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1.
PLoS One ; 19(2): e0298724, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38377103

RESUMO

Candida albicans is a commensal yeast that has important impacts on host metabolism and immune function, and can establish life-threatening infections in immunocompromised individuals. Previously, C. albicans colonization has been shown to contribute to the progression and severity of alcoholic liver disease. However, relatively little is known about how C. albicans responds to changing environmental conditions in the GI tract of individuals with alcohol use disorder, namely repeated exposure to ethanol. In this study, we repeatedly exposed C. albicans to high concentrations (10% vol/vol) of ethanol-a concentration that can be observed in the upper GI tract of humans following consumption of alcohol. Following this repeated exposure protocol, ethanol small colony (Esc) variants of C. albicans isolated from these populations exhibited increased ethanol tolerance, altered transcriptional responses to ethanol, and cross-resistance/tolerance to the frontline antifungal fluconazole. These Esc strains exhibited chromosomal copy number variations and carried polymorphisms in genes previously associated with the acquisition of fluconazole resistance during human infection. This study identifies a selective pressure that can result in evolution of fluconazole tolerance and resistance without previous exposure to the drug.


Assuntos
Candida albicans , Fluconazol , Humanos , Fluconazol/farmacologia , Etanol/farmacologia , Variações do Número de Cópias de DNA , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Testes de Sensibilidade Microbiana , Farmacorresistência Fúngica/genética
2.
Int J Mol Sci ; 25(3)2024 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-38338944

RESUMO

We aimed to test how the postbiotic butyrate impacts select gut bacteria, small intestinal epithelial integrity, and microvascular endothelial activation during acute ethanol exposure in mice and primary human intestinal microvascular endothelial cells (HIMECs). Supplementation during an acute ethanol challenge with or without tributyrin, a butyrate prodrug, was delivered to C57BL/6 mice. A separate group of mice received 3 days of clindamycin prior to the acute ethanol challenge. Upon euthanasia, blood endotoxin, cecal bacteria, jejunal barrier integrity, and small intestinal lamina propria dendritic cells were assessed. HIMECs were tested for activation following exposure to ethanol ± lipopolysaccharide (LPS) and sodium butyrate. Tributyrin supplementation protected a butyrate-generating microbe during ethanol and antibiotic exposure. Tributyrin rescued ethanol-induced disruption in jejunal epithelial barrier, elevated plasma endotoxin, and increased mucosal vascular addressin cell-adhesion molecule-1 (MAdCAM-1) expression in intestinal microvascular endothelium. These protective effects of tributyrin coincided with a tolerogenic dendritic response in the intestinal lamina propria. Lastly, sodium butyrate pre- and co-treatment attenuated the direct effects of ethanol and LPS on MAdCAM-1 induction in the HIMECs from a patient with ulcerative colitis. Tributyrin supplementation protects small intestinal epithelial and microvascular barrier integrity and modulates microvascular endothelial activation and dendritic tolerizing function during a state of gut dysbiosis and acute ethanol challenge.


Assuntos
Células Endoteliais , Etanol , Camundongos , Humanos , Animais , Etanol/farmacologia , Ácido Butírico/farmacologia , Ácido Butírico/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos Endogâmicos C57BL , Mucosa Intestinal/metabolismo
3.
Int J Neuropsychopharmacol ; 27(2)2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38315678

RESUMO

BACKGROUND: Previous preclinical and human studies have shown that a high-fat ketogenic diet and ketone supplements (KS) are efficacious in reducing alcohol craving, alcohol consumption, and signs of alcohol withdrawal. However, the effects of KS on alcohol sensitivity are unknown. METHODS: In this single-blind, cross-over study, 10 healthy participants (3 females) were administered a single, oral dose of a KS (25 g of ketones from D-ß-hydroxybutyric acid and R-1,3-butanediol) or placebo 30 minutes before an oral alcohol dose (0.25 g/kg for women; 0.31 g/kg for men). Assessments of breath alcohol concentration and blood alcohol levels (BAL) and responses on the Drug Effect Questionnaire were repeatedly obtained over 180 minutes after alcohol consumption. In a parallel preclinical study, 8 Wistar rats (4 females) received an oral gavage of KS (0.42 g ketones/kg), water, or the sweetener allulose (0.58 g/kg) followed 15 minutes later by an oral alcohol dose (0.8 g/kg). BAL was monitored for 240 minutes after alcohol exposure. RESULTS: In humans, the intake of KS before alcohol significantly blunted breath alcohol concentration and BAL, reduced ratings of alcohol liking and wanting more, and increased disliking for alcohol. In rats, KS reduced BAL more than either allulose or water. CONCLUSION: KS altered physiological and subjective responses to alcohol in both humans and rats, and the effects were likely not mediated by the sweetener allulose present in the KS drink. Therefore, KS could potentially reduce the intoxicating effects of alcohol.


Assuntos
Alcoolismo , Síndrome de Abstinência a Substâncias , Masculino , Humanos , Ratos , Feminino , Animais , Estudos Cross-Over , Cetonas/farmacologia , Voluntários Saudáveis , Método Simples-Cego , Ratos Wistar , Etanol/farmacologia , Edulcorantes , Concentração Alcoólica no Sangue , Suplementos Nutricionais , Água
4.
Transl Psychiatry ; 14(1): 122, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38413577

RESUMO

Estrogens promote binge alcohol drinking and contribute to sex differences in alcohol use disorder. However, the mechanisms are largely unknown. This study aims to test if estrogens act on 5-hydroxytryptamine neurons in the dorsal raphe nucleus (5-HTDRN) to promote binge drinking. We found that female mice drank more alcohol than male mice in chronic drinking in the dark (DID) tests. This sex difference was associated with distinct alterations in mRNA expression of estrogen receptor α (ERα) and 5-HT-related genes in the DRN, suggesting a potential role of estrogen/ERs/5-HT signaling. In supporting this view, 5-HTDRN neurons from naïve male mice had lower baseline firing activity but higher sensitivity to alcohol-induced excitation compared to 5-HTDRN neurons from naïve female mice. Notably, this higher sensitivity was blunted by 17ß-estradiol treatment in males, indicating an estrogen-dependent mechanism. We further showed that both ERα and ERß are expressed in 5-HTDRN neurons, whereas ERα agonist depolarizes and ERß agonist hyperpolarizes 5-HTDRN neurons. Notably, both treatments blocked the stimulatory effects of alcohol on 5-HTDRN neurons in males, even though they have antagonistic effects on the activity dynamics. These results suggest that ERs' inhibitory effects on ethanol-induced burst firing of 5-HTDRN neurons may contribute to higher levels of binge drinking in females. Consistently, chemogenetic activation of ERα- or ERß-expressing neurons in the DRN reduced binge alcohol drinking. These results support a model in which estrogens act on ERα/ß to prevent alcohol-induced activation of 5-HTDRN neurons, which in return leads to higher binge alcohol drinking.


Assuntos
Consumo Excessivo de Bebidas Alcoólicas , Receptor alfa de Estrogênio , Camundongos , Feminino , Masculino , Animais , Receptor alfa de Estrogênio/agonistas , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Núcleo Dorsal da Rafe/metabolismo , Receptor beta de Estrogênio/agonistas , Receptor beta de Estrogênio/metabolismo , Serotonina/metabolismo , Estrogênios/farmacologia , Etanol/farmacologia
5.
Sci Rep ; 14(1): 2687, 2024 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-38302628

RESUMO

Alcohol consumption during pregnancy can result in a range of adverse postnatal outcomes among exposed children. However, identifying at-risk children is challenging given the difficulty to confirm prenatal alcohol exposure and the lack of early diagnostic tools. Placental surveys present an important opportunity to uncover early biomarkers to identify those at risk. Here, we report the first transcriptome-wide evaluation to comprehensively evaluate human placental pathways altered by fetal alcohol exposure. In a prospective longitudinal birth cohort in Cape Town, South Africa, we performed bulk tissue RNAseq in placenta samples from 32 women reporting heavy drinking during pregnancy and 30 abstainers/light drinkers. Weighted gene co-expression network analysis (WGCNA) and differential gene expression analysis were performed to assess associations between fetal alcohol exposure and placental gene expression patterns at a network-wide and single gene level, respectively. The results revealed altered expression in genes related to erythropoiesis and angiogenesis, which are implicated in established postnatal phenotypes related to alcohol exposure, including disruptions in iron homeostasis, growth, and neurodevelopment. The reported findings provide insights into the molecular pathways affected by prenatal alcohol exposure and highlight the potential of placental biomarkers for detecting and understanding the effects of alcohol on fetal development.


Assuntos
Placenta , Efeitos Tardios da Exposição Pré-Natal , Criança , Humanos , Feminino , Gravidez , Placenta/metabolismo , Estudos Prospectivos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , África do Sul , Etanol/farmacologia , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/genética , Biomarcadores/metabolismo
6.
Alcohol Alcohol ; 59(2)2024 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-38364318

RESUMO

AIMS: This study examined how adolescent social isolation affects adult binge-like alcohol drinking and stress-axis function, via basal levels of circulating corticosterone (CORT), in male and female mice with a genetic predisposition toward high alcohol preference (HAP). METHODS: Male and female HAP2 mice were randomly assigned to a group-housed or social isolation (ISO) group. Social isolation began at postnatal Days 40-42 and lasted for 21 days prior to assessment of binge-like alcohol drinking using a 4-day drinking-in-the-dark (DID) procedure. Blood samples to assess basal CORT were taken 6 days after social isolation ended and 24 h before DID started, and again 60 h after DID ended, during the light portion of the light cycle. RESULTS: Adolescent social isolation increased adult binge-like alcohol drinking in male but not female mice. All groups showed significantly lower CORT after DID compared to before DID. Pearson bivariate correlation coefficients between the first 2 h of grams-per-kilogram alcohol intake on Day 4 and CORT levels indicated a significant positive correlation in ISO males only after DID and negative correlations in ISO females before and after DID. CONCLUSIONS: These findings demonstrate that adolescent social isolation increased binge-like alcohol drinking in male but not female adult HAP2 mice. Stress-axis adaptations in male HAP2 mice may be associated with the social-isolation-induced increase in binge-like alcohol drinking.


Assuntos
Consumo de Bebidas Alcoólicas , Consumo Excessivo de Bebidas Alcoólicas , Camundongos , Masculino , Feminino , Animais , Etanol/farmacologia , Isolamento Social , Corticosterona , Predisposição Genética para Doença , Consumo Excessivo de Bebidas Alcoólicas/complicações , Camundongos Endogâmicos C57BL
7.
Anim Sci J ; 95(1): e13923, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38337192

RESUMO

This study was done to investigate which components of rice bran (RB) are involved in the inhibition of methanogenesis by fractionating the rice bran and adding it to a rumen in vitro culture system. The RB extract obtained using ethanol and water was screened in an in vitro fermentation system. The experimental treatment conditions were as follows: a control group containing a substrate without supplements; substrates with 0.06 g of RB; 0.6 mL of ethanol; 0.6 mL of distilled water (DW); 0.6 mL of ethanol-soluble fraction (ESF); 0.06 g of ethanol-insoluble rice bran (EIRB); 0.6 mL of water-soluble fraction (WSF); and 0.06 g of water-insoluble rice bran (WIRB). Based on the result of the analysis, the addition of ESF significantly decreased CH4 and CH4 /g dry matter digested, methanogen population (p < 0.05), while gas and dry matter digestibility (DMD) were comparable with the control group. Total short-chain fatty acid (SCFA), and proportion of propionate were reduced, and the proportion of butyrate was increased by the addition of ethanol and ESF (p < 0.05). This result suggests that the supplementation of 10% ESF can substantially reduce methane production in vitro without a negative effect on substrate digestibility.


Assuntos
Oryza , Rúmen , Animais , Rúmen/metabolismo , Fermentação , Água , Metano/metabolismo , Etanol/metabolismo , Etanol/farmacologia , Extratos Vegetais/farmacologia , Dieta , Digestão , Ração Animal/análise
8.
Int J Mol Sci ; 25(3)2024 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-38338883

RESUMO

The rates of alcohol use disorder among women are growing, yet little is known about how the female brain is affected by alcohol. The neuroimmune system, and specifically microglia, have been implicated in mediating alcohol neurotoxicity, but most preclinical studies have focused on males. Further, few studies have considered changes to the microglial phenotype when examining the effects of ethanol on brain structure and function. Therefore, we quantified microglial reactivity in female rats using a binge model of alcohol dependence, assessed through morphological and phenotypic marker expression, coupled with regional cytokine levels. In a time- and region-dependent manner, alcohol altered the microglial number and morphology, including the soma and process area, and the overall complexity within the corticolimbic regions examined, but no significant increases in the proinflammatory markers MHCII or CD68 were observed. The majority of cytokine and growth factor levels examined were similarly unchanged. However, the expression of the proinflammatory cytokine TNFα was increased, and the anti-inflammatory IL-10, decreased. Thus, female rats showed subtle differences in neuroimmune reactivity compared to past work in males, consistent with reports of enhanced neuroimmune responses in females across the literature. These data suggest that specific neuroimmune reactions in females may impact their susceptibility to alcohol neurotoxicity and other neurodegenerative events with microglial contributions.


Assuntos
Alcoolismo , Humanos , Masculino , Ratos , Animais , Feminino , Alcoolismo/metabolismo , Microglia/metabolismo , Etanol/farmacologia , Encéfalo/metabolismo , Citocinas/metabolismo
9.
Int J Mol Sci ; 25(3)2024 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-38338880

RESUMO

Plants and plant extracts are a relevant source of bioactive compounds widely employed as functional foods. In the Mediterranean area, the shrub Sarcopoterium spinosum is traditionally used as an herbal medicine for weight loss and a diabetes treatment. Inflammation is a protective mechanism involved in the development of many pathological conditions, including cardiovascular diseases. The present study aimed to investigate in vitro the antioxidant and cytoprotective properties of an ethanolic extract from S. spinosum fruits (SEE) in a cellular model of endothelium dysfunction. Corilagin and quercetin are two polyphenols abundant in SEE and were tested for comparison. The exposure of HECV cells for 24 h to 30 µM hydrogen peroxide (H2O2) lead to an oxidative stress condition. When HECV cells were treated with 10 µg/mL of SEE or single compounds after or before the oxidative insult, the results showed their ability to (i) decrease the reactive oxygen species (ROS) production quantified using fluorometric analysis and the lipid peroxidation measured with a spectrophotometric assay; (ii) rescue both the glutathione reduced to oxidized (GSH/GSSG) ratio and nitric oxide impair and the protein denaturation; and (iii) accelerate the wound repair measured using a T-scratch assay. Taken together, our findings indicate that the ethanolic extract from S. spinosum fruits could be a potential candidate for nutraceutical application.


Assuntos
Frutas , Peróxido de Hidrogênio , Peróxido de Hidrogênio/toxicidade , Células Endoteliais , Antioxidantes/farmacologia , Estresse Oxidativo , Extratos Vegetais/farmacologia , Anti-Inflamatórios/farmacologia , Glutationa/farmacologia , Etanol/farmacologia
10.
Int J Mol Sci ; 25(3)2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38339113

RESUMO

Delta 9 tetrahydrocannabinol (THC), the main component of cannabis, has adverse effects on the cardiovascular system, but whether concomitant ethanol (EtOH) and aging modulate its toxicity is unknown. We investigated dose responses of THC and its vehicle, EtOH, on mitochondrial respiration and reactive oxygen production in both young and old rat cardiac mitochondria (12 and 90 weeks). THC dose-dependently impaired mitochondrial respiration in both groups, and such impairment was enhanced in aged rats (-97.5 ± 1.4% vs. -75.6 ± 4.0% at 2 × 10-5 M, and IC50: 0.7 ± 0.05 vs. 1.3 ± 0.1 × 10-5 M, p < 0.01, for old and young rats, respectively). The EtOH-induced decrease in mitochondrial respiration was greater in old rats (-50.1 ± 2.4% vs. -19.8 ± 4.4% at 0.9 × 10-5 M, p < 0.0001). Further, mitochondrial hydrogen peroxide (H2O2) production was enhanced in old rats after THC injection (+46.6 ± 5.3 vs. + 17.9 ± 7.8%, p < 0.01, at 2 × 10-5 M). In conclusion, the deleterious cardiac effects of THC were enhanced with concomitant EtOH, particularly in old cardiac mitochondria, showing greater mitochondrial respiration impairment and ROS production. These data improve our knowledge of the mechanisms potentially involved in cannabis toxicity, and likely support additional caution when THC is used by elderly people who consume alcohol.


Assuntos
Etanol , Peróxido de Hidrogênio , Humanos , Ratos , Animais , Idoso , Espécies Reativas de Oxigênio , Etanol/farmacologia , Mitocôndrias Cardíacas , Respiração
11.
J Ethnopharmacol ; 319(Pt 3): 117362, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38380575

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Colorectal cancer (CRC) remains a significant global health concern, and targeting inflammation has emerged as a promising approach for its prevention and treatment. Medicinal plants and phytochemicals have garnered attention for their potential efficacy against inflammation with minimal toxicity. Osmanthus fragrans var. aurantiacus Makino (O. fragrans) has a history of traditional use in Korea and China in treating various inflammation-related conditions, but its potential use for CRC has not been uncovered. AIM OF THE STUDY: This study aims to explore the potential anti-proliferative and pro-apoptotic properties of O. fragrans, focusing on its impact on CRC treatment. By investigating O. fragrans, we aim to uncover its anti-proliferative and apoptotic effects in human CRC cells, potentially paving the way for effective and well-tolerated therapeutic strategies for CRC patients. MATERIALS AND METHODS: Ethanol (EtOH) extracts of O. fragrans leaf and flower, along with specific fractions (n-hexane, ethyl acetate (EtOAc), n-butanol, and the aqueous residue) were evaluated for their anti-proliferative effects in human CRC cells using MTT assays, and compared to normal colon cells. Mechanistic insights and chemical profiling were obtained through flow cytometry, colorimetric assays, western blotting, and molecular docking, and high-performance liquid chromatography (HPLC) system. RESULTS: Both flower and leaf EtOH extracts of O. fragrans exhibited significant anti-proliferative effects in human CRC cells, with the leaf extract demonstrating higher potency. The EtOAc fraction from the leaf extract displayed the strongest anti-CRC cell proliferative effects while no cytotoxic effects in normal colon cells. Chemical profiling of these fractions identified triterpenoids as significant components in the EtOAc fractions. The leaf EtOAc fraction caused cell cycle arrest and apoptosis, accompanied by elevating intracellular reactive oxygen species and mitochondrial dysfunction in CRC cells. Additionally, it inhibited NF-κB and ERK1/2 signaling, leading to reduced COX2 expression. Notably, two triterpenoids isolated from the leaf EtOAc fraction, maslinic acid and corosolic acid, displayed potent anti-cancer activity in CRC cells without affecting normal colon cells. Corosolic acid exhibited a strong binding affinity to COX2 and reduced its expression, supporting its role in the anti-inflammatory and anti-cancer effects. CONCLUSIONS: Our findings suggest that O. fragrans, particularly its triterpenoid-rich EtOAc fraction, holds promise as a novel therapeutic agent for CRC prevention and therapy. These results provide valuable insights into the potential application of O. fragrans and its bioactive compounds in combating CRC.


Assuntos
Acetatos , Neoplasias Colorretais , Triterpenos , Humanos , NF-kappa B , Extratos Vegetais/uso terapêutico , Ciclo-Oxigenase 2 , Simulação de Acoplamento Molecular , Triterpenos/farmacologia , Triterpenos/uso terapêutico , Inflamação/tratamento farmacológico , Etanol/farmacologia , Proliferação de Células , Neoplasias Colorretais/tratamento farmacológico
12.
Addict Biol ; 29(2): e13366, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38380710

RESUMO

Adolescent alcohol use is a strong predictor for the subsequent development of alcohol use disorders later in life. Additionally, adolescence is a critical period for the onset of affective disorders, which can contribute to problematic drinking behaviours and relapse, particularly in females. Previous studies from our laboratory have shown that exposure to adolescent intermittent ethanol (AIE) vapour alters glutamatergic transmission in the bed nucleus of the stria terminalis (BNST) and, when combined with adult stress, elicits sex-specific changes in glutamatergic plasticity and negative affect-like behaviours in mice. Building on these findings, the current work investigated whether BNST stimulation could substitute for stress exposure to increase the latency to consume a palatable food in a novel context (hyponeophagia) and promote social avoidance in adult mice with AIE history. Given the dense connections between the BNST and the parabrachial nucleus (PBN), a region involved in mediating threat assessment and feeding behaviours, we hypothesized that increased negative affect-like behaviours would be associated with PBN activation. Our results revealed that the chemogenetic stimulation of the dorsolateral BNST induced hyponeophagia in females with AIE history, but not in female controls or males of either group. Social interaction remained unaffected in both sexes. Notably, this behavioural phenotype was associated with higher activation of calcitonin gene-related peptide and dynorphin cells in the PBN. These findings provide new insights into the neurobiological mechanisms underlying the development of negative affect in females and highlight the potential involvement of the BNST-PBN circuitry in regulating emotional responses to alcohol-related stimuli.


Assuntos
Alcoolismo , Núcleos Parabraquiais , Núcleos Septais , Masculino , Camundongos , Feminino , Animais , Etanol/farmacologia
13.
Sci Rep ; 14(1): 4343, 2024 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-38383569

RESUMO

Antibiotic resistance in staphylococcal strains and its impact on public health and agriculture are global problems. The development of new anti-staphylococcal agents is an effective strategy for addressing the increasing incidence of bacterial resistance. In this study, ethanolic extracts of Cannabis sativa L. made from plant parts harvested during the whole vegetation cycle under various nutritional treatments were assessed for in vitro anti-staphylococcal effects. The results showed that all the cannabis extracts tested exhibited a certain degree of growth inhibition against bacterial strains of Staphylococcus aureus, including antibiotic-resistant and antibiotic-sensitive forms. The highest antibacterial activity of the extracts was observed from the 5th to the 13th week of plant growth across all the nutritional treatments tested, with minimum inhibitory concentrations ranging from 32 to 64 µg/mL. Using HPLC, Δ9-tetrahydrocannabinolic acid (THCA) was identified as the most abundant cannabinoid in the ethanolic extracts. A homolog of THCA, tetrahydrocannabivarinic acid (THCVA), reduced bacterial growth by 74%. These findings suggest that the cannabis extracts tested in this study can be used for the development of new anti-staphylococcal compounds with improved efficacy.


Assuntos
Canabinoides , Cannabis , Alucinógenos , Canabinoides/farmacologia , Extratos Vegetais/farmacologia , Staphylococcus , Dronabinol/farmacologia , Antibacterianos/farmacologia , Alucinógenos/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Etanol/farmacologia
14.
Neurosci Lett ; 824: 137666, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38331019

RESUMO

Alcohol Use Disorder (AUD) presents a significant and challenging public health concern, marked by a dearth of effective pharmacological treatments. Understanding the neurobiological underpinnings of AUD is of paramount importance for the development of efficacious interventions. The process of addiction entails the acquisition of associative behaviors, prominently engaging the dorsal region of the hippocampus for encoding these associative memories. Nicotinic receptor systems have been implicated in mediating the rewarding effects of ethanol, as well as memory and learning processes. In our current investigation, we delved into the role of α4ß2 nicotinic acetylcholine receptors (nAChRs) within the dorsal hippocampus in the context of ethanol-induced conditioned place preference (CPP), a robust model for scrutinizing the rewarding properties and drug-associated behaviors. To establish CPP, ethanol (2 g/kg) was administered intraperitoneally during a 8-day conditioning phase. Fos immunohistochemistry was employed to assess the involvement of discrete subregions within the dorsal hippocampus in ethanol-induced CPP. Additionally, we probed the influence of α4ß2 nAChRs on CPP via microinjections of a selective nAChR antagonist, dihydro-ß-erythroidine (DHBE, at dosages of 6, 12, and 18 µg/0.5 µL per hemisphere) within the hippocampus. Our results unveiled that ethanol-induced CPP was associated with an increase Fos -positive cells in various subregions of the dorsal hippocampus, including CA1, CA2, CA3, and the dentate gyrus. Intrahippocampal administration of DHBE (at doses of 6 and 18 µg/0.50 µL per hemisphere) effectively blocked ethanol-induced CPP, while leaving locomotor activity unaffected. These findings underscore the critical involvement of the dorsal hippocampus and α4ß2 nAChRs in the acquisition of ethanol-associated learning and reward.


Assuntos
Etanol , Receptores Nicotínicos , Camundongos , Animais , Etanol/farmacologia , Receptores Nicotínicos/metabolismo , Hipocampo/metabolismo , Antagonistas Nicotínicos/farmacologia
15.
Cells ; 13(4)2024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38391934

RESUMO

Alcohol use disorder (AUD) requires new neurobiological targets. Problematic drinking involves underactive indirect pathway medium spiny neurons (iMSNs) that subserve adaptive behavioral selection vs. overactive direct pathway MSNs (dMSNs) that promote drinking, with a shift from ventromedial to dorsolateral striatal (VMS, DLS) control of EtOH-related behavior. We hypothesized that inhibiting phosphodiesterase 10A (PDE10A), enriched in striatal MSNs, would reduce EtOH self-administration in rats with a history of chronic intermittent ethanol exposure. To test this, Wistar rats (n = 10/sex) with a history of chronic intermittent EtOH (CIE) vapor exposure received MR1916 (i.p., 0, 0.05, 0.1, 0.2, and 0.4 µmol/kg), a PDE10A inhibitor, before operant EtOH self-administration sessions. We determined whether MR1916 altered the expression of MSN markers (Pde10a, Drd1, Drd2, Penk, and Tac1) and immediate-early genes (IEG) (Fos, Fosb, ΔFosb, and Egr1) in EtOH-naïve (n = 5-6/grp) and post-CIE (n = 6-8/grp) rats. MR1916 reduced the EtOH self-administration of high-drinking, post-CIE males, but increased it at a low, but not higher, doses, in females and low-drinking males. MR1916 increased Egr1, Fos, and FosB in the DLS, modulated by sex and alcohol history. MR1916 elicited dMSN vs. iMSN markers differently in ethanol-naïve vs. post-CIE rats. High-drinking, post-CIE males showed higher DLS Drd1 and VMS IEG expression. Our results implicate a role and potential striatal bases of PDE10A inhibitors to influence post-dependent drinking.


Assuntos
Etanol , Compostos Orgânicos , Inibidores de Fosfodiesterase , Masculino , Feminino , Ratos , Animais , Etanol/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/uso terapêutico , Ratos Wistar , Diester Fosfórico Hidrolases/genética , Diester Fosfórico Hidrolases/metabolismo , Expressão Gênica
16.
J Physiol Sci ; 74(1): 13, 2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38408944

RESUMO

The TGF-ß1/Smad3-signaling pathway and gender differences were investigated in alcoholic liver fibrosis. Mice were divided into female normal, female model, male normal, and male model groups. Liver injury and fibrosis were assessed using histopathology and serology. Western blotting was performed to analyze the expression of relevant factors. HSC-T6 cells were divided into estradiol + saline, estradiol + ethanol, testosterone + saline, and testosterone + ethanol groups, and similar assessments were conducted in vitro. Compared with the female model group, the male model group exhibited significantly increased GPT, GOT, TNF-α, IL-6, and testosterone levels, fibrosis rate, and TGF-ß1, Smad3, and PCNA expression, and significantly decreased estradiol levels and Caspase-3 expression. The apoptosis rate was higher in the estradiol + ethanol group than in the testosterone + ethanol group, although the testosterone + ethanol group exhibited significantly increased TNF-α, IL-6, Collagen-I, α-SMA, TGF-ß1, Smad3, and PCNA expression, and significantly decreased Caspase-3 expression. Alcoholic liver fibrosis showed significant gender differences associated with the TGF-ß1/Smad3-signaling pathway.


Assuntos
Fator de Crescimento Transformador beta1 , Fator de Necrose Tumoral alfa , Camundongos , Masculino , Feminino , Animais , Fator de Crescimento Transformador beta1/metabolismo , Caspase 3/metabolismo , Interleucina-6 , Antígeno Nuclear de Célula em Proliferação/metabolismo , Fatores Sexuais , Cirrose Hepática , Fibrose , Transdução de Sinais , Etanol/farmacologia , Testosterona , Estradiol
17.
Int J Mol Sci ; 25(4)2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38397125

RESUMO

Alcohol misuse and HIV independently induce myopathy. We previously showed that chronic binge alcohol (CBA) administration, with or without simian immunodeficiency virus (SIV), decreases differentiation capacity of male rhesus macaque myoblasts. We hypothesized that short-term alcohol and CBA/SIV would synergistically decrease differentiation capacity and impair bioenergetic parameters in female macaque myoblasts. Myoblasts from naïve (CBA-/SIV-), vehicle [VEH]/SIV, and CBA/SIV (N = 4-6/group) groups were proliferated (3 days) and differentiated (5 days) with 0 or 50 mM ethanol (short-term). CBA/SIV decreased differentiation and increased non-mitochondrial oxygen consumption rate (OCR) versus naïve and/or VEH/SIV. Short-term alcohol decreased differentiation; increased maximal and non-mitochondrial OCR, mitochondrial reactive oxygen species (ROS) production, and aldolase activity; and decreased glycolytic measures, ATP production, mitochondrial membrane potential (ΔΨm), and pyruvate kinase activity. Mitochondrial ROS production was closely associated with mitochondrial network volume, and differentiation indices were closely associated with key bioenergetic health and function parameters. Results indicate that short-term alcohol and CBA non-synergistically decrease myoblast differentiation capacity. Short-term alcohol impaired myoblast glycolytic function, driving the bioenergetic deficit. Results suggest potentially differing mechanisms underlying decreased differentiation capacity with short-term alcohol and CBA, highlighting the need to elucidate the impact of different alcohol use patterns on myopathy.


Assuntos
Consumo Excessivo de Bebidas Alcoólicas , Doenças Musculares , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Feminino , Animais , Masculino , Macaca mulatta , Síndrome de Imunodeficiência Adquirida dos Símios/complicações , Espécies Reativas de Oxigênio , Etanol/farmacologia , Mioblastos , Metabolismo Energético , Doenças Musculares/complicações , Carga Viral
18.
Cell Mol Life Sci ; 81(1): 34, 2024 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-38214802

RESUMO

This review provides an update on recent findings from basic, translational, and clinical studies on the molecular mechanisms of mitochondrial dysfunction and apoptosis of hepatocytes in multiple liver diseases, including but not limited to alcohol-associated liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), and drug-induced liver injury (DILI). While the ethanol-inducible cytochrome P450-2E1 (CYP2E1) is mainly responsible for oxidizing binge alcohol via the microsomal ethanol oxidizing system, it is also responsible for metabolizing many xenobiotics, including pollutants, chemicals, drugs, and specific diets abundant in n-6 fatty acids, into toxic metabolites in many organs, including the liver, causing pathological insults through organelles such as mitochondria and endoplasmic reticula. Oxidative imbalances (oxidative stress) in mitochondria promote the covalent modifications of lipids, proteins, and nucleic acids through enzymatic and non-enzymatic mechanisms. Excessive changes stimulate various post-translational modifications (PTMs) of mitochondrial proteins, transcription factors, and histones. Increased PTMs of mitochondrial proteins inactivate many enzymes involved in the reduction of oxidative species, fatty acid metabolism, and mitophagy pathways, leading to mitochondrial dysfunction, energy depletion, and apoptosis. Unique from other organelles, mitochondria control many signaling cascades involved in bioenergetics (fat metabolism), inflammation, and apoptosis/necrosis of hepatocytes. When mitochondrial homeostasis is shifted, these pathways become altered or shut down, likely contributing to the death of hepatocytes with activation of inflammation and hepatic stellate cells, causing liver fibrosis and cirrhosis. This review will encapsulate how mitochondrial dysfunction contributes to hepatocyte apoptosis in several types of liver diseases in order to provide recommendations for targeted therapeutics.


Assuntos
Gastroenteropatias , Hepatopatias Alcoólicas , Doenças Mitocondriais , Humanos , Fígado/metabolismo , Etanol/farmacologia , Apoptose , Estresse Oxidativo , Inflamação/patologia , Gastroenteropatias/metabolismo , Hepatócitos/metabolismo , Processamento de Proteína Pós-Traducional , Proteínas Mitocondriais/metabolismo , Doenças Mitocondriais/metabolismo
19.
Viruses ; 16(1)2024 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-38257804

RESUMO

BACKGROUND: Mpox virus (MPXV) infections have increased in many countries since May 2022, increasing demand for diagnostic tests and research on the virus. To ensure personnel safety, appropriate and reliable measures are needed to disinfect and inactivate infectious samples; Methods: We evaluated the stability of infectious MPXV cultures stored at different temperatures and through freeze-thaw cycles. Heat physical treatment (56 °C, 70 °C, 95 °C), chemical treatment (beta-propiolactone (BPL)) and two commercialized disinfectants (Micro-Chem Plus (MCP) and ethanol) were tested against infectious MPXV cultures; Results: The results indicated that MPXV stability increases with lower temperatures. The MPXV titer was stable within three freeze-thaw cycles and only decreased by 1.04 log10 (lg) 50% cell culture infective dose (CCID50) per milliliter (12.44%) after twelve cycles. MPXV could be effectively inactivated at 56 °C for 40 min, 70 °C for 10 min, and 95 °C for 5 min. For BPL inactivation, a 1:1000 volume ratio (BPL:virus) could also effectively inactivate MPXV. A total of 2% or 5% MCP and 75% ethanol treated with MPXV for at least 1 min could reduce >4.25 lg; Conclusions: MPXV shows high stability to temperature and freeze-thaw. Heat and BPL treatments are effective for the inactivation of MPXV, while MCP and ethanol are effective for disinfection, which could help laboratory staff operate the MPXV under safer conditions and improve operational protocols.


Assuntos
Desinfetantes , Desinfecção , Humanos , Vírus da Varíola dos Macacos , Desinfetantes/farmacologia , Técnicas de Cultura de Células , Etanol/farmacologia , Propiolactona
20.
J Biomed Mater Res B Appl Biomater ; 112(1): e35356, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38247241

RESUMO

Sterilization of structural bone allografts is a critical process prior to their clinical use in large cortical bone defects. Gamma irradiation protocols are known to affect tissue integrity in a dose dependent manner. Alternative sterilization treatments, such as supercritical carbon dioxide (SCCO2 ), are gaining popularity due to advantages such as minimal exposure to denaturants, the lack of toxic residues, superior tissue penetration, and minor impacts on mechanical properties including strength and stiffness. The impact of SCCO2 on the fracture toughness of bone tissue, however, remains unknown. Here, we evaluate crack initiation and growth toughness after 2, 6, and 24 h SCCO2 -treatment using Novakill™ and ethanol as additives on ~11 samples per group obtained from a pair of femur diaphyses of a canine. All mechanical testing was performed at ambient air after 24 h soaking in Hanks' balanced salt solution (HBSS). Results show no statistically significant difference in the failure characteristics of the Novakill™-treated groups whereas crack growth toughness after 6 and 24 h of treatment with ethanol significantly increases by 37% (p = .010) and 34% (p = .038), respectively, compared to an untreated control group. In contrast, standard 25 kGy gamma irradiation causes significantly reduced crack growth resistance by 40% (p = .007) compared to untreated bone. FTIR vibrational spectroscopy, conducted after testing, reveals a consistent trend of statistically significant differences (p < .001) with fracture toughness. These trends align with variations in the ratios of enzymatic mature to immature crosslinks in the collagen structure, suggesting a potential association with fracture toughness. Additional Raman spectroscopy after testing shows a similar trend with statistically significant differences (p < .005), which further supports that collagen structural changes occur in the SCF-treated groups with ethanol after 6 and 24 h. Our work reveals the benefits of SCCO2 sterilization compared to gamma irradiation.


Assuntos
Dióxido de Carbono , Fraturas Ósseas , Animais , Cães , Dióxido de Carbono/farmacologia , Etanol/farmacologia , Osso e Ossos , Osso Cortical , Colágeno/farmacologia
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