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Diabetes is the most important non-infectious disease affecting 5% of the general population. Different plant and mushroom extracts with hypoglycemic and antioxidant properties have been used traditionally as antidiabetic herbal medicines. The aim of this study was to study the in vivo effect of extracts obtained from the edible mushroom, Lactarius deterrimus (Ld), and chestnut, Castanea sativa (Cs), on the alleviation of liver damage in streptozotocin (STZ)-induced diabetic rats. The extracts were applied, either alone or in combination, for four weeks, starting from the last day of STZ administration. Diabetic rats treated with the extracts exhibited reduced hyperglycemia and lower hepatic oxidative stress. Extract treatment decreased the level of O-linkage of N-acetylglucosamine modified superoxide dismutase, catalase and NF-κB. Masson trichrome staining showed a decrease in collagen fiber deposition in the liver. Immunoblot analysis revealed the activation of the prosurvival Akt kinase after extract application. The obtained results revealed that the hyperglycemiareducing and antioxidant effects of the Ld and Cs extracts suppressed cytotoxic signaling pathways, attenuating the negative effects of diabetes on the liver. The examined extracts are beneficial in the prevention of liver damage and could be considered for prediabetes and diabetes management after a definitive phytochemical description of extract constituents and subsequent evaluation in preclinical and clinical studies. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 451-03-68/2020-14/200007]

Oxidative stress is one of the major mechanisms that underlies the damage of pancreatic β-cells and defects in insulin secretion in diabetes. As herbal preparations can alleviate oxidative stress through their redox-active secondary metabolites, in this study we investigated the cytoprotective effects of Centaurium erythraea extract (CEe) against H2O2- and SNP-induced oxidative/nitrosative stress in Rin-5F β-cells. The antioxidant activity of CEe and its effect on cell survival and insulin expression/secretion were evaluated. The CEe increased cell viability and ameliorated the disturbance of redox homeostasis in H2O2- and SNP-treated cells by decreasing DNA damage, lipid peroxidation and protein S-glutathionylation. The CEe restored GSH homeostasis in H2O2-treated β-cells and attenuated the SNP-induced disturbance of the GSH/ GSSG ratio. The H2O2- and SNP-induced disruption of CAT, GPx, GR, MnSOD and CuZnSOD activities was adjusted by the CEe towards control values, as well as mRNA and protein levels of GPx, MnSOD and CAT. The CEe increased insulin expression/secretion particularly in H2O2-treated β-cells, which was in accordance with the more pronounced antioxidant effect of the CEe observed in H2O2-treated β-cells as compared to SNP-treated cells. These findings support the beneficial effect of the CEe in preventing or slowing down β-cell damage and dysfunction caused by oxidative/nitrosative stress during diabetes development. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 173020]

Previously, we described the link between C-X-C motif chemokine 12 (Cxcl12) gene induction and DNA hypomethylation in the absence of poly(ADP-ribose) polymerase 1 (PARP-1). We have now firmly established that demethylation is the primary cause of gene induction on the basis of Cxcl12 gene upregulation upon treatment with the demethylating agent 5-azacytidine (5-aza). Since the demethylation state of Cxcl12 is favored by PARP-1 absence, we investigated the presence of ten-eleven translocation (TET) proteins on the Cxcl12 promoter in order to corroborate the relationship between the demethylation process and increased gene expression that occurs in the absence of PARP-1. Analysis was performed on the promoter region within CpG islands of Cxcl12 from control mouse embryonic fibroblasts (NIH3T3) and PARP-1 knock-out mouse embryonic fibroblasts (PARP1-/-). The lack of PARP-1 increased the abundance of TET2 on the Cxcl12 promoter, suggesting that TET-mediated demethylation provoked by the absence of PARP-1 could account for the observed increased expression of this chemokine. Deciphering the regulation of DNA (de)methylation factors that control Cxcl12 expression may provide an additional therapeutic approach in pharmacological interventions where gene switching on or off based on targeted stimulation or inhibition is necessary. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 173020]

We examined whether CXCL12α improves insulin secretion by influencing the Ca2+ oscillation pattern and Ca2+ influx ([Ca2+]i), thereby enhancing the viability of pancreatic islet cells in oxidative stress. The islets of Langerhans were isolated from male OF1 mice and pretreated with 40 ng/mL of CXCL12α prior to exposure to 7.5 μM hydrogen peroxide, which served to induce oxidative stress. Incubation of islets with CXCL12α induced pancreatic β-cell proliferation and improved the ability of β-cells to withstand oxidative stress. Consecutive treatments of isolated islets with hydrogen peroxide caused a decline in β-cell functioning over time, while the CXCL12α pretreatment of islets exhibited a physiological response to high glucose that was comparable to control islets. The attenuated response of islets to a high D-glucose challenge was observed as a partial to complete abolishment of [Ca2+]i. Treatments with increasing concentrations of CXCL12α decreased the number of Ca2+ oscillations that lasted longer, thus pointing to an overall increase in [Ca2+]i, which was followed by increased insulin secretion. In addition, treatment of islets with CXCL12α enhanced the transcription rate for insulin and the CXCR4 gene, pointing to the importance of CXCL12/CXCR4 signaling in the regulation of Ca2+ intake and insulin secretion in pancreatic islet cells. We propose that a potential treatment with CXCL12α could help to remove preexisting glucotoxicity and associated temporary β-cell stunning that might be present at the time of diabetes diagnosis in vivo. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 173020]

This review summarizes the effects of α-lipoic acid (LA) on liver damage and complications in diabetes and drug toxicity. LA is a naturally occurring dithiol compound that plays an essential role in mitochondrial metabolism in its protein-bound form. In contrast, free LA in supplements has diverse biological actions, and its antioxidant effect is its most studied and important activity. Due to its strong antioxidant potential, LA could have a promising role in the treatment of pathologies resulting from an imbalance in redox homeostasis. This includes diabetes, which produces deleterious effects on many organs, including the liver. In diabetes specifically, LA prevents β-cell destruction, enhances glucose uptake, and its antioxidant effects may be particularly useful in slowing down the development of diabetic complications. Diabetesrelated liver damage is a serious complication in which oxidative stress is the main contributor to tissue injury. Oxidative stress is regarded as one of the main pathological mechanisms underlying liver pathologies provoked by other insults, such as drug toxicity, where LA could also be a useful agent in therapeutic intervention. However, before wider application of LA in a clinical setting, experimental and clinical research needs to be extended. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 173020]

We examined the functions of the rat lymphocyte nuclear matrix after a single exposure to total body irradiation with doses ranging from sublethal to lethal. Irradiation induced systemic oxidative stress, detected as increased activities of serum SOD and catalase, lymphocyte DNA damage, detected by the Comet assay, and apoptosis. After irradiation with lower doses, the recruitment of DNA repair centers on the matrix was observed by Western analysis as increased levels of matrix-associated PARP-1, p53 and PCNA. Augmented partitioning of the pro-survival transcription factor NF-κB on the matrix was also detected after irradiation. Exposure to a lethal dose caused breakdown of the matrix, observed as lamin B cleavage, and of the matrix-associated DNA repair centers, detected as caspase-mediated PARP-1 proteolysis and loss of protein associations with the matrix. These findings suggest that the nuclear matrix establishes functional 2 interactions in a defensive mechanism, integrated in a decision-making process that resolves cell fate. [Projekat Ministarstva nauke Republike Srbije, br. 173020]

The mechanisms underlying the beneficial effect observed in diabetic rats after treatment with a commercially available β-glucan-enriched extract (BGEE) were examined. Multiple low-dose streptozotocin (STZ) diabetes was used (40 mg STZ/kg) as a model for type 1 diabetes. BGEE was administered daily (80 mg/kg) for 4 weeks, starting from the last day of the STZ treatment. In vitro and in vivo experiments suggest that significant free radical scavenging and antioxidant activities of BGEE were responsible for a systemic adjustment of the redox disturbance and reduction of DNA damage in the liver and kidney of diabetic rats. BGEE-treated diabetic rats also displayed increased Akt kinase activity and decreased pro-caspase-3 degradation, implying that BGEE mediates its beneficial effects through activation of the cellular pro-survival pathway. We conclude that β-glucan administration under diabetic conditions promotes a systemic improvement that can be expected to increase the organism’s resistance to the onset of diabetic complications.

Given that oxidative stress plays a major role in pancreatic β-cell dysfunction and ultimate destruction, as well as in different complications of diabetes, therapy with antioxidants has assumed an important place in diabetes management. The relatively limited effects of established antioxidant compounds have stimulated efforts to develop new therapeutic strategies, e.g. to increase the endogenous antioxidant defenses through pharmacological modulation of key antioxidant enzymes. Plant extracts are gaining popularity in treating diabetes because many substances synthesized by higher plants and fungi possess antioxidant activities and can prevent or protect tissues against the damaging effects of free radicals. This review summarizes experimental models of diabetes and possible mechanisms that lie behind the antioxidative effects of α-lipoic acid (LA), a powerful antioxidant and compound that stimulates cellular glucose uptake, as well as of plant extracts from sweet chestnut (Castanea sativa), edible mushroom (Lactarius deterrimus) and natural products containing β-glucans in the treatment of diabetes. Their roles in preventing pancreatic β-cell death and in ameliorating the effects of severe diabetic complications are discussed. [Projekat Ministarstva nauke Republike Srbije, br. 173020]