Association of the dopamine D2 receptor rs1800497 polymorphism with food addiction, food reinforcement, and eating behavior in Chilean adults.

PURPOSE: The regulation of food intake and body weight involves two interacting systems: (a) The homeostatic system (including biological regulators of hunger and satiety) and (b) the non-homeostatic system, (involving concepts of food reinforcement and food addiction). Studies have established a strong genetic component in eating behavior and obesity. The TaqI A1 polymorphism (rs1800497) has previously been associated with eating behavior, diminished dopamine D2 receptor (DRD2) density, higher body mass, and food reinforcement, but relations to food addiction remain unclear. AIM: To evaluate the association between the polymorphism rs1800497 with eating behavior, food reinforcement and food addiction in Chilean adults. METHODS: This cross-sectional study recruited a convenience sample of 97 obese, 25 overweight and 99 normal-weight adults (18-35 years). Anthropometric measurements were performed by standard procedures. Eating behavior was assessed using the: Yale Food Addiction Scale (YFAS), the Three Factor Eating Behavior Questionnaire and the Food Reinforcement Value Questionnaire (FRVQ). The DRD2 genotype (rs1800497) was determined by taqman assays. RESULTS: Twenty-two percentage of the participants met the criteria for food addiction. Food addiction was higher in women than men (26% vs 10.7%) and in obese compared to non-obese (40% vs 6%). There was no relationship between food addiction and DRD2 genotype. However when stratified by sex and nutritional status, obese female carriers of the A1 allele reported greater scores on emotional eating and snack food reinforcement compared to non-carriers. CONCLUSIONS: The DRD2 polymorphism is associated with some hedonic aspects of eating behavior, namely food reinforcement and emotional eating but not food addiction, and this association may be moderated by sex and obesity status, with obese women who are carriers of this genetic variant at higher risk. LEVEL OF EVIDENCE: Level V: evidence obtained from a cross-sectional descriptive study.

HIF1α-dependent metabolic reprogramming governs mesenchymal stem/stromal cell immunoregulatory functions.

Hypoxia-inducible factor 1 α (HIF1α), a regulator of metabolic change, is required for the survival and differentiation potential of mesenchymal stem/stromal cells (MSC). Its role in MSC immunoregulatory activity, however, has not been completely elucidated. In the present study, we evaluate the role of HIF1α on MSC immunosuppressive potential. We show that HIF1α silencing in MSC decreases their inhibitory potential on Th1 and Th17 cell generation and limits their capacity to generate regulatory T cells. This reduced immunosuppressive potential of MSC is associated with a metabolic switch from glycolysis to OXPHOS and a reduced capacity to express or produce some immunosuppressive mediators including Intercellular Adhesion Molecule (ICAM), IL-6, and nitric oxide (NO). Moreover, using the Delayed-Type Hypersensitivity murine model (DTH), we confirm, in vivo, the critical role of HIF1α on MSC immunosuppressive effect. Indeed, we show that HIF1α silencing impairs MSC capacity to reduce inflammation and inhibit the generation of pro-inflammatory T cells. This study reveals the pivotal role of HIF1α on MSC immunosuppressive activity through the regulation of their metabolic status and identifies HIF1α as a novel mediator of MSC immunotherapeutic potential.

The role of tanycytes in hypothalamic glucosensing.

Tanycytes are elongated hypothalamic glial cells that cover the basal walls of the third ventricle; their apical regions contact the cerebrospinal fluid (CSF), and their processes reach hypothalamic neuronal nuclei that control the energy status of an organism. These nuclei maintain the balance between energy expenditure and intake, integrating several peripheral signals and triggering cellular responses that modify the feeding behaviour and peripheral glucose homeostasis. One of the most important and well-studied signals that control this process is glucose; however, the mechanism by which this molecule is sensed remains unknown. We along with others have proposed that tanycytes play a key role in this process, transducing changes in CSF glucose concentration to the neurons that control energy status. Recent studies have demonstrated the expression and function of monocarboxylate transporters and canonical pancreatic ß cell glucose sensing molecules, including glucose transporter 2 and glucokinase, in tanycytes. These and other data, which will be discussed in this review, suggest that hypothalamic glucosensing is mediated through a metabolic interaction between tanycytes and neurons through lactate. This article will summarize the recent evidence that supports the importance of tanycytes in hypothalamic glucosensing, and discuss the possible mechanisms involved in this process. Finally, it is important to highlight that a detailed analysis of this mechanism could represent an opportunity to understand the evolution of associated pathologies, including diabetes and obesity, and identify new candidates for therapeutic intervention.

The oxidized form of vitamin C, dehydroascorbic acid, regulates neuronal energy metabolism.

Vitamin C is an essential factor for neuronal function and survival, existing in two redox states, ascorbic acid (AA), and its oxidized form, dehydroascorbic acid (DHA). Here, we show uptake of both AA and DHA by primary cultures of rat brain cortical neurons. Moreover, we show that most intracellular AA was rapidly oxidized to DHA. Intracellular DHA induced a rapid and dramatic decrease in reduced glutathione that was immediately followed by a spontaneous recovery. This transient decrease in glutathione oxidation was preceded by an increase in the rate of glucose oxidation through the pentose phosphate pathway (PPP), and a concomitant decrease in glucose oxidation through glycolysis. DHA stimulated the activity of glucose-6-phosphate dehydrogenase, the rate-limiting enzyme of the PPP. Furthermore, we found that DHA stimulated the rate of lactate uptake by neurons in a time- and dose-dependent manner. Thus, DHA is a novel modulator of neuronal energy metabolism by facilitating the utilization of glucose through the PPP for antioxidant purposes.

Regulatory T cells administration reduces anxiety-like behavior in mice submitted to chronic restraint stress.

Background: Major depression disorder (MDD) and anxiety are common mental disorders that significantly affect the quality of life of those who suffer from them, altering the person's normal functioning. From the biological perspective, the most classical hypothesis explaining their occurrence relies on neurotransmission and hippocampal excitability alterations. However, around 30% of MDD patients do not respond to medication targeting these processes. Over the last decade, the involvement of inflammatory responses in depression and anxiety pathogenesis has been strongly acknowledged, opening the possibility of tackling these disorders from an immunological point of view. In this context, regulatory T cells (Treg cells), which naturally maintain immune homeostasis by suppressing inflammation could be promising candidates for their therapeutic use in mental disorders. Methods: To test this hypothesis, C57BL/6 adult male mice were submitted to classical stress protocols to induce depressive and anxiety-like behavior; chronic restriction stress (CRS), and chronic unpredictable stress (CUS). Some of the stressed mice received a single adoptive transfer of Treg cells during stress protocols. Mouse behavior was analyzed through the open field (OFT) and forced swim test (FST). Blood and spleen samples were collected for T cell analysis using cell cytometry, while brains were collected to study changes in microglia by immunohistochemistry. Results: Mice submitted to CRS and CUS develop anxiety and depressive-like behavior, and only CRS mice exhibit lower frequencies of circulating Treg cells. Adoptive transfer of Treg cells decreased anxiety-like behavior in the OFT only in CRS model, but not depressive behavior in FST in neither of the two models. In CRS mice, Treg cells administration lowered the number of microglia in the hippocampus, which increased due this stress paradigm, and restored its arborization. However, in CUS mice, Treg cells administration increased microglia number with no significant effect on their arborization. Conclusion: Our results for effector CD4+ T cells in the spleen and microglia number and morphology in the hippocampus add new evidence in favor of the participation of inflammatory responses in the development of depressive and anxiety-like behavior and suggest that the modulation of key immune cells such as Treg cells, could have beneficial effects on these disorders.

Dynamic expression of the sodium-vitamin C co-transporters, SVCT1 and SVCT2, during perinatal kidney development.

Isoform 1 of the sodium-vitamin C co-transporter (SVCT1) is expressed in the apical membrane of proximal tubule epithelial cells in adult human and mouse kidneys. This study is aimed at analyzing the expression and function of SVCTs during kidney development. RT-PCR and immunohistochemical analyses revealed that SVCT1 expression is increased progressively during postnatal kidney development. However, SVCT1 transcripts were barely detected, if not absent, in the embryonic kidney. Instead, the high-affinity transporter, isoform 2 (SVCT2), was strongly expressed in the developing kidney from E15; its expression decreased at postnatal stages. Immunohistochemical analyses showed a dynamic distribution of SVCT2 in epithelial cells during kidney development. In renal cortex tubular epithelial cells, intracellular distribution of SVCT2 was observed at E19 with distribution in the basolateral membrane at P1. In contrast, SVCT2 was localized to the apical and basolateral membranes between E17 and E19 in medullary kidney tubular cells but was distributed intracellularly at P1. In agreement with these findings, functional expression of SVCT2, but not SVCT1 was detected in human embryonic kidney-derived (HEK293) cells. In addition, kinetic analysis suggested that an ascorbate-dependent mechanism accounts for targeted SVCT2 expression in the developing kidney during medullary epithelial cell differentiation. However, during cortical tubular differentiation, SVCT1 was induced and localized to the apical membrane of tubular epithelial cells. SVCT2 showed a basolateral polarization only for the first days of postnatal life. These studies suggest that the uptake of vitamin C mediated by different SVCTs plays differential roles during the ontogeny of kidney tubular epithelial cells.

Current Research on Molecular Biomarkers for Colorectal Cancer in Stool Samples.

Colorectal cancer (CRC) is one of the most diagnosed cancers worldwide, with a high incidence and mortality rate when diagnosed late. Currently, the methods used in healthcare to diagnose CRC are the fecal occult blood test, flexible sigmoidoscopy, and colonoscopy. However, the lack of sensitivity and specificity and low population adherence are driving the need to implement other technologies that can identify biomarkers that not only help with early CRC detection but allow for the selection of more personalized treatment options. In this regard, the implementation of omics technologies, which can screen large pools of biological molecules, coupled with molecular validation, stands out as a promising tool for the discovery of new biomarkers from biopsied tissues or body fluids. This review delves into the current state of the art in the identification of novel CRC biomarkers that can distinguish cancerous tissue, specifically from fecal samples, as this could be the least invasive approach.

No association of the dopamine D2 receptor genetic bilocus score (rs1800497/rs1799732) on food addiction and food reinforcement in Chilean adults.

Purpose: Different systems regulate food intake. In the reward system, dopamine (DA) is the main neurotransmitter, and a variety of genetic variants (rs1799732 and rs1800497) are associated with addiction. Addiction is a highly polygenic disease, where each allelic variant adds a small amount of vulnerability. Polymorphisms rs1799732 and rs1800497 are associated with eating behavior and hedonic hunger, but links to food addiction remain unclear. Aim: To evaluate the association between the bilocus profile (rs1799732-rs1800497) of the dopaminergic pathway with food reinforcement and food addiction in Chilean adults. Methods: A cross-sectional study recruited a convenience sample of 97 obese, 25 overweight, and 99 normal-weight adults (18-35 years). Anthropometric measurements were performed by standard procedures and eating behavior was assessed using the: Food Reinforcement Value Questionnaire (FRVQ) and Yale Food Addiction scale (YFAS). The DRD2 genotypes were determined by TaqMan assays (rs1800497 and rs1799732). A bilocus composite score was calculated. Results: In the normal weight group, individuals who were heterozygous for the rs1977932 variant (G/del) showed higher body weight (p-value 0.01) and abdominal circumference (p-value 0.01) compared to those who were homozygous (G/G). When analyzing rs1800497, a significant difference in BMI was observed for the normal weight group (p-value 0.02) where heterozygous showed higher BMI. In the obese group, homozygous A1/A1 showed higher BMI in comparison to A1/A2 and A2/A2 (p-value 0.03). Also, a significant difference in food reinforcement was observed in the rs1800497, where homozygous for the variant (A1A1) show less reinforcement (p-value 0.01).In relation to the bilocus score in the total sample, 11% showed "very low dopaminergic signaling", 24.4% were "under", 49.7% showed "intermediate signaling", 12.7% showed "high" and 1.4% showed "very high". No significant genotypic differences were observed in food reinforcement and food addiction by bilocus score. Conclusions: The results indicate that the genetic variants rs1799732 and rs1800497 (Taq1A) were associated with anthropometric measurements but not with food addiction or food reinforcement in Chilean university students. These results suggest that other genotypes, such as rs4680 and rs6277, which affect DA signaling capacity through a multilocus composite score, should be studied. Level V: Evidence obtained from a cross-sectional descriptive study.

Lactate: an alternative pathway for the immunosuppressive properties of mesenchymal stem/stromal cells.

BACKGROUND: The metabolic reprogramming of mesenchymal stem/stromal cells (MSC) favoring glycolysis has recently emerged as a new approach to improve their immunotherapeutic abilities. This strategy is associated with greater lactate release, and interestingly, recent studies have proposed lactate as a functional suppressive molecule, changing the old paradigm of lactate as a waste product. Therefore, we evaluated the role of lactate as an alternative mediator of MSC immunosuppressive properties and its contribution to the enhanced immunoregulatory activity of glycolytic MSCs. MATERIALS AND METHODS: Murine CD4+ T cells from C57BL/6 male mice were differentiated into proinflammatory Th1 or Th17 cells and cultured with either L-lactate, MSCs pretreated or not with the glycolytic inductor, oligomycin, and MSCs pretreated or not with a chemical inhibitor of lactate dehydrogenase A (LDHA), galloflavin or LDH siRNA to prevent lactate production. Additionally, we validated our results using human umbilical cord-derived MSCs (UC-MSCs) in a murine model of delayed type 1 hypersensitivity (DTH). RESULTS: Our results showed that 50 mM of exogenous L-lactate inhibited the proliferation rate and phenotype of CD4+ T cell-derived Th1 or Th17 by 40% and 60%, respectively. Moreover, the suppressive activity of both glycolytic and basal MSCs was impaired when LDH activity was reduced. Likewise, in the DTH inflammation model, lactate production was required for MSC anti-inflammatory activity. This lactate dependent-immunosuppressive mechanism was confirmed in UC-MSCs through the inhibition of LDH, which significantly decreased their capacity to control proliferation of activated CD4+ and CD8+ human T cells by 30%. CONCLUSION: These findings identify a new MSC immunosuppressive pathway that is independent of the classical suppressive mechanism and demonstrated that the enhanced suppressive and therapeutic abilities of glycolytic MSCs depend at least in part on lactate production.

Typical and atypical stem cells in the brain, vitamin C effect and neuropathology.

Stem cells are considered a valuable cellular resource for tissue replacement therapies in most brain disorders. Stem cells have the ability to self-replicate and differentiate into numerous cell types, including neurons, oligodendrocytes and astrocytes. As a result, stem cells have been considered the "holy grail" of modern medical neuroscience. Despite their tremendous therapeutic potential, little is known about the mechanisms that regulate their differentiation. In this review, we analyze stem cells in embryonic and adult brains, and illustrate the differentiation pathways that give origin to most brain cells. We also evaluate the emergent role of the well known anti-oxidant, vitamin C, in stem cell differentiation. We believe that a complete understanding of all molecular players, including vitamin C, in stem cell differentiation will positively impact on the use of stem cell transplantation for neurodegenerative diseases.