Metabolic Circumstances Research Articles

Оцінка впливу феруму, цинку і селену на перебіг метаболічних процесів при вірусних захворюваннях

The deficiency of macro- and microelements and the disturbance of their balance are widely recognized issues in healthcare, with poor nutrition exacerbating disruptions in metabolic processes at both the cellular and organismal levels. All these metabolic circumstances and disruptions in metabolic processes contribute to the development of various pathological conditions, including viral infections. Macro- and microelements play a crucial role in many metabolic processes that affect the course of infectious diseases. These processes include oxidative phosphorylation, which is altered in patients with systemic inflammation and protection against mediators, including oxidants. Microelements are necessary for direct antioxidant activity and also function as cofactors for various antioxidant enzymes. Immune function also depends on an adequate level of vitamins and microelements. It can be enhanced by restoring microelement deficiencies to recommended levels, thereby increasing resistance to infection and promoting faster recovery after infection. Balanced nutrition alone is insufficient, hence the need for the supplementation of microelements tailored to specific age-related requirements. In this article, we explore the importance of the optimal balance of individual macro- and microelements for effectively combating viral infections.

The Importance of Intra-Islet Communication in the Function and Plasticity of the Islets of Langerhans during Health and Diabetes.

Islets of Langerhans are anatomically dispersed within the pancreas and exhibit regulatory coordination between islets in response to nutritional and inflammatory stimuli. However, within individual islets, there is also multi-faceted coordination of function between individual beta-cells, and between beta-cells and other endocrine and vascular cell types. This is mediated partly through circulatory feedback of the major secreted hormones, insulin and glucagon, but also by autocrine and paracrine actions within the islet by a range of other secreted products, including somatostatin, urocortin 3, serotonin, glucagon-like peptide-1, acetylcholine, and ghrelin. Their availability can be modulated within the islet by pericyte-mediated regulation of microvascular blood flow. Within the islet, both endocrine progenitor cells and the ability of endocrine cells to trans-differentiate between phenotypes can alter endocrine cell mass to adapt to changed metabolic circumstances, regulated by the within-islet trophic environment. Optimal islet function is precariously balanced due to the high metabolic rate required by beta-cells to synthesize and secrete insulin, and they are susceptible to oxidative and endoplasmic reticular stress in the face of high metabolic demand. Resulting changes in paracrine dynamics within the islets can contribute to the emergence of Types 1, 2 and gestational diabetes.

Viral hepatocellular carcinoma and the potential involvement of mitochondrial DNA

Mito-Nuclear organelles are cellular organelles that regulate metabolic balance and ATP production, but they also play a crucial role in other processes, such as cell death after immunological signaling. Mitochondria set a limit on metabolites in order to create a hope object among the mitochondria. itself, however, operate as signaling molecules in response to ignoble components in terms of the prison cell While the discovery of the genetic mannequin explains susceptibility and risk, it is followed by the identification of the genetic mannequin. Despite the fact that disease has been studied for decades, no clear model has emerged as a result of it. elucidate the genetic basis as a result of advancements in polygenic/complex ailment The mitochondrial coalition of conformance with the kernel by course on metabolites generated by means of mitochondrial ability provides cells with a potential regulatory regimen above in the hope of conformity. comprising a response that changes with changing metabolic circumstances Nonetheless, the preliminary data is encouraging. impregnate as a result of tribunal after bed examinations are likely to find a clearer feature into hepatic therapies. In that review, we aspire to appear in-depth at 1 Above mitochondria, there are a variety of interactions. includes hepatitis unfavorable infection or inside result with heightened consequences due Appreciation of pathogenesis or the development of medicine

Fatty Pancreas: Linking Pancreas Pathophysiology to Nonalcoholic Fatty Liver Disease.

Currently, scientific interest has focused on fat accumulation outside of subcutaneous adipose tissue. As various imaging modalities are available to quantify fat accumulation in particular organs, fatty pancreas has become an important area of research over the last decade. The pancreas has an essential role in regulating glucose metabolism and insulin secretion by responding to changes in nutrients under various metabolic circumstances. Mounting evidence has revealed that fatty pancreas is linked to impaired β-cell function and affects insulin secretion with metabolic consequences of impaired glucose metabolism, type 2 diabetes, and metabolic syndrome. It has been shown that there is a connection between fatty pancreas and the presence and severity of nonalcoholic fatty liver disease (NAFLD), which has become the predominant cause of chronic liver disease worldwide. Therefore, it is necessary to better understand the pathogenic mechanisms of fat accumulation in the pancreas and its relationship with NAFLD. This review summarizes the epidemiology, diagnosis, risk factors, and metabolic consequences of fatty pancreas and discusses its pathophysiology links to NAFLD.

Cu/Zn-superoxide dismutase and wild-type like fALS SOD1 mutants produce cytotoxic quantities of H2O2 via cysteine-dependent redox short-circuit

The Cu/Zn−superoxide dismutase (SOD1) is a ubiquitous enzyme that catalyzes the dismutation of superoxide radicals to oxygen and hydrogen peroxide. In addition to this principal reaction, the enzyme is known to catalyze, with various efficiencies, several redox side-reactions using alternative substrates, including biological thiols, all involving the catalytic copper in the enzyme’s active-site, which is relatively surface exposed. The accessibility and reactivity of the catalytic copper is known to increase upon SOD1 misfolding, structural alterations caused by a mutation or environmental stresses. These competing side-reactions can lead to the formation of particularly toxic ROS, which have been proposed to contribute to oxidative damage in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease that affects motor neurons. Here, we demonstrated that metal-saturated SOD1WT (holo-SOD1WT) and a familial ALS (fALS) catalytically active SOD1 mutant, SOD1G93A, are capable, under defined metabolic circumstances, to generate cytotoxic quantities of H2O2 through cysteine (CSH)/glutathione (GSH) redox short-circuit. Such activity may drain GSH stores, therefore discharging cellular antioxidant potential. By analyzing the distribution of thiol compounds throughout the CNS, the location of potential hot-spots of ROS production can be deduced. These hot-spots may constitute the origin of oxidative damage to neurons in ALS.

Ghrelin regulation of glucose metabolism.

Ghrelin and its receptor, the growth hormone secretagogue receptor 1a (GHSR1a), are implicated in the regulation of glucose metabolism via direct actions in the pancreatic islet, as well as peripheral insulin-sensitive tissues and the brain. Although many studies have explored the role of ghrelin in glucose tolerance and insulin secretion, a complete mechanistic understanding remains to be clarified. This review highlights the local expression and function of ghrelin and GHSR1a in pancreatic islets and how this axis may modulate insulin secretion from pancreatic β-cells. Additionally, we discuss the effect of ghrelin on in vivo glucose metabolism in rodents and humans, as well as the metabolic circumstances under which the action of ghrelin may predominate.

Boron: the essential element for vascular plants that never was.

Although a requirement for boron is a well-established feature of vascular plants, its designation, for almost a century, as essential is challenged and, instead, the proposal is made that it has never been so as conventionally defined. This is because an alternative interpretation of published evidence negates its compliance with one of the criteria for essentiality, that its effects are direct. The alternative, here postulated, is that boron is, and always has been, potentially toxic, a feature which, for normal growth, development and reproduction, needed to be nullified. This was enabled by exploitation of boron's ability to be chemically bound to compounds with cis-hydroxyl groups. Although particular cell wall carbohydrate polymers, glycoproteins and membrane glycolipids are among candidates for this role, it is here proposed that soluble phenolic metabolites of, or related to, the components of the pathway of lignin biosynthesis, themselves potentially toxic, are primarily used by vascular plants. When metabolic circumstances allow these phenolics to accumulate endogenously in the cytoplasm, their own inherent toxicity is also alleviated, partially at least, by formation of complexes with boron. This chemical reciprocity, enhanced by physical sequestration of the complexes in vacuoles and/or apoplast, thus achieves, in a flexible but indirect manner, a minimization of the inherent toxicities of both boron and relevant phenolics. In these ways, the multifarious outcomes of impairments, natural or experimental, to this interplay are responsible for the lackof consensus to explain the diverse effects observed in the manysearches for boron's primary metabolic role, here considered to be nonexistent. In particular, since a toxic element cannot have'deficiency symptoms', those previously so-called are postulated to be largely due to the expressed toxicity of phenylpropanoids. A principal requirement for the otherwise toxic boronis to nullify, by means of its indirect chemical and physicalsequestration, such expression. In these ways, it is therefore neither an essential nor a beneficial element as currently strictly defined.

Natural Killer Cell Activity and Interleukin-12 in Metabolically Healthy versus Metabolically Unhealthy Overweight Individuals.

The purpose of this study was to determine whether the immune system is involved in the different metabolic circumstances in healthy and unhealthy overweight individuals. We examined the metabolic and immune characteristics of 117 overweight individuals. Subjects were classified as metabolically healthy overweight (MHO, n = 72) or metabolically unhealthy overweight (MUO, n = 45). The immune response was measured by circulating levels of natural killer (NK) cell activity and cytokines. Both groups were comparable with regards to age, sex distribution, smoking and drinking status, and body mass index. When compared to the MHO group, the MUO group showed higher systolic and diastolic blood pressure, serum levels of triglyceride, glucose, glucose-related markers, and lower levels of HDL cholesterol. Compared to the MHO group, the MUO group showed 39% lower interferon-γ levels (not significant) and 41% lower interleukin (IL)-12 levels (significant). The MUO group also showed lower NK cell activity at E:T ratios of 10:1, 5:1, 2.5:1, and 1.25:1 (all Ps < 0.05) than the MHO group. This study indicates that individuals displaying the MUO phenotype present an unfavorable immune system with lower NK cell activities under all assay conditions and lower serum levels of IL-12 than the activities and levels in similarly overweight MHO individuals. This result suggests that the immune system may be altered in overweight individuals who are at risk for overweight/obesity-related comorbidities.

Influence of vitamin intake and MTHFR polymorphism on the levels of DNA damage in tobacco farmers.

Genetic damage may occur spontaneously under normal metabolic circumstances, inadequate intake of nutrients, and excessive exposure to environmental mutagens. To evaluate the influence of the intake of micronutrients vitamin B12, vitamin B6, and folate and of the polymorphism methylenetetrahydrofolate reductase (MTHFR) C677T on the induction of DNA damage in tobacco farmers. The study involved 66 men and 44 women engaged in tobacco cultivation in the region of Venâncio Aires (Rio Grande do Sul state, Brazil). Peripheral blood samples were collected to analyze DNA damage using the Comet assay, the micronucleus (MN) test and MTHFR C677T polymorphism. Dietary intake was evaluated based on the mean values obtained from three 24-h diet recall questionnaires, and nutrient intake data were computerized and estimated in the Food Processor SQL 10.9 program. The statistical tests used to generate the stated results were Kruskal-Wallis test, Exact Fisher's test, and multivariate linear regression analysis. DNA damage was significantly higher in individuals who had an inadequate intake of folate, vitamin B12, and vitamin B6 (P<0.01) assessed by Comet assay. In relation to MN test results, buccal cells showed MN frequency higher in individuals with inadequate intake of vitamin B6 (P<0.01). No difference was observed in MN lymphocytes frequency. No significant association was detected between MTHFR C677T polymorphism and DNA damage in tobacco farmers. Our results suggest that folate, vitamin B12, and vitamin B6 deficiency may be associated with genotoxic effect in individuals exposed to pesticides.

(727) - The Impact of Perfusate Oxygenation During Ex Vivo Lung Perfusion on Post-transplant Outcomes: Deoxygenated vs. Fully-Oxygenated

Purpose: The metabolic circumstances in lung grafts on ex vivo lung perfu- sion (EVLP) are compromised as compared with those in lungs in vivo as described in previous studies. While the current EVLP protocol suggests using deoxygenated perfusate with acellular solution, little evidence supports that is the optimal condition. This study aimed to evaluate the quality of lung grafts in the different modes of oxygenated perfusate during EVLP and to define their impact on posttransplant functional outcomes. Methods: Using rat heart-lung blocks after 1 hr cold preservation, the EVLP sys- tem was established with Steen solution at 37°C for 4 hrs. We compared the results of four different modes of perfusate O2 during EVLP: 6%, 40%, 60% and 100%. The evaluation included lung graft function, compliance (Cdyn), and vascular resistance (PVR) as well as circulating glucose, lactate levels and other biochemi-

The second coming of epigenetic drugs: a more strategic and broader research framework could boost the development of new drugs to modify epigenetic factors and gene expression.

The second coming of epigenetic drugs: a more strategic and broader research framework could boost the development of new drugs to modify epigenetic factors and gene expression.

HDL and Cardiovascular Risk

High-density lipoprotein cholesterol (HDL-C) has been dubbed the good cholesterol because it is thought to reflect the ability of HDL particles to remove excess cholesterol molecules from peripheral cells (including those in atherosclerotic plaques) for return to the liver. Not surprisingly, then, HDL-C has frequently been assumed to be a biomarker of HDL function, consistent with the inverse relationship in observational studies between plasma levels of HDL-C and risk of coronary artery disease. Recently, Voight et al have challenged this assumption by showing that genetically elevated HDL-C did not protect against myocardial infarction. This finding has fueled a lively discussion in the lay, scientific, and medical press about the relationship between HDL-C and HDL function, and the potential effectiveness of various HDL-C raising strategies.

Protective effect of lutein against benzo(a)pyrene-induced oxidative stress in human erythrocytes

The present study was carried out to evaluate the in vitro antioxidant properties and protective effect of lutein in human erythrocyte against benzo(a)pyrene (B(a)P). It is a well-known environmental carcinogen that produces free radicals under normal metabolic circumstances. B(a)P reacts with cellular macromolecules and produces oxidation of protein, lipid and DNA. Lutein is a carotenoid possessing antioxidant, anticarcinogenic and anti-inflammatory properties. In the present investigation, the protective effect of lutein was assessed in vitro against B(a)P-induced oxidative stress by monitoring antioxidant enzymes, lipid peroxidation (LPO), protein carbonyl content, total sulfhydryl (SH) and nonprotein SH groups and methemoglobin in five groups of erythrocytes that include (i) control group, (ii) vehicle control group, (iii) B(a)P-exposed group, (iv) lutein-exposed group and (v) B(a)P coincubation with lutein group. It was observed that the activities of antioxidant enzymes and SH groups were significantly decreased in B(a)P-treated group when compared with control group. LPO level and protein carbonyl and methemoglobin contents were increased in B(a)P-treated group when compared with control group. The erythrocyte that was coincubated with B(a)P and lutein showed significant increase in the antioxidant enzyme activities and a significant reduction in the level of LPO, methemoglobin and protein carbonyl contents when compared with B(a)P-treated group. The results of the present investigation suggest that lutein possess protective effect against B(a)P-induced oxidative stress, possibly by combating oxidative stress by its free radical scavenging activity.

Exogenous ornithine is an effective precursor and the δ-ornithine amino transferase pathway contributes to proline accumulation under high N recycling in salt-stressed cashew leaves

The role of the δ-ornithine amino transferase (OAT) pathway in proline synthesis is still controversial and was assessed in leaves of cashew plants subjected to salinity. The activities of enzymes and the concentrations of metabolites involved in proline synthesis were examined in parallel with the capacity of exogenous ornithine and glutamate to induce proline accumulation. Proline accumulation was best correlated with OAT activity, which increased 4-fold and was paralleled by NADH oxidation coupled to the activities of OAT and Δ 1-pyrroline-5-carboxylate reductase (P5CR), demonstrating the potential of proline synthesis via OAT/P5C. Overall, the activities of GS, GOGAT and aminating GDH remained practically unchanged under salinity. The activity of P5CR did not respond to NaCl whereas Δ 1-pyrroline-5-carboxylate dehydrogenase was sharply repressed by salinity. We suggest that if the export of P5C from the mitochondria to the cytosol is possible, its subsequent conversion to proline by P5CR may be important. In a time-course experiment, proline accumulation was associated with disturbances in amino acid metabolism as indicated by large increases in the concentrations of ammonia, free amino acids, glutamine, arginine and ornithine. Conversely, glutamate concentrations increased moderately and only within the first 24 h. Exogenous feeding of ornithine as a precursor was very effective in inducing proline accumulation in intact plants and leaf discs, in which proline concentrations were several times higher than glutamate-fed or salt-treated plants. Our data suggest that proline accumulation might be a consequence of salt-induced increase in N recycling, resulting in increased levels of ornithine and other metabolites involved with proline synthesis and OAT activity. Under these metabolic circumstances the OAT pathway might contribute significantly to proline accumulation in salt-stressed cashew leaves.

Autophagy as a target for anticancer therapy.

Autophagy is an important homeostatic cellular recycling mechanism responsible for degrading unnecessary or dysfunctional cellular organelles and proteins in all living cells. Autophagy is particularly active during metabolic stress. In the cancer cell it fulfils a dual role, having tumor-promoting and tumor-suppressing properties. Functional autophagy prevents necrosis and inflammation, which can lead to genetic instability. On the other hand, autophagy might be important for tumor progression by providing energy through its recycling mechanism during unfavorable metabolic circumstances. A central checkpoint that negatively regulates autophagy is mTOR, and anticancer drugs inhibiting the PI3K/Akt/mTOR axis putatively stimulate autophagy. However, whether autophagy contributes to the antitumor effect of these drugs or to drug resistance is largely unknown. The antimalarial drugs chloroquine and hydroxychloroquine inhibit autophagy, leading to increased cytotoxicity in combination with several anticancer drugs in preclinical models. The therapeutic clinical roles of autophagy induction and inhibition remain to be defined. To improve our understanding of autophagy in human cancers new methods for measuring autophagy in clinical samples need to be developed. This Review delineates the possible role of autophagy as a novel target for anticancer therapy.

Erythrocyte glutathione concentration and production during hyperinsulinemia, hyperglycemia, and endotoxemia in healthy humans

In diabetes mellitus and sepsis, low erythrocyte glutathione (GSH) concentrations are found. Whether this is caused by lowered GSH production has not been clarified. To obtain insight in the relationship between erythrocyte GSH concentrations and GSH production, GSH kinetics were measured in healthy male volunteers during 4 different clamps (low-dose or medium-dose insulin [100 or 400 pmol/L] and euglycemia or hyperglycemia [5 or 12 mmol/L]) in a control setting (n = 6; all 4 clamps in the same subject) or after systemic administration of lipopolysaccharide (to mimic sepsis) (4 groups of n = 6; each clamp in a different subject). Hyperinsulinemia decreased erythrocyte GSH concentration (P = .042), but did not affect fractional synthetic rate (FSR) of GSH. Hyperglycemia did not affect erythrocyte GSH concentration, but decreased FSR of GSH (P = .025). Lipopolysaccharide decreased erythrocyte GSH concentration (P < .001), but increased FSR of erythrocyte GSH (P = .035). Depending on the metabolic circumstances, we found either stable GSH concentrations with lower production rates or decreased levels with either no change or an increase in production rate. Based upon these data, it seems inappropriate to infer conclusions about changes in synthesis rate of GSH from changes in its concentration.

Type 2 diabetes in children and adolescents

Arlen L. Rosenblooma, Janet H. Silversteinb, Shin Amemiyac, Phil Zeitlerd and Georgeanna J Klingensmithe abDivision of Endocrinology, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA; cDivision of Endocrinology, Department of Pediatrics, Saitama Medical University, Saitama, Japan; dDivision of Endocrinology, Department of Pediatrics, The Children’s Hospital, University of Colorado Denver, Aurora, CO, USA; eDepartment of Pediatrics, The Children’s Hospital and Barbara Davis Center, University of Colorado Denver, Aurora, CO, USA. Corresponding author: Professor Emeritus Arlen L Rosenbloom Division of Endocrinology Department of Pediatrics, University of Florida College of Medicine, 1701 SW 16th Avenue Gainesville, FL 32608 USA. e-mail: rosenal@peds.ufl.edu

Therapeutic Targeting of HDL and Reverse Cholesterol Transport

Reverse cholesterol transport (RCT) is one pathway for removing excessive cholesterol from extrahepatic cells and tissues and eventual transport to the liver for excretion thus reducing the accumulation of cholesterol in arteries. Activity of RCT is believed to be affected at least partially by the high density lipoprotein (HDL) concentration in the blood, since HDL is the major carrier of cellular cholesterol through RCT. This presumption lead to an assertion that raising HDL-C levels alone would improve RCT and provide enhanced protection against development of atherosclerosis. However, studies on RCT show that the concentration of HDL required for maximum recruitment of cellular cholesterol is far below the concentration of HDL in plasma. A more likely explanation is that the rate of RCT and the HDL concentration, which is partially determined by RCT, protect against atherosclerosis independently of each other. RCT may result in formation of dysfunctional HDL and a high level of HDL-C is not always synonymous with an efficient RCT. RCT consists of three major stages: cholesterol efflux, transport of cholesterol through the plasma compartment and uptake and excretion of cholesterol by liver. Each stage is a muti-step pathway or a combination of parallel pathways. The contribution and overall efficiency of these pathways often depends on specific metabolic circumstances. Finding the determinants of RCT would be valuable for choosing targets and evaluating the efficiency of possible therapy aimed at boosting RCT, raising HDL and enhancing protection against atherosclerosis.

Usage of an intronic promoter for stable gene expression in Saccharomyces cerevisiae

To construct expression vectors capable of switching promoters under different metabolic circumstances to obtain stable gene expression. In this study, we designed a series of constructs for the expression of the chicken lactate dehydrogenase (cldh) gene under the control of galactose-inducible GAL1 promoter and the high glucose-inducible HXT1 promoter in Saccharomyces cerevisiae. In one construct, the HXT1 promoter was placed between artificial splicing sequences to function as an intronic promoter. We checked all constructs for the usage of promoters by reverse transcriptional polymerase chain reaction and assayed the expression level of the reporter gene under different culturing conditions. In the presence of galactose, when the GAL1 promoter was linked with the intronic HXT1 promoter, the cldh gene showed 1.5-fold activity compared with single GAL1 promoter, while in the presence of glucose, the construct showed over twofold activity compared with that without splicing sequences. The intronic HXT1 promoter could be induced by the presence of high glucose concentration. This is the first report detailing the use of an intronic promoter in the construction of stable expression vectors and the novel system could serve as a model of expression vectors for fermentation or other purposes.

Transcriptional regulation of the gene encoding an alcohol dehydrogenase in the archaeon Sulfolobus solfataricus involves multiple factors and control elements.

A transcriptionally active region has been identified in the 5' flanking region of the alcohol dehydrogenase gene of the crenarchaeon Sulfolobus solfataricus through the evaluation of the activity of putative transcriptional regulators and the role of the region upstream of the gene under specific metabolic circumstances. Electrophoretic mobility shift assays with crude extracts revealed protein complexes that most likely contain TATA box-associated factors. When the TATA element was deleted from the region, binding sites for both DNA binding proteins, such as the small chromatin structure-modeling Sso7d and Sso10b (Alba), and transcription factors, such as the repressor Lrs14, were revealed. To understand the molecular mechanisms underlying the substrate-induced expression of the adh gene, the promoter was analyzed for the presence of cis-acting elements recognized by specific transcription factors upon exposure of the cell to benzaldehyde. Progressive dissection of the identified promoter region restricted the analysis to a minimal responsive element (PAL) located immediately upstream of the transcription factor B-responsive element-TATA element, resembling typical bacterial regulatory sequences. A benzaldehyde-activated transcription factor (Bald) that specifically binds to the PAL cis-acting element was also identified. This protein was purified from heparin-fractionated extracts of benzaldehyde-induced cells and was shown to have a molecular mass of approximately 16 kDa. The correlation between S. solfataricus adh gene activation and benzaldehyde-inducible occupation of a specific DNA sequence in its promoter suggests that a molecular signaling mechanism is responsible for the switch of the aromatic aldehyde metabolism as a response to environmental changes.