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1.
Eur J Neurosci ; 54(10): 7710-7732, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34670326

RESUMO

Treatment of post-traumatic stress disorder is complicated by the presence of alcohol use disorder comorbidity. Little is known about the underlying brain mechanisms. We have recently shown, in mice, that the post-traumatic stress disorder-like phenotype is characterised by the increase and decrease in total dendritic number and length in the prelimbic and infralimbic areas of the medial prefrontal cortex, respectively. Here, we examined whether repeated ethanol exposure would exacerbate these changes and whether this would be associated with difficulty to extinguish passive avoidance behaviour, as an indicator of treatment resistance. We also analysed whether other known trauma-associated changes, like increased or decreased corticosterone and decreased brain-derived neurotrophic factor levels, would also be exacerbated. Male mice underwent trauma exposure (1.5-mA footshock), followed, 8 days later, by a conditioned place preference training with ethanol. Tests for fear sensitization, passive avoidance, anxiety-like behaviour, extinction acquisition and relapse susceptibility were used to assess behaviour changes. Plasma corticosterone and brain-derived neurotrophic factor levels and prefrontal dendritic changes were subsequently measured. Trauma-susceptible mice exposed to ethanol acquired a strong place preference and behaved differently from those not exposed to ethanol, with delayed avoidance extinction and higher avoidance relapse vulnerability. Ethanol potentiated trauma-associated dendritic changes in the prelimbic area and suppressed trauma-associated dendritic changes in the infralimbic area. However, ethanol had no effect on trauma-induced increased corticosterone and decreased brain-derived neurotrophic factor levels. These data suggest that the modification of prefrontal trauma-related changes, due to alcohol use, can characterise, and probably support, treatment-resistant post-traumatic stress disorder.


Assuntos
Transtornos de Estresse Pós-Traumáticos , Animais , Condicionamento Clássico , Etanol/toxicidade , Extinção Psicológica , Medo , Masculino , Camundongos , Córtex Pré-Frontal
2.
Ethiop J Health Sci ; 31(3): 673-682, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34483625

RESUMO

Background: Alcohol consumption can cause hepatitis and long-term cirrhosis of the liver. The aim of this study was to evaluate the protective effects of curcumin (CUR) and ursodeoxycholic acid (UDCA) alone and together in the prevention and treatment of liver damage caused by overuse of ethanol. Methods: Adult Wistar rats were divided into 8 groups of 5, including the control group and various combinations of ethanol, CUR and UDCA groups. Twenty-eight days after the oral treatment, serum levels of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT) and Arginase I (ArgI) as well as serum levels of Albumin (Alb), total protein (TP) and Blood Urea Nitrogen (BUN) were measured, and liver tissue was evaluated histopathologically. Results: The solo administration of CUR, UDCA and CUR+UDCA had no effect on the blood parameters and liver tissue compared to the control group (p>0.05). The solo administration of CUR and UDCA in ethanol-treated rats significantly reduced ALT, AST, ALP, GGT, ArgI and BUN levels (p<0.05), while the solo administration increased Alb and TP levels compared to the ethanol group (p<0.05). In these groups, a significant decrease in cell necrosis and local inflammation of hepatocytes was observed, and the liver damage was mild. However, co-administration of ethanol, CUR and UDCA made significantly greater decrease in ALT, AST, ALP, GGT, ArgI and BUN levels (p>0.05), while the co-administration greatly increased Alb and TP levels compared to the ethanol group (p<0.05). Histopathologically, a decrease in structural changes in liver tissue and inflammation was observed, resulting in the improvement of liver tissue. Conclusion: The solo administration of CUR and UDCA could reduce ethanol-induced liver damage in rats and improve liver's serum and blood parameters. However, the coadministration of CUR and UDCA has a greater efficacy.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Curcumina , Animais , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Curcumina/farmacologia , Etanol/toxicidade , Ratos , Ratos Wistar , Ácido Ursodesoxicólico
3.
Int J Mol Sci ; 22(18)2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34575850

RESUMO

Alcohol is a psychoactive substance that is widely used and, unfortunately, often abused. In addition to acute effects such as intoxication, it may cause many chronic pathological conditions. Some of the effects are very well described and explained, but there are still gaps in the explanation of empirically co-founded dysfunction in many alcohol-related conditions. This work focuses on reviewing actual knowledge about the toxic effects of ethanol and its degradation products.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Transtornos Relacionados ao Uso de Álcool/metabolismo , Etanol/efeitos adversos , Etanol/metabolismo , Acetaldeído/metabolismo , Álcool Desidrogenase/genética , Álcool Desidrogenase/metabolismo , Transtornos Relacionados ao Uso de Álcool/etiologia , Etanol/toxicidade , Regulação Enzimológica da Expressão Gênica , Humanos , Redes e Vias Metabólicas , Especificidade de Órgãos , Estresse Oxidativo
4.
Altern Ther Health Med ; 27(5): 120-128, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34582364

RESUMO

Alcohol intake can cause a wide range of visual system abnormalities. In this study, we characterized how ethanol affects the growth, external morphology and locomotion of zebrafish, particularly with regard to retinal development. Zebrafish embryos were divided into 5 groups and put into hatching liquid for 6 hours. The embryos from 4 groups were treated with varying concentrations of ethanol (0.5%, 1.5%, 2.5% and 3% by volume) from 6 to 24 hours post-fertilization. The toxic effects of ethanol on embryonic development were assessed by mortality, hatching rate and morphologic deformity. The effects of ethanol on locomotive activity were assessed by autonomous motion detection and swimming behavior analysis. The effects of ethanol on retinal morphology were assessed by histologic, immunohistochemical and electron microscopy analyses. Ethanol treatment increased the mortality and induced growth retardation in zebrafish larvae. The locomotive activities of zebrafish embryos/larvae were impeded by exposure to higher (1.5% and 2.5%) concentrations of ethanol. Embryos exposed to higher levels of ethanol at the early developmental stage had a reduction in eye size. The ethanol treatment disrupts the architecture of the retina and reduces retinal size. Embryos exposed to 2.5% concentration of ethanol had morphologic abnormalities of the photoreceptors. Ethanol exposure also inhibited retinal cell differentiation and proliferation, but did not affect apical epithelial polarity. These findings suggest that ethanol affects the growth and external morphology of zebrafish, and higher levels of ethanol exposure can cause defects of locomotor activity and photoreceptor development.


Assuntos
Etanol , Peixe-Zebra , Animais , Proliferação de Células , Embrião não Mamífero , Etanol/toxicidade , Locomoção
5.
Alcohol ; 96: 43-53, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34358666

RESUMO

Fetal alcohol spectrum disorders (FASD) are alarmingly common, result in significant personal and societal loss, and there are no effective treatments for these disorders. Cerebellar neuropathology is common in FASD and can cause impaired cognitive and motor function. The current study evaluates the effects of ethanol on oligodendrocyte-lineage cells, as well as molecules that modulate oligodendrocyte differentiation and function in the cerebellum in a postnatal mouse model of FASD. Neonatal mice were treated with ethanol from P4-P9 (postnatal day), the cerebellum was isolated at P10, and mRNAs encoding oligodendrocyte-associated molecules were quantitated by qRT-PCR. Our studies demonstrated that ethanol significantly reduced the expression of markers for multiple stages of oligodendrocyte maturation, including oligodendrocyte precursor cells, pre-myelinating oligodendrocytes, and mature myelinating oligodendrocytes. Additionally, we determined that ethanol significantly decreased the expression of molecules that play critical roles in oligodendrocyte differentiation. Interestingly, we also observed that ethanol significantly reduced the expression of myelin-associated inhibitors, which may act as a compensatory mechanism to ethanol toxicity. Furthermore, we demonstrate that ethanol alters the expression of a variety of molecules important in oligodendrocyte function and myelination. Collectively, our studies increase our understanding of specific mechanisms by which ethanol modulates myelination in the developing cerebellum, and potentially identify novel targets for FASD therapy.


Assuntos
Transtornos do Espectro Alcoólico Fetal , Animais , Cerebelo , Etanol/toxicidade , Feminino , Transtornos do Espectro Alcoólico Fetal/genética , Camundongos , Bainha de Mielina , Oligodendroglia , Gravidez
6.
PLoS Comput Biol ; 17(8): e1009110, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34351898

RESUMO

Ethanol is one of the most widely used recreational substances in the world and due to its ubiquitous use, ethanol abuse has been the cause of over 3.3 million deaths each year. In addition to its effects, ethanol's primary metabolite, acetaldehyde, is a carcinogen that can cause symptoms of facial flushing, headaches, and nausea. How strongly ethanol or acetaldehyde affects an individual depends highly on the genetic polymorphisms of certain genes. In particular, the genetic polymorphisms of mitochondrial aldehyde dehydrogenase, ALDH2, play a large role in the metabolism of acetaldehyde. Thus, it is important to characterize how genetic variations can lead to different exposures and responses to ethanol and acetaldehyde. While the pharmacokinetics of ethanol metabolism through alcohol dehydrogenase have been thoroughly explored in previous studies, in this paper, we combined a base physiologically-based pharmacokinetic (PBPK) model with a whole-body genome-scale model (WBM) to gain further insight into the effect of other less explored processes and genetic variations on ethanol metabolism. This combined model was fit to clinical data and used to show the effect of alcohol concentrations, organ damage, ALDH2 enzyme polymorphisms, and ALDH2-inhibiting drug disulfiram on ethanol and acetaldehyde exposure. Through estimating the reaction rates of auxiliary processes with dynamic Flux Balance Analysis, The PBPK-WBM was able to navigate around a lack of kinetic constants traditionally associated with PK modelling and demonstrate the compensatory effects of the body in response to decreased liver enzyme expression. Additionally, the model demonstrated that acetaldehyde exposure increased with higher dosages of disulfiram and decreased ALDH2 efficiency, and that moderate consumption rates of ethanol could lead to unexpected accumulations in acetaldehyde. This modelling framework combines the comprehensive steady-state analyses from genome-scale models with the dynamics of traditional PK models to create a highly personalized form of PBPK modelling that can push the boundaries of precision medicine.


Assuntos
Acetaldeído/metabolismo , Alcoolismo/genética , Alcoolismo/metabolismo , Etanol/metabolismo , Modelos Biológicos , Acetaldeído/farmacocinética , Acetaldeído/toxicidade , Inibidores de Acetaldeído Desidrogenases/farmacologia , Dissuasores de Álcool/farmacologia , Alcoolismo/tratamento farmacológico , Aldeído-Desidrogenase Mitocondrial/genética , Aldeído-Desidrogenase Mitocondrial/metabolismo , Biologia Computacional , Simulação por Computador , Dissulfiram/farmacologia , Etanol/farmacocinética , Etanol/toxicidade , Humanos , Absorção Intestinal/fisiologia , Cinética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Distribuição Tecidual
7.
Alcohol ; 96: 63-71, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34461247

RESUMO

BACKGROUND: Stressful conditions increase alcohol consumption in men. Clinical studies link disruption of the neuroendocrine stress system with alcoholism, but the effect of alcohol in a stress condition on male fertility is still relatively poorly understood. This project was undertaken to evaluate the effect of sub-chronic alcohol in a stress condition on male fertility in a rat model. METHODS: Male Sprague-Dawley rats were randomly divided into a control group, a stress group that was exposed to restraint stress, an ethanol group that was injected with ethanol daily, and a stress + ethanol group that was injected with ethanol daily and was exposed to restraint stress, simultaneously. Furthermore, testis tissue was evaluated histomorphometrically and immunohistochemically for apoptosis using a TUNEL assay after 12 days. Epididymis sperm analysis was done. Blood cortisol and testosterone were measured and expression of hypothalamic kisspeptin (Kiss1), RFRP-3, and MC4R mRNA were evaluated. RESULTS: Ethanol exposure during restraint stress did not alter body weight. Ethanol exposure decreased the cellular diameter and area, and stress increased the cellular diameter and area, in comparison with the control group. In the stress group, in comparison with the other groups, the number of seminiferous tubules decreased and the numerical density of seminiferous tubules increased. In addition, ethanol exposure and/or stress reduced semen analysis parameters (sperm viability and motility), but did not change serum testosterone concentrations. Apoptosis increased in spermatogonia with ethanol exposure, but spermatocytes were not affected. Our data present the novel finding that ethanol and stress reduced hypothalamic Kiss1 mRNA expression, while ethanol exposure decreased hypothalamic RFRP-3 and MC4R mRNA expression. CONCLUSIONS: Ethanol decreased cortisol hormone level during the restraint stress condition and attenuated hypothalamic reproductive-related gene expressions. Therefore, ethanol exposure may induce reduction of sperm viability, increased sperm mortality, and increased apoptosis, with long-term effects, and may induce permanent male subfertility.


Assuntos
Etanol , Infertilidade Masculina , Estresse Psicológico , Testículo , Animais , Apoptose , Etanol/toxicidade , Infertilidade Masculina/induzido quimicamente , Kisspeptinas , Masculino , Ratos , Ratos Sprague-Dawley , Receptor Tipo 4 de Melanocortina , Motilidade Espermática , Espermatogênese , Testosterona
8.
Toxicol Lett ; 351: 78-88, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34454011

RESUMO

We previously found that prenatal ethanol exposure (PEE) induced adrenal dysplasia in offspring, which was related to intrauterine maternal glucocorticoid overexposure. This study investigated the intergenerational genetic effect and sex differences of PEE-induced changes in the synthetic function of adrenal corticosterone in offspring, and to clarify the intrauterine origin programming mechanism. Wistar pregnant rats were gavaged with ethanol (4 g/kg bw/d) from gestation day (GD) 9-20, and F1 generation was born naturally. The F1 generation female rats in the PEE group were mated with normal male rats to produce F2 generation. Serum and adrenal glands of fetal rats and F1/F2 adult rats were collected at GD20 and postnatal week 28. PEE increased the serum corticosterone level, while diminishing the expression of adrenal steroid synthases of fetal rats. Moreover, PEE enhanced the mRNA expression of GR and HDAC1, but inhibited the mRNA expression of SF1 and reduced the H3K9ac level of P450scc in the fetal adrenal gland. In PEE adult offspring of F1 and F2 generation the serum corticosterone level, the H3K9ac level of P450scc and its expression were decreased in males but were increased in females. In NCI-H295R cells, cortisol reduced the production of endogenous cortisol, down-regulated SF1, and up-regulated HDAC1 expression by activating GR, and decreased H3K9ac level and expression of P450scc. In conclusion, PEE could induce adrenal dysplasia in offspring with sex differences and intergenerational genetic effects, and the adrenal insufficiency in male offspring was related to the induction of low functional genetic programming of P450scc by intrauterine high corticosterone through the GR/SF1/HDAC1 pathway.


Assuntos
Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/metabolismo , Corticosterona/biossíntese , Etanol/toxicidade , Glândulas Suprarrenais/crescimento & desenvolvimento , Animais , Linhagem Celular , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Hidrocortisona , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Fatores de Processamento de RNA/genética , Fatores de Processamento de RNA/metabolismo , Ratos , Ratos Wistar , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Fatores Sexuais , Organismos Livres de Patógenos Específicos
9.
Biomed Khim ; 67(4): 323-330, 2021 Jul.
Artigo em Russo | MEDLINE | ID: mdl-34414890

RESUMO

We investigated the levels of biogenic monoamines and their metabolites in the rat hypothalamus, midbrain and cerebellum in acute complex intoxication with morphine and alcohol. The distinctive features of neurotransmitter disorders in various parts of the rat brain under a single exposure to ethanol and morphine, as well as the differences between acute morphine-alcohol and alcohol-morphine intoxication were established. Complex intoxication with alcohol and morphine resulted in signs of dopamine consumption only in the hypothalamus, regardless of the order of alcohol and morphine administration. Under conditions of alcohol-morphine intoxication an increase in the level of metabolites of the serotonergic system was noted in the investigated parts of the brain. In the midbrain and cerebellum the manifestation of combined action of ethanol and morphine is mainly determined by the effect of the last of the administered substances. There are features of changes in the indices of the dopaminergic and serotonergic systems in these experimental conditions, confirmed by the processes of dopamine catabolism and a decrease in the norepinephrine and serotonin concentration in the hypothalamus, which are not observed under individual action of ethanol and morphine.


Assuntos
Morfina , Neurotransmissores , Animais , Encéfalo , Etanol/toxicidade , Ratos , Serotonina
10.
Artigo em Inglês | MEDLINE | ID: mdl-34444449

RESUMO

Ethanol consumption remains a major concern at a world scale in terms of transient or irreversible neurological consequences, with motor, cognitive, or social consequences. Cerebellum is particularly vulnerable to ethanol, both during development and at the adult stage. In adults, chronic alcoholism elicits, in particular, cerebellar vermis atrophy, the anterior lobe of the cerebellum being highly vulnerable. Alcohol-dependent patients develop gait ataxia and lower limb postural tremor. Prenatal exposure to ethanol causes fetal alcohol spectrum disorder (FASD), characterized by permanent congenital disabilities in both motor and cognitive domains, including deficits in general intelligence, attention, executive function, language, memory, visual perception, and communication/social skills. Children with FASD show volume deficits in the anterior lobules related to sensorimotor functions (Lobules I, II, IV, V, and VI), and lobules related to cognitive functions (Crus II and Lobule VIIB). Various mechanisms underlie ethanol-induced cell death, with oxidative stress and endoplasmic reticulum (ER) stress being the main pro-apoptotic mechanisms in alcohol abuse and FASD. Oxidative and ER stresses are induced by thiamine deficiency, especially in alcohol abuse, and are exacerbated by neuroinflammation, particularly in fetal ethanol exposure. Furthermore, exposure to ethanol during the prenatal period interferes with neurotransmission, neurotrophic factors and retinoic acid-mediated signaling, and reduces the number of microglia, which diminishes expected cerebellar development. We highlight the spectrum of cerebellar damage induced by ethanol, emphasizing physiological-based clinical profiles and biological mechanisms leading to cell death and disorganized development.


Assuntos
Ataxia Cerebelar , Transtornos do Espectro Alcoólico Fetal , Morte Celular , Cerebelo , Etanol/toxicidade , Feminino , Humanos , Gravidez
11.
Free Radic Biol Med ; 174: 249-263, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34390780

RESUMO

Alcohol metabolism in the liver simultaneously generates toxic metabolites and disrupts redox balance, but the regulatory mechanisms have not been fully elucidated. The study aimed to characterize the role of PPARα in alcohol detoxification. Hepatic PPARα and catalase levels were examined in patients with severe alcoholic hepatitis. Mouse studies were conducted to determine the effect of PPARα reactivation by Wy14,643 on alcoholic hepatotoxicity and how catalase is involved in mediating such effects. Cell culture study was conducted to determine the effect of hydrogen peroxide on cellular NAD levels. We found that the protein levels of PPARα and catalase were significantly reduced in the livers of patients with severe alcoholic hepatitis. PPARα reactivation by Wy14,643 effectively reversed alcohol-induced liver damage in mice. Global and targeted metabolites analysis revealed a fundamental role of PPARα in regulating the tryptophan-NAD pathway. Notably, PPARα activation completely switched alcohol metabolism from the CYP2E1 pathway to the catalase pathway along with accelerated alcohol clearance. Catalase knockout mice were incompetent in alcohol metabolism and hydrogen peroxide clearance and were more susceptible to alcohol-induced liver injury. Hydrogen peroxide-treated hepatocytes had a reduced size of cellular NAD pool. These data demonstrate a key role of PPARα in regulating hepatic alcohol detoxification. Catalase-mediated hydrogen peroxide removal represents an underlying mechanism of how PPARα preserves the NAD pool. The study provides a new angle of view about the PPARα-catalase pathway in combating alcohol toxicity.


Assuntos
NAD , PPAR alfa , Animais , Catalase/genética , Etanol/toxicidade , Humanos , Fígado , Camundongos , Camundongos Endogâmicos C57BL , PPAR alfa/genética
12.
Neuroscience ; 473: 52-65, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34450212

RESUMO

During adolescence, heavy binge-like ethanol consumption can lead to frontocortical structural and functional impairments. These impairments are likely driven by adolescence being a critical time point for maturation of brain regions associated with higher-order cognitive functioning. Rodent models of heavy binge-like ethanol exposure show consistent disruptions to the typical development of the prefrontal cortex (PFC). All deep cortical layers receive cholinergic projections that originate from the Nucleus basalis of Meynert (NbM) complex. These cholinergic projections are highly involved in learning, memory, and attention. Adolescent intermittent ethanol exposure (AIE) induces cholinergic dysfunction as a result of an epigenetic suppression of the genes that drive the cholinergic phenotype. The current study used a model of AIE to assess structural and functional changes to the frontal cortex and NbM following binge-like ethanol exposure in adolescence. Western blot analysis revealed long-term disruptions of the cholinergic circuit following AIE: choline acetyltransferase (ChAT) was suppressed in the NbM and vesicular acetylcholine transporter (VAChT) was suppressed in the orbitofrontal cortex (OFC). In vivo microdialysis for acetylcholine efflux during a spatial memory task determined changes in cholinergic modulation within the PFC following AIE. However, AIE spared performance on the spatial memory task and on an operant reversal task. In a second study, Golgi-Cox staining determined that AIE increased apical dendritic complexity in the OFC, with sex influencing whether the increase in branching occurred near or away from the soma. Spine density or maturity was not affected, likely compensating for a disruption in neurotransmitter function following AIE.


Assuntos
Etanol , Córtex Pré-Frontal , Encéfalo , Colinérgicos , Etanol/toxicidade , Lobo Frontal
13.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445488

RESUMO

Prenatal alcohol exposure (PAE) can have immediate and long-lasting toxic and teratogenic effects on an individual's development and health. As a toxicant, alcohol can lead to a variety of physical and neurological anomalies in the fetus that can lead to behavioral and other impairments which may last a lifetime. Recent studies have focused on identifying mechanisms that mediate the immediate teratogenic effects of alcohol on fetal development and mechanisms that facilitate the persistent toxic effects of alcohol on health and predisposition to disease later in life. This review focuses on the contribution of epigenetic modifications and intercellular transporters like extracellular vesicles to the toxicity of PAE and to immediate and long-term consequences on an individual's health and risk of disease.


Assuntos
Etanol/toxicidade , Desenvolvimento Fetal/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/genética , Teratogênese/genética , Adolescente , Desenvolvimento do Adolescente/efeitos dos fármacos , Adulto , Epigênese Genética/efeitos dos fármacos , Vesículas Extracelulares/efeitos dos fármacos , Vesículas Extracelulares/genética , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Gravidez
14.
Redox Biol ; 46: 102081, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34343907

RESUMO

BACKGROUND: Alcoholic liver disease (ALD) is the most common liver disease worldwide and its underlying molecular mechanisms are still poorly understood. Moreover, conflicting data have been reported on potentially protective autophagy, the exact role of ethanol-metabolizing enzymes and ROS. METHODS: Expression of LC3B, CYP2E1, and NOX4 was studied in a mouse model of acute ethanol exposure by immunoblotting and immunohistochemistry. Autophagy was further studied in primary mouse hepatocytes and huh7 cells in response to ethanol and its major intermediator acetaldehyde. Experiments were carried out in cells overexpressing CYP2E1 and knock down of NOX4 using siRNA. The response to external H2O2 was studied by using the GOX/CAT system. Autophagic flux was monitored using the mRFP-GFP-LC3 plasmid, while rapamycin and chloroquine served as positive and negative controls. RESULTS: Acute ethanol exposure of mice over 24 h significantly induced autophagy as measured by LC3B expression but also induced the ROS-generating CYP2E1 and NOX4 enzymes. Notably, ethanol but not its downstream metabolite acetaldehyde induced autophagy in primary mouse hepatocytes. In contrast, autophagy could only be induced in huh7 cells in the presence of overexpressed CYP2E1. In addition, overexpression of NOX4 also significantly increased autophagy, which could be blocked by siRNA mediated knock down. The antioxidant N-acetylcysteine (NAC) also efficiently blocked CYP2E1-and NOX4-mediated induction of autophagy. Finally, specific and non-toxic production of H2O2 by the GOX/CAT system as evidenced by elevated peroxiredoxin (Prx-2) also induced LC3B which was efficiently blocked by NAC. H2O2 strongly increased the autophagic flux as measured by mRFP-GFP-LC3 plasmid. CONCLUSION: We here provide evidence that short-term ethanol exposure induces autophagy in hepatocytes both in vivo and in vitro through the generation of ROS. These data suggest that suppression of autophagy by ethanol is most likely due to longer alcohol exposure during chronic alcohol consumption with the accumulation of e.g. misfolded proteins.


Assuntos
Peróxido de Hidrogênio , Hepatopatias Alcoólicas , Animais , Autofagia , Citocromo P-450 CYP2E1/genética , Etanol/toxicidade , Hepatopatias Alcoólicas/genética , Camundongos
15.
Toxicol Mech Methods ; 31(9): 699-710, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34376109

RESUMO

The purpose of this study was designed to evaluate the protective effect of probiotics fortified with Aloe vera pulp nanoemulsion on ethanol-induced gastric ulcer (GU). Freshly harvested Aloe vera pulp nanoemulsion was prepared and subsequently inoculated with 2% of the activated yogurt starter culture of Streptococcus thermophilus and Lactobacillus delbreukii subsp. bulgaricus (1:1). Chemical composition and physicochemical characterization of yogurt and the Aloe vera pulp nanoemulsion were assessed. GU was induced by ethanol. Rats were randomly assigned into control, GU, and four prophylactic groups including probiotics fortified with Aloe vera pulp nanoemulsion in the percentage of 0%, 10%, 20%, and 30% respectively. Serum levels of paraoxynase (POX) and tissue levels of malondialdehyde (MDA), nitric oxide (NO), and catalase (CAT) activity were assessed. Serum levels of nuclear factor kappa B (NF-κB), interleukin-1beta (IL-1ß), matrix metalloproteinase-9 (MMP-9), ceramide, and homocysteine (Hcy) were evaluated. Results indicated that the Aloe vera pulp nanoemulsion was appeared in spherical nano form with droplets diameter around 330 nm. Ethanol induces GU to cause a significant increase in the levels of MDA, NO, NF-κB, IL-1ß, MMP-9, Hcy, and ceramide along with a significant decrease in POX and CAT activities compared to the control group (p < 0.05). Pretreatment with different concentrations of probiotics fortified with Aloe vera pulp nanoemulsion with, especially the 30% concentration, significantly reduce the oxidative stress and ameliorate the release of different inflammatory mediators suggesting it as a promising approach in the protection against GU via scavenging superoxide radicals and inhibiting the activation of the inflammatory signaling cascades.


Assuntos
Aloe , Probióticos , Úlcera Gástrica , Animais , Etanol/toxicidade , Malondialdeído , Extratos Vegetais/uso terapêutico , Ratos , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/prevenção & controle
16.
Biochem Pharmacol ; 192: 114678, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34265279

RESUMO

Fibroblast growth factor 21 (FGF21) is mainly regulated by peroxisome proliferator-activated receptor α (PPARα) in liver. The PPARα-FGF21 axis protects against alcohol-related liver disease (ALD). FGF21 exerts its effect via FGF receptor 1 (FGFR1). However, liver specific FGFR1 abrogation had no effect on ALD. Adipose tissues highly express FGFR1. When adipocyte specific FGFR1 knockout (fgfr1adipoQ-cre) mice and corresponding normal control (fgfr1fl/fl) mice were fed with Lieber-DeCarli ethanol liquid diet for 3 weeks, liver triglyceride (TG) accumulation was increased in the fgfr1fl/fl mice to a greater extent than in the fgfr1adipoQ-cre mice. When PPARα agonist WY-14,643 was added in the liquid ethanol diet at 10 mg/L, the ethanol-induced liver TG accumulation was blunted in the fgfr1fl/fl mice but not in the fgfr1adipoQ-cre mice. There was no significant difference in WY-14,643-induced fatty acid oxidation, ethanol metabolism, and oxidative stress between the fgfr1fl/fl and fgfr1adipoQ-cre mice. Interestingly, adipose atrophy was induced by WY-14,643 in the fgfr1adipoQ-cre mice but not in the fgfr1fl/fl mice. Serum free fatty acid was also decreased by WY-14,643 in the fgfr1adipoQ-cre mice but not in the fgfr1fl/fl mice. These results suggest that WY-14,643 inhibits alcoholic fatty liver and regulates adipose tissue mass and fat mobilization from adipose tissues to liver in an adipocyte FGFR1-dependent manner.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Etanol/toxicidade , Fígado Gorduroso Alcoólico/prevenção & controle , PPAR alfa/agonistas , Pirimidinas/uso terapêutico , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/deficiência , Tecido Adiposo/metabolismo , Animais , Atrofia/induzido quimicamente , Atrofia/metabolismo , Etanol/administração & dosagem , Fígado Gorduroso Alcoólico/metabolismo , Feminino , Camundongos , Camundongos Knockout , PPAR alfa/metabolismo , Proliferadores de Peroxissomos/uso terapêutico , Proliferadores de Peroxissomos/toxicidade , Pirimidinas/toxicidade , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética
17.
Alcohol ; 96: 1-14, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34228989

RESUMO

Garnered literature points toward the role of the dorsal hippocampus (CA1) in ethanol withdrawal-induced responses, wherein a strong presence of the histaminergic system is also reported. Therefore, the present study investigated the effect of an enhanced CA1 histaminergic transmission on the expression of chronic ethanol withdrawal-induced despair in mice on the tail suspension test (TST). The results revealed that mice who were on an ethanol-fed diet (5.96%, v/v) for 8 days exhibited maximum immobility time on the TST, and decreased locomotion at 24 h post-ethanol withdrawal (10th day), indicating ethanol withdrawal-induced despair. Enhancement of CA1 histaminergic activity achieved by the treatment of intra-CA1 microinjection of histaminergic agents such as histamine (0.1, 10 µg/mouse, bilateral), the histamine precursor l-histidine (1, 10 µg/mouse, bilateral), the histamine neuronal releaser/H3 receptor antagonist thioperamide (2, 10 µg/mouse, bilateral), the histamine H1 receptor agonist FMPH (2, 6.5 µg/mouse, bilateral), or the H2 receptor agonist amthamine (0.1, 0.5 µg/mouse, bilateral) to ethanol-withdrawn mice, 10 min before the 24-h post-ethanol withdrawal time point, significantly alleviated the expression of ethanol withdrawal-induced despair in mice on the TST. On the other hand, only the pre-treatment of the histamine H1 receptor agonist FMPH (2, 6.5 µg/mouse, intra-CA1 bilateral) reversed the reduction in locomotor activity induced in ethanol-withdrawn mice, whereas other employed histaminergic agents were devoid of any effect on this behavior. Therefore, our findings indicate that an enhanced CA1 histaminergic transmission, probably via stimulation of CA1 postsynaptic histamine H1 or H2 receptor, could preclude the behavioral despair, while H1 stimulation affects motor deficit expressed after ethanol withdrawal.


Assuntos
Hipocampo , Histamínicos , Animais , Etanol/toxicidade , Histamina , Camundongos , Receptores Histamínicos H2
18.
Int J Mol Sci ; 22(14)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34299083

RESUMO

Dihydromyricetin is a natural bioactive flavonoid with unique GABAA receptor activity with a putative mechanism of action to reduce the intoxication effects of ethanol. Although dihydromyricetin's poor oral bioavailability limits clinical utility, the promise of this mechanism for the treatment of alcohol use disorder warrants further investigation into its specificity and druggable potential. These experiments investigated the bioavailability of dihydromyricetin in the brain and serum associated with acute anti-intoxicating effects in C57BL/6J mice. Dihydromyricetin (50 mg/kg IP) administered 0 or 15-min prior to ethanol (PO 5 g/kg) significantly reduced ethanol-induced loss of righting reflex. Total serum exposures (AUC0→24) of dihydromyricetin (PO 50 mg/kg) via oral (PO) administration were determined to be 2.5 µM × h (male) and 0.7 µM × h (female), while intraperitoneal (IP) administration led to 23.8-fold and 7.2- increases in AUC0→24 in male and female mice, respectively. Electrophysiology studies in α5ß3γ2 GABAA receptors expressed in Xenopus oocytes suggest dihydromyricetin (10 µM) potentiates GABAergic activity (+43.2%), and the metabolite 4-O-methyl-dihydromyricetin (10 µM) negatively modulates GABAergic activity (-12.6%). Our results indicate that administration route and sex significantly impact DHM bioavailability in mice, which is limited by poor absorption and rapid clearance. This correlates with the observed short duration of DHM's anti-intoxicating properties and highlights the need for further investigation into mechanism of DHM's potential anti-intoxicating properties.


Assuntos
Intoxicação Alcoólica/prevenção & controle , Encéfalo/metabolismo , Etanol/toxicidade , Flavonóis/farmacologia , Intoxicação Alcoólica/etiologia , Intoxicação Alcoólica/metabolismo , Intoxicação Alcoólica/patologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Depressores do Sistema Nervoso Central/toxicidade , Feminino , Flavonóis/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL
19.
Nanomedicine (Lond) ; 16(19): 1657-1671, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34261362

RESUMO

Aim: To evaluate the gastroprotective effects of Nelumbinis Rhizomatis Nodus carbon dots (NRN-CDs) on ethanol-induced gastric ulcers in rats. Materials & methods: NRN-CDs synthesized and characterized by transmission electron microscopy, ultraviolet, fluorescence and Fourier transform infrared spectroscopy, x-ray photoelectron spectroscopy, x-ray diffraction and zeta potential analyzer. Their gastroprotective effects toward ethanol-induced gastric ulcers were evaluated in male Sprague-Dawley rats. Results: NRN-CDs showed an average diameter of 2.33 ± 0.42 nm and a lattice spacing of 0.29 nm. Pretreatment with NRN-CDs significantly decreased the ulcer index and attenuated the severity of gastric mucosal damage, indicating that NRN-CDs exerted potent gastric protective effect. Moreover, the gastroprotection effect was related to the regulation of oxidative stress and inflammatory factors. Conclusion: NRN-CDs could be developed as a potential drug for the treatment of gastric ulcers.


Assuntos
Medicamentos de Ervas Chinesas , Úlcera Gástrica , Animais , Carbono , Etanol/toxicidade , Masculino , Ratos , Ratos Sprague-Dawley , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico
20.
Artigo em Inglês | MEDLINE | ID: mdl-34203568

RESUMO

Although cancer is traditionally considered a genetic disease, the epigenetic abnormalities, including DNA hypermethylation, histone deacetylation, and/or microRNA dysregulation, have been demonstrated as a hallmark of cancer. Compared with gene mutations, aberrant epigenetic changes occur more frequently, and cellular epigenome is more susceptible to change by environmental factors. Excess cancer risks are positively associated with exposure to occupational and environmental chemical carcinogens, including those from gasoline combustion exhausted in vehicles. Of note, previous studies proposed particulate matter index (PMI) as a measure for gasoline sooting tendency, and showed that, compared with the other molecules in gasoline, 1,2,4-Trimethylbenzene, 2-methylnaphthalene and toluene significantly contribute to PMI of the gasoline blends. Mechanistically, both epigenome and genome are important in carcinogenicity, and the genotoxicity of chemical agents has been thoroughly studied. However, less effort has been put into studying the epigenotoxicity. Moreover, as the blending of ethanol into gasoline substitutes for carcinogens, like benzene, toluene, xylene, butadiene, and polycyclic aromatic hydrocarbons, etc., a reduction of secondary aromatics has been achieved in the atmosphere. This may lead to diminished cancer initiation and progression through altered cellular epigenetic landscape. The present review summarizes the most important findings in the literature on the association between exposures to carcinogens from gasoline combustion, cancer epigenetics and the potential epigenetic impacts of biofuels.


Assuntos
Poluentes Atmosféricos , Neoplasias , Poluentes Atmosféricos/análise , Etanol/toxicidade , Gasolina/análise , Gasolina/toxicidade , Neoplasias/induzido quimicamente , Neoplasias/epidemiologia , Material Particulado/análise , Tolueno , Emissões de Veículos/análise
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