Despite the success in the tactics of treating COVID-19, there are many unexplored issues related to the development and progression of the process in the lungs, brain, and other organs, as well as the role of individual elements, in particular, nitric oxide (NO), and in the pathogenesis of organ damage. Based on the analyzed literature data, we considered a possible pathophysiological mechanism of action of NO and its derivatives in COVID-19. It can be noted that hyperimmune systemic inflammation and “cytokine storm” are enhanced by the production of NO, products of its oxidation (“nitrosative stress”). It is noted in the work that as a result of the oxidation of NO, a large amount of the toxic compound peroxynitrite is formed, which is a powerful proinflammatory agent. Its presence significantly damages the endothelium of the vascular walls and also oxidizes lipids, hemoglobin, myoglobin, and cytochrome, binds SH-groups of proteins, and damages DNA in the target cells. This is confirmed by the picture of the vessels of the lungs on computed tomography and the data of biochemical studies. In case of peroxynitrite overproduction, inhibition of the synthesis of NO and its metabolic products seems to be justified. Another aspect considered in this work is the mechanism of damage by the virus to the central and peripheral nervous system, which remains poorly understood but may be important in understanding the consequences, as well as predicting brain functions in persons who have undergone COVID-19. According to the analyzed literature, it can be concluded that brain damage is possible due to the direct effect of the virus on the peripheral nerves and central structures, and indirectly through the effect on the endothelium of cerebral vessels. Disturbances in the central nervous regulation of immune responses may be associated with the insufficient function of the acetylcholine anti-inflammatory system. It is proposed to further study several approaches to influence various links of NO exchange, which are of interest for theoretical and practical medicine.

Heart rate variability (HRV) and cardiorespiratory phase synchronization (CRPS) were employed to study the cardio- and respiratory interactions in patients with asthma receiving inhalation of beta2-agonist (Berotec 200 mcg) for routine bronchodilator test. Both time- and frequency-domain parameters were used to analyze the HRV. A weighted G-index was introduced to study the quality of the CRPS. The HRV parameters, in both the time and frequency domains, exhibited significant changes pointing to a sympathetic activation of the autonomic balance immediately after the inhalation. On the other hand, the CRPS index barely changed throughout the entire process. This indicates that inhalation of beta2-agonist does not alter the CRPS appreciably, and that the CRPS, in contrast to HRV, is relatively stable in response to the inhalation of beta2-agonist in patients with asthma.

Adult hippocampal neurogenesis (AHN) is suppressed by chronic stress. The negative effect of stress is mainly attributed to increased levels of stress hormones (e.g. glucocorticoids, GCs). Exercise enhances AHN, yet it also stimulates GC secretion. To delineate the paradoxical role of GCs, we took the advantage of a unique mouse strain (L/L) which exhibits an inert response to stress-induced secretion of GCs to study the role of GCs in exercise-induced AHN. Our results showed that basal corticosterone (CORT), the main GCs in rodents, levels were similar between the L/L mice and wild-type (WT) mice. However, levels of CORT in the L/L mice were barely altered and significantly lower than those of the WT mice during treadmill running (TR). AHN was enhanced by 4 weeks of TR in the WT mice, but not L/L mice. WT mice that received daily injection of CORT to evoke serum CORT levels similar to those during exercise for 4 weeks did not affect AHN, whereas injection with large amount of CORT inhibited AHN. Taken together, our results indicated that exercise-related elevation of CORT participates in exercise-enhanced AHN. CORT alone is not sufficient to elicit AHN and may inhibit AHN if the levels are high.

Chronic kidney disease is one of the major global health problems. Chronic renal failure is stimulated by many cytokines and chemokines. Adropin and spexin (SPX) are peptides hormones. These peptides could affect inflammatory conditions, but this is unclear. Due to the limited information, we planned to investigate the impact of adropin and SPX hormones on systemic inflammation in adenine induced chronic kidney failure rat model. Chronic kidney failure was induced by administering adenine hemisulfate. Renal functions were measured by an autoanalyzer. Granulocyte colony-stimulating factor (G-CSF), interferon-gamma (IFN-γ), interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-10, IL-12, IL-13, IL-17A, tumor necrosis factor-alpha, Eotaxin, growth-regulated oncogene-alpha, IP-10, monocyte chemoattractant protein (MCP)-1, MCP-3, macrophage inflammatory protein (MIP)-1α, MIP-2, and RANTES levels were determined by Luminex. We observed an increase in 24-h urine volume and serum creatinine. Blood urea nitrogen (BUN) and urine protein levels were also significantly higher in the chronic kidney failure (CKF) group. Urine protein and 24-h urine volume were reduced with adropin and SPX treatments. Furthermore, G-CSF, IFN-γ, IL-4, IL-5, IL-10, IL-12, IL-17A, and GRO-α significantly increased by CKF induction; however, these cytokines and chemokines significantly decreased by adropin treatment in the CKF group. Furthermore, adropin increased IP-10, MCP-1, MIP-1α, and MIP-2 levels. In addition, SPX treatment had a more limited effect, decreasing only G-CSF, IFN-γ, and IL-5 levels. The combined adropin + SPX treatment significantly reduced G-CSF, IFN-γ, IL-4, IL-5, IL-12, and IL-17A. Furthermore, IP-10, MCP-1, MCP-3, and MIP-2 were significantly increased by these combined treatments. Our findings indicate that renal functions and inflammatory response were modulated by adropin and SPX peptides. These peptides may have protective effects on systemic inflammation and renal failure progression.

Gamma-linolenic acid (GLA), a natural fatty acid obtained from oils of various vegetables and seeds, has been demonstrated as an anticancer agent. In this work, we investigated the anticancer effects of GLA on breast cancer BT-474 cells. GLA at 30 μM, a concentration reportedly within the range of circulating concentrations in clinical studies, caused apoptotic cell death. GLA caused an elevation in mitochondrial Ca²⁺ level and a decrease in mitochondrial membrane potential. GLA treatment depleted cyclopiazonic acid (CPA)-sensitive Ca²⁺ store and triggered substantial Ca²⁺ influx. Intracellular Ca²⁺ release triggered by GLA was suppressed by 3 μM xestospongin C (XeC, IP₃ receptor-channel blocker) and 100 μM ryanodine (ryanodine receptor-channel blocker), suggesting that the Ca²⁺ release was via IP₃ receptor-channel and ryanodine receptor-channel. Increased expressions of p-eIF2α and CHOP were observed in GLA-treated cells, suggesting GLA-treated cells had increased expressions of p-eIF2α and CHOP, which suggest endoplasmic reticulum (ER) stress. In addition, GLA elicited increased production of reactive oxygen species. Taken together, our results suggest a basal level of GLA induced apoptotic cell death by causing Ca²⁺ overload, mitochondrial dysfunction, Ca²⁺ store depletion, ER stress, and oxidative stress. This is the first report to show that GLA caused Ca²⁺ store depletion and ER stress. GLA-induced Ca²⁺ store depletion resulted from opening of IP₃ receptor-channel and ryanodine receptor-channel.