupted proteostasis associated with multiple pathologies and aging. Pharmacological regulation of proteasome functions is already an important part of the treatment of several diseases. 1,4-dihydropyridine (1,4-DHP) derivatives possess different pharmacological activities, including antiaging and neuroprotective. The aim of this study was to investigate the effects of several 1,4-DHP derivatives on mRNA expression levels of proteasomal genes Psma3, Psmb5, and Psmc6 in several organs of rats. Rats were treated with metcarbatone, etcarbatone, glutapyrone, styrylcarbatone, AV-153-Na, or AV-153-Ca per os for three days. mRNA expression levels were determined with real-time polymerase chain reaction (PCR). For AV-153-Na and AV-153-Ca, we also determined the expression of the Psma6 gene. In the kidney, metcarbatone, etcarbatone, styrylcarbatone, and AV-153-Na increased the expression of all analysed genes. Glutapyrone increased the expression of Psmb5 and Psmc6 but did not affect the expression of Psma3. In the blood, glutapyrone increased Psmb5 expression. In the liver, AV-153-Na increased the expression of Psma6 and Psmc6 but lowered the expression of Psmb5, while AV-153-Ca only increased Psma6 expression. The ability of 1,4-DHP derivatives to increase the expression of proteasome subunit genes might hold a therapeutic potential in conditions associated with impaired proteasomal functions, but further research is needed.

Nitric oxide metabolism is impaired by type 1 diabetes and diabetic nephropathy.

Diabetes leads to reduced nitric oxide bioavailability, resulting in endothelial dysfunction. However, overproduction of nitric oxide due to hyperglycaemia is associated with oxidative stress and tissue damage. The objective of this study was to characterise nitric oxide production (NO) and added nitrite and nitrate (NO2 -+NO3 -) concentration in the blood and urine of patients with and without diabetic nephropathy. A total of 268 patients with type 1 diabetes and 69 healthy subjects were included. Diabetic nephropathy was defined as macroalbuminuria and/or estimated glomerular filtration rate below 60 ml/min/1.73 cm2. NO2 -+NO3 - concentration was measured by Griess reaction. Production of NO was detected by electron paramagnetic resonance spectroscopy. Blood NO was demonstrated to be higher (P<0.001) and serum NO2 -+NO3 - was lower (P=0.003) in patients with type 1 diabetes and no nephropathy vs. healthy subjects. However, serum NO2 -+NO3 - concentration in patients with diabetes and nephropathy did not differ from the levels observed in healthy controls. Urine excretion of NO2 -+NO3 - was significantly decreased in patients with nephropathy, compared with patients without diabetic kidney disease (P=0.006) and healthy subjects (P=0.010). A significant positive correlation was observed between urine NO2 -+NO3 - and estimated glomerular filtration rate in patients with type 1 diabetes (P=0.002) and healthy subjects (P=0.008). Estimated glomerular filtration rate, albuminuria and diabetic nephropathy status were significant predictors of the whole blood NO and NO2 -+NO3 - in serum and urine in patients with type 1 diabetes, as identified by linear regression models. The present study concludes that NO metabolism is impaired by type 1 diabetes and diabetic nephropathy.