Diabetic retinopathy (DR) is a multifactorial disease characterized by reactive gliosis and disbalance of angiogenesis regulators, contributing to endothelial dysfunction and microvascular complications. This study was organized to elucidate whether poly(ADP-ribose) polymerase-1 (PARP-1) inhibition could attenuate diabetes-induced damage to macroglia and correct angiogenic disbalance in diabetic rat retina. After 8 weeks of streptozotocin (STZ)-induced diabetes, Wistar male rats were treated with PARP-1 inhibitors, nicotinamide (NAm) or 3-aminobenzamide (3-AB) (100 and 30 mg/kg/daily i.p., respectively), for 14 days. After the 10-weeks experiment period, retinas were undergone an immunohistochemical staining for glial fibrillary acidic protein (GFAP), while western blots were performed to evaluate effects of PAPR-1 inhibitors on the levels of PARP-1, poly(ADP-ribosyl)ated proteins (PARs), GFAP, and angiostatin isoforms. Diabetes induced significant up-regulation and activation of retinal PARP-1, reactive gliosis development, and GFAP overexpression compared to non-diabetic control. Moreover, extensive fragmentation of both PARP-1 and GFAP (hallmarks of apoptosis and macroglia reactivation, respectively) in diabetic retina was also observed. Levels of angiostatin isoforms were dramatically decreased in diabetic retina, sustaining aberrant pro-angiogenic condition. Both NAm and 3-AB markedly attenuated damage to macroglia, evidenced by down-regulation of PARP-1, PARs and total GFAP compared to diabetic non-treated group. PARP-1-inhibitory therapy prevented formation of PARP-1 and GFAP cleavage-derived products. In retinas of anti-PARP-treated diabetic animals, partial restoration of angiostatin's levels was shown. Therefore, PARP-1 inhibitors counteract diabetes-induced injuries and manifest retinoprotective effects, including attenuation of reactive gliosis and improvement of angiogenic status, thus, such agents could be considered as promising candidates for DR management.
The molecular pathogenesis of diabetic encephalopathy (De), one of the serious complications of diabetes mellitus, is complex. In this study, we examined whether expression levels of SIrT1 and SIrT2 were the key for the development of brain dysfunctions and whether PARP-1 inhibitors could affect the expression of these proteins for prevention the development of De in rats with type 1 diabetes. after 10 weeks of the streptozotocin-induced diabetes mellitus (70 mg/kg), Wistar male rats were treated by i.p. injection with ParP-1 inhibitors, 1.5-isoquinolinediol (ISo) or nicotinamide (Nam) (3 or 100 mg/kg/daily i.p., respectively) for 2 weeks. The rats with blood glucose levels over 19.7 ± 2.1 mmol/l were taken into experiments. Western blots were performed to evaluate effects of PAPR-1 inhibitors on the levels of sirtuins, SIRT1 and SIRT2 expression. Diabetes induced significant reduction of SIRT1 expression and SIRT2 overexpression in brain nuclear extracts of diabetic rats compared to non-diabetic control. In brain, Nam attenuated SIrT2 overexpression in nuclear extracts of diabetic rats and slightly elevated SIRT1 expression, while ISO didn't affect expression of both sirtuins in diabetic rats. Furthermore, it was observed that in brain of diabetic rats, the ratio of free NaD/NaDh couples decreased 3.1-fold compared to non-diabetic control. The administration of ISo increased only slightly the ratio of free NaD/NaDh couples in the brain of diabetic rats while Nam increased this parameter 1.7-fold compared to diabetic rats. Therefore, we concluded that alterations in the expression of SIrT1 and SIrT2 in brain cell nuclei of diabetic rats can lead to the development of brain dysfunctions. one of the neuroprotective mechanisms of Nam action can also be realized through inhibition of SIrT2 expression in brain cell nuclei that down-regulate progression of diabetes-induced alterations and can be a therapeutic option for treatment of brain dysfunctions.
Досліджено вплив специфічних інгібіторів полі(ADP-рибозо)полімерази-1 (PARP-1), зокрема нікотинаміду та 1,5-ізохіноліндіолу на лейкоцити крові щурів за цукрового діабету (цД). із використанням флуоресцентного зонда 2′,7′-дихлородигідрофлуоресцеїн діацетату оцінено продукування активних форм оксигену в лейкоцитах. Встановлено, що розвиток цД, індукованого стрептозотоцином, супроводжується інтенсифікацією окислювального стресу та значним зниженням життєздатності лейкоцитів порівняно з контрольною групою тварин. Введення інгібіторів PARP-1 запобігало розвитку окислювального стресу в лейкоцитах та підвищувало їх життєздатність. Виявлено зниження активності супероксиддисмутази в сироватці крові за цД. Досліджувані інгібітори PARP-1 не впливали на активність супероксиддисмутази та на рівень глюкози в крові. Одержані дані свідчать про інтенсифікацію окислювального стресу в лейкоцитах тварин з цД і здатність нікотинаміду та 1,5-ізохіноліндіолу запобігати його розвитку. к л ю ч о в і с л о в а: нікотинамід, 1,5-ізохіноліндіол, полі(ADP-рибозо)полімераза-1, лейкоцити крові, активні форми оксигену, життєздатність клітин, експериментальний цукровий діабет.
Objectives. The present study was designed to assess whether apoptosis-related genes as parp-1 and bax could be targets for treatment of diabetes mellitus and whether vitamin D may exert beneficial effects. Methods. Vitamin D3 treatment for 4 weeks, starting after 4 weeks of the diabetes duration. The expression of parp-1 and bax genes was estimated on mRNA levels using real time quantitative polymerase chain reaction. Results. After 8 weeks, diabetic rats had weight loss, while blood glucose was increased about 4.9-fold compared to control group. Vitamin D3 administration to diabetic animals had no effect on these parameters. It was found that total serum alkaline phosphatase activity was significantly elevated in diabetic rats as compared to control animals and was restored by vitamin D3. Diabetes was accompanied by reduction of nicotinamidadenindinucleotide, a substrate of poly-ADP-ribosylation, level by 31.7% as compared to control rats, which was not reversed in response to vitamin D3 treatment. In diabetic hearts, the mRNA expression level of parp-1 gene was 2.8-fold higher compared to control rats and partially decreased by vitamin D3 treatment. Less significant alterations were observed in diabetic hearts for the mRNA expression level of bax gene that was 2.0-fold higher compared to control animals and vitamin D3 normalized it. These results indicate that cardiomyocytes have a tendency to apoptosis. Conclusions. The findings suggest that investigated genes can be targets at the transcriptional level for vitamin D action that may be contributed to the improving metabolic/signaling pathways induced by diabetes mellitus.
connective tissue is highly susceptible to imbalances induced by diabetes. Diabetes-related osteopenia, decreased bone strength etc. may be associated with altered metabolism of various collagens. although it is assumed that alterations in collagen amino acids (aa) may strongly affect protein properties and physiological functions, however, very limited evidences are present at the moment regarding aa composition of bone type I collagen and its relevance to abnormal availability of vitamins which are necessary for collagen synthesis in diabetes. We have tested whether nicotinamide (NAm) can influence type I collagen formation and aa composition as well as vitamins availability in diabetes. after 4 weeks of STz-induced diabetes (60 mg/ kg) male Wistar rats were injected for 2 weeks with/without Nam (200 mg/kg b. w.). acid extraction of type I collagen from the bones was performed with following stepwise salting out. The content of type I collagen after its acid extraction from the bones was estimated by the amounts of hydroxyproline. amino acids were assayed by cation exchange chromatography. Diabetes-associated changes in aa composition of type I collagen mainly affect those amino acids which are known to be involved in helix formation and cross-linking of the molecules. Diabetes was found to significantly reduce bone collagen contents of o- Pro, Gly, Ala, whereas Lys, his, arg, Glu, Thr, Leu, Phe contents were elevated (P < 0.05 bone collagen amino acids, vitamin c, vitamin B 3 , T ype 1 diabetes results from active immunemediated destruction of insulin-producing β-cells in the pancreas by T-cells and macrophages infiltrating the islets [1]. It is likely that many pathways may lead to autoimmune destruction of the islet β-cells and actual mechanism in each individual depends on genetics and environment [2].The results of numerous investigations clearly demonstrate that modern diabetes pharmacological treatment is unable to prevent completely diabetes complications among which cardiovascular disease and nephropathy have the highest levels of incidence and the poorest prognosis [3,4]. It is known that during this disease proteins are targets for numerous injuries and could have pathologically altered turnover rates.Connective tissue disturbances and especially qualitative changes of collagen synthesis always accompany these pathological processes [5]. Diabetes induces structural and functional changes of the extracellular matrix proteins in many tissues [6]. It could not be excluded that alterations in levels of bone collagen amino acids may contribute to diabetes.Processing and secretion of collagen was previously shown to be controlled by insulin at a post- [7]. Other authors demonstrated that the α2(I) collagen gene contains two functional promoters, and its expression in cells is regulated at both transcriptional and post-transcriptional levels [8]. On the other hand there were no evidences of qualitative changes in connective tissue collagens caused by lack of insulin. Diabetes-related connective tissue ch...
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