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

JOURNAL/nrgr/04.03/01300535-202504000-00030/figure1/v/2024-07-06T104127Z/r/image-tiff Our previous studies have reported that activation of the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3)-inflammasome complex in ethanol-treated astrocytes and chronic alcohol-fed mice could be associated with neuroinflammation and brain damage. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have been shown to restore the neuroinflammatory response, along with myelin and synaptic structural alterations in the prefrontal cortex, and alleviate cognitive and memory dysfunctions induced by binge-like ethanol treatment in adolescent mice. Considering the therapeutic role of the molecules contained in mesenchymal stem cell-derived extracellular vesicles, the present study analyzed whether the administration of mesenchymal stem cell-derived extracellular vesicles isolated from adipose tissue, which inhibited the activation of the NLRP3 inflammasome, was capable of reducing hippocampal neuroinflammation in adolescent mice treated with binge drinking. We demonstrated that the administration of mesenchymal stem cell-derived extracellular vesicles ameliorated the activation of the hippocampal NLRP3 inflammasome complex and other NLRs inflammasomes (e.g., pyrin domain-containing 1, caspase recruitment domain-containing 4, and absent in melanoma 2, as well as the alterations in inflammatory genes (interleukin-1ß, interleukin-18, inducible nitric oxide synthase, nuclear factor-kappa B, monocyte chemoattractant protein-1, and C-X3-C motif chemokine ligand 1) 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 novel evidence of the therapeutic potential of MSC-derived EVs to ameliorate the hippocampal neuroinflammatory response associated with NLRP3 inflammasome activation induced by binge drinking in adolescence.

Region-Specific Gene Expression Changes Associated with 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 targets 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, Oprm) as well as immune-related proteins (Il-6, Il-1ß, 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 the extinction of alcohol seeking. Biochemical analyses showed that OEA induced gene expression changes in dopamine and cannabinoid receptors in the striatum and hippocampus. In addition, 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.

Novel insight into the lipid network of plasma extracellular vesicles reveal sex-based differences in the lipidomic profile of alcohol use disorder patients.

BACKGROUND: Alcohol use disorder (AUD) is one of the most common psychiatric disorders, with the consumption of alcohol considered a leading cause of preventable deaths worldwide. Lipids play a crucial functional role in cell membranes; however, we know little about the role of lipids in extracellular vesicles (EVs) as regulatory molecules and disease biomarkers. METHODS: We employed a sensitive lipidomic strategy to characterize lipid species from the plasma EVs of AUD patients to evaluate functional roles and enzymatic activity networks to improve the knowledge of lipid metabolism after alcohol consumption. We analyzed plasma EV lipids from AUD females and males and healthy individuals to highlight lipids with differential abundance and biologically interpreted lipidomics data using LINEX2, which evaluates enzymatic dysregulation using an enrichment algorithm. RESULTS: Our results show, for the first time, that AUD females exhibited more significant substrate-product changes in lysophosphatidylcholine/phosphatidylcholine lipids and phospholipase/acyltransferase activity, which are potentially linked to cancer progression and neuroinflammation. Conversely, AUD males suffer from dysregulated ceramide and sphingomyelin lipids involving sphingomyelinase, sphingomyelin phosphodiesterase, and sphingomyelin synthase activity, which relates to hepatotoxicity. Notably, the analysis of plasma EVs from AUD females and males demonstrates enrichment of lipid ontology terms associated with "negative intrinsic curvature" and "positive intrinsic curvature", respectively. CONCLUSIONS: Our methodological developments support an improved understanding of lipid metabolism and regulatory mechanisms, which contribute to the identification of novel lipid targets and the discovery of sex-specific clinical biomarkers in AUD.

Alcohol use disorder (AUD) is one of the most common psychiatric disorders, with the consumption of alcohol considered a leading cause of preventable deaths worldwide. Lipids play a crucial functional role in cell membranes; however, we know little about the role of lipids in extracellular vesicles (EVs) as regulatory molecules and disease biomarkers. We employed a sensitive lipidomic strategy to characterize lipid species from the plasma EVs of AUD patients to evaluate functional roles and enzymatic activity networks to improve the knowledge of lipid metabolism after alcohol consumption. We analyzed plasma EV lipids from AUD females and males and healthy individuals to highlight lipids with differential abundance and biologically interpreted lipidomics data using LINEX², which evaluates enzymatic dysregulation using an enrichment algorithm. Our results show, for the first time, that AUD females exhibited more significant substrate-product changes in lysophosphatidylcholine/phosphatidylcholine lipids and phospholipase/acyltransferase activity, which are potentially linked to cancer progression and neuroinflammation. Conversely, AUD males suffer from dysregulated ceramide and sphingomyelin lipids involving sphingomyelinase, sphingomyelin phosphodiesterase, and sphingomyelin synthase activity, which relates to hepatotoxicity. Notably, the analysis of plasma EVs from AUD females and males demonstrates enrichment of lipid ontology terms associated with "negative intrinsic curvature" and "positive intrinsic curvature", respectively. Our methodological developments support an improved understanding of lipid metabolism and regulatory mechanisms, which contribute to the identification of novel lipid targets and the discovery of sex-specific clinical biomarkers in AUD.

Therapeutic role of mesenchymal stem cell-derived extracellular vesicles in neuroinflammation and cognitive dysfunctions induced by binge-like ethanol treatment in adolescent mice.

BACKGROUND: Extracellular vesicles (EVs) are heterogeneous membrane vesicles secreted by cells in extracellular spaces that play an important role in intercellular communication under both normal and pathological conditions. Mesenchymal stem cells (MSC) are anti-inflammatory and immunoregulatory cells capable of secreting EVs, which are considered promising molecules for treating immune, inflammatory, and degenerative diseases. Our previous studies demonstrate that, by activating innate immune receptors TLR4 (Toll-like receptor 4), binge-like ethanol exposure in adolescence causes neuroinflammation and neural damage. AIMS: To evaluate whether the intravenous administration of MSC-derived EVs is capable of reducing neuroinflammation, myelin and synaptic alterations, and the cognitive dysfunction induced by binge-like ethanol treatment in adolescent mice. MATERIALS & METHODS: MSC-derived EVs obtained from adipose tissue were administered in the tail vein (50 microg/dose, one weekly dose) to female WT adolescent mice treated intermittently with ethanol (3.0 g/kg) during two weeks. RESULTS: MSC-derived EVs from adipose tissue ameliorate ethanol-induced up-regulation of inflammatory genes (e.g., COX-2, iNOS, MIP-1α, NF-κB, CX3CL1, and MCP-1) in the prefrontal cortex of adolescent mice. Notably, MSC-derived EVs also restore the myelin and synaptic derangements, and the memory and learning impairments, induced by ethanol treatment. Using cortical astroglial cells in culture, our results further confirm that MSC-derived EVs decrease inflammatory genes in ethanol-treated astroglial cells. This, in turn, confirms in vivo findings. CONCLUSION: Taken together, these results provide the first evidence for the therapeutic potential of the MSC-derived EVs in the neuroimmune response and cognitive dysfunction induced by binge alcohol drinking in adolescence.

Oleoylethanolamide attenuates cocaine-primed reinstatement and alters dopaminergic gene expression in the striatum.

The lipid oleoylethanolamide (OEA) has been shown to affect reward-related behavior. However, there is limited experimental evidence about the specific neurotransmission systems OEA may be affecting to exert this modulatory effect. The aim of this study was to evaluate the effects of OEA on the rewarding properties of cocaine and relapse-related gene expression in the striatum and hippocampus. For this purpose, we evaluated male OF1 mice on a cocaine-induced CPP procedure (10 mg/kg) and after the corresponding extinction sessions, we tested drug-induced reinstatement. The effects of OEA (10 mg/kg, i.p.) were evaluated at three different timepoints: (1) Before each cocaine conditioning session (OEA-C), (2) Before extinction sessions (OEA-EXT) and (3) Before the reinstatement test (OEA-REINST). Furthermore, gene expression changes in dopamine receptor D1 gene, dopamine receptor D2 gene, opioid receptor µ, cannabinoid receptor 1, in the striatum and hippocampus were analyzed by qRT-PCR. The results obtained in the study showed that OEA administration did not affect cocaine CPP acquisition. However, mice receiving different OEA treatment schedules (OEA-C, OEA-EXT and OEA-REINST) failed to display drug-induced reinstatement. Interestingly, the administration of OEA blocked the increase of dopamine receptor gene D1 in the striatum and hippocampus caused by cocaine exposure. In addition, OEA-treated mice exhibited reduced striatal dopamine receptor gene D2 and cannabinoid receptor 1. Together, these findings suggest that OEA may be a promising pharmacological agent in the treatment of cocaine use disorder.

Age-Related Inflammation and Oxidative Stress in the Cochlea Are Exacerbated by Long-Term, Short-Duration Noise Stimulation.

We have previously reported that young adult rats exposed to daily, short-duration noise for extended time periods, develop accelerated presbycusis starting at 6 months of age. Auditory aging is associated with progressive hearing loss, cell deterioration, dysregulation of the antioxidant defense system, and chronic inflammation, among others. To further characterize cellular and molecular mechanisms at the crossroads between noise and age-related hearing loss (ARHL), 3-month-old rats were exposed to a noise-accelerated presbycusis (NAP) protocol and tested at 6 and 16 months of age, using auditory brainstem responses, Real-Time Reverse Transcription-Quantitative PCR (RT-qPCR) and immunocytochemistry. Chronic noise-exposure leading to permanent auditory threshold shifts in 6-month-old rats, resulted in impaired sodium/potassium activity, degenerative changes in the lateral wall and spiral ganglion, increased lipid peroxidation, and sustained cochlear inflammation with advancing age. Additionally, at 6 months, noise-exposed rats showed significant increases in the gene expression of antioxidant enzymes (superoxide dismutase 1/2, glutathione peroxidase 1, and catalase) and inflammation-associated molecules [ionized calcium binding adaptor molecule 1, interleukin-1 beta (IL-1ß), and tumor necrosis factor-alpha]. The levels of IL-1ß were upregulated in the spiral ganglion and spiral ligament, particularly in type IV fibrocytes; these cells showed decreased levels of connective tissue growth factor and increased levels of 4-hydroxynonenal. These data provide functional, structural and molecular evidence that age-noise interaction contributes to exacerbating presbycusis in young rats by leading to progressive dysfunction and early degeneration of cochlear cells and structures. These findings contribute to a better understanding of NAP etiopathogenesis, which is essential as it affects the life quality of young adults worldwide.

Imagen corporal de mujeres con obesidad tipo I tras 2-5 años de una gastrectomía subtotal vertical / Body image of women with type I obesity after 2-5 years of subtotal gastrectomy vertical

Resumen La imagen corporal es un constructo multidimensional, dinámico e influido socialmente. El objetivo de este trabajo fue analizar la vivencia acerca de la imagen corporal de mujeres con obesidad tipo I después de dos-cinco años de haber sido sometidas a cirugía bariátrica. En este estudio cualitativo, de carácter descriptivo, participaron 20 mujeres (21-49 años de edad) con obesidad tipo I, 13 de ellas con reganancia de peso. Los datos fueron recabados a través de entrevista semiestructurada, y se analizaron en función de seis categorías: emociones asociadas al cuerpo, satisfacción corporal y zonas de agrado/desagrado, evitación de actividades cotidianas por la figura, cohibición por el cuerpo con sexo opuesto y/o personas en general, comparación con otras mujeres respecto a la figura y percepción asociada al peso mínimo. Con relación a las pacientes que no reganaron peso, presentan una emocionalidad fundamentalmente positiva y de satisfacción general con su imagen corporal. Como conclusión general, se identifica un incremento de la satisfacción corporal, dada la disminución del volumen corporal; sin embargo la insatisfacción persiste, desplazándose a zonas y aspectos específicos del cuerpo. Por tanto, se confirma que la disminución de peso no necesariamente predice la reducción de la insatisfacción corporal.

Abstract Body image is a multidimensional, dynamic and socially influenced construct. The aim of this research was to analyze the experiences associated to body image in women with obesity type I after two-five years undergoing bariatric surgery. In this qualitative-descriptive study were included 20 women (21 -49 years old) with obesity type I, 13 of them with regaining weight. Data were obtained through semi-structured interview and was analyzed based on six categories: Emotions associated with body, body satisfaction and like/dislike with body parts, avoidance of daily activities because of the body figure, discomfort with the own body with the opposite sex/general people, comparison with other women considering the body figure, and perception associated to the minimum weight. Regarding the patients who did not regain weight, they have a positive emotionality and general satisfaction with their body image. As a general conclusion, an increase in body satisfaction was identified, due to the decrease in body volume. However, the dissatisfaction persists, moving to specific areas and aspects of the body. Therefore, it is confirmed that body weight reduction does not necessarily predict the reduction of body dissatisfaction.