Biology subjects

Mellado, S.

Publications and source records attributed to Mellado, S..

5 recordsLinked to original sources

bioRxiv2023

Emerging role of mesenchymal stem cell-derived extracellular vesicles to ameliorate hippocampal NLRP3 inflammation induced by binge-like ethanol treatment in adolescence

NOD-like receptors are innate immunity sensors that provide an early and effective response to pathogenic or injury conditions. However, abnormalities in these receptors may cause excessive inflammation. Our studies have reported that an activation of the NLRP3-inflammasome complex in ethanol-treated astrocytes and in chronic alcohol-fed mice could be associated with neuroinflammation and brain damage. Considering the therapeutic role of the molecules contained in the extracellular vesicles (EVs) derived by mesenchymal stem cells (MSC-EVs), the present study aims to evaluate whether the intravenous administration of MSC-EVs from adipose tissue, through inhibiting the NLRP3 inflammasome activation, is capable of reducing hippocampal neuroinflammation in adolescent mice treated with binge drinking. We demonstrate that MSC-EVs ameliorate the activation of the hippocampal NLRP3 inflammasome complex and other NLRs inflammasomes (e.g., NLRP1, NLRC4 and AIM2), as well as the alterations of inflammatory genes (IL-1{beta}, IL-18, iNOS, NF-{kappa}B, MCP-1 and CX3CL1) and miRNAs (miR-21a-5p, miR-146a-5p and miR-141-5p) induced by binge-like ethanol treatment in adolescent mice. Bioinformatic analysis further revealed the involvement of miR-21a-5p and miR-146a-5p with inflammatory target genes and NOD-like receptor signaling pathways. Taken together, these findings provide, for the first time, evidence of the therapeutic potential of MSC-derived EVs to restore the hippocampal neuroinflammatory response through the NLRP3 inflammasome activation induced by binge drinking in adolescence.

neuroscience↗

bioRxiv2023

Novel role of Periploca laevigata extracts as anti-diabetic and anti-inflammatory function in pancreatic β cells exposed to hyperglycaemia

Type 2 Diabetes (T2D) is a major health problem worldwide. This metabolic disease is associated with high blood glucose levels due to insufficient insulin production by the pancreas, leading to an inflammatory immune response. Considering the beneficial roles of medicinal plants to control the diabetic complications of T2D, as well as the therapeutic roles of the extracts from Periploca laevigata (PL), this study evaluates the anti-diabetic and anti-inflammatory properties of PL extracts in the pancreatic {beta} cell line INS-1E under hyperglycaemic. Our findings demonstrated, for the first time, that whereas PL extracts tends to upregulate the insulin gene expression, PL extract from leaves increase significantly the gene expression of GLUT-2 and the transcription factor PDX-1 in glucose-treated INS-1E cells. Notably, some PL extracts are also capable to decrease significantly the gene expression of iNOS and to increase the IL-10 gene expression in glucose-treated INS-1E cells. However, the PL extracts show a tendency to decrease the gene expression of NF-kB and MCP-1 in glucose-treated INS-1E cells. In conclusion, our findings suggest that the treatment with PL extracts could benefit the pancreatic {beta} cell function and alleviate the pancreatic inflammation, thereby representing potential advantages of the glucose metabolism in the T2D.

physiology↗

bioRxiv2023

Oleoylethanolamide effects on stress-induced alcohol consumption: a lipid at crossroads between stress, reward and neuroinflammation

The endocannabinoid system is involved in multiple drug-related behavior as well as in the stress response. The transient increase in endogenous cannabinoids as well as endocannabinoid-like molecules contributes to healthy adaptation to stress exposure. In this study, we tested the effect of systemic OEA treatment (10mg/kg) before or after social defeat (SD) on alcohol self-administration (SA). Mice were divided into non-stressed (EXP) and stressed mice (SD) and randomly assigned to a treatment condition (CTRL, OEA or 10OEA). Mice in the EXP/SD-OEA group received four doses before each SD encounter while mice in the EXP/SD-10OEA mice received 10 daily doses after stress exposure. Three weeks after SD, mice were trained to alcohol 20% (vol/vol) SA. Upon extinction, a cue-induced reinstatement test was performed. Our results showed that only multiple-dose chronic OEA treatment (SD-10OEA group) was effective in preventing the stress-induced increase in alcohol consumption observed in defeated mice. We did not observe any effects of OEA on relapse-like behavior. Altogether, these data suggest that exogenously increasing OEA levels counteracts the adverse effects of stress on alcohol drinking.

animal behavior and cognition↗

bioRxiv2023

Region-specific gene expression changes associated to oleoylethanolamide-induced attenuation of alcohol self-administration

Oleoylethanolamide (OEA) is a lipid with anti-inflammatory activity that modulates multiple reward-related behaviors. Previous studies have shown that OEA treatment reduces alcohol self-administration (SA) while inhibiting alcohol-induced inflammatory signaling. Nevertheless, the specific mechanisms that OEA is targeting to achieve these effects have not been widely explored. Here, we tested the effects of OEA treatment during alcohol SA, extinction or previous to cue-induced reinstatement of alcohol seeking. In addition, we measured gene expression changes in the striatum and hippocampus of relevant receptors for alcohol consumption (DrD1, DrD2, CNR1, OPRM1) as well as immune-related proteins (IL-6, IL-1{beta}, TLR4) and the brain-derived neurotrophic factor (BDNF). Our results confirmed that when administered contingently, systemic OEA administration reduced alcohol SA and attenuated cue-induced reinstatement. Interestingly, we also observed that OEA treatment reduced the number of sessions needed for extinction of alcohol seeking. Biochemical analyses showed region-specific OEA dopaminergic and cannabinoid receptor gene expression alterations. Also, OEA treatment modulated the long-term immune response and increased BDNF expression. These results suggest that boosting OEA levels may be an effective strategy for reducing alcohol SA and preventing relapse.

neuroscience↗

bioRxiv2023

Lipid network of plasma extracellular vesicles reveals sex-based differences in the lipidomic profile from patients with alcohol use disorder

Alcohol use disorder (AUD) is one of the most common psychiatric disorders, and the consumption of this substance is considered one of the main causes of preventable deaths worldwide. Lipids play a crucial functional role in cell membranes, however little is known about the role of lipids containing extracellular vesicles (EVs), as regulatory molecules and biomarkers. In this study, a highly sensitive lipidomic strategy is employed to characterize plasma EV lipid species from individuals with AUD, to evaluate differential functional roles and enzymatic activity networks to improve the knowledge of lipid metabolism in the alcohol consumption. Plasma EV lipids from female and male patients with AUD and healthy individuals were analyzed to obtain lipid differential abundance, as well as biological interpretation of LINEX2 lipidomics data, evaluating enzymatic dysregulation through an enrichment algorithm. Our results showed for the first time that females with AUD exhibit greater substrate-product changes in LPC and PC lipids, as well as phospholipases and acyltransferases activity, potentially linked to cancer progression and neuroinflammation. Conversely, males with AUD showed dysregulation in Cer and SM lipid, involving sphingomyelinases, sphingomyelin phosphodiesterase, and sphingomyelin synthase, which could be related with hepatotoxicity. Notably, females with AUD showed LION-terms associated with "positive intrinsic curvature", while males exhibited "negative intrinsic curvature, contributing to vesicle fusion processes. These methodological developments allow a better understanding of lipid metabolism and its regulatory mechanisms, which contributes not only to identify novel lipid targets, but also the discovery of sex-specific clinical biomarkers in the AUD.

pathology↗