An overview of the pathogenic mechanisms involved in severe cases of COVID-19 infection, and the proposal of salicyl-carnosine as a potential drug for its treatment

Multiple organ failure in COVID-19 patients is a serious problem which can result in a fatal outcome. Damage to organs and tissues, including general lung dysfunction, develops as a consequence of ischemia, which, in turn, is caused by thrombosis in small blood vessels and hypoxia, leading to oxidative stress and inflammation. Currently, research is underway to screen existing drugs for antioxidant, antiplatelet and anti-inflammatory properties. Having studied the available publications concerning the mechanisms of damage to tissues and organs of patients with COVID-19, as well as the available treatment strategies, we propose to investigate salicyl-carnosine as a potential drug for treating COVID-19 patients. In a recent study, we described the drug's synthesis procedure, and showed that salicyl-carnosine possesses antioxidant, anti-inflammatory, and antiplatelet effects. Therefore, it can simultaneously act on the three pathogenetic factors involved in tissue and organ damage in COVID-19. Thus, we propose to consider salicyl-carnosine as a potential drug for the treatment of patients with severe cases of COVID-19 infection. © 2020 Elsevier B.V

Effects of antioxidants on the viability of the human neuroblastoma SH-SY5Y cell culture under the conditions of heavy-metal toxicity

Protective action of antioxidants (mexidol, carnosine, N-acetyl cysteine) and the metal chelator Ca, Na2-EDTA was studied in the culture of human neuroblastoma SH-SY5Y cells after the addition of salts of heavy metals-lead, cadmium, cobalt, and molybdenum-to the culture medium. Cells were incubated with heavy metals and protectors for 24 h, and cell viability and cell death were evaluated. All the metals lowered cell viability in a concentration-related manner. Different protective agents were studied based on this model. The most pronounced capability of increasing the cell viability in conditions of heavy-metal toxicity was demonstrated by N-acetyl cysteine (the protective effect was demonstrated at the concentrations 0.5-1.0 mM and higher). Protective potential of carnosine was somewhat lower and that of mexidol was minimal. © 2016 Kulikova et al

Effects of antioxidants on the viability of the human neuroblastoma SH-SY5Y cell culture under the conditions of heavy-metal toxicity

Protective action of antioxidants (mexidol, carnosine, N-acetyl cysteine) and the metal chelator Ca, Na2-EDTA was studied in the culture of human neuroblastoma SH-SY5Y cells after the addition of salts of heavy metals-lead, cadmium, cobalt, and molybdenum-to the culture medium. Cells were incubated with heavy metals and protectors for 24 h, and cell viability and cell death were evaluated. All the metals lowered cell viability in a concentration-related manner. Different protective agents were studied based on this model. The most pronounced capability of increasing the cell viability in conditions of heavy-metal toxicity was demonstrated by N-acetyl cysteine (the protective effect was demonstrated at the concentrations 0.5-1.0 mM and higher). Protective potential of carnosine was somewhat lower and that of mexidol was minimal. © 2016 Kulikova et al

Neuroprotective effect of the carnosine – α-lipoic acid nanomicellar complex in a model of early-stage Parkinson's disease

In a model of early-stage Parkinson's disease induced by a single intranasal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to Wistar rats, a neuroprotective effect of a new derivative of carnosine and α-lipoic acid (C/LA nanomicellar complex) was demonstrated. Acute intraperitoneal administration of carnosine, α-lipoic acid and C/LA complex following MPTP administration normalized the total antioxidant activity in the brain tissue. Of all the compounds tested only C/LA complex normalized the metabolism of dopamine (DA) and serotonin (5-HT), while its components did not show similar effects when used separately. C/LA complex effectively restored the level of DA metabolites: the level of DOPAC was increased by 24.7 ± 5.6% compared to the animals that had received MPTP only, and the level of HVA was restored to the values observed in the intact animals. Integral metabolic indices of DA (DOPAC/DA and HVA/DA ratios) and 5-HT turnover (5-HIAA/5-HT ratio) in the striatum tended to increase in case of C/LA complex administration. © 2018 Elsevier Inc

Изучение механизмов токсического действия уабаина на культуру клеток мозжечка крысы

Both endogenous and exogenous cardiotonic steroids (CTS), specific inhibitors of Na,K-ATPase, can evoke different physiological responses in the central nervous system by influencing synaptic transmission and intracellular signal cascades. In addition, they might participate in the development of neurodegenerative processes in the central nervous system. The toxicity of CTS for neurons has been shown earlier, but it has not been sufficiently characterized, and the mechanism of neuronal death has not been described in detail. In the present study it was shown that the viability of the primary cell culture of rat cerebellum under the action of 10 pM ouabain already decreases at 12 h of incubation and does not further decrease after 24 and 48 h of incubation, which suggests that this is a fast process, presumably apoptotic. At 12 h of incubation, the action of both toxic (10 pM) and nontoxic (1 pM) concentrations of ouabain leads to a shift in the ratio of apoptosis regulating proteins of the Bcl-2 family towards proapoptotic ones. At the same time, reducing the time of incubation of cells with 10 pM ouabain, but not with 1 pM ouabain, to 3 hours also leads to a decrease in the ratios of antiapoptotic proteins Bcl-2 and Bcl-xL to proapoptotic Bax and Bak, respectively, which indicates a fast development of apoptotic processes in response to ouabain neurotoxicity. Thus, it can be assumed that the effect of toxic concentrations of ouabain which cause neuronal death, is carried out through the mechanism of the mitochondrial apoptotic pathway.Изучены механизмы нейротоксического действия специфического ингибитора Na, К-АТФазы кардиотонического стероида уабаина. Показано, что уабаин в концентрации более 1 мкМ вызывает снижение жизнеспособности первичной культуры клеток мозжечка крысы при 12 ч инкубации; после 24 ч дальнейшее снижение жизнеспособности не наблюдается. При этом токсичные концентрации уабаина вызывают снижение отношения антиапоптотических белков семейства Bcl-2 к проапоптотическим

Neuroprotective effect of the carnosine – α-lipoic acid nanomicellar complex in a model of early-stage Parkinson's disease

In a model of early-stage Parkinson's disease induced by a single intranasal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to Wistar rats, a neuroprotective effect of a new derivative of carnosine and α-lipoic acid (C/LA nanomicellar complex) was demonstrated. Acute intraperitoneal administration of carnosine, α-lipoic acid and C/LA complex following MPTP administration normalized the total antioxidant activity in the brain tissue. Of all the compounds tested only C/LA complex normalized the metabolism of dopamine (DA) and serotonin (5-HT), while its components did not show similar effects when used separately. C/LA complex effectively restored the level of DA metabolites: the level of DOPAC was increased by 24.7 ± 5.6% compared to the animals that had received MPTP only, and the level of HVA was restored to the values observed in the intact animals. Integral metabolic indices of DA (DOPAC/DA and HVA/DA ratios) and 5-HT turnover (5-HIAA/5-HT ratio) in the striatum tended to increase in case of C/LA complex administration. © 2018 Elsevier Inc

Modulation of the primary astrocyte-enriched cultures’ oxylipin profiles reduces neurotoxicity

Recently, manipulations with reactive astrocytes have been viewed as a new therapeutic approach that will enable the development of treatments for acute brain injuries and neurodegenerative diseases. Astrocytes can release several substances, which may exert neurotoxic or neuroprotective effects, but the nature of these substances is still largely unknown. In the present work, we tested the hypothesis that these effects may be attributed to oxylipins, which are synthesized from n-3 or n-6 polyunsaturated fatty acids (PUFAs). We used astrocyte-enriched cultures and found that: (1) lipid fractions secreted by lipopolysaccharide (LPS)—stimulated rat primary astrocyte-enriched cultures—possessed neurotoxic activity in rat primary neuronal cultures; (2) both of the tested oxylipin synthesis inhibitors, ML355 and Zileuton, reduce the LPS-stimulated release of interleukin 6 (IL-6) by astrocyte cultures, but only ML355 can change lipid fractions from neurotoxic to non-toxic; and (3) oxylipin profiles, measured by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) from neurotoxic and non-toxic lipid fractions, reveal a group of n-3 docosahexaenoic acid derivatives, hydroxydocosahexaenoic acids (HdoHEs)-4-HdoHE, 8-HdoHE, and 17-HdoHE, which may reflect the neuroprotective features of lipid fractions. Regulating the composition of astrocyte oxylipin profiles may be suggested as an approach for regulation of neurotoxicity in inflammatory processes. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Carnosine as an effective neuroprotector in brain pathology and potential neuromodulator in normal conditions

Carnosine (b-alanyl-l-histidine) is an endogenous dipeptide widely distributed in excitable tissues, such as muscle and neural tissues—though in minor concentrations in the latter. Multiple benefits have been attributed to carnosine: direct and indirect antioxidant effect, antiglycating, metal-chelating, chaperone and pH-buffering activity. Thus, carnosine turns out to be a multipotent protector against oxidative damage. However, the role of carnosine in the brain remains unclear. The key aspects concerning carnosine in the brain reviewed are as follows: its concentration and bioavailability, mechanisms of action in neuronal and glial cells, beneficial effects in human studies. Recent literature data and the results of our own research are summarized here. This review covers studies of carnosine effects on both in vitro and in vivo models of cerebral damage, such as neurodegenerative disorders and ischemic injuries and the data on its physiological actions on neuronal signaling and cerebral functions. Besides its antioxidant and homeostatic properties, new potential roles of carnosine in the brain are discussed. © 2018, Springer-Verlag GmbH Austria, part of Springer Nature

Oxylipin profiles in plasma of patients with wilson’s disease

Wilson’s disease (WD) is a rare autosomal recessive metabolic disorder resulting from mutations in the copper-transporting, P-type ATPase gene ATP7B gene, but influences of epigenetics, environment, age, and sex-related factors on the WD phenotype complicate diagnosis and clinical manifestations. Oxylipins, derivatives of omega-3, and omega-6 polyunsaturated fatty acids (PUFAs) are signaling mediators that are deeply involved in innate immunity responses; the regulation of inflammatory responses, including acute and chronic inflammation; and other disturbances related to any system diseases. Therefore, oxylipin profile tests are attractive for the diagnosis of WD. With UPLC-MS/MS lipidomics analysis, we detected 43 oxylipins in the plasma profiles of 39 patients with various clinical manifestations of WD compared with 16 healthy controls (HCs). Analyzing the similarity matrix of oxylipin profiles allowed us to cluster patients into three groups. Analysis of the data by VolcanoPlot and partial least square discriminant analysis (PLS-DA) showed that eight oxylipins and lipids stand for the variance between WD and HCs: eicosapentaenoic acid EPA, oleoylethanolamide OEA, octadecadienoic acids 9-HODE, 9-KODE, 12-hydroxyheptadecatrenoic acid 12-HHT, prostaglandins PGD2, PGE2, and 14,15-dihydroxyeicosatrienoic acids 14,15-DHET. The compounds indicate the involvement of oxidative stress damage, inflammatory processes, and peroxisome proliferator-activated receptor (PPAR) signaling pathways in this disease. The data reveal novel possible therapeutic targets and intervention strategies for treating WD. © 2020 by the authors

Lipoylcarnosine: Synthesis, Study of Physico-Chemical and Antioxidant Properties, Biological Activity

Abstract—: Synthesis of lipoylcarnosine (LipС), a conjugated molecule based on two natural antioxidants, carnosine and α-lipoic acid, is described and its physico-chemical, antioxidant properties and biological activity are characterized. According to reversed-phase HPLC with a UV detector, purity of the final product was 89.3%. The individuality of the obtained sodium salt of LipС was confirmed by tandem HPLC-mass spectrometry. LipC demonstrated high resistance to hydrolysis with serum carnosinase. The antioxidant activity of LipC evaluated by the reaction with the formation of thiobarbituric acid reacting substances and kinetic parameters of iron-induced chemiluminescence was higher than that of carnosine and lipoic acid. LipC did not affect viability of SH-SY5Y human neuroblastoma cells, differentiated to the dopaminergic phenotype, at concentrations not exceeding 5 mM. In the concentration range of 0.1–0.25 mM LipC protected neuronal cells against 1-methyl-4-phenylpyridinium (MPP+)-induced toxicity. © 2018, Pleiades Publishing, Ltd