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On mouse neuroblastoma (Neuro-2a) and human glioblastoma (U-87 MG) cell lines, we studied the effect of inducers and inhibitors of redox-sensitive signaling system of the antioxidant-responsive element Keap1/Nrf2/ARE on the main processes that determine nerve cell viability and vital activity (proliferative activity, apoptosis, autophagy, and activation of the Keap1/Nrf2/ARE system). Inhibitors of the Keap1/Nrf2/ARE system stimulate apoptosis more pronouncedly than inducers, have a weaker effect on autophagy, and do not change the nuclear to cytoplasmic Nrf2 ratio. In general, the revealed effects testify in favor of the potential effectiveness of stimulating the Keap1/Nrf2/ARE system for the prevention and adjuvant therapy of neurodegenerative diseases., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)

The development of means of the prevention and treatment of age-related neurodegenerative diseases, as well as geroprotectors, among other things, is based on the inflammatory and free radical theories of aging. In this context, we studied the effect of sodium monophenol 3-(3'-tert-butyl-4'-hydroxyphenyl)propyl thiosulfonate (TS-13) on the behavioral and locomotor activity of C57BL/6 mice in modeling Parkinson's disease by MPTP neurotoxin injection. TS-13 administration significantly improved orientation and exploratory activity and emotional response of the animals in the open field test, but did not affect the increase in anxiety caused by MPTP injection. Long-term (6 months) TS-13 administration did not suppress spontaneous motor activity in BALB/c mice and slightly increased their exploratory activity., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature.)

The redox-sensitive signaling system Keap1/Nrf2/ARE is a premier protective mechanism against oxidative stress that plays a key role in the pathogenesis and development of various diseases, including tuberculous granulomatous inflammation. We have previously reported that novel water-soluble phenolic antioxidant TS-13 (sodium 3-(4'-methoxyphenyl)propyl thiosulfonate) induces Keap1/Nrf2/ARE and attenuates inflammation. The aim of this study is the examination of the effect of TS-13 on tuberculous granulomatous inflammation. BALB/c mice were administered TS-13 (100 mg kg -1 day -1 ) through their drinking water starting immediately after Bacillus Calmette-Guérin (BCG) intravenous injection. Histological changes, production of reactive oxygen species (ROS) (activity of free-radical oxidation processes), and mRNA expression of Nrf2-driven, NF- κ B-, AP-1-, and autophagy-dependent signal pathway genes in the liver and peritoneal exudate were evaluated 30 days later. After the 30th day of infection, the activity of the Keap1/Nrf2/ARE system was decreased and its effector genes entailed increasing ROS production in the liver. Therapeutic intervention with TS-13 is aimed at activating the Keap1/Nrf2/ARE system that leads to an increase in Nrf2 and Nrf2-mediated gene expression and a decrease in NF- κ B expression. Changes in these pathways resulted in a decline of ROS production and a decrease in the number and the size of granulomas. In total, the results indicate that the Keap1/Nrf2/ARE system can be an effective pharmacological target in host-adjunctive treatment of tuberculosis., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 Elena B. Menshchikova et al.)

Mood disorders affect nearly 300 million humans worldwide, and it is a leading cause of death from suicide. In the last decade, the habenula has gained increased attention due to its major role to modulate emotional behavior and related psychopathologies, including depression and bipolar disorder, through the modulation of monoamines' neurotransmission. However, it is still unclear which genetic factors may directly affect the function of the habenula and hence, could contribute to the psychopathological mechanisms of mood disorders. Disrupted-In-Schizophrenia-1 (DISC1) gene is among robust gene-candidates predisposing to major depression, bipolar disorder and schizophrenia in humans. DISC1-Q31L, a well-established genetic mouse model of depression, offers a unique opportunity for translational studies. The current study aimed to probe morphological features of the habenula in the DISC1-Q31L mouse line and detect novel behavioral endophenotypes, including the increased emotionality in mutant females, high aggression in mutant males and deficient extinction of fear memory in DISC1 mutant mice of both sexes. The histological analysis found the increased neural density in the lateral and medial habenula in DISC1-Q31L mice regardless of sex, hence, excluding direct association between the habenular neurons and emotionality in mutant females. Altogether, our findings demonstrated, for the first time, the direct impact of the DISC1 gene on the habenular neurons and affective behavior in the DISC1-Q31L genetic mouse line. These new findings suggest that the combination of the DISC1 genetic analysis together with habenular neuroimaging may improve diagnostics of mood disorder in clinical studies., (Copyright © 2020 Elsevier B.V. All rights reserved.)

ROS are important intracellular messengers; their ambiguous role in malignant processes was demonstrated in many studies. The effects of a synthetic phenolic antioxidant sodium 3-(3'-tert-butyl-4'-hydroxyphenyl)propyl thiosulfonate sodium (TS-13) on the tumor growth and oncolytic properties of doxorubicin were studied in the experimental model of Lewis lung carcinoma in mice. In mice receiving TS-13 with drinking water (100 mg/kg), suppression of tumor growth by 32.3% was observed on day 21 after inoculation of Lewis lung carcinoma cells. Two-fold intraperitoneal injections of doxorubicin in a cumulative dose of 8 mg/kg were followed by inhibition of tumor growth by 49.5%. Combined treatment with TS-13 and doxorubicin suppressed the tumor growth by 55.4%. In contrast to doxorubicin, TS-13 inhibited NO generation by peritoneal macrophages. The results show the prospect of studying TS-13 in the context of overcoming drug-resistance of tumors.

Objectives: We evaluated the hypolipidaemic effect of mannan Candida albicans serotype A, relative to atorvastatin, in a mouse model of hyperlipidaemia., Methods: Mannan serotype A was investigated in vitro and in vivo to determine its effects on macrophage proliferation, nitric oxide (NO) production by cultured macrophages, serum and liver lipids, changes in liver morphology and serum chitotriosidase activity and its expression in the liver., Key Findings: Mannan serotype A stimulates the macrophage proliferation and NO production in murine peritoneal macrophages in vitro. The activity of serum chitotriosidase (an enzyme released from the activated macrophages) was found to be significantly increased in P-407-induced hyperlipidaemic mice pretreated with low-dose mannan compared with mice administered P-407 only. Mannan treatment in mice was shown to significantly increase the chitotriosidase expression in the liver of both non-hyperlipidaemic and P-407-induced hyperlipidaemic mice. Lastly, mice pretreated with mannan before the induction of hyperlipidaemia with P-407 showed a significant reduction in the serum concentration of atherogenic LDL cholesterol, total cholesterol, triglycerides and liver triglycerides., Conclusions: It is suggested that mannan serotype A, like β-glucan, may represent another hypolipidaemic agent, which could potentially be used as an adjunctive therapy with conventional antihyperlipidaemic drugs (statins and fibrates) in humans., (© 2016 Royal Pharmaceutical Society.)

We studied biological effects of mannan, a polysaccharide immunomodulator from C. albicans, that interacts with mannose receptor in vivo. It is shown that preliminary administration of mannan (5 times in a dose of 50 mg/kg or 2 times in a dose of 100 mg/kg) to mice with acute lipemia induced by lipase inhibitor poloxamer 407 (300 mg/kg) reduces the serum concentrations of atherogenic LDL, cholesterol, and triglycerides. Administration of mannan to intact mice and animals with acute lipemia reduces triglyceride concentration and causes labilization of lysosomal membranes in the liver. Serum activity of chitotriosidase, a marker of macrophage activation, was elevated in mice with acute lipemia treated with mannan. Thus, mannan from C. albicans is a promising hypolipidemic polysaccharide compound, similar by its activity to β-glycan, a component of LPS.

We studied the effects of melatonin on the status of immune organs and parameters of lipid metabolism in rats with alimentary obesity and parameters of lipid metabolism and immune status in Wistar rats kept on high-fat diet and receiving melatonin solution per os. Melatonin leveled the changes in blood and liver parameters of lipid metabolism, which was paralleled by normalization of cellular composition of immune organs. We conclude that melatonin can be a promising agent for the treatment of lipid metabolism and immune status disorders in alimentary obesity.

We studied the influence of high-fat diet on the development of metabolic syndrome in rats of hypertensive ISIAH strain and normotensive WAG strain. In contrast to ISIAH rats, high-fat diet in WAG rats led visceral obesity, glucose tolerance, and dyslipidemia. DNA-binding activity of the peroxisome proliferator-activated receptor α (PPARα) decreased in the liver of WAG rats and increased in ISIAH rats. Blood levels of TNF-α, IL-6, and corticosterone increased more significantly in WAG rats. Corticosterone content in the adrenal glands was more markedly reduced in WAG rats. High-fat diet had no effect on BP in ISIAH and WAG rats. It was concluded that ISIAH rats can be used as a genetic model in studies of the mechanism of resistance to the metabolic syndrome.

It has been shown recently that significant number (to 40% from total population) of macrophage foam cells (MFC) is formed during early time (24 h) of zymosan-induced peritonitis resolution and agonists of peroxisome proliferation activated receptors-α, -γ (PPAR-α, -γ) exert anti-inflammatory action, protecting their formation (Dushkin et al., 2007). The work is devoted to investigate of the influence of cholesterol-containing liposomes (CHL) on dinamic of zimozan-induced peritonitis in C57Bl/6 mice. The accumulation of cholesterol, the change of cytokine production, PPAR-γ activity and cholesterol efflux in macrophages of C57Bl/6 mice has been investigated. The infiltration of neutrophils, amounts of mononuclear cells and MFC formation were significantly increased in peritonel cavity of zymosan-induced mice that led to in expansion of the period of inflammatory resolution and of the period of MFC resolution. If macrophages obtained after zymosan injection mainly accumulated triglycerides (TG) and at high speed incorporated [1-14C]oleate into TG, the injection of CHL after zymosan-indused inflammation lead to dramatic promotion MFC containing primarily free cholesterol and Ch ethers and been aggravation of [1-14C]oleate incorporation into cholesterol ethers in macrophages (mainly for 2 days). It has to shown that CHL against a background of inflammation promoted reduction of fluorescent NBD-cholesterol efflux from macrophages throughout the studied period (5 days) whereas zymosan inhibited cholesterol efflux at the early stages of inflammation (1 and 2 days), then, on 3ed day, the cholesterol efflux was recovered and increased on day 5. At the same time CHL stimulated the production of TNFα and TGFβ and inhibited the production of IL-10 and DNA-binding activity of PPAR-γ macrophages obtained at early as well as late stages of zymosan-induced peritonitis (compared with injection zymosan only). Thus, accumulation of cholesterol in inflammatory macrophages and promotion of MFC formation prolog timely resoluti- on of acute inflammation inducing alteration of pro- and anti-inflammatory cytokine balance and evoking the repression of macrophage DNA-binding activity of PPAR-γ and cholesterol efflux.

We studied the effect of bezafibrate on hepatic PPARα activity and immune parameters in hypertensive ISIAH rats in comparison with normotensive WAG rats under conditions of LPS treatment. Bezafibrate increased activity of PPARα in WAG rats, but not in ISIAH rats. As differentiated from WAG rats, bezafibrate produced a potent effect on the content of T cell subpopulations in the thymus and spleen of ISIAH rats. Administration of LPS after injection of bezafibrate caused death of 50% ISIAH animals (but not WAG rats), which was associated with low level of HDL cholesterol and increased triglyceride content. Our results suggest that the hypolipidemic treatment (e.g., bezafibrate) can increase the severity of complications in patients with infectious and inflammatory diseases in association with low level of HDL.

We studied the influence of abnormal illumination regimen on cell composition of the central and peripheral organs of the immune system in ISIAH rats and control WAG rats. In ISIAH rats, 24-h illumination for 14 days led to more pronounced inhibition of cell proliferation and differentiation in the thymus and more pronounced decrease in splenocyte proliferation and T and B cell counts in the spleen in comparison with WAG rats; however, the level of antigen-presenting cells in the spleen of ISIAH increased. We concluded that ISIAH rats are more sensitive to abnormal illumination regimen than WAG rats. Twenty-four-hour illumination was associated with impairments of central differentiation of T cells and activation of systemic inflammation followed by impairment of differentiation regulation, which can aggravate metabolic dysfunctions in these animals.

Some aspects of peroxisome proliferator activated receptors (PPAR) involvement in regulation of stress-dependent biological processes leading to insulin resistance, lipid imbalance, hypertension and inflammation are reviewed. Analysis of literature data clearly shows the main role of PPAR in stress signal transduction following to metabolic disbalance development under prolonged stress conditions. The interplay of three PPAR isoforms functional activity with metabolic process disturbances during stress is under special emphasis. Taking into account experimental data described in literature we suggest that PPAR activation under acute stress is an adaptive response while stable PPAR hyperexpression under prolonged stress can cause insulin resistance, hypertension, and visceral obesity. The strategy of PPAR using as pharmacological targets in metabolic syndrome correction is under consideration.

Possible relationship between changes in behavior and hormone response to a sex stimulus was studied by comparing these parameters in mice of 10 genotypes. All males spent more time near the wall during the very first 5 min after appearance of the female. Strains with the minimum (DBA/2, C57Bl/6J) and maximum (SWR, CBA) time spent near the wall were distinguished. Genotypical differences in hormone response during sexual activation were detected. Considerable increase in testosterone concentration in the peripheral blood was observed in males of 6 of the 10 mouse strains 30 min after appearance of the female. Mouse strains with contrast sexual activation were distinguished. No correlation between behavioral and hormonal response was detected. The detected genetically determined variability of the behavioral and hormonal components of sexual activation is determined by hereditary peculiarities of central mechanisms regulating the studied functions.

Special features of anxious behavior in the elevated plus maze test and acoustic startle response were analyzed in 11 inbred mouse strains. A significant influence of the genotype both on the startle amplitude and behavior in the elevated plus maze was found. However, analysis of covariance did not reveal a genotype-related association between anxiety and startle amplitude. The data indicates that the fear-induced acoustic startle response and anxious behavior in the elevated plus maze (agoraphobia) are not genetically related.