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1.
Psychopharmacology (Berl) ; 239(10): 3355-3366, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36063206

RESUMO

RATIONALE: Serotonin (5-HT) is a monoamine neuromodulator that plays a key role in the organization of the central nervous system. 5-HT alterations may be associated to the emergence of social deficits and psychiatric disorders, including anxiety, depression, and substance abuse disorders. Notably, disruption of the 5-HT system during sensitive periods of development seems to exert long-term consequences, including altered anxiety responses and problematic use of alcohol. OBJECTIVE: We analyzed, in mice, the effects of transient 5-HT depletion at gestation (a developmental stage when medial prefrontal cortex (mPFC) 5-HT levels depend exclusively on placental 5-HT availability) on 5-HT central synthesis and reuptake at weaning. We also explored if 5-HT disruption at the embryonic stage influences behavioral outcomes that may serve as a proxy for autistic- or anxiety-like phenotypes. METHODS: C57/BL6 male and female mice, born from dams treated with a 5-HT synthesis inhibitor (PCPA; 4-Chloro-DL-phenylalanine methyl ester hydrochloride) at gestational days (G)13.5-16.5, were subjected to a behavioral battery that assesses social preference and novelty, compulsive behavior, stereotypies, and ethanol's anti-anxiety effects, at postnatal days (P) 21-28. Afterwards, expression of the genes that encode for 5-HT synthesis (Tph2) and SERT (5-HT transporter) were analyzed in mPFC via real-time RT-PCR. Dopamine 2 receptor (D2R) expression was also analyzed via RT-PCR to further explore possible effects of PCPA on dopaminergic transmission. RESULTS: Transient 5-HT disruption at G13.5-16.5 reduced Tph2 expression of both male and female mice in mPFC at P23. Notably, female mice also exhibited higher SERT expression and reduced D2R expression in mPFC. Mice derived from 5-HT depleted dams displayed heightened compulsive behavior at P21, when compared to control mice. Alcohol anti-anxiety effects at early adolescence (P28) were exhibited by mice derived from 5-HT depleted dams, but not by control counterparts. No social deficits or stereotyped behaviors were observed. CONCLUSION: Transient 5-HT inhibition at gestation resulted in altered expression of genes involved in 5-HT synthesis and reuptake in mPFC at weaning, a period in which the 5-HT system is still developing. These alterations may exert lingering effects, which translate to significant compulsivity and heightened sensitivity to the anxiolytic effects of alcohol at early adolescence.


Assuntos
Ansiolíticos , Serotonina , Animais , Ansiolíticos/farmacologia , Comportamento Animal , Dopamina/metabolismo , Etanol/farmacologia , Feminino , Fenclonina/farmacologia , Humanos , Masculino , Camundongos , Placenta/metabolismo , Gravidez , Piridinolcarbamato , Serotonina/metabolismo , Desmame
2.
Mol Med Rep ; 26(5)2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36082821

RESUMO

Coriandrum sativum L. (CSL) is an aromatic plant that belongs to the Apiaceae family. The present study aimed to determine the effects of the ethanol extract of the aerial part of CSL on osteoclast formation in vitro and in vivo, and the underlying molecular mechanism of its anti­osteoclastogenic effect. The levels of osteoclast formation and bone resorption were evaluated by tartrate­resistant acid phosphatase staining and bone resorption pit assays. The expression levels of osteoclast­related molecules were analyzed by reverse transcription­quantitative PCR and western blotting. The ethanol extract of CSL suppressed osteoclast formation in a mouse co­culture system. In osteoblasts, CSL exerted a minor effect on the mRNA ratio of receptor activator of nuclear factor­κB (NF­κB) ligand (RANKL) to osteoprotegerin, suggesting a direct effect of CSL on osteoclast precursors. Notably, CSL inhibited RANKL­induced osteoclast differentiation and bone resorption activity in bone marrow­derived macrophage cultures. Mechanistically, CSL abolished RANKL­induced NF­κB and extracellular signal­regulated kinase (ERK) MAPK activation, which effectively impaired the induction of c­Fos and nuclear factor of activated T cells (NFATc1). Finally, the ethanol extract of CSL prevented osteoclast formation in a lipopolysaccharide­induced calvarial bone loss model in vivo. The findings of the present study suggested that CSL may suppress osteoclast differentiation and function by downregulating the NF­κB and ERK/c­Fos/NFATc1 signaling pathways. Thus, CSL could be explored as a potential candidate for the prevention and treatment of osteolytic diseases.


Assuntos
Reabsorção Óssea , Coriandrum , Animais , Reabsorção Óssea/metabolismo , Diferenciação Celular , Coriandrum/metabolismo , Etanol/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Camundongos , NF-kappa B/metabolismo , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/metabolismo , Osteoclastos/metabolismo , Ligante RANK/metabolismo , Transdução de Sinais
3.
Psychopharmacology (Berl) ; 239(10): 3249-3261, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35951078

RESUMO

RATIONALE: Alcohol consumption is a common antecedent of aggressive behavior. The effects of alcohol on the decision to engage in aggression in preference over pro-social interaction are hypothesized to arise from augmented function within the medial prefrontal cortex (mPFC). OBJECTIVE: In a newly developed procedure, we studied social decision-making in male C57BL/6 J mice based on preferentially seeking access to either sociosexual interactions with a female partner or the opportunity to attack an intruder male. While deciding to engage in aggressive vs. sociosexual behavior, corresponding neural activation was assessed via c-Fos immunoreactivity in cortical, amygdaloid and tegmental regions of interest. A further objective was to investigate how self-administered alcohol impacted social choice. METHODS: During repeated confrontations with an intruder male in their home cage, experimental mice engaged in species-specific sequence of pursuit, threat, and attack behavior within < 2 min. Mice were then conditioned to respond at one of two separate illuminated operanda in an experimental chamber (octagon) attached to their home cage; completion of 10 responses (fixed ratio 10; FR10) was reinforced by access to either a female or a male intruder which were presented in the resident's home cage. Brains were harvested following choice between the concurrently available aggressive and sociosexual options and processed for c-Fos immunoreactivity across 10 brain regions. In two separate groups, mice were trained to rapidly self-administer ethanol prior to a social choice trial in order to examine the effects of alcohol on social choice, sociosexual, aggressive acts and postures, and concurrent c-Fos activity in the mPFC and limbic regions. RESULTS AND DISCUSSION: Eight out of 65 mice consistently chose to engage in aggressive behavior in preference to sociosexual contact with a female when each outcome was concurrently available. Self-administered alcohol (experiment 1: 1.2 ± 0.02 g/kg; experiment 2: 0, 1.0, 1.5, and 1.8 g/kg) increased responding for the aggressive option in mice that previously opted predominantly for access to sociosexual interactions with the female. When choosing the aggressive, but not the sociosexual option, the prelimbic area of the mPFC revealed increased c-Fos activity, guiding future detailed inquiry into the neural mechanisms for aggressive choice.


Assuntos
Agressão , Consumo de Bebidas Alcoólicas , Animais , Modelos Animais de Doenças , Etanol/farmacologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-fos
4.
J Dairy Sci ; 105(10): 8054-8068, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36028344

RESUMO

In a randomized complete block design, 40 lactating Holstein cows (average 98 d in milk and 41 kg/d of milk yield) were randomly assigned to 1 of 4 diets: (1) containing soybean meal as the major protein supplement (CON diet); (2) CON diet with high-protein dried corn distillers grains at 20% on a dry matter (DM) basis by replacing mainly soybean meal (DG diet); (3) DG diet except that high-protein dried corn distillers grains with yeast bodies (extracted after corn ethanol production) was used (DGY diet); or (4) DG diet supplemented with sodium bicarbonate and potassium carbonate to elevate the dietary cation and anion difference (DCAD; DG-DCAD diet). The DCAD of CON, DG, DGY, and DG-DCAD were 185, 62, 67, and 187 mEq/kg of DM, respectively. The experiment began with a 10-d covariate period and then cows were fed the experimental diets for 5 wk (2-wk diet adaptation and 3-wk data collection periods). Dry matter intake and milk yield were measured daily, and spot urine and fecal samples were collected in the last week of the experiment to measure nutrient digestibility; N, S, and P utilization and excretion; and in vitro NH3 and H2S emissions from manure. All data were analyzed using the MIXED procedure of SAS (random effect: block; fixed effects: diets, repeated week, and interactions). During data collection, DM intake was not different among treatment groups, but milk yield tended to be lower (42.4 vs. 39.9 kg/d) for DG, DGY, and DG-DCAD versus CON, which could have been caused by decreases in organic matter and neutral detergent fiber digestibility. Milk protein yield tended to be lower (1.33 vs. 1.24 kg/d) for DG, DGY, and DG-DCAD versus CON. Milk fat yield was lower (1.26 vs. 1.55 kg/d) for DG and DGY versus CON, but that for DG-DCAD (1.43 kg/d) did not differ from CON. Similarly, energy-corrected milk was lower (38.0 vs. 43.3 kg/d) for cows on DG and DGY versus those on CON, but it did not differ between DG-DCAD (40.7 kg/d) and CON. Urinary and fecal N excretion were greater for DG, DGY, and DG-DCAD compared with CON due to greater dietary crude protein content and N intake. However, NH3 emissions did not differ across treatments. Intakes of dietary P and S were greater for DG, DGY, and DG-DCAD, resulting in greater excretion of those in manure and greater H2S emissions from manure compared with CON. These data suggest that the negative effects of feeding distillers grains on production of lactating cows can be partly explained by a decrease in nutrient digestibility (milk yield) and excessive anion load (milk fat). The milk fat response to DG-DCAD suggests that milk fat depression observed with a diet with high content of distillers grains can be partially alleviated by supplementation of cations. In the current study, we observed no beneficial effects of DG containing yeast bodies.


Assuntos
Lactação , Esterco , Ração Animal/análise , Animais , Ânions , Cátions , Bovinos , Detergentes , Dieta/veterinária , Proteínas na Dieta/farmacologia , Etanol/farmacologia , Feminino , Lactação/fisiologia , Proteínas do Leite/farmacologia , Nutrientes , Saccharomyces cerevisiae , Bicarbonato de Sódio/farmacologia , Zea mays
5.
Biomed Pharmacother ; 154: 113550, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35994814

RESUMO

Silver nanoparticles (Ag NPs) have unique properties and display an important role in bioactivities such as antimicrobial, antiviral, antifungal, and anticancer. Stable Ag NPs were prepared by reaction of silver nitrate solution with extract of Melissa and characterized by UV-Vis spectroscopy, AFM, SEM, XRD, and Zeta potential. The resulted Ag NPs have a size range between 20 and 35 nm. The current study aims to evaluate the gastroprotective effect of Ag NPs against ethanol-induced gastric ulcers in rats. Thirty rats were randomly divided into five groups. The experimental groups were fed 175 and 350 ppm/p.o of Ag NPs orally. Ag NPs improved the adversative influence of ethanol-induced stomach damage as confirmed by declining ulcer index and raised the percentage of ulcer prevention. Significantly reduced ethanol-induced gastric lesions were evidenced by increased mucus secretion and pH of stomach content, decreased ulcer area, nonappearance of edema, and leucocyte penetration of the subcutaneous layer. In gastric homogenate, Ag NPs displayed a substantial upsurge in superoxide dismutase (SOD), catalase (CAT) activities, and significantly reduced malondialdehyde (MDA) levels., Ag NPs increased the intensity of periodic acid Schiff stained (PAS) and produced over-regulation of HSP-70 and down-regulation of Bax proteins. Ag NPs confirmed gastro-protection which might be attributed to its antioxidant effect, increased mucus secretion, increased SOD, and CAT, reduced MDA level, over-regulation of HSP-70 protein, and down-regulation of Bax protein.


Assuntos
Antiulcerosos , Nanopartículas Metálicas , Úlcera Gástrica , Animais , Antiulcerosos/efeitos adversos , Antioxidantes/metabolismo , Etanol/farmacologia , Mucosa Gástrica , Proteínas de Choque Térmico HSP70/metabolismo , Extratos Vegetais/farmacologia , Ratos , Ratos Sprague-Dawley , Prata/farmacologia , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico , Úlcera Gástrica/prevenção & controle , Superóxido Dismutase/metabolismo , Úlcera/tratamento farmacológico , Úlcera/metabolismo , Úlcera/patologia
6.
Chem Biodivers ; 19(9): e202200296, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36026557

RESUMO

We investigated whether three extractable fractions of lemongrass (Cymbopogon citratus): aqueous and ethanol extracts and lemongrass essential oil exhibited any antimicrobial resistance modulatory effects if used in combination with selected antibiotics ampicillin, tetracycline, streptomycin, cefloxacin and amoxicillin on methicillin-resistant Staphylococcus aureus (MRSA). MRSA growth inhibition (zones of inhibition) was greatest for the lemongrass oil at concentrations of 1, 2, 5, 10 and 20 % (wt/vol). The MIC for lemongrass oil was 0.5 mg/mL, while it was 4 mg/mL for both the aqueous and ethanol extracts. Evaluation of extracts for antibacterial resistance modifying activities when used in combination with either of the five antibiotics at sub-inhibitory concentrations, showed that lemongrass oil highly potentiated the activities of three antibiotics; amoxicillin, streptomycin and tetracycline. The ethanol extract enhanced the activity of tetracycline and ampicillin, while the aqueous extract only increased the activity of tetracycline against MRSA. The activity of cefloxacin with the extracts was either indifferent. Analysis of the lemongrass oil by GC/MS showed the prominence of three compounds: the two isomers neral and geranial of citral and, the acetate geranyl acetate, which together made up 94 % of the composition. The compounds were also observed in the ethanol and water extracts but to a lesser extent when analyzed by HPLC-UV (λ 233 nm). Our study confirms the antibacterial properties of the extracts especially, lemongrass oil. It also demonstrates that lemongrass oil potentiates the activities of three antibiotics against the biofilm-forming MRSA. This biocidal, anti-biofilm disruption and antibiotic potentiating abilities are mainly attributable to citral and geranyl acetate, further evidence of lemongrass oil as a very useful source of phytochemicals, especially citral for the fight against antibiotic resistance.


Assuntos
Cymbopogon , Staphylococcus aureus Resistente à Meticilina , Óleos Voláteis , Acetatos/farmacologia , Monoterpenos Acíclicos , Amoxicilina/farmacologia , Ampicilina/farmacologia , Antibacterianos/farmacologia , Cymbopogon/química , Etanol/farmacologia , Testes de Sensibilidade Microbiana , Óleos Voláteis/química , Óleos Voláteis/farmacologia , Extratos Vegetais/farmacologia , Óleos Vegetais , Estreptomicina/farmacologia , Terpenos , Tetraciclina/farmacologia , Água
7.
Addict Biol ; 27(5): e13208, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36001427

RESUMO

BACKGROUND: Previous studies have characterized the impact of substance use on cerebral structure and function in adolescents. Yet, the great majority of prior studies employed a small sample, presented cross-sectional findings, and omitted potential sex differences. METHODS: Using data based on 724 adolescents (370 females) curated from the NCANDA study, we investigated how gray matter volumes (GMVs) decline longitudinally as a result of alcohol and cannabis use. The impacts of alcohol and cannabis co-use and how these vary across assigned sex at birth and age were examined. Brain imaging data comprised the GMVs of 34 regions of interest and the results were evaluated with a Bonferroni correction. RESULTS: Mixed-effects modeling showed faster volumetric declines in the caudal middle frontal cortex, fusiform, inferior frontal, superior temporal (STG), and supramarginal (SMG) gyri, at -0.046 to -0.138 cm3 /year in individuals with prior-year alcohol and cannabis co-use, but not those engaged in alcohol or cannabis use only. These findings cannot be explained by more severe alcohol use among co-users. Further, alcohol and cannabis co-use in early versus late adolescence predicted faster volumetric decline in the STG and SMG across assigned sex at birth. CONCLUSIONS: Findings highlight the longitudinal impact of alcohol and cannabis co-use on brain development, especially among youth reporting early adolescent onset of use. The volumetric decline was noted in cortical regions in support of attention, memory, executive control, and social cognition, suggesting the pervasive effect of alcohol and cannabis co-use on brain development.


Assuntos
Cannabis , Substância Cinzenta , Adolescente , Encéfalo/diagnóstico por imagem , Córtex Cerebral , Estudos Transversais , Etanol/farmacologia , Feminino , Substância Cinzenta/diagnóstico por imagem , Humanos , Recém-Nascido , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino
8.
Addict Biol ; 27(5): e13197, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36001429

RESUMO

Several lines of evidence suggest that endocannabinoid signalling may influence alcohol consumption. Preclinical studies have found that pharmacological blockade of cannabinoid receptor 1 leads to reductions in alcohol intake. Furthermore, variations in endocannabinoid metabolism between individuals may be associated with the presence and severity of alcohol use disorder. However, little is known about the acute effects of alcohol on the endocannabinoid system in humans. In this study, we evaluated the effect of acute alcohol administration on circulating endocannabinoid levels by analysing data from two highly-controlled alcohol administration experiments. In the first within-subjects experiment, 47 healthy participants were randomized to receive alcohol and placebo in a counterbalanced order. Alcohol was administered using an intravenous clamping procedure such that each participant attained a nearly identical breath alcohol concentration of 0.05%, maintained over 3 h. In the second experiment, 23 healthy participants self-administered alcohol intravenously; participants had control over their exposure throughout the paradigm. In both experiments, circulating concentrations of two endocannabinoids, N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), were measured at baseline and following alcohol exposure. During the intravenous clamping procedure, acute alcohol administration reduced circulating AEA but not 2-AG levels when compared to placebo. This finding was confirmed in the self-administration paradigm, where alcohol reduced AEA levels in an exposure-dependent manner. Future studies should seek to determine whether alcohol administration has similar effects on brain endocannabinoid signalling. An improved understanding of the bidirectional relationship between endocannabinoid signalling and alcohol intake may deepen our understanding of the aetiology and repercussions of alcohol use disorder.


Assuntos
Alcoolismo , Endocanabinoides , Consumo de Bebidas Alcoólicas , Alcoolismo/metabolismo , Endocanabinoides/metabolismo , Etanol/farmacologia , Humanos
9.
Addict Biol ; 27(5): e13222, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36001422

RESUMO

Alcohol use and high-risk alcohol drinking behaviours among women are rapidly rising. In rodent models, females typically consume more ethanol (EtOH) than males. Here, we used the four core genotypes (FCG) mouse model to investigate the influence of gonadal hormones and sex chromosome complement on EtOH drinking behaviours. FCG mice were given access to escalating concentrations of EtOH in a two-bottle, 24-h continuous access drinking paradigm to assess consumption and preference. Relapse-like behaviour was measured by assessing escalated intake following repeated cycles of deprivation and re-exposure. Twenty-four-hour EtOH consumption was greater in mice with ovaries (Sry-), relative to those with testes, and in mice with the XX chromosome complement, relative to those with XY sex chromosomes. EtOH preference was higher in XX versus XY mice. For both consumption and preference, the influences of the Sry gene and sex chromosomes were concentration dependent. Escalated intake following repeated cycles of deprivation and re-exposure emerged only in XX mice (vs. XY). Mice with ovaries (Sry- FCG mice and C57BL/6J females) were also found to consume more water than mice with testes. These results demonstrate that aspects of EtOH drinking behaviour may be independently regulated by sex hormones and chromosomes and inform our understanding of the neurobiological mechanisms which contribute to EtOH dependence in male and female mice. Future investigation of the contribution of sex chromosomes to EtOH drinking behaviours is warranted. We used the FCG mouse model to investigate the influence of gonadal hormones and sex chromosome complement on EtOH drinking behaviours, including the alcohol deprivation effect. Escalated intake following repeated cycles of deprivation and re-exposure emerged only in XX mice (vs. XY). These results demonstrate that aspects of EtOH drinking behaviour may be independently regulated by sex hormones and chromosomes.


Assuntos
Etanol , Cromossomos Sexuais , Consumo de Bebidas Alcoólicas/genética , Animais , Etanol/farmacologia , Feminino , Genótipo , Hormônios Gonadais , Hormônios Esteroides Gonadais , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Recidiva
10.
Addict Biol ; 27(5): e13219, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36001440

RESUMO

Most individuals with cocaine use disorder also use alcohol; however, little is known about the behavioural and pharmacological mechanisms that promote co-abuse. For example, although studies in humans and animals have documented that chronic use of either alcohol or cocaine alone decreases D2-like receptor (D2R) availability, effects of co-abuse of these substances on dopamine receptor function have not been characterized. These studies examined the effects of long-term cocaine self-administration in 12 male rhesus monkeys who also consumed either ethanol or an ethanol-free solution each day (n = 6 per group). Specifically, all monkeys self-administered cocaine (0.1 mg/kg per injection) 5 days per week in the morning. In the afternoon, six monkeys consumed 2.0 g/kg ethanol over 1 h to model binge drinking and six monkeys drank an ethanol-free solution. Assessment of D2R availability using positron emission tomography (PET) and [11 C]raclopride occurred when monkeys were drug-naïve and again when monkeys had self-administered approximately 400-mg/kg cocaine. D3 R function was assessed at the same time points by determining the potency of the D3 R-preferring agonist quinpirole to elicit yawns. Chronic cocaine self-administration decreased D2R availability in subregions of the basal ganglia in control monkeys, but not those that also drank ethanol. In contrast, D3 R sensitivity increased significantly after chronic cocaine self-administration in ethanol-drinking monkeys but not controls. These results suggest that co-use of ethanol substantially changes the effects of chronic cocaine self-administration on dopamine receptors, specifically implicating D3 R as a target for medications in these individuals.


Assuntos
Cocaína , Transtornos Relacionados ao Uso de Substâncias , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Cocaína/farmacologia , Relação Dose-Resposta a Droga , Etanol/farmacologia , Humanos , Macaca mulatta/metabolismo , Masculino , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Autoadministração
11.
Pak J Pharm Sci ; 35(4): 1015-1021, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36008897

RESUMO

As a popular medicinal plant traditionally used in Tibet of China, Nepeta angustifolia C. Y. Wu is mainly administered to treat apoplexia, cerebral haemorrhage, fainting and epilepsy and other symptoms, while its effect on hyperuricemia is still unclear. In the present study, we evaluated the improvement of the 70% ethanol extract of Nepeta angustifolia C. Y. Wu in fructose-induced hyperuricemic mice. The results revealed that Nepeta angustifolia C. Y. Wu significantly decreased blood glucose and blood lipid levels, as well as lowering the urinary levels of uric acid, creatinine and urea nitrogen. Meanwhile, it effectively restored the serum levels of uric acid, creatinine and urea nitrogen and inhibited serum and hepatic XOD activities and renal oxidative stress, while suppressing the secretions of TNF-α, IL-1ß and IL-6 in kidney. Nepeta angustifolia C. Y. Wu also attenuated the infiltration of inflammatory cells and reduced the production and accumulation of glycogen and collagen, while restoring the dysregulated protein expressions of renal URAT1, GLUT9, OAT1 and OAT3. In summary, our results support the idea that Nepeta angustifolia C. Y. Wu is a promising agent for treating hyperuricemia.


Assuntos
Medicamentos de Ervas Chinesas , Hiperuricemia , Nepeta , Animais , Creatinina/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Etanol/farmacologia , Frutose/efeitos adversos , Hiperuricemia/induzido quimicamente , Hiperuricemia/tratamento farmacológico , Hiperuricemia/metabolismo , Rim , Camundongos , Nitrogênio/metabolismo , Ureia/metabolismo , Ácido Úrico
12.
Acta Cir Bras ; 37(5): e370505, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35976342

RESUMO

PURPOSE: To investigate the effects of Periplaneta americana L. on ulcerative colitis (UC) induced by a combination of chronic stress (CS) and 2,4,6-trinitrobenzene sulfonic acid enema (TNBS) in rats. METHODS: The experiment UC model with CS was established in rats by a combination of chronic restraint stress, excess failure, improper, and TNBS. The body weight, disease activity index (DAI), colonic mucosal injury index (CMDI), histopathological score (HS) and pro-inflammatory mediators were measured. The content of corticotropin-releasing hormone (CRH) in hypothalamus or adrenocorticotropic hormone (ACTH) and corticosteroids (CORT) in plasma were evaluated by enzyme-linked immunosorbent assay. The proportion of T lymphocyte subsets was detected by flow cytometry, and gut microbiota was detected by 16S rDNA amplicon sequencing. RESULTS: Weight loss, DAI, CMDI, HS and proinflammatory mediators were reversed in rats by P. americana L. treatment after UC with CS. Increased epidermal growth factor (EGF) was observed in P. americana L. groups. In addition, P. americana L. could reduce the content of CRH and ACTH and regulate the ratio of CD3+, CD3+CD8+ and CD3+CD4+CD25+/CD4+ in spleen. Comparably, P. americana L. changes composition of gut microbiota. CONCLUSIONS: The ethanol extract of Periplaneta Americana L. improves UC induced by a combination of CS and TNBS in rats.


Assuntos
Colite Ulcerativa , Colite , Periplaneta , Hormônio Adrenocorticotrópico/metabolismo , Hormônio Adrenocorticotrópico/farmacologia , Hormônio Adrenocorticotrópico/uso terapêutico , Animais , Colite/patologia , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colo/patologia , Modelos Animais de Doenças , Enema , Etanol/farmacologia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Ratos , Ácido Trinitrobenzenossulfônico/metabolismo
13.
J Dairy Sci ; 105(9): 7266-7275, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35931485

RESUMO

The effect of ethanol on milk has been shown to be temperature-dependent, with higher ethanol concentrations and temperatures reversibly dissociating casein micelles. This work looked to expand on this knowledge, while also demonstrating the efficiency and precision of a custom-made continuous monitoring unit that combines solutions at defined concentrations and temperatures while measuring various parameters (i.e., absorbance, fluorescence, pressure). Caseins were found to self-associate at moderate ethanol concentrations (i.e., 12-36% vol/vol ethanol); however, they dissociated and remained in the serum at higher ethanol concentrations (≥48% vol/vol) and temperatures (24 and 34°C). Although serum casein content was found to be positively correlated with protein hydrophobicity, the addition of ethanol only increased protein hydrophobicity when the sample was held at high temperatures (34-64°C). Overall, the greatest dissociation of casein micelles was found between 40 and 60% (vol/vol) ethanol concentration at elevated temperatures (≥34°C). At these ethanol concentrations and temperatures, skim milk absorbance was minimized, serum casein content (including ß-casein content) was maximized, and protein hydrophobicity reached a relative maximum.


Assuntos
Caseínas , Micelas , Animais , Etanol/farmacologia , Concentração de Íons de Hidrogênio , Leite
14.
J Ethnopharmacol ; 298: 115660, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-35995277

RESUMO

ETHNOPHARMACOLOGICAL IMPORTANCE: Casearia sylvestris Sw. (Salicaceae) is a native plant from the Americas, where it is also known as "guaçatonga" or "erva-de-bugre." Although its leaves have been commonly used to treat inflammation and gastrointestinal disorders in South America, the antiulcer effects of an aqueous extract from this medicinal plant, similar to popular use, have not to be investigated yet. AIM OF THE STUDY: This study evaluated the hypothesis that the aqueous extract a of C. sylvestris (AEC) prevents the gastric ulcers and accelerates the healing of ulcers already installed, by assessing ultrasound imaging, histological and biochemical analyses. MATERIALS AND METHODS: Rats (females) were treated with AEC (3, 30 or 300 mg/kg) prior to the ethanol or piroxicam-induced gastric ulcers. The healing effect of AEC (300 mg/kg) was examined in 80% acetic acid-induced ulcer in rats, whereas the quality of healing was evaluated in recurrent 10% acetic acid-induced ulcer in mice with recurrence induced by interleukin 1ß. To assess the responses of the lesions, in addition to the classical methods used to analyze gastroprotection (ex vivo), we also measured the gastric wall thickness (in vivo) using ultrasonography. After euthanasia, the extent of ulcer was determined and the levels of reduced glutathione (GSH), lipid hydroperoxides (LOOH), nitrate, and the activities of myeloperoxidase (MPO), N-acetyl-ß-D-glycosaminidase (NAG), superoxide dismutase (SOD), and glutathione S-transferase (GST) were measured. The antisecretory activity of AEC was also examined based on pylorus ligated rats. Furthermore, gastric tissue samples were analyzed histologically, and phytochemical analyses of the C. sylvestris extract were parallelly performed. RESULTS: The AEC (30 or 300 mg/kg) prevented ulcers in the ethanol- and piroxicam-induced acute. Moreover, the AEC at a dose of 300 mg/kg also accelerated the gastric healing of acetic acid-induced ulcer in rats by 48% and the ultrasonography records shown a decrease in the wall thickness and the extent of edema of ulcerous lesions promoted by the extract. The gastric healing effect of AEC was also accompanied by reduced MPO and NAG activities at acetic acid-induced ulcer in rats; as well as was by the reduction in the nitrate and LOOH levels, the increase in mucin and SOD activity, and by a partial recovery of GSH levels. The AEC (300 mg/kg) minimized the ulcer recurrence in mice exposed to IL-1ß, but the extract administration did not change pH or peptic activity of gastric juice in pylorus ligated rats. CONCLUSION: The results of this study provide convincing evidence for the therapeutic efficacy of C. sylvestris with respect to gastroprotection and indicate that ultrasound examination would be a potentially promising approach for evaluating gastroprotective effects in vivo. Collectively, our findings indicate that the gastric the gastroprotective and healing effects of aqueous extract C. sylvestris involve a reduction in acid secretion, promotion of the antioxidant system, reductions in the migration of neutrophils and mast cells, with a consequent lower inflammatory response, and the preservation of mucin.


Assuntos
Antiulcerosos , Casearia , Úlcera Gástrica , Ácido Acético/uso terapêutico , Animais , Antiulcerosos/farmacologia , Antiulcerosos/uso terapêutico , Etanol/farmacologia , Feminino , Mucosa Gástrica , Camundongos , Mucinas , Nitratos , Fitoterapia , Piroxicam/efeitos adversos , Extratos Vegetais/efeitos adversos , Ratos , Ratos Wistar , Roedores , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico , Úlcera Gástrica/patologia , Superóxido Dismutase , Úlcera/tratamento farmacológico , Ultrassonografia
15.
Alcohol Clin Exp Res ; 46(9): 1665-1676, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35915568

RESUMO

BACKGROUND: The basolateral nucleus of the amygdala (BLA) plays an important role in the development of fear and anxiety-related behaviors. The BLA receives inputs from all sensory stimuli. After processing those stimuli, BLA neurons signal neurons within the central amygdala and other brain regions, including the ventral and dorsal striatum and frontal cortex. Studies suggest that the BLA is involved in drug dependence and in the reinforcing actions of ethanol. For example, acute exposure to ethanol reduces anxiety, while withdrawal from chronic ethanol exposure alters BLA synaptic transmission, which increases anxiety, a common underlying cause of relapse. Exposure to and withdrawal from chronic alcohol also disrupts many brain areas that connect with the BLA. Despite these important findings, the acute actions of alcohol on the intrinsic excitability of BLA neurons have not been fully characterized. METHODS: Brain slices containing the BLA were prepared from adult C57BL/6J male mice. Whole-cell and sharp electrode electrophysiological recordings were performed to characterize the effects of acute ethanol on BLA neuronal and astrocyte function, respectively. RESULTS: Ethanol inhibited action potential (AP) firing of BLA neurons but had no effect on BLA astrocyte resting membrane potential. The ethanol-induced inhibition of firing was concentration-dependent (11 to 66 mM) and accompanied by a reduction in the input resistance and an increase in the rheobase of BLA neurons. The inhibitory effect of ethanol was suppressed by picrotoxin, which blocks both γ-aminobutyric acid type A (GABAA ) and glycine receptors, but not by the selective glycine receptor antagonist strychnine, which suggests an involvement of GABAA receptors. Ethanol did not affect spontaneous inhibitory postsynaptic currents suggesting that the inhibition of BLA neuronal excitability by ethanol was not due to an increase in GABAA -mediated synaptic transmission. However, acute ethanol enhanced the amplitude of the holding current of BLA neurons, an effect that was prevented by picrotoxin, which by itself reduced the holding current. CONCLUSIONS: These results suggest that BLA neurons express a GABA-mediated tonic current that is enhanced by acute ethanol, which leads to reduced excitability of BLA neurons.


Assuntos
Complexo Nuclear Basolateral da Amígdala , Núcleo Central da Amígdala , Animais , Etanol/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios , Picrotoxina/farmacologia , Receptores de GABA-A/fisiologia , Receptores de Glicina , Estricnina/farmacologia , Transmissão Sináptica , Ácido gama-Aminobutírico/farmacologia
16.
Behav Pharmacol ; 33(6): 395-401, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35942846

RESUMO

A defining characteristic of individuals diagnosed with alcohol use disorder (AUD) is that negative outcomes related to drinking do not lead them to reduce their alcohol use. In rodent models of AUD, this characteristic has been studied by adding the bitter tastant quinine to an ethanol solution. In this study, we extended this approach to a nonhuman primate model in which the ability of quinine to decrease the choice of a 4% ethanol solution vs. water was measured. Five adult female rhesus monkeys with 7.3 years of experience drinking ethanol were given access to a 4% ethanol solution and water for 3 h per day. When ethanol choice was stable, a single quinine concentration (0.03-5.6 g /L) was added to the ethanol solution for 1 day until a quinine concentration-effect curve was generated. After determining the quinine concentration that reduced ethanol choice by half (the quinine EC 50 ), the relative reinforcing strength of ethanol was manipulated by adding quinine or sucrose to the water alternative depending on the monkey's baseline choice. Adding quinine to ethanol produced a concentration-dependent decrease in ethanol choice and intake. Importantly, water intake increased, indicating an effect on response allocation rather than simply a decrease in fluid consumption. Consistent with this conclusion, the addition of quinine or sucrose to the water alternative resulted in predictable increases and decreases, respectively, in ethanol choice. These studies establish a model of punishment of ethanol choice in nonhuman primates that can be used to understand the contextual, biologic and pharmacologic factors that influence sensitivity to the punishment of alcohol drinking.


Assuntos
Alcoolismo , Etanol , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Animais , Etanol/farmacologia , Feminino , Macaca mulatta , Punição , Quinina/farmacologia , Sacarose , Água
17.
Psychopharmacology (Berl) ; 239(10): 3145-3159, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35939082

RESUMO

RATIONALE: Alcohol use disorder (AUD) is shown to have an overall heritability of around 50%. One of the genes associated with AUD is SLC6A4 (solute carrier family 6 member A4) which codes for the serotonin transporter (SERT). The study looked at serotonin dysfunction on ethanol consumption in adolescents and the subsequent intergenerational effects of drinking by using a rat model: SERT+/+ (regular functioning), SERT+/- (50% transporter reduction) and SERT-/- (complete reduction). OBJECTIVES: We investigated sex and genotype differences in ethanol consumption in SERT knock-out Wistar rats (F0) followed by studying behaviour in the offspring (F1) of the male drinkers to assess effects of paternal alcohol consumption. METHODS: An intermittent access two-bottle choice paradigm (IA2BC) was used to yield ethanol drinking behaviour in F0 adolescent Wistar rats. The highest drinking males were mated to alcohol-naive females and their offspring were compared with controls. Drinking behaviour (IA2BC) and ethanol-induced motor coordination effects (via rotarod) were measured in the F1s. RESULTS: F0 drinking saw no SERT genotype differences in males. However, females consumed higher volumes of ethanol compared to males, with SERT-/- females showing the highest intake. A clearer genotype effect was seen in the F1 animals, with reduction in SERT activity leading to enhanced ethanol intake in both sexes. Importantly, paternal exposure to ethanol significantly reduced the ethanol induced motor side effects in offspring, independent of sex and genotype. CONCLUSIONS: These indicate a difference in the way genetic factors may act across sexes and suggest the involvement of epigenetic mechanisms in the intergenerational effects of alcohol.


Assuntos
Alcoolismo , Etanol , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/genética , Alcoolismo/genética , Animais , Etanol/farmacologia , Feminino , Masculino , Ratos , Ratos Wistar , Serotonina , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética
18.
Biomaterials ; 288: 121720, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35961822

RESUMO

Alcoholic liver disease (ALD) is a global healthcare problem and socioeconomic issue that is primarily driven by chronic and/or excessive alcohol consumption. Upon alcohol exposure, parenchymal hepatocytes (HCs) up-regulate endoplasmic reticulum (ER)-localized monooxygenase Cytochrome P450 family 2 subfamily E member 1 (CYP2E1) to accelerate the metabolism of ethanol (EtOH), which concurrently exacerbates the production and accumulation of toxic metabolic intermediates, especially reactive oxygen species (ROS), playing a decisive role in the initiation and perpetuation of alcohol-induced liver injury. ALD patients without timely intervention may develop a spectrum of metabolic and functional disorders in the liver, including hepatic steatosis, hepatitis, fibrosis, and even cirrhosis. However, up to now, there have been no FDA-approved pharmacological or nutritional therapeutics for treating patients with ALD, and an effective amelioration of alcohol-induced hepatotoxicity with satisfactory biosafety is still demanding. In this study, antioxidant Vitamin E-incorporating nanoemulsions modified with ER-targetable small molecule p-dodecylbenzene sulfonamide (p-DBSN) was constructed to load and deliver CYP2E1 inhibitor Clomethiazole (CMZ) to the ER of HCs for site-specific inhibition, which displayed remarkable hepatoprotective effects against chronic alcohol exposure without off-target toxicity, both intravenously injected and orally administrated. Generally, our work may provide a promising nanoplatform for reversing ALD.


Assuntos
Citocromo P-450 CYP2E1 , Hepatopatias Alcoólicas , Citocromo P-450 CYP2E1/metabolismo , Citocromo P-450 CYP2E1/farmacologia , Retículo Endoplasmático/metabolismo , Etanol/farmacologia , Etanol/toxicidade , Hepatócitos/metabolismo , Humanos , Fígado/metabolismo , Hepatopatias Alcoólicas/tratamento farmacológico , Hepatopatias Alcoólicas/metabolismo , Estresse Oxidativo , Vitamina E/farmacologia
19.
Addict Biol ; 27(5): e13203, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36001417

RESUMO

Ethanol, also known as alcohol, is one of the most common drinks in the world. Chronic ethanol exposure has been reported to induce mental disorders. Ethanol also has a strong effect on the gut microbiota. The gut microbiota has been reported to affect the brain via multiple pathways, including changes in γ-aminobutyric acid (GABA) system, and cause a variety of mental disorders. The GABA system in the cortex is associated with anxiety. However, the role of gut microbiota played in ethanol exposure-induced changes in the GABA system and anxiety is still not clear. We established a 30-day ethanol exposure mouse model and investigated the effects of microbiota using the antibiotic minocycline. Minocycline alleviated ethanol-induced anxiety-like behaviour, dysbiosis of microbiota, intestinal barrier disruption, increased serum endotoxin and interleukin (IL)-6. Minocycline also attenuated ethanol-induced apoptosis and decreased expression of glutamate decarboxylases (GADs) and GABRA1 in the prefrontal cortex. Our results indicated that gut microbiota plays an important role in ethanol-induced anxiety-like behaviour by altering the function of GABA system. In addition, causal mediation analysis showed that endotoxin and IL-6 may mediate the connection between the gut microbiota and the expression of GABAA receptor in the prefrontal cortex.


Assuntos
Etanol , Microbioma Gastrointestinal , Animais , Ansiedade/induzido quimicamente , Endotoxinas , Etanol/farmacologia , Humanos , Camundongos , Minociclina/farmacologia , Ácido gama-Aminobutírico
20.
Addict Biol ; 27(5): e13209, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36001428

RESUMO

Binge alcohol consumption is common among adolescents and may impair normal brain development. Emerging, longitudinal studies in adolescents suggest that the effects of binge alcohol exposure on brain structure differ between sexes. To test the hypothesis that the effects of binge alcohol exposure on developmental brain growth trajectories are influenced by age of exposure and sex, adolescent and adult, male and female C57Bl/6 mice (n = 32), were exposed to a binge-like ethanol (EtOH) exposure paradigm (i.e., 5 cycles of 2 on/2 off days of 5 g/kg EtOH intraperitoneal) or served as saline controls. Longitudinal structural magnetic resonance imaging was acquired at baseline, following binge EtOH exposure, and after 2 weeks of recovery. Alcohol treatment showed interactions with age and sex in altering whole brain volume: adolescents of both sexes demonstrated inhibited whole brain growth relative to their control counterparts, although significance was only attained in female mice which showed a larger magnitude response to EtOH compared to male mice. In region of interest analyses, the somatosensory cortex and cerebellum showed inhibited growth in male and female adolescent mice exposed to EtOH, but the difference relative to controls did not reach multiple comparison-corrected statistical significance. These data suggest that in mice exposed to binge EtOH treatment, adolescent age of exposure and female sex may confer a higher risk to the detrimental effects of EtOH on brain structure and reinforce the need for direct testing of both sexes.


Assuntos
Consumo Excessivo de Bebidas Alcoólicas , Animais , Encéfalo/diagnóstico por imagem , Etanol/farmacologia , Feminino , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL
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