Mitochondrial Dysfunction and Diabetic Nephropathy: Nontraditional Therapeutic Opportunities

Diabetic nephropathy (DN) is a progressive microvascular diabetic complication. Growing evidence shows that persistent mitochondrial dysfunction contributes to the progression of renal diseases, including DN, as it alters mitochondrial homeostasis and, in turn, affects normal kidney function. Pharmacological regulation of mitochondrial networking is a promising therapeutic strategy for preventing and restoring renal function in DN. In this review, we have surveyed recent advances in elucidating the mitochondrial networking and signaling pathways in physiological and pathological contexts. Additionally, we have considered the contributions of nontraditional therapy that ameliorate mitochondrial dysfunction and discussed their molecular mechanism, highlighting the potential value of nontraditional therapies, such as herbal medicine and lifestyle interventions, in therapeutic interventions for DN. The generation of new insights using mitochondrial networking will facilitate further investigations on nontraditional therapies for DN.

EFFECT OF MELANOCORTINS AND EXPERIMENTAL SOCIAL STRESS ON THE LEVEL OF CASPASE-3 AND CASPASE-8

At present the study of stress-generating effects and key mechanisms of regulation of apoptosis remain in the focus of attention of researchers. Stress causes dysfunctions of many body systems which lead to disruption of homeostasis and molecular cell mechanisms of programmed cell death. In this context, the problem of pharmacological regulation and correction of these disorders poses an urgent problem. Neuropeptide compounds such as melanocortins are interesting in this direction as regulators and correctors. Under conditions of experimental social stress activation of apoptotic processes was established due to an increase in the level of caspase-3 and caspase-8. The studied neuropeptides Semax (ACTH (4-7)-Pro-Gly-Pro) and ACTH (6-9)-Pro-Gly-Pro exhibit antiapoptotic effects under conditions of induced social stress in rats. This action of neuropeptides is manifested by a decrease in the activity of the initiating and effector caspases in the blood serum of experimental animals.

VDAC Modulation of Cancer Metabolism: Advances and Therapeutic Challenges

Most anionic metabolites including respiratory substrates, glycolytic adenosine triphosphate (ATP), and small cations that enter mitochondria, and mitochondrial ATP moving to the cytosol, cross the outer mitochondrial membrane (OMM) through voltage dependent anion channels (VDAC). The closed states of VDAC block the passage of anionic metabolites, and increase the flux of small cations, including calcium. Consequently, physiological or pharmacological regulation of VDAC opening, by conditioning the magnitude of both anion and cation fluxes, is a major contributor to mitochondrial metabolism. Tumor cells display a pro-proliferative Warburg phenotype characterized by enhanced aerobic glycolysis in the presence of partial suppression of mitochondrial metabolism. The heterogeneous and flexible metabolic traits of most human tumors render cells able to adapt to the constantly changing energetic and biosynthetic demands by switching between predominantly glycolytic or oxidative phenotypes. Here, we describe the biological consequences of changes in the conformational state of VDAC for cancer metabolism, the mechanisms by which VDAC-openers promote cancer cell death, and the advantages of VDAC opening as a valuable pharmacological target. Particular emphasis is given to the endogenous regulation of VDAC by free tubulin and the effects of VDAC-tubulin antagonists in cancer cells. Because of its function and location, VDAC operates as a switch to turn-off mitochondrial metabolism (closed state) and increase aerobic glycolysis (pro-Warburg), or to turn-on mitochondrial metabolism (open state) and decrease glycolysis (anti-Warburg). A better understanding of the role of VDAC regulation in tumor progression is relevant both for cancer biology and for developing novel cancer chemotherapies.

Epigenetic Targeting of Histone Deacetylases in Diagnostics and Treatment of Depression

Depression is a highly prevalent, disabling, and often chronic illness that places substantial burdens on patients, families, healthcare systems, and the economy. A substantial minority of patients are unresponsive to current therapies, so there is an urgent need to develop more broadly effective, accessible, and tolerable therapies. Pharmacological regulation of histone acetylation level has been investigated as one potential clinical strategy. Histone acetylation status is considered a potential diagnostic biomarker for depression, while inhibitors of histone deacetylases (HDACs) have garnered interest as novel therapeutics. This review describes recent advances in our knowledge of histone acetylation status in depression and the therapeutic potential of HDAC inhibitors.

Regulation of high-frequency rhythms of the behavioral activity by oligopeptides structurаlly related to oxytocin

The pharmacological regulation of high-frequency rhythms of the behavioral activity (with a period of up to 1/2 hour) is an actual direction of modern medical science. The aim of the study was to assess the influence of oligopeptides structurally related to oxytocin on the parameters of ultradian rhythms of locomotor activity (LA) in outbred ICR laboratory mice. LA was recorded automatically in a multichannel actometer (Ugo Basile, Italy) in the conditions of individual detection. Amplitude, acrophase, and mesor of biorhythms’ were determined by the Cosinor analysis. Oligopeptides structurally related to oxytocin fragments, as well as memantine under systemic (intraperitoneal) administration, had a pronounced influence on the ultradian LA biorhythms of mice. Memantine (10.0 mg/kg), Cyclo-(Leu-Gly) (0.025 mg/kg), Pro-Leu (0.5 mg/kg), and Leu-Gly (0.1 mg/kg) triggered the migration to the right of the acrophase of statistically significant 24-minute LA rhythms versus control. A further study of the peptidergic mechanisms of regulation of fluctuations in ultradian biorhythms can contribute to the development of the theoretical foundations of chronobiology, as well as to the search for the means correcting the desynchronoses.