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Background/objectives: The neurometabolic function is controlled by a complex multi-level physiological system that includes neurochemical, hormonal, immunological, sensory, and metabolic components. Functional disorders of monoamine systems are often detected in clinical practice together with metabolic dysfunctions. An important part of the mentioned pathological conditions are associated with disturbances in protein metabolism, some of the most important biomarkers which are aminotransferases and transcription factors that regulate and direct the most important metabolic reactions. Another important part of energy metabolism is the dopamine-mediated regulation of protein metabolism., Methods: The review describes research results into the dopamine-mediated mechanism of metabolic regulation in humans and animals. Particular attention is paid to the neurometabolic mechanisms of protein metabolism., Results: The dopamine-aminotransferase system of the energy metabolism regulation is a separate, independent, regulatory and diagnostically significant biochemical pathway controlled by the hormonal system, the key hormone is cortisol, the key neurotransmitter is dopamine, the key transcription factor is CREB, and the key regulatory enzymes are alanine aminotransferase, aspartate aminotransferase, and tyrosine aminotransferase., Conclusions: This review presents an original study describing the discovery of a new regulatory mechanism for neurometabolic physiological function in humans and animals. A key part of this mechanism is the dopamine-aminotransferase system.

Trace amines are a separate, independent group of biogenic amines, close in structure to classical monoamine neurotransmitters such as dopamine, serotonin, and norepinephrine that include many products of the endogenous or bacteria-mediated decarboxylation of amino acids. A family of G protein-coupled trace amine-associated receptors (in humans, TAAR1, TAAR2, TAAR5, TAAR6, TAAR8, and TAAR9) that senses trace amines was discovered relatively recently. They are mostly investigated for their involvement in the olfaction of volatile amines encoding innate behaviors and their potential contribution to the pathogenesis of neuropsychiatric disorders, but the expression of the TAAR family of receptors is also observed in various populations of cells in the immune system. This review is focused on the basic information of the interaction of trace amines and their receptors with cells of the general immune systems of humans and other mammals. We also overview the available data on TAARs' role in the function of individual populations of myeloid and lymphoid cells. With further research on the regulatory role of the trace amine system in immune functions and on uncovering the contribution of these processes to the pathogenesis of the immune response, a significant advance in the field could be expected. Furthermore, the determination of the molecular mechanisms of TAARs' involvement in immune system regulation and the further investigation of their potential chemotactic role could bring about the development of new approaches for the treatment of disorders related to immune system dysfunctions.

Dopamine transporter knockout (DAT-KO) rats represent a valuable rodent model for studying the molecular and phenotypical outcomes of the effects of excessive dopamine accumulation in the synaptic cleft and the prolonged action of dopamine on neurons. Animals with DAT deficiency are characterized by hyperactivity, stereotypy, cognitive deficits, and impairments in behavioral and biochemical indicators. Several key pathophysiological mechanisms are known to be common to psychiatric, neurodegenerative, metabolic, and other diseases. Among these mechanisms, oxidative stress systems play a particularly important role. One of the main antioxidant systems in the brain is glutathione: specifically, glutathione S-transferase, glutathione reductase, and catalase play a significant role in the regulation of vital oxidative processes, and their dysfunction has been shown in Parkinson's disease, Alzheimer's disease, and other neurodegenerative diseases. The current study aimed to analyze the dynamics of the activity levels of glutathione reductase and glutathione S-transferase in erythrocytes, as well as catalase in the blood plasma, of DAT-deficient, homo- and heterozygous, neonatal and juvenile rats (both male and female). Their behavioral and physiological parameters were evaluated at the age of 1.5 months. For the first time, changes in physiological and biochemical parameters were shown in DAT-KO rats at 1.5 months of postnatal life. The key role of glutathione S-transferase, glutathione reductase, and catalase in the regulation of oxidative stress in DAT-KO rats at the 5th week of life was demonstrated. A positive effect of a slightly increased dopamine level on memory function was shown in DAT-heterozygous animals., (© 2023 Wiley Periodicals LLC.)

Trace amines and their receptors are a family of G protein-coupled receptors widely distributed in the central nervous system and periphery. The trace amine-associated receptor 1 (TAAR1) plays a significant role as a therapeutic target for schizophrenia, depression, diabetes, and obesity. In this study, TAAR1 knockout mice and WT groups were tested in conditions of a high-fructose diet. The consumption of a high-fructose diet may be due to the influence on the metabolism processes by dopamine in the brain, neuromotor function, and level of anxiety of TAAR1 knockout mice. During a comparative analysis of behavioral, biochemical, and morphological parameters, significant differences were found between liver and biochemical parameters, the regulation of protein metabolism (AST/ALT ratio, creatine kinase activity, urea), and alterations in behavior. An elevated plus maze analysis showed the influence of fructose and genetic factors on the level of anxiety. A new marker of the grooming microstructure (depression ratio) was tested, which showed high efficiency as a marker of depression-like behavioral changes and a possible association with dopamine-dependent regulation of protein metabolism. These results confirm a possible association of the TAAR1 gene knockout with an increase in catabolic reaction levels by AST/ALT-dependent and possible dopamine-mediated protein metabolism regulation and depression-like behavior.

Objectives: Transresveratrol (Res) and l-carnitine (l-Car) are proposed to alleviate metabolic and immune disorders and increase physical activity in obese individuals. This study aims to estimate the effect of Res and l-Car in rats with diet-induced obesity., Methods: Male Wistar rats were fed a diet with excess fat and fructose (high-fat high-carbohydrate diet [HFCD]) supplemented with Res and l-Car at doses of 25 and 300 mg/kg of body weight, respectively, for 63 d. An assessment of grip strength, behavioral reactions, as well as biochemical, morphological, and immunological parameters, was performed., Results: Res supplementation did not affect energy consumption, but l-Car increased when animals had free access to feed. Body weight gains were the highest in animals fed the HFCD, lowest in rats receiving the control balanced diet, and intermediate in animals receiving Res and l-Car. Feeding with Res and l-Car canceled the decrease in long-term memory in rats fed the HFCD, as well as reduced anxiety and increased mobility. With both supplements, bilirubin, triglycerides, and low-density lipoprotein levels in the blood plasma returned to normal values, but only l-Car increased the ratio of aspartic and alanine transaminases. In addition, l-Car lowered the levels of leptin and ghrelin and increased transforming growth factor beta 1 in the blood plasma, and consumption of Res was accompanied by a decrease in interleukin-17A and increase in interferon gamma in spleen lysates. Moreover, l-Car reduced the number of cells with lipid inclusions in the liver., Conclusions: The consumption of Res and l-Car leads to a significant reduction in dyslipidemia and inflammation with potentially favorable changes in behavioral responses., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We studied the effects of the addition of large neutral amino acids, such as tyrosine (Tyr) and tryptophan (Trp), in mice DBA/2J and tetrahybrid mice DBCB receiving a high-fat, high-carbohydrate diet (HFCD) for 65 days. The locomotor activity, anxiety, muscle tone, mass of internal organs, liver morphology, adipokines, cytokines, and biochemical indices of animals were assessed. The Tyr supplementation potentiated increased anxiety in EPM and contributed to a muscle tone increase, a decrease in the AST/ALT ratio, and an increase in protein anabolism in both mice strains. Tyr contributed to a decrease in liver fatty degeneration and ALT reduction only in DBCB that were sensitive to the development of obesity. The addition of Trp caused an increase in muscle tone and potentiated an increase in anxiety with age in animals of both genotypes. Trp had toxic effects on the livers of mice, which was manifested in increased fatty degeneration in DBCB, edema, and the appearance of micronuclei in DBA/2J. The main identified effects of Tyr on mice are considered in the light of its modulating effect on the dopamine neurotransmitter metabolism, while for the Trp supplement, effects were presumably associated with the synthesis of its toxic metabolites by representatives of the intestinal microflora.

In the last two decades, interest has grown significantly in the investigation of the role of trace amines and their receptors in mammalian physiology and pathology. Trace amine-associated receptor 9 (TAAR9) is one of the least studied members of this receptor family with unidentified endogenous ligands and an unknown role in the central nervous system and periphery. In this study, we generated two new TAAR9 knockout (TAAR9-KO) rat strains by CRISPR-Cas9 technology as in vivo models to evaluate the role of TAAR9 in mammalian physiology. In these mutant rats, we performed a comparative analysis of a number of hematological and biochemical parameters in the blood. Particularly, we carried out a complete blood count, erythrocyte osmotic fragility test, and screening of a panel of basic biochemical parameters. No significant alterations in any of the hematological and most biochemical parameters were found between mutant and WT rats. However, biochemical studies revealed a significant decrease in total and low-density lipoprotein cholesterol levels in the blood of both strains of TAAR9-KO rats. Such role of TAAR9 in cholesterol regulation not only brings a new understanding of mechanisms and biological pathways of lipid exchange but also provides a new potential drug target for disorders involving cholesterol-related pathology, such as atherosclerosis.

Amino acids tyrosine (Tyr) and tryptophan (Trp) play a significant role in the regulation of energy metabolism, locomotor activity, and eating behavior. We studied the possibility of modulating these processes in obesity by increasing the pool of Tyr and Trp in the experimental diet. As a model of obesity, we used Wistar rats fed a diet with an excess specific energy value (HFCD) for 64 days. Trp led to a normalization of the rats' body weight almost to the control level, but increased anxiety-like behavior and decreased long-term memory. The consumption of amino acids resulted in increased grip strength and impairment of short-term memory. The locomotor activity of animals decreased with age as a result of Tyr consumption, while Trp, on the contrary, prevented this. The Tyr supplementation led to the normalization of triglycerides and LDL. In the spleen cell lysates, amino acids suppressed the production of proinflammatory cytokines. The liver tissue morphology showed that the consumption of Tyr noticeably weakened the signs of fatty degeneration. The addition of Trp, on the contrary, led to an unfavorable effect, consisting of the appearance of a high number of large rounded fatty vacuoles. The data obtained indicate a more pronounced anti-inflammatory effect of Tyr as compared to Trp.

The use of nutraceuticals with anti-inflammatory and hypolipidemic activity in the composition of foods for special dietary uses and dietary supplements is one of the effective methods of dietary therapy of alimentary obesity and related diseases. The aim was to study the effect of the combined intake of resveratrol and L-carnitine (RC) on the expression of genes responsible for the metabolism of carbohydrates, fats and inflammatory reactions in the liver and kidneys of rats in normal conditions and with diet-induced obesity. Material and methods . Male Wistar rats received for 63 days a standard balanced diet or a high-fat-high-carbohydrate diet (HFCD) with an excess of total fat (30%) and fructose (20% solution instead of drinking water), or the same diets supplemented with RC in a low (25 mg/kg body weight as resveratrol and 300 mg/kg as L-carnitine) or high (50 and 600 mg/kg body weight, respectively) doses. The expression of genes (Khk, Gck, Pklr, Acaca, Acacb, Fasn, Scd, Srebf1, Mlxipl, Ppara, Pparg, Actb, Gapdh) in liver cells was studied by the method of real-time reverse transcription polymerase chain reaction (RT-PCR). The distribution of tyrosine aminotransferase (TAT), nuclear factor erythroid 2-related factor 2 (NRF-2) and intercellular adhesion molecule type 2 (ICAM-2) in the liver and kidneys was assessed by confocal laser microscopy and immunohistochemistry. Results . Increased expression of Fasn (fatty acid synthase) in rats treated with high-fat high-carbohydrate diet (HFCD) decreased under RC intake. RC consumption caused a decrease in the number of TAT-, NRF-2- and ICAM-2-positive cells in the liver of rats treated with HFCD, but had the opposite effect in the kidneys. The consumption of RC at the low dose by rats fed HFCD caused changes in the expression profiles of the studied marker genes, indicating a possible hypolipidemic effect. However, observed increased expression of lipogenic genes in the liver and elevated level of NRF-2 and ICAM-2 in kidney against the background of consumption of RC with the standard balanced diet cannot be assessed as unambiguously positive. Conclusion . Thus, possible negative effects caused, most likely, by the interaction of nutraceuticals with various mechanisms of action should be taken into account when developing formulations of dietary supplements and foods for special dietary uses for dietary therapy of obesity., Competing Interests: The authors declare no overt and potential conflict of interest related to the publication of this article., (Copyright© GEOTAR-Media Publishing Group.)

Background: Quercetin (Q; 3,3',4',5,7 - pentahydroxyflavone) can help alleviate the pathological effects of nutritional obesity and metabolic syndrome when taken as part of products for special dietary needs and food supplements. The mechanisms of action of Q at the genetic level are not well understood., Aims: To study gene expression in liver tissue of mice with alimentary and genetically determined obesity upon intake of Q with diet., Materials and Methods: During 46 days of the experiment on 32 male C57Bl/6J mice fed a diet with an excess of fat and fructose and 24 male genetically obese db/db mice the effect of Q in dose of 25 or 100 mg/kg of body weight was studied on differential expression of 39430 genes in mice livers by full transcriptome profiling on microchip according to the Agilent One-Color Microarray-Based Gene Expression Analysis Low Input Quick Amp Labeling protocol (version 6.8). To identify metabolic pathways (KEGGs) that were targets of Q exposure, transcriptomic data were analyzed using bioinformatics methods in an "R" environment., Results: Differences were revealed in the nature of Q supplementation action in animals with dietary induced and genetically determined obesity on a number of key metabolic pathways, including the metabolism of lipids and steroids (Saa3, Cidec, Scd1, Apoa4, Acss2, Fabp5, Car3, Acacb, Insig2 genes), amino acids and nitrogen bases (Ngef, Gls2), carbohydrates (G6pdx, Pdk4), regulation of cell growth, apoptosis and proliferation (Btg3, Cgref1, Fst, Nrep Tuba8), neurotransmission (Grin2d, Camk2b), immune system reactions (CD14i, Jchain, Ifi27l2b)., Conclusions: The data obtained help to explain the ambiguous effectiveness of Q, like other polyphenols, in the dietary treatment of various forms of obesity in humans, as well as to form a set of sensitive biomarkers that allow us to elucidate the effectiveness of minor biologically active food substances in preclinical trials of new means of metabolic correction of obesity and metabolic syndrome.

Quercetin can affect some pathological manifestations in obesity. The mechanism underlying the presumed therapeutic effect of quercetin is probably related to the influence on the central processes regulating energy homeostasis. Thus, the purpose of this study was to examine the effect of quercetin on the neuromotor and behavioral functions in Zucker (Z) and Wistar (W) rats with genetically and/or diet-induced obesity. Rats of both strains received balanced or high fat and fructose diet (HFCD) in a 62-day experiment or the same diets supplemented with quercetin at the dose of 50 mg/kg body weight per day. The neuromotor function and behavioral responses were examined using the grip strength test, open field test, elevated plus maze test and conditioned passive avoidance response (CPAR) test. The quercetin potentiated a decrease in anxiety in W rats consumed HFCD and this effect was absent in Z rats with a defect in the leptin receptor gene. In contrast, quercetin increased locomotor activity and impaired short-term memory in the CPAR test only in Z rats with the absence of normal leptin reception. Against the background of the identified changes quercetin exerted significant effects on the lipid and nitrogen metabolism indices such as HDL cholesterol, AsAT/AlAT activities ratio, urea level as well as body and fat mass that were different in Z and W rats. The data obtained show that the effects of quercetin on behavior vary significantly between two strains of rat and consequently are mediated by processes of leptin reception., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Quercetin (Q) is known to be a powerful chelating agent for metal ions. Due to this property, Q, when ingested, is able to intervene actively in microelement homeostasis. The assessment of the possible significance of these effects for the dietary use of Q in obesity is complicated by the fact that in obese patients there are numerous changes in mineral metabolism and microelement homeostasis due to the pathogenesis of the disease. Thus, it is of considerable interest to identify the systemic effects of biologically active substances, including Q, on mineral metabolism in biological in vivo models (due to the limited choice of biosubstrates in clinical observations - blood plasma, urine, hair). The aim was to study the possible effects of Q on the levels of essential, non-essential and toxic elements in mice of three lines: db/db with knockout of the leptin receptor gene, prone to spontaneous development of obesity, inbred line C57Bl/6J, relatively resistant to the development of nutritional obesity, and complex hybrid of the 2nd generation DBCB, genetically more prone to developing obesity and fatty hepatosis when consuming diets with an excess quota of fat and simple carbohydrates. Material and methods . The content of 16 chemical elements (Fe, Mg, Cu, Mn, Co, Se, Zn, Cr, Al, Cd, As, Pb, Ni, Ag, V, Cs) was determined by mass spectrometry with inductively coupled plasma in the liver, kidneys, brain of genetically obese db/db mice (8-10 weeks old) receiving standard semisynthetic ration (SSD) and Q for 47 days at doses of 25 and 100 mg/kg body weight, C57Bl/6J mice treated with SPR or a high-fat high-carb diet (HFCD - 30% fats and 20% fructose solution instead of water) and Q supplementation at the same doses, DBCB tetrahybrid mice treated with SSD, HFCD and HFCD supplemented with Q for 63 days (25 mg/kg body weight). The compounds of Fe, Zn, Cu, Mn, Mg, Cr, Ni, Se, and V were included in the salt mixture in the form of inorganic salts or oxides in amounts close to physiological needs; Al, Cd, As, Pb, Ag, Cs, Co - were present in the diets in background amounts. Results and discussion . In db/db mice, in comparison with C57Bl/6J, a decreased content of Pb in the liver and increased in the kidneys and brain, decreased Co in the kidneys, increased Cs and As in the brain, which could not be explained by differences in the consumption of these elements with feed. The consumption of Q decreased the content of Mn, Cs, V, Ni, As in the liver in db/db mice and increased Cu and did not significantly affect the level of trace elements in the liver in animals C57Bl/6J. In kidneys of C57Bl/ 6J receiving Q, the content of As and Al increased. In brain of db/db mice, Q supplementation caused a decrease in the content of As, Pb, Cs and Se. In tetrahybrids DBCB, Q increased Pb levels in liver and brain and decreased in kidneys; increased the level of V in liver and brain; decreased As content in kidneys and increased in liver. Multiple correlations were noted between the organ content of elements in various valence forms, as well as between the content of trace elements and biochemical indicators of the intensity of catabolic and anabolic processes. Conclusion . Quercetin has an effect on the homeostasis of microelements, depending both on the animal genotype and on the diet, and not having unambiguous physiological significance. Indicators of the status of essential and toxic trace elements are recommended to be included in the protocols of preclinical trials of the efficacy and safety of minor biologically active food substances., Competing Interests: The authors declare no overt and potential conflict of interest related to the publication of this article., (Copyright© GEOTAR-Media Publishing Group.)

The maintenance of energy homeostasis of the body according to modern data is carried out with the active participation of dopaminergic neurons of the central nervous system. The synthesis and metabolism of dopamine (DA) occurs both in the brain and in peripheral tissues. Violation of the synthesis and metabolism of DA is considered as a link in the vicious cycle which it formed during the development of diet-induced obesity. According to modern data, a number of essential and toxic trace elements, such as Cd, Al, As, Mn, Fe, Cu, Zn, are actively involved in the exchange of DA in the brain and peripheral organs and tissues. One way to assess this relationship is to compare changes in the microelement status of the organism when consuming hypercaloric diets in animals with normal and impaired DA transport. The latter can be animals with a knockout of the DAT transporter gene, which performs DA reabsorption with subsequent storage in the composition of secretory granules. The aim is a comparative study of the content of a number of essential and toxic elements in the brain, liver, and kidneys of rats that differ in the allelic variants of the DAT gene fed balanced diet and the diet with an excess of energy value. Material and methods . The study was carried out on 30 male rats of the DAT-KO knockout line (homozygotes DAT-/- and heterozygotes DAT+/-), 8-10 weeks old, and 13 males rats of the outbred Wistar line (DAT+/+) of the same age. For 62 days the animals (6 groups) received a semi-synthetic diet containing essential elements in the salt mixture or a similar high-fat-highcarbohydrate diet (HFCD) with 30% fat and 20% fructose solution instead of drinking water. The content of 16 trace elements (Fe, Mg, Cu, Mn, Co, Se, Zn, Cr, V, Cs, Ag, Al, Cd, As, Pb, Ni) were determined by inductively coupled plasma mass spectrometry in the liver, kidneys, and brain of rats with a knockout of the dopamine DAT transporter gene: homozygotes (DAT -/-) and heterozygotes (DAT+/-), as well as wild-type rats (DAT+/+) of the Wistar strain. Results and discussion . In the liver, DAT knockout led to an increase in the content of As, Cd, Co, and Cs and a decrease in Fe; in the kidneys - to an increase in the levels of Pb, As, Cd and Se, in the brain - an increase in the content of most of the studied trace elements, including Pb, As, Cs, Al and Cu. Conclusion . Against the background of consumption of HFCD, the effect of DAT knockout on the content of a number of elements was more pronounced compared with the consumption of the control diet. The revealed changes in the trace element content in DAT knockout rats are considered in terms of the effect of DA metabolism in the central nervous system and in peripheral tissues on the status of trace elements., Competing Interests: The authors declare no overt and potential conflict of interest related to the publication of this article., (Copyright© GEOTAR-Media Publishing Group.)

Differential expression of 30,003 genes was studied in the liver of female Wistar rats fed with isocaloric diets with the excess of fat, fructose, or cholesterol, or their combinations for 62 days using the method of whole-transcriptome profiling on a microchip. Relative mRNA expression levels of the Asah2, Crot, Crtc2, Fmo3, GSTA2, LOC1009122026, LOC102551184, NpY, NqO1, Prom1, Retsat, RGD1305464, Tmem104, and Whsc1 genes were also determined by RT-qPCR. All the tested diets affected differently the key metabolic pathways (KEGGs). Significant changes in the expression of steroid metabolism gene were observed in the liver of animals fed with the tested diets (except the high-fat high fructose diet). Both high-fat and high-fructose diets caused a significant decrease in the expression of squalene synthase (FDFT1 gene) responsible for the initial stage of cholesterol synthesis. On the contrary, in animals fed with the high-cholesterol diet (0.5% cholesterol), expression of the FDFT1 gene did not differ from the control group; however, these animals were characterized by changes in the expression of glucose and glycogen synthesis genes, which could lead to the suppression of glycogen synthesis and gluconeogenesis. At the same time, this group demonstrated different liver tissue morphology in comparison with the animals fed with the high-fructose high-fat diet, manifested as the presence of lipid vacuoles of a smaller size in hepatocytes. The high-fructose and high-fructose high-fat diets affected the metabolic pathways associated with intracellular protein catabolism (endocytosis, phagocytosis, proteasomal degradation, protein processing in the endoplasmic reticulum), tight junctions and intercellular contacts, adhesion molecules, and intracellular RNA transport. Rats fed with the high-fructose high-fat or high-cholesterol diets demonstrated consistent changes in the expression of the Crot, Prom1, and RGD1305464 genes, which reflected a coordinated shift in the regulation of lipid and carbohydrate metabolisms.

The expression of JNK1 isoform of cJun-N-terminal kinase in hepatocytes of rats receiving excess of simple carbohydrates dissolved in drinking water was studied by immunohisto-chemical staining and confocal microscopy. In experiment I (60 days), the highest expression of JNK1 was observed in female Wistar rats receiving fructose (the difference with the group receiving a mixture of glucose and fructose was significant, p<0.05, the difference with the control group at the trend level, p=0.077; Mann-Whitney U test). In experiment II (120 days), an increase in JNK1 expression was observed in Wistar rats (males and females) receiving 30% fructose. In Dark Aguti rats (females and males) of comparable age, increased basal level of JNK1 expression was observed in comparison with Wistar rats. Three-way ANOVA showed that JNK1 expression was significantly (p<0.05) associated with consumption of fructose and animal line, but not sex. The level of JNK1 expression corresponded to previously identified changes in the biochemical markers of the metabolic syndrome.

The accumulation of lipofuscin-like granules in liver, kidneys, and spleen cells in mice and rats of different lines receiving 30% sugar solutions (fructose, glucose, their mixture, and sucrose) in addition to balanced semisynthetic diet for 62 or 122 days was studied by the method of laser scanning confocal microscopy. The granules were detected by their autofluorescence at maximum λ ex =570-600 nm and λ ex =488 nm. In the kidneys of rats receiving glucose and, especially, the mixture of glucose and fructose, significant accumulation of lipofuscin-like granules was found that was absent in the control group animals receiving water. Intensive accumulation of the granules was observed in the kidneys of all groups of mice receiving sugars (except for glucose). Lipofuscin-like granules were located in the cytoplasm of epithelial cells of the distal and proximal convoluted tubules. In the liver of rats and mice, the signs of accumulation of lipofuscin-like granules were absent or minimal. In rat spleen, lipofuscinlike granules were found in the red pulp in all groups, but their accumulation significantly increased in animals receiving the diet enriched with glucose and sucrose.

We compared anxiety, neuromotor, and cognitive functions in mutant rats with different allelic variants of dopamine transporter DAT knockout receiving balanced or excess in fat and fructose diet. The experiments were performed in DAT-/- homozygotes, DAT+/- heterozygotes, and DAT+/+ wild type rats. The genotype of DAT-KO rats was confirmed by restriction analysis of DAT gene compared to behavioral responses in the open field test (OF). Animals in the first groups of each strain were fed a balanced AIN93M diet; and those in the second groups with a high-fat/high-fructose diet. Neuromotor function was studied as grip strength, and behavioral responses were assessed in the elevated plus maze and conditioned passive avoidance response tests. The mass of the internal organs and white and brown fat, as well as selected lipid and nitrogen metabolism parameters in blood plasma were determined at the end of the experiment. DAT-/- had the highest specific grip strength, and showed an increase in initial exploratory activity in comparison with DAT+/- and DAT +/+. The exploratory activity was significantly reduced in the second test compared to the first one in DAT-/- and DAT+/- of first but not second group. Anxiety decreased with age in the second groups of DAT+/- and DAT+/+ (but not in DAT-/-) and was higher in DAT+/+ than in DAT+/- and DAT-/-. Excess fat and fructose resulted in the deterioration of short-term memory in DAT+/+. Lipidomic indices of blood plasma were less responsive to diet in DAT-/- and DAT-/+ in comparison to DAT+/+. The increased AsAT/AlAT activity ratio in DAT-/- compared with those in DAT+/+ suggests the activation of catabolism activity in the mutants. The consumption of excess fat and fructose significantly modified the effects produced by DAT gene allelic variants presumably due to the influence on the processes of dopamine metabolism., (© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Changes in plasma levels of the main groups of cytokines and adipokines may correlate with the severity of metabolic disorders in hyperlipidemia and obesity. The aim of the study was to assess the significance of ghrelin, leptin, their ratio (L/Gh), and the cytokine profile as biomarkers at dietary-induced hyperlipidemia. Material and methods . We used 48 female Wistar rats with an initial body weight of 123±1 g, which were divided into 6 groups. Group 1 (control) received a balanced semi-synthetic diet according to AIN93; group 2 - diet with excess fat (30% by weight); group 3 - a diet with the addition of 20% fructose solution instead of drinking water, group 4 - a diet with excess fat and fructose, group 5 - a diet with added cholesterol (0.5%), group 6 - a diet with cholesterol and fructose. On the 64th day of the experiment, the mass of internal organs was determined; the levels of cytokines and adipokines in blood plasma were measured by multiplex immunoassay. Results and discussion . A decrease in the level of leptin was found in group 5 compared with the control and with groups 2, 4 and 6 groups (p<0.05). The lowest level of ghrelin was found in group 2 (p<0.05) against the background of high concentrations of leptin. Significant correlations were found between L/Gh and the total mass of animals (r=0.321; р=0.034), the relative mass of adipose tissue (r=0.439; р=0.003) and with the relative mass of the spleen (r=-0.460; р=0.003). In group 2, at the maximum L/Gh ratio, a significantly higher weight of adipose tissue was found, whereas in groups 3 and 5, at the lowest L/Gh ratio, the relative amount of total fat was the lowest. L/Gh ratio correlated with the level of monocyte chemotactic protein-1 (MCP-1), RANTES, IL-18 and macrophage colony-stimulating factor (M-CSF). The concentrations of IL-17, IL-18, IL-4, IL-5, MIP-3a, IFN-γ, M-CSF and RANTES in the experimental groups were reduced compared with the control, with the most pronounced effect in group 5 together with the lowest L/Gh ratio. Conclusion . The presence of a significant correlation between L/Gh ratio and changes in the weight of rats' body, spleen, adipose tissue, as well as levels of cytokines involved in inflammation regulation, confirms the importance of L/Gh ratio as a biomarker in an in vivo model of dyslipidemia., Competing Interests: The authors declare no overt and potential conflict of interest related to the publication of this article., (Copyright© GEOTAR-Media Publishing Group.)

Quercetin (Q; 3,3',4',5,7-pentahydroxyflavone) is considered as a promising component of specialized products for the correction of metabolic disorders in obesity and metabolic syndrome. At the same time, the results of evaluating the clinical efficacy of Q are ambiguous, and the mechanisms of its influence on lipid and carbohydrate-energy metabolism are not well understood. The aim of the work was to study the effect of quercetin (Q 3,3',4',5,7-pentahydroxyflavone) on the expression of key glycolysis and lipogenesis enzymes' genes in Zucker-Leprfa (Z) rats characterized by hereditary obesity, compared to «wild-type» Wistar (W) rats. Material and methods . 24 male Z rats and 32 male W rats aged 8-10 weeks were used. Animals of each line were divided into 4 groups of equal numbers. For 62 days the animals of the first groups (controls) received a balanced diet according to AIN93M, the seconds - the same diet with Q added in a dose of 50 mg/kg body weight. Animals of the third groups received a high-fat, high-carbohydrate diet (HFCD) with fat 30% by weight and with the replacement of drinking water with a 20% solution of fructose, the fourths groups - the same diet and supplementation with Q. After removing animals from the experiment, expression levels of liver carbohydrate and lipid metabolism genes Khk, Gck, Pklr, Acaca, Fasn, Scd, Srebf1, Mlxipl, Ppara and Pparg were determined by real-time polymerase chain reaction (RT-PCR) with reverse transcription using Actb and Gapdh as reference genes. The levels of triglycerides, total and HDL cholesterol, lipolytic activity and immunoreactive leptin were determined in plasma. Results and discussion . When comparing two animal lines, a significantly higher level of expression of Ppara, Pparg, Mlxipl, Acaca, Fasn, Scd was shown in Z rats compared to W rats, which is consistent with the development of dyslipidemia in the first ones and elevated levels of leptin under both types of diets used. The addition of Q caused in W rats a decrease in the expression of Scd, Mlxipl, Khk and Gck, more pronounced on the background of HFCD whereas in Z rats there were no similar effects, or they had the opposite direction. In addition, in Z rats, consumption of Q led to increased expression of Pklr, which was not observed in W rats. Conclusion . The modulating effect of Q on the expression of key genes of lipid and carbohydrate metabolism enzymes significantly differs in wild-type W rats and mutant Z rats with hereditary obesity, and this difference appears to be potentiated by the consumption of excess fat and fructose., Competing Interests: The authors declare no overt and potential conflict of interest related to the publication of this article., (Copyright© GEOTAR-Media Publishing Group.)

Integral, biochemical, and morphological parameters and concentrations of vitamins, particularly lipid soluble vitamins, were analyzed in female mice of inbred DBA/2J line, outbred ICR-1 (CD-1) line, and DBCB tetrahybrid mice on the in vivo model of metabolic syndrome induced by consumption of 30% sucrose for 2 days. In contrast to inbred and outbred lines, DBCB tetrahybrid mice developed abdominal obesity, hypercholesterolemia, and pronounced morphological picture of fatty liver disease. The lipid-coupled transport of vitamin E to the liver is also enhanced in these animals, which compensated decreased supply of vitamin E to the liver under conditions of high-sugar ration. The observed interstrain differences can be related to genetic features of the used mouse lines and DBCB tetrahybrid mice and require further genomic, transcriptomic, proteomic, and morphological studies. The results of the study based on the in vivo model of metabolic syndrome allow identifying the key biomarkers for complex diagnostics and prognosis of metabolic syndrome complications, such as nonalcoholic steatosis of the liver.

We assessed the effect of intake of easily digested carbohydrates for 133 days on quantitative parameters of neuromotorics and cognitive function in Wistar rats and C57Bl/6J mice. Neuromotorics (muscle tone) was assessed in rats and mice by the forelimb muscle force (grip strength) over 4 months. Anxiety was assessed in the elevated plus-maze test and cognitive function (short-term and long-term memory) was evaluated by conditioned passive avoidance response (CPAR) test over 3 months. The mice, in contrast to rats, receiving the diet with easily digested sugars demonstrated suppression of neuromotorics. Anxiety increased with age in female mice, but not in rats, irrespective of the diet. Cognitive function in rats receiving experimental rations did not change significantly in comparison with the control. In mice, consumption of equimolar mixture of fructose and glucose impared short-term, but not long-term memory, in comparison with the group receiving glucose alone. We revealed a small (by 14-17%), but statistically significant increase in the brain weight in mice receiving fructose and sucrose. The study demonstrates sufficient interspecies differences in the influence of carbohydrate rations on neuromotorics and behavioral responses in the in vivo metabolic syndrome model.

Biochemical, vitamin, trace element and immunological changes were searched for the combined nutritional deficiency of vitamins B1, B2, B6 on in vivo models in rats and mice. Female rats of Wistar (W) strain and hybrids of the 1st generation of Dark Aguti and Wistar (DA x W) strains, female mice of BALB/c strain and DBCB tetrahybrids were used in experiment. Animals received for 35 days a balanced diet (control) according to AIN-93 or a similar diet with the exception of vitamins B1, B2, B6 (experimental groups). The content of vitamins B1, B2 in liver, riboflavin blood plasma level and urinary excretion of thiamine, riboflavin and 4-pyridoxic acid were determined, as well as in rats: blood and liver content of α-tocopherol and retinol, blood biochemical indices of lipid and nitrogen metabolism, activity of cytochrome P isoforms-450 (CYP) in liver; in mice: the circulating levels of pro- and anti-inflammatory cytokines of blood plasma, in animals of both species - the content of essential and toxic elements in the kidneys. DAxW rats compared to W and DBCB mice compared to BALB/c were more sensitive to the development of B-vitamin deficiency judging by the B-vitamin status indicators. In the rats of the experimental groups, there were signs of a deterioration in blood and liver levels of vitamin E, multidirectional shifts in vitamin A sufficiency, increased activity of the CYP3A isoform (6β-TG), a decrease in triglycerides, total protein and albumin fraction levels with an increase in urea level. Manifestation degree of these effects depended on the choice of the animal's line. In mice, the B-vitamin deficiency was characterized by an increase in the levels of proinflammatory cytokines TNF-α, IL-10, IL-Ιβ, IL-6 and a decrease in IFN-γ and IL-17A. The content of magnesium, copper, zinc, chromium and silver was lowered, of cesium - was increased in the kidneys of the rats of the experimental groups. In mice, B-vitamin deficiency resulted in diminishment of magnesium, copper, zinc, chromium, selenium, cadmium and lead content, excess accumulation of cobalt and cesium. Some of these biomarkers are supposed to be used in pre-clinical evaluation of the effectiveness of new vitamin complexes, specialized foods and dietary supplements, as well as studies of interactions of various vitamins., Competing Interests: The authors declare no overt and potential conflict of interest related to the publication of this article., (Copyright© GEOTAR-Media Publishing Group.)

Consumption of diets that are inadequate in energy value to the actual energy expenditure can lead to the development of metabolic syndrome (MS), which has consequences such as type 2 diabetes mellitus, non-alcoholic steatohepatosis, atherosclerosis, gout, allergic diseases. Experimental models of MS are needed to develop new approaches to its dietary and drug correction. The aim of the work was a comparative analysis of functional, biochemical and vitamin markers characterizing the effect of a diet with a high content of fructose (F) on males and females of various rat lines and the selection on this basis of an optimal in vivo MS model. Male and female rats of the outbred Wistar line (W) and the inbred Dark Agouti line (DA) were used in the work number of 16 individuals of each sex and line. The animals of the 1st (control) groups of each sex and line received a balanced semi-synthetic diet according to AIN93, and the animals of the 2nd (experimental) groups - the same diet and 30% solution of F instead of water in the regime of free access. Within 121 days, energy value of diets consumed, the increase in body weight and blood pressure were determined; relative mass of internal organs, biochemical parameters of blood plasma, content of fat-soluble vitamins A and E in blood plasma and liver were determined at withdrawal of animals from experiment. It was shown that, in spite of the increased energy value of the diet in the experimental groups throughout experiment, DA males and females practically did not respond to this by an increase in body weight gain, in contrast to W rats (in particular, females). Consumption of diets with F led to an increase in glucose level irrespective of gender and line, whereas triglyceride level (TG) significantly increased only in the case of W female. Addition of F caused in DA rats of both sexes an increase in the mass of the kidneys, as well as more pronounced, in comparison with W rats manifestation of markers of toxic effects on the liver (increases alanine aminotransferase and γ-glutamyltransferase activity, elevated urea and bilirubin level in blood plasma). In rats of both lines intake of F suppressed the accumulation of retinol palmitate in the liver in terms of its specific content. The total content of α-tocopherol in liver was significantly higher in W compared with DA. At the same time, α-tocopherol levels in blood plasma correlated with TG, and the α-tocopherol/TG ratio significantly decreased in female W receiving F, which were characterized by hyperlipidemia. Thus, the effect of F on W males and, in particular, females, basically corresponded to the classical picture of MS with body weight increasing, elevated blood pressure, glycemia and TG increase, whereas the toxic effect of F prevailed in DA liver and, possibly, kidneys without development of marked dyslipidemia and obesity., (Copyright© GEOTAR-Media Publishing Group.)

Behavioral indicators characterizing specific features of the pathological process of alimentary-dependent diseases were studied using in vivo model of alimentary hyperlipidemia in rats and mice. Rats and mice of the control groups received balanced semisynthetic diet for 63 days; animals of the experimental groups received a diet with high fat content (30% dry weight), balanced or high-fat diet with fructose solution instead of water, balanced cholesterol-enriched diet (0.5% dry weight), or balanced cholesterol-enriched diet with fructose solution. During the experiment, the mass of food, consumed by the animals, was monitored daily. Muscle tone was assessed by the front paw grip strength on days 33 and 54 of the experiment. Anxiety was tested in the elevated plus maze on days 36 and 57. Behavior and memory were assessed by conditioned passive avoidance reflex on days 39, 40, and 61. A significant increase in muscle tone was revealed on day 54 in rats fed with a balanced diet with fructose, and in mice, that received a similar diet, supplemented with fructose and cholesterol. Anxiety in the second test (day 57) was significantly decreased in rats fed high-fat diet and increased in mice fed high fat diet and high fat diet with fructose. In the second test, additional amount of cholesterol in the diet was the factor that significantly improved both short-term and long-term memory in both species. In mice, in contrast to rats, addition of fructose, including combination with high-fat diet, significantly worsened short-term and long-term memory. Thus, dietary factors, contributing to alimentary dyslipidemia development in rats and mice, can significantly affect the indices of neuromotor activity, anxiety level and cognitive functions, and the nature and direction of these changes are largely species-specific.

Metabolic syndrome (MS) is one of the leading causes of non-infectious pathology among the population of developed countries. It is necessary to have experimental in vivo models of MS for pre-clinical testing of new approaches to its dietary therapy. The purpose of the study was a comparative analysis of functional, biochemical and vitamin markers that characterize the effect of diets with different composition of simple carbohydrates (sugars) on female Wistar rats and female C57Black/6J mice. Animals of each species (n=80) were divided into 5 groups of equal numbers. The animals of the 1st (control) group received a balanced semi-synthetic diet, and the animals of groups from the 2nd to the 5th - the same diet and 30% solutions of sugars - glucose (Gl), fructose (Fr), equimolar mixture Gl and Fr and sucrose instead of water, in the regime of free access for up to 133 days. Measured values included blood pressure, mass of internals, biochemical parameters of blood plasma, the activity of CYP1A1, CYP1A2, CYP2B1, CYP3A and glutathione transferase (GT) in liver, glutathione peroxidase (GP) in erythrocytes, the content of vitamins A and E in blood plasma and in liver, the level of vitamins B 1 and B 2 and nicotinamide coenzymes in liver. Interspecific differences in the response to sugars manifested in a decrease in the solid diet consumption in mice (in contrast to rats), so that the total consumed energy value in experimental groups of mice did not differ systematically from control, and the weight gain was reduced. Liver was the most sensitive organ to addition of sugars in both rats and mice with mass significantly increasing by the 2nd and the 4th months of the experiment. Hyperglycemia and triglyceridemia were the most noticeable in rats receiving Fr. The concentration of phosphorus increased significantly in blood plasma of all rats groups that received sugars. In rats there was a decrease in the activity of CYP1A1 and CYP1A2 in groups 3 and 5, the activity of CYP2B1 in groups 2 and 5, the increase in HT activity in groups 2, 4 and 5, and GP in group 3 at 56th day of experiment. There was a significant decrease in this index in group 3 at the 56th and the 133rd days of the experiment, and in groups 4 and 5 - at the 56th day. Plasma tocopherol to triglycerides ratio decreased in rats of group 3 at the 56th and 133rd days, groups 4 и 5 - at 56th day, which indicated the decrease of vitamin E safety. Sugars consumption suppressed retinol palmitate accumulation in the liver of rats and mice, and alpha-tocopherol in mice. It was concluded that Fr had the greatest effect on the studied indicators of the organism, and the rats showed the most significant similarity with the clinical picture of MS., (Copyright© GEOTAR-Media Publishing Group.)

Rats and mice of different strains are used as a model of metabolic disturbances, caused by the consumption of diets with unbalanced content of macro-nutrients (fat, carbohydrate), as well as having elevated cholesterol quota. The aim of this study was to determine the magnitude and direction in change of vitamins status indices produced in rats and mice with experimental-mental hyperlipidemia, developing under consumption of high fat diet (HFD), fructose (Fr) and cholesterol (Cho). The experiment was conducted on 48 female growing Wistar rats with initial body weight 122±12 g, and 48 female growing C57Black/6 mice with initial body weight 18±1 g, which were divided into 12 groups of 8 animals per group. Within 63 days the rats and mice of the first (control) group received a balanced semi-synthetic (BD), 2nd groups - HFD with 30% of the total fat by weight of dry feed, 3rd groups - BD and Fr solution instead of water, 4th groups - HFD+Fr, 5th groups - BD supplemented with 0.5% Cho by weight of dry food, 6th groups - the same ration and Fr. After removal of animals from the experiment there were determined the content of vitamin A (retinol and retinol palmitate) and E (α-tocopherol) in blood plasma and liver by HPLC, 25-hydroxycholecalciferol [25(OH)D] in blood plasma by HPLC-MS, vitamins B 1 , B 2 and oxidized NAD coenzymes in liver by fluorimetric methods. Consumption of HFD resulted in marked increase in the concentration of vitamin A by 32% and by 45% in rat blood plasma and in the mice liver respectively, elevation of vitamin E level by 46% in the rat liver. Unlike rats, vitamin E in the liver of mice treated with HFD was lower by 32% compared with the control. Cho additive resulted in increased vitamin E accumulation in rat and mice liver (α-tocopherol level was 2.5 и 1.5 fold higher than in control respectively). Convincing evidence wasn't revealed of the impact of the additional Fr on vitamins A and E safety in rats and mice. Consumption of Fr on background of HFD in rats significantly reduced the level of 25(OH)D compared with HFD without Fr. Fr reception in combination with the addition of Cho significantly reduced stores of vitamin A and increased - of vitamin E in the liver of rats and mice. 25(OH)D level for this type of diet was significantly reduced. Cho consumption in rats significantly decreased the content of NAD+NADP in the liver by 12%; the introduction of fructose into the diet neutralized this impact. Feeding rats with HFD resulted in a significant improvement, and uptake of Cho in reduce of vitamin B 2 levels in the liver by 12.8 and 28%, respectively. Fr partially neutralized these effects. Thus, changes in the ratio of macronutrients and Cho in the diet of rats and mice may lead to a partially species-specific vitamin sufficiency variations, including in some cases the development of functional deficiency of vitamins А, B 2 , D and NAD coenzymes., (Copyright© GEOTAR-Media Publishing Group.)

Neurodevelopmental disorders (NDDs) are highly prevalent and severely debilitating brain illnesses caused by aberrant brain growth and development. Resulting in cognitive, social, motor, language and affective disabilities, common NDDs include autism spectrum disorder (ASD), intellectual disability, communication/speech disorders, motor/tic disorders and attention deficit hyperactivity disorder. Affecting neurogenesis, glia/neuronal proliferation and migration, synapse formation and myelination, aberrant neural development occurs over a substantial period of time. Genetic, epigenetic, and environmental factors play a key role in NDD pathogenesis. Animal models are an indispensable tool to study NDDs. Paralleling clinical findings, we comprehensively evaluate various preclinical tests and models which target key (social, cognitive, motor) neurobehavioral domains of ASD and other common NDDs. Covering both traditional (rodent) and alternative NDD models, we outline the emerging areas of research and emphasize how preclinical models play a key role in gaining translational and mechanistic insights into NDDs and their therapy., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: Neurodevelopmental disorders (NDDs) are common and severely debilitating. Their chronic nature and reliance on both genetic and environmental factors makes studying NDDs and their treatment a challenging task., Areas Covered: Herein, the authors discuss the neurobiological mechanisms of NDDs, and present recommendations on their translational research and therapy, outlined by the International Stress and Behavior Society. Various drugs currently prescribed to treat NDDs also represent a highly diverse group. Acting on various neurotransmitter and physiological systems, these drugs often lack specificity of action, and are commonly used to treat multiple other psychiatric conditions. There has also been relatively little progress in the development of novel medications to treat NDDs. Based on clinical, preclinical and translational models of NDDs, our recommendations cover a wide range of methodological approaches and conceptual strategies., Expert Opinion: To improve pharmacotherapy and drug discovery for NDDs, we need a stronger emphasis on targeting multiple endophenotypes, a better dissection of genetic/epigenetic factors or "hidden heritability," and a careful consideration of potential developmental/trophic roles of brain neurotransmitters. The validity of animal NDD models can be improved through discovery of novel (behavioral, physiological and neuroimaging) biomarkers, applying proper environmental enrichment, widening the spectrum of model organisms, targeting developmental trajectories of NDD-related behaviors and comorbid conditions beyond traditional NDDs. While these recommendations cannot be addressed all in once, our increased understanding of NDD pathobiology may trigger innovative cross-disciplinary research expanding beyond traditional methods and concepts.

In vivo simulation of lipid disorders (hyperlipidemia, obesity, metabolic syndrome, atherosclerosis) is of considerable interest to search for genomic, transcriptomic and metabolomic markers that allow for differential diagnosis, prognosis and selection of personalized diet therapy in patients with such pathology. The aim of the study was the development and characterization of basic biochemical parameters of in vivo models of alimentary hyperlipidemia in outbred rats and inbred mice. The experiment was con­ducted on 48 growing female Wistar rats, and 48 growing female mice of line C57Black/6, which were divided into 12 groups of 8 animals per group. Within 63 days the rats and mice of first (control) group received a balanced semi synthetic diet (BD), the animals of the second groups - high-fat diet (HFD) with 30% of the total fat by weight of dry feed, third groups - BD and fructose solution (Fr) instead of water, the fourth groups -HFD + Fr, fifth groups - BD supplemented with 0.5% cholesterol (Cho) by weight of dry feed, sixth groups - BD with Cho and Fr. The amount and composition of diets consumed were corrected during the experiment for their closest approach in calories. After removal of animals from the experiment there were determined the mass of internal organs, HDL, LDL, total cholesterol, triglycerides, glucose in blood plasma, total lipids and their fatty acid composition in liver, ghrelin, GIP, GLP-1, glucagon, leptin, PAI-1, resistin levels in blood plasma. It was found that in both species the liver is the most sensitive to nutritional imbalance, nutrient exerting the greatest impact on this was Fr. In rats, as compared to mice, there was significantly more pronounced shifts in lipoprotein spectrum in response to nutritional imbalances, especially to the consumption of additional Cho, which was manifested in an increase of LDL, decrease of HDL and magnification of atherogenic index. In the liver of rats fed diets with Cho, marked steatosis developed manifested in a disproportionate increase in the lipid content and accompanied by changes in their fatty acid composition, especially in the ratio ω6 to ω3 PUFAs. Changing of hormones - regula­tors of carbohydrate metabolism (GLP, glucagon) and ghrelin was significantly greater in mice than in rats as a result of consumption of additional Fr. Effect had the opposite direction in two species of Cho and Fr combining on leptin levels. The significance is dis­cussed of the revealed interspecies differences in the light of the characteristics of lipid and glucose metabolism in these two lines of animals that are the most common models of alimentary-dependent diseases.