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1.
Phytomedicine ; 80: 153382, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33113506

RESUMO

BACKGROUND: Although gastroprotective drugs have been used for peptic ulcer disease prevention and treatment, side effects have been observed. Finding a safe and effective treatment strategy is important. PURPOSE: Edible Trichodesma khasianum (T. khasianum) Clarke leaves are considered to protect against peptic ulcers. However, scientific evidence of this effect of T. khasianum Clarke leaves remains limited. STUDY DESIGN/METHODS: In this study, we aimed to evaluate the effect of T. khasianum Clarke leaves on ethanol-induced gastric injury and gut microbiota using RAW 264.7 cells, RGM-1 cells, and BALB/c mice, respectively. RESULT: The rosmarinic acid was identified as the major component of T. khasianum Clarke leaves extracted by 80% ethanol (80EETC). The results showed that 80EETC suppressed inflammatory mediator protein levels in LPS-induced RAW 264.7 cells. Additionally, heat shock protein expression, antiapoptotic ability, and wound healing migration capability were increased by 80EETC pretreatment in RGM-1 cells with the ethanol-induced injury. Remarkably, pretreatment with 80EETC (150 mg/kg b.w.) promoted gastric mucosal healing by decreasing oxidative stress, inflammatory response, proapoptotic protein expression, and gastric mucosa damage in ethanol-induced gastric injury in mice. Crucially, no liver or kidney toxicities were observed by 80EETC oral gavage. Moreover, 80EETC increased gut microbiota diversity and short-chain fatty acid production. CONCLUSION: Our results illustrated the remarkable gastroprotective effect by 80EETC treatment in vitro and in vivo. These findings are the first to demonstrate the powerful protective effect of T. khasianum Clarke leaves against gastric mucosal injury development.


Assuntos
Boraginaceae/química , Cinamatos/farmacologia , Depsídeos/farmacologia , Mucosa Gástrica/efeitos dos fármacos , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/metabolismo , Cinamatos/análise , Depsídeos/análise , Etanol/toxicidade , Ácidos Graxos Voláteis/metabolismo , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Microbioma Gastrointestinal/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estresse Oxidativo/efeitos dos fármacos , Úlcera Péptica/prevenção & controle , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Folhas de Planta/química , Substâncias Protetoras/química , Células RAW 264.7
2.
Steroids ; 165: 108759, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33181144

RESUMO

Gastric ulcers are a very common public health problem affecting up to 10% worldwide. Russelioside B is a steroidal glycoside isolated from several Caralluma species. No study tested the ulcer healing potential of the compound. The current study aimed to assess the protective effect of russelioside B against ethanol-induced gastric mucosal injury in rats. Ulcer was induced on rats by a single intragastric dose of absolute ethanol (5 mL/kg). Rats were randomly assorted into four groups (n = 8) and given treatments (Antodine, 20 mg/kg or russelioside B, 50 mg/kg) by oral gavage 1 h before ulcer induction. Pretreatment with russelioside B (50 mg/kg) attenuated the gastric mucosal injury as proved by a decrease of ulcer index, and histological scores. It suppressed the gastric inflammation by a significant lowering the tumor necrosis factor-α and interleukin-6 levels with myeloperoxidase activity (which are also aggravating factors in the case of Covid-19 infection). In addition, administration of russelioside B halted the gastric oxidative stress via inhibition of lipid peroxides by maintaining reduced glutathione and by decreasing malondialdehyde. It was able also to restore the sharp drop in the levels of heat shock protein-70, vascular endothelial growth factor and prostaglandin E2 induced by ethanol. Additionally, it showed carbonic anhydrase inhibition activity. The gastroprotective action of russelioside B was umpired through multi mechanistic actions; suppression of gastric oxidative stress, inflammation, anti-apoptotic activities and enhanced gastric mucosal protection by up-regulation of endothelial growth factor, normalization of heat shock protein-70 and prostaglandin E2. These actions were comparable in part to some classical antiulcer drugs such as Antodine.


Assuntos
Dinoprostona/genética , Glicosídeos/farmacologia , Proteínas de Choque Térmico HSP70/genética , Pregnanos/farmacologia , Úlcera Gástrica/tratamento farmacológico , Animais , Antiulcerosos/farmacologia , Apocynaceae/química , /genética , Modelos Animais de Doenças , Etanol/toxicidade , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glicosídeos/química , Humanos , Interleucina-6/genética , Estresse Oxidativo/efeitos dos fármacos , Peroxidase/genética , Pregnanos/química , Ratos , /patogenicidade , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/genética , Úlcera Gástrica/patologia , Fator de Necrose Tumoral alfa/genética
3.
Life Sci ; 264: 118678, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33127518

RESUMO

AIMS: The reversible protein S-glutathionylation (PSSG) modification of Fas augments apoptosis, which can be reversed by the cytosolic deglutathionylation enzyme glutaredoxin-1 (Grx1), but its roles in alcoholic liver injury remain unknown. Therefore, the objective of this study was to investigate the impact of genetic ablation of Grx1 on Fas S-glutathionylation (Fas-SSG) in regulating ethanol-induced injury. MATERIALS AND METHODS: We evaluated the Grx1 activity and oxidative damage, hepatic injury related indicators, Fas-SSG, we also assess the nuclear factor-κB (NF-κB) signaling, its downstream signal, and Akt signaling cascades, Furthermore, the number of Kupffer cells and related proinflammatory cytokines between WT and Grx1- groups after alcohol exposure. KEY FINDINGS: Ethanol-fed mice had increased Grx1 activity and oxidative damage in the liver. Grx1-deficient mice had more serious liver damage when exposed to ethanol compared to that of wild-type mice, accompanied by increased alanine aminotransferase and aspartate aminotransferase levels, Fas-SSG, cleaved caspase-3 and hepatocyte apoptosis. Grx1 ablation resulted in the suppression of ethanol-induced NF-κB signaling, its downstream signal, and Akt signaling cascades, which are required for protection against Fas-mediated apoptosis. Accordingly, blocking NK-κB prevented Fas-induced apoptosis in WT mice but not Grx1-/- mice. Furthermore, the number of Kupffer cells and related proinflammatory cytokines, including Akt, were lower in Grx1-/- livers than those of the controls. SIGNIFICANCE: Grx1 is essential for adaptation to alcohol exposure-induced oxidative injury by modulating Fas-SSG and Fas-induced apoptosis.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Etanol/toxicidade , Glutarredoxinas/deficiência , Glutationa/metabolismo , Receptor fas/metabolismo , Animais , Doença Hepática Induzida por Substâncias e Drogas/patologia , Feminino , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Camundongos Knockout
4.
Toxicology ; 446: 152625, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33161052

RESUMO

Chronic alcoholism has become a major public health problem. Long-term and excessive drinking can lead to a variety of diseases. Chronic ethanol exposure can induce neuroinflammation and anxiety-like behavior, and this may be induced through the Toll-like receptor 3/nuclear factor-κB (TLR3/NF-κB) pathway. Animal experiments were performed using healthy adult male C57BL/6 N mice given 10 % (m/V) or 20 % ethanol solution as the only choice of drinkable fluid for 60, 90 or 180 d. In cell culture experiments, H4 human glioma cells were treated with 100 mM ethanol for 2 d, with the TLR3 gene silenced by RNAi and NF-κB inhibited by ammonium pyrrolidine dithiocarbamate (PDTC, 10 µM). After treatment with ethanol solution for a specific time, the anxiety-like behavior of the mice was tested using the open field test and the elevated plus maze test. Western blotting was used to detect the expression of TLR3, TLR4, NF-κB, IL-1ß, IL-6, and TNF-α in the mouse hippocampus and H4 cells. The expression of IL-1ß, IL-6 and TNF-α in the supernatant of cell culture medium was detected by ELISA. The open field test showed a decrease in time spent in the central area, and the elevated plus maze test showed a decrease in activity time in the open arm region. These behavioral tests indicated that ethanol caused anxiety-like behavior in mice. The expression levels of TLR3, TLR4, NF-κB, IL-1ß, IL-6, and TNF-α increased after ethanol exposure in both the hippocampus of mice and H4 cells. Silencing of the TLR3 gene by RNAi or inhibition of NF-κB by PDTC attenuated the ethanol-induced increase in the expression of inflammatory factors in H4 cells. These findings indicated that chronic ethanol exposure increases the expression of TLR3 and NF-κB and produces neuroinflammation and anxiety-like behavior in male C57BL/6 mice and that ethanol-induced neuroinflammation can be caused through the TLR3/NF-κB pathway.


Assuntos
Ansiedade/induzido quimicamente , Ansiedade/metabolismo , Etanol/toxicidade , Mediadores da Inflamação/metabolismo , NF-kappa B/metabolismo , Receptor 3 Toll-Like/metabolismo , Adulto , Animais , Linhagem Celular Tumoral , Etanol/administração & dosagem , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
5.
Biomed Khim ; 66(5): 419-422, 2020 Sep.
Artigo em Russo | MEDLINE | ID: mdl-33140737

RESUMO

We studied the effects of acute, subacute, and chronic alcohol treatment of rats on the content of fibroblast growth factor 2 (FGF2) mRNA in various brain structures. Results suggest a possible role of FGF2 in the functioning of dopaminergic neurons in the midbrain. In our experiment, ethanol treatment of rats was accompanied by an increase in the FGF2 mRNA level in the emotiogenic structures of the brain. This effect was blocked by pretreatment of animals with chlorpromazine. This suggests FGF2 involvement in the mechanisms of alcohol dependence and can be considered as a possible diagnostic and therapeutic target in alcoholism.


Assuntos
Encéfalo , Alcoolismo/genética , Animais , Etanol/toxicidade , Fator 2 de Crescimento de Fibroblastos/genética , RNA Mensageiro/genética , Ratos
6.
Toxicol Appl Pharmacol ; 408: 115283, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33068620

RESUMO

Marijuana or synthetic cannabinoids and alcohol are often used together, with these combinations causing motor impairments that can subsequently lead to motor vehicle accidents. This study investigated the combined use of both synthetic cannabinoids and ethanol and their effect on motor coordination in mice in addition to examining the neurochemical changes in the cerebellum. Ethanol (2 g/kg, i.p.) significantly induced motor impairment in the accelerating rotarod test in mice. Furthermore, ethanol-induced motor impairments were further accentuated when combined with the synthetic cannabinoid, JWH-018 or AB-CHMINACA. The enhancement effects of the synthetic cannabinoids were completely antagonized by pretreatment with the selective CB1 receptor antagonist AM251, but not by the selective CB2 receptor antagonist AM630. Neurochemical study results showed that ethanol caused a reduction in the extracellular glutamate levels in the cerebellum during periods of ethanol-induced motor impairment. In addition to the enhanced motor impairment seen when ethanol was combined with JWH-018, these combinations also enhanced the reduction of the extracellular glutamate levels in the cerebellum. We additionally used microelectrode array recordings to examine the effects of ethanol and/or JWH-018 on the spontaneous network activity in primary cultures from mouse cerebellum. Results showed that ethanol combined with JWH-018 significantly reduced spontaneous neuronal network activity in the primary cerebellar culture. Our findings demonstrate that ethanol-induced motor impairments are enhanced by synthetic cannabinoids, with these effects potentially mediated by CB1 receptors. An accentuated reduction of neurotransmissions in the cerebellum may play an important role in motor impairments caused by ethanol combined with synthetic cannabinoids.


Assuntos
Canabinoides/toxicidade , Etanol/toxicidade , Ácido Glutâmico/metabolismo , Indazóis/toxicidade , Indóis/toxicidade , Transtornos Motores/induzido quimicamente , Naftalenos/toxicidade , Transmissão Sináptica/efeitos dos fármacos , Valina/análogos & derivados , Animais , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Cerebelo/fisiologia , Sinergismo Farmacológico , Masculino , Camundongos Endogâmicos ICR , Transtornos Motores/metabolismo , Transtornos Motores/fisiopatologia , Valina/toxicidade
7.
Toxicology ; 445: 152584, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33017621

RESUMO

Alcoholic liver disease (ALD) is one of the severe liver diseases, resulting in high morbidity and mortality. However, frataxin, a mitochondrial protein mainly participating in iron homeostasis and oxidative stress, remains uncertain in the pathogenesis of ALD. In the present study, the role of frataxin in ALD was investigated. Ethanol (100 mM) decreased frataxin expression at 48 and 72 h in HepG2. Dramatically, in HepG2 overexpressing cytochrome P450 2E1 (HepG2CYP2E1+/+), frataxin level was down-regulated with ethanol stimulation at 12 h. Moreover, chronically feeding ethanol to mice via Lieber-DeCarli liquid diet (30 % of total calories) for 15 weeks significantly inhibited frataxin expression. Ferroptosis signature proteins were dysregulated, accompanied by mitochondrial damage of morphology, enhanced malondialdehyde and decreased glutathione in the liver, as well as accumulation of reactive oxygen species and mitochondrial labile iron pool in primary hepatocytes. Notably, proteomics screening of frataxin deficient-HepG2 further suggested frataxin was associated with ferroptosis. Furthermore, the ferroptosis inhibitor ferrostatin-1 blocked the increase of lactate dehydrogenase release by ethanol in HepG2CYP2E1+/+. Most importantly, frataxin deficiency enhanced ferroptosis driven by ethanol via evaluating the levels of lactate dehydrogenase, cell morphological changes, mitochondrial labile iron pool, and lipid peroxidation. Conversely, restoring frataxin alleviated the sensitivity to ferroptosis. In addition, frataxin overexpression mitigated the sensitivity of ethanol-induced ferroptosis in HepG2CYP2E1+/+. Collectively, our study revealed that frataxin-mediated ferroptosis contributed to ALD, highlighting a potential therapeutic strategy for ALD.


Assuntos
Etanol/toxicidade , Ferroptose/efeitos dos fármacos , Proteínas de Ligação ao Ferro/antagonistas & inibidores , Proteínas de Ligação ao Ferro/metabolismo , Hepatopatias Alcoólicas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Animais , Células Cultivadas , Ferroptose/fisiologia , Técnicas de Silenciamento de Genes , Células Hep G2 , Humanos , Hepatopatias Alcoólicas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/fisiologia , Distribuição Aleatória
8.
Arh Hig Rada Toksikol ; 71(3): 261-264, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-33074170

RESUMO

All COVID-19 prevention strategies include regular use of surface disinfectants and hand sanitisers. As these measures took hold in Croatia, the Croatian Poison Control Centre started receiving phone calls from the general public and healthcare workers, which prompted us to investigate whether the risk of suspected/symptomatic poisonings with disinfectants and sanitisers really increased. To that end we compared their frequency and characteristics in the first half of 2019 and 2020. Cases of exposures to disinfectants doubled in the first half of 2020 (41 vs 21 cases in 2019), and exposure to sanitisers increased about nine times (46 vs 5 cases in 2019). In 2020, the most common ingredients of disinfectants and sanitisers involved in poisoning incidents were hypochlorite/glutaraldehyde, and ethanol/isopropyl alcohol, respectively. Exposures to disinfectants were recorded mostly in adults (56 %) as accidental (78 %) through ingestion or inhalation (86 %). Fortunately, most callers were asymptomatic (people called for advice because they were concerned), but nearly half reported mild gastrointestinal or respiratory irritation, and in one case severe symptoms were reported (gastrointestinal corrosive injury). Reports of exposure to hand sanitisers highlighted preschool children as the most vulnerable group. Accidental exposure through ingestion dominated, but, again, only mild symptoms (gastrointestinal or eye irritation) developed in one third of the cases. These preliminary findings, however limited, confirm that increased availability and use of disinfectants and sanitisers significantly increased the risk of poisoning, particularly in preschool children through accidental ingestion of hand sanitisers. We therefore believe that epidemiological recommendations for COVID-19 prevention should include warnings informing the general public of the risks of poisoning with surface and hand disinfectants in particular.


Assuntos
2-Propanol/toxicidade , Infecções por Coronavirus/prevenção & controle , Desinfetantes/toxicidade , Etanol/toxicidade , Glutaral/toxicidade , Higienizadores de Mão/toxicidade , Ácido Hipocloroso/toxicidade , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus , Criança , Pré-Escolar , Infecções por Coronavirus/epidemiologia , Croácia/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Pneumonia Viral/epidemiologia , Adulto Jovem
9.
Life Sci ; 262: 118546, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33035580

RESUMO

Studies have reported that taraxasterol (TAR) is effective in the treatment of immune liver injury and alcoholic liver injury. The mechanism of action is mainly related to the inhibition of inflammation. To determine the key molecular mechanisms for the effect of TAR on alleviating ethanol and high-fat diet-induced liver injury, pathological morphology, biochemistry, oxidative stress, inflammatory response and lipid metabolism were examined. Our results showed that TAR could inhibit ethanol-induced hepatocyte death or lipid accumulation, and suppress oxidative stress, inflammatory response and lipid metabolism disorders. More specifically, ethanol-induced TLR-4 and MyD88 inflammatory response were down-regulated, when treated with TAR. Production of CYP2E1, Nrf2 and HO-1, which produced in response to increased oxidative stress, were regulated in TAR treated, ethanol-induced hepatocytes. In summary, TAR could inhibit the inflammatory response and oxidative stress, which was related to the regulation of TAR on TLR-4/MyD88/NF-κB and Nrf2/HO-1 pathways.


Assuntos
Hepatopatias Alcoólicas/prevenção & controle , Hepatopatias/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Esteróis/farmacologia , Triterpenos/farmacologia , Animais , Dieta Hiperlipídica/efeitos adversos , Etanol/toxicidade , Heme Oxigenase-1/metabolismo , Inflamação/prevenção & controle , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fator 88 de Diferenciação Mieloide/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo
10.
Mymensingh Med J ; 29(4): 871-878, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33116090

RESUMO

Recent studies indicate that cellular lipid peroxidation by free radical is an underlying mechanism of acute renal failure induced by gentamicin (GM). Tinospora cordifolia (Tc) extract has been reported to have antioxidant and free radical scavenging activities that is why it is used in present study with the expectation to interrupt the toxic free radical chain reaction of lipid peroxidation in the course of gentamicin administration. For this purpose, sixty rats were divided into six equal groups. Gentamicin (80mg/kg/day, 7 days) was administered to produce nephrotoxicity and structural alterations were evidenced from histopathology of renal tissues which indicates the renal injury and dysfunction in rats. The ethanol extract of Tinospora (200mg/kg/day) was administered with gentamicin simultaneously and also sequentially to observe preventive and curative effects respectively. Both the groups recovered from the gentamicin-induced nephrotoxicity, evidenced from improvement of histopathological features, though accurate mechanism and safety profile is not confirmed by this study.


Assuntos
Tinospora , Animais , Antioxidantes , Etanol/toxicidade , Gentamicinas/toxicidade , Humanos , Rim , Extratos Vegetais/farmacologia , Ratos
11.
Sci Rep ; 10(1): 15558, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32968110

RESUMO

Advanced fibrosis and portal hypertension influence short-term mortality. Lipocalin 2 (LCN2) regulates infection response and increases in liver injury. We explored the role of intrahepatic LCN2 in human alcoholic hepatitis (AH) with advanced fibrosis and portal hypertension and in experimental mouse fibrosis. We found hepatic LCN2 expression and serum LCN2 level markedly increased and correlated with disease severity and portal hypertension in patients with AH. In control human livers, LCN2 expressed exclusively in mononuclear cells, while its expression was markedly induced in AH livers, not only in mononuclear cells but also notably in hepatocytes. Lcn2-/- mice were protected from liver fibrosis caused by either ethanol or CCl4 exposure. Microarray analysis revealed downregulation of matrisome, cell cycle and immune related gene sets in Lcn2-/- mice exposed to CCl4, along with decrease in Timp1 and Edn1 expression. Hepatic expression of COL1A1, TIMP1 and key EDN1 system components were elevated in AH patients and correlated with hepatic LCN2 expression. In vitro, recombinant LCN2 induced COL1A1 expression. Overexpression of LCN2 increased HIF1A that in turn mediated EDN1 upregulation. LCN2 contributes to liver fibrosis and portal hypertension in AH and could represent a new therapeutic target.


Assuntos
Colágeno Tipo I/genética , Hepatite Alcoólica/genética , Lipocalina-2/genética , Cirrose Hepática/genética , Animais , Tetracloreto de Carbono/toxicidade , Modelos Animais de Doenças , Etanol/toxicidade , Feminino , Regulação da Expressão Gênica/genética , Hepatite Alcoólica/sangue , Hepatite Alcoólica/patologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Hipertensão Portal/sangue , Hipertensão Portal/genética , Hipertensão Portal/patologia , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/sangue , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Masculino , Camundongos , Camundongos Knockout , Análise em Microsséries/métodos , Inibidor Tecidual de Metaloproteinase-1/genética
12.
Toxicol Appl Pharmacol ; 407: 115249, 2020 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-32979392

RESUMO

The zebrafish embryo toxicity test (ZFET) is a simple medium-throughput test to inform about (sub)acute lethal effects in embryos. Enhanced analysis through morphological and teratological scoring, and through gene expression analysis, detects developmental effects and the underlying toxicological pathways. Altogether, the ZFET may inform about hazard of chemical exposure for embryonal development in humans, as well as for lethal effects in juvenile and adult fish. In this study, we compared the effects within a series of 12 aliphatic alcohols and related carboxylic acid derivatives (ethanol, acetic acid, 2-methoxyethanol, 2-methoxyacetic acid, 2-butoxyethanol, 2-butoxyacetic acid, 2-hydroxyacetic acid, 2-ethylhexan-1-ol, 2-ethylhexanoic acid, valproic acid, 2-aminoethanol, 2-(2-hydroxyethylamino)ethanol) in ZFET and early life stage (ELS, 28d) exposures, and compared ZFET results with existing results of rat developmental studies and LC50s in adult fish. High correlation scores were observed between compound potencies in ZFET with either ELS, LC50 in fish and developmental toxicity in rats, indicating similar potency ranking among the models. Compounds could be mapped to specific pathways in an adverse outcome pathway (AOP) network through morphological scoring and gene expression analysis in ZFET. Similarity of morphological effects and gene expression profiles in pairs of alcohols with their acid metabolites suggested metabolic activation of the parent alcohols, although with additional, metabolite-independent activity independent for ethanol and 2-ethylhexanol. Overall, phenotypical and gene expression analysis with these compounds indicates that the ZFET can potentially contribute to the AOP for developmental effects in rodents, and to predict toxicity of acute and chronic exposure in advanced life stages in fish.


Assuntos
Ácidos Carboxílicos/toxicidade , Embrião não Mamífero/metabolismo , Álcoois Graxos/toxicidade , Peixe-Zebra/metabolismo , Animais , Desenvolvimento Embrionário/efeitos dos fármacos , Etanol/toxicidade , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Hexanóis/toxicidade , Dose Letal Mediana , Gravidez , Ratos , Testes de Toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/crescimento & desenvolvimento
13.
ACS Nano ; 14(10): 13161-13171, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-32975412

RESUMO

The regeneration of filtering facepiece respirators (FFRs) is of critical importance because of the severe shortage of FFRs during large-scale outbreaks of respiratory epidemics, such as COVID-19. Comprehensive experiments regarding FFR regeneration were performed in this study with model bacteria to illustrate the decontamination performance of the regeneration processes. The results showed that it is dangerous to use a contaminated FFR without any microbe inactivation treatment because the bacteria can live for more than 8 h. The filtration efficiency and surface electrostatic potential of 75% ethanol-treated FFRs were significantly reduced, and a most penetrating particle size of 200 nm was observed. Steam and microwave irradiation (MWI) showed promising decontamination performances, achieving 100% inactivation in 90 and 30 min, respectively. The filtration efficiencies of steam-treated FFRs for 50 and 100 nm particles decreased from 98.86% and 99.51% to 97.58% and 98.79%, respectively. Ultraviolet irradiation (UVI) effectively inactivated the surface bacteria with a short treatment of 5 min and did not affect the filtration performance. However, the UV dose reaching different layers of the FFP2 mask sample gradually decreased from the outermost layer to the innermost layer, while the model bacteria on the second and third layers could not be killed completely. UVI+MWI and steam were recommended to effectively decontaminate the used respirators and still maintain the respirators' filtration efficiency. The present work provides a comprehensive evaluation for FFR regeneration in terms of the filtration efficiencies for 50-500 nm particles, the electrostatic properties, mechanical properties, and decontamination effects.


Assuntos
Bactérias/efeitos da radiação , Desinfecção/métodos , Máscaras/microbiologia , Dispositivos de Proteção Respiratória/microbiologia , Bactérias/efeitos dos fármacos , Bactérias/patogenicidade , Desinfecção/normas , Etanol/toxicidade , Filtração , Humanos , Máscaras/normas , Micro-Ondas , Dispositivos de Proteção Respiratória/normas , Vapor , Têxteis/microbiologia , Têxteis/normas , Raios Ultravioleta
14.
Life Sci ; 260: 118439, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32950574

RESUMO

AIMS: This study aims to investigate the effects of intrauterine perfusion of granulocyte colony-stimulating factor (G-CSF) on a thin-endometrium rat model. MAIN METHODS: Twenty rats in two groups of 10 were used. Group I was perfused with normal saline (NS) in the right uterine horn and 95% ethanol in the left one. Group II was bilaterally perfused with 95% ethanol into the uterine horns. After three estrous cycles, Group II was perfused with NS in the right uterine horn and G-CSF (30 µg/kg) in the left one. Hematoxylin-eosin (HE) and immunohistochemistry (IHC) staining were used to detect changes in endometrial thickness and expression of cytokeratin 19 (CK19) and vimentin (Vim). The relative expression levels of vascular endothelial growth factor (Vegf) and leukemia inhibitory factor (Lif) were also tested via reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR) and Western-blot analyses. KEY FINDINGS: G-CSF treatment significantly increased the thickness of the endometrium in the 95% ethanol-induced thin-endometrium rat model. The expression levels of endometrial glandular epithelial cell marker for CK19 and stromal cell marker Vim were augmented in the G-CSF-treated group compared with the control group. Moreover, G-CSF treatment stimulated the expression of VEGF and LIF in the 95% ethanol-induced thin-endometrium rat model. SIGNIFICANCE: G-CSF intrauterine perfusion improved endometrial receptivity in the thin-endometrium rat model by stimulating endometrial proliferation and angiogenesis.


Assuntos
Endométrio/efeitos dos fármacos , Endométrio/fisiopatologia , Fator Estimulador de Colônias de Granulócitos/farmacologia , Animais , Endométrio/fisiologia , Etanol/toxicidade , Feminino , Expressão Gênica/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Inibidor de Leucemia/genética , Perfusão , Ratos Sprague-Dawley , Útero/fisiologia , Fator A de Crescimento do Endotélio Vascular/genética , Vimentina/metabolismo
15.
Nat Commun ; 11(1): 3664, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32694532

RESUMO

Ethanol is a ubiquitous environmental stressor that is toxic to all lifeforms. Here, we use the model eukaryote Saccharomyces cerevisiae to show that exposure to sublethal ethanol concentrations causes DNA replication stress and an increased mutation rate. Specifically, we find that ethanol slows down replication and affects localization of Mrc1, a conserved protein that helps stabilize the replisome. In addition, ethanol exposure also results in the recruitment of error-prone DNA polymerases to the replication fork. Interestingly, preventing this recruitment through mutagenesis of the PCNA/Pol30 polymerase clamp or deleting specific error-prone polymerases abolishes the mutagenic effect of ethanol. Taken together, this suggests that the mutagenic effect depends on a complex mechanism, where dysfunctional replication forks lead to recruitment of error-prone polymerases. Apart from providing a general mechanistic framework for the mutagenic effect of ethanol, our findings may also provide a route to better understand and prevent ethanol-associated carcinogenesis in higher eukaryotes.


Assuntos
Replicação do DNA/efeitos dos fármacos , DNA Polimerase Dirigida por DNA/metabolismo , Etanol/toxicidade , Taxa de Mutação , Saccharomyces cerevisiae/genética , Sistemas CRISPR-Cas/genética , Proteínas de Ciclo Celular/metabolismo , DNA Fúngico/genética , Mutagênese , Testes de Mutagenicidade , Antígeno Nuclear de Célula em Proliferação/genética , Antígeno Nuclear de Célula em Proliferação/metabolismo , Saccharomyces cerevisiae/efeitos dos fármacos , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo
16.
PLoS One ; 15(7): e0236161, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32730269

RESUMO

BACKGROUND: Periodontitis is a multifactorial inflammatory disease of tooth supporting tissues caused by oral biofilms, influenced by environmental and genetic factors, among others. Ethanol consumption has been considered a factor that enhances alveolar bone loss, especially in high doses. The present study aims to investigate the changes promoted by ethanol binge drinking per se or associated with ligature-induced periodontal breakdown on alveolar bone loss. MATERIALS AND METHODS: Thirty-two Wistar rats were randomly allocated into four groups: control (C), ethanol (3g/kg/day; 3 days On-4 days Off protocol by gavage for 28 days, EtOH), experimental periodontitis (EP) and experimental periodontitis plus ethanol administration (EP+EtOH). On day 14th, periodontitis was induced by ligatures that were placed around the lower first molars. On day 28th, the animals were euthanized and mandibles were submitted to stereomicroscopy for exposed root area analysis and micro-computed tomography (micro-CT) for the evaluation of alveolar bone loss and microstructural parameters. RESULTS: The results revealed that ligature-induced alveolar bone loss is aggravated by ethanol binge drinking compared to controls (1.06 ± 0.10 vs 0.77 ± 0.04; p<0.0001). In addition, binge drinking per se altered the alveolar bone quality and density demonstrating a reduction in trabecular thickness, trabecular number parameter and bone density percentual. Periodontal disorder plus ethanol binge drinking group also demonstrated reduction of the quality of bone measured by trabecular thickness. CONCLUSIONS: In conclusion, intense and episodic ethanol intake decreased alveolar bone quality in all microstructural parameters analyzed which may be considered a modifying factor of periodontitis, intensifying the already installed disease.


Assuntos
Perda do Osso Alveolar/etiologia , Bebedeira/complicações , Densidade Óssea/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/toxicidade , Etanol/toxicidade , Periodontite/complicações , Animais , Masculino , Periodontite/induzido quimicamente , Periodontite/patologia , Ratos , Ratos Wistar
17.
Chem Biol Interact ; 328: 109193, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32668205

RESUMO

Embryonic studies have demonstrated the neurotoxic, teratogenic, and neurobehavioral toxicity of ethanol (EtOH). Although multiple mechanisms may contribute to these effects, oxidative stress has been described as the major damage pathway. In this regard, natural antioxidants have the potential to counteract oxidative stress-induced cellular damage. Therefore, the present study aimed to investigate the potential protective role of 24-epibrassinolide (24-EPI), a natural brassinosteroid with proved antioxidant properties, in EtOH-induced teratogenic effects during early zebrafish development. Embryos (~2 h post-fertilization - hpf) were exposed to 1 % EtOH, co-exposed to 24-EPI (0.01, 0.1 and 1 µM) and to 24-EPI alone (1 µM) for 24 h. Following exposure, biochemical evaluations were made at 26 hpf, developmental analysis was made throughout the embryo-larval period, and behavioural responses were evaluated at 120 hpf. Exposure to 1 % EtOH caused an increase in the number of malformations, which were diminished by 24-EPI. In addition, EtOH induced an accumulation of GSSG and consequent reduction of GSH:GSSG ratio, indicating the involvement of oxidative mechanisms in the EtOH-induced effects. These were reverted by 24-EPI as proved by the GSSG levels and GSH:GSSG ratio that returned to control values. Furthermore, exposure to EtOH resulted in behavioural deficits at 120 hpf as observed by the disrupted response to an aversive stimulus, suggesting the involvement of neurotoxic mechanisms. 24-EPI restored the behavioural deficits observed in a dose-dependent manner. The absence of effects in the embryos exposed solely to 24-EPI showed its safety during the exposure period. In conclusion, EtOH caused developmental teratogenicity and behavioural toxicity by inducing glutathione changes, which were prevented by 24-EPI.


Assuntos
Comportamento Animal , Brassinosteroides/farmacologia , Embrião não Mamífero/patologia , Etanol/toxicidade , Substâncias Protetoras/farmacologia , Esteroides Heterocíclicos/farmacologia , Teratogênese/efeitos dos fármacos , Peixe-Zebra/embriologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Embrião não Mamífero/anormalidades , Embrião não Mamífero/efeitos dos fármacos , Glutationa/metabolismo , Larva/efeitos dos fármacos , Comportamento Social
18.
Bratisl Lek Listy ; 121(8): 589-599, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32726123

RESUMO

AIM: The aim of the present study was to investigate the effect of apoptosis on rat skeletal muscle caused by chronic alcohol and statin consumption with modified liquid diet and to elucidate protective effects of betaine supplementation. METHODS: TNF-α (tumor necrosis factor), NF-kB (Nuclear Factor kappa B), cytochrome c and caspase-3 levels with or without betaine treatment in alcohol and/or statin-induced skeleton muscle apoptosis rats as well as in controls were measured in serum and tissue. Histologic examinations of the muscle tissues were also performed. RESULTS: In our study, betaine treated treatment groups we found that calpain and caspase activities and cytokine c release were decreased caused by alcohol, statin and more importantly alcohol+statin group and TNF and NF-kB levels were also close to the levels of control group. Similarly, significant improvements have been observed in our morphological and histological examination results also supporting our biochemical data. CONCLUSION: We found that combined consumption of ethanol and statin is capable of triggering apoptotic cell death in rat muscles more than the consumption of only alcohol or only statin. Betaine was able to reduced this muscle cell death induced by alcohol and/or statin consumption (Tab. 4, Fig. 4, Ref. 43).


Assuntos
Apoptose , Betaína , Etanol , Inibidores de Hidroximetilglutaril-CoA Redutases , Animais , Apoptose/efeitos dos fármacos , Betaína/farmacologia , Etanol/toxicidade , Inibidores de Hidroximetilglutaril-CoA Redutases/toxicidade , Músculo Esquelético/efeitos dos fármacos , NF-kappa B , Ratos , Fator de Necrose Tumoral alfa
19.
Sci Rep ; 10(1): 12448, 2020 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-32709896

RESUMO

Corneal chemical burns can lead to blindness following serious complications. As most of these complications are caused by failure of reepithelization during the acute phase, treatment at this stage is critical. Although there have been some studies on corneal injury recovery using adipose tissue-derived stem cells (ADSCs), none has reported the effect of topical cell-free conditioned culture media (CM) derived from ADSCs on corneal epithelial regeneration. Here, the best conditions for CM were selected and used for in vitro and in vivo experiments. Corneal burn in rats was induced using 100% alcohol. The chosen CM was administered to corneal burn rats (CM-treated [CT] group) four times a day for three days and this group was compared with the normal control and corneal burn (CB) groups. Biomicroscopic fluorescence images and the actual physical corneas were taken over time and used for analysis. mRNA levels of hepatocyte growth factor and epidermal growth factor (EGF) were significantly increased, whereas those of vascular endothelial growth factor, interleukin (IL)-1ß, IL-6, IL-10, and matrix metalloproteinase-9 were significantly decreased in the CT group compared with those in the CB group. The numbers of proliferating cell nuclear antigen- and zonular occludens-1-positive cells in the CT group were significantly higher than those in the CB group. The macrophage-infiltrating corneas in the CT group expressed significantly more of the M2 marker arginase than corneas in the CB group. Optimal CM (× 0.5 concentration) treatment significantly accelerated the migration of corneal epithelial cells and induced upregulation of the expression of IL-6, EGF, and C-X-C chemokine receptor type 4 mRNAs. Overall, in this study, topical administration of cell-free CM promoted regeneration of the corneal epithelium after induction of chemical burns.


Assuntos
Terapia Biológica/métodos , Queimaduras Químicas/terapia , Lesões da Córnea/terapia , Meios de Cultivo Condicionados , Queimaduras Oculares/terapia , Células-Tronco/fisiologia , Tecido Adiposo/citologia , Administração Oftálmica , Animais , Queimaduras Químicas/etiologia , Queimaduras Químicas/patologia , Células Cultivadas , Lesões da Córnea/induzido quimicamente , Lesões da Córnea/patologia , Modelos Animais de Doenças , Epitélio Anterior/efeitos dos fármacos , Epitélio Anterior/patologia , Etanol/toxicidade , Queimaduras Oculares/induzido quimicamente , Queimaduras Oculares/patologia , Humanos , Masculino , Cultura Primária de Células , Ratos , Reepitelização/fisiologia , Cicatrização/fisiologia
20.
Sci Rep ; 10(1): 12417, 2020 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-32709984

RESUMO

To develop a reproducible and stable closed chest model of ischemic cardiogenic shock in sheep, with high survival rate and potential insight into human pathology. We established a protocol for multi-step myocardial alcoholisation of the left anterior descending coronary artery by percutaneous ethanol injection. A thorough hemodynamic assessment was obtained by invasive and non-invasive monitoring devices. Repeated blood samples were obtained to determine haemoglobin and alcohol concentration, electrolytes, blood gas parameters and cardiac troponin I. After sacrifice, tissue was excised for quantification of infarction and histology. Cardiogenic shock was characterized by a significant decrease in mean arterial pressure (- 33%), cardiac output (- 29%), dP/dtmax (- 28%), carotid blood flow (- 22%), left ventricular fractional shortening (- 28%), and left ventricle end-systolic pressure-volume relationship (- 51%). Lactate and cardiac troponin I levels increased from 1.4 ± 0.2 to 4.9 ± 0.7 mmol/L (p = 0.001) and from 0.05 ± 0.02 to 14.74 ± 2.59 µg/L (p = 0.001), respectively. All haemodynamic changes were stable over a three-hour period with a 71% survival rate. The necrotic volume (n = 5) represented 24.0 ± 1.9% of total ventricular mass. No sham exhibited any variation under general anaesthesia. We described and characterized, for the first time, a stable, reproducible sheep model of cardiogenic shock obtained by percutaneous intracoronary ethanol administration.


Assuntos
Modelos Animais de Doenças , Etanol/administração & dosagem , Injeções Intra-Arteriais/métodos , Choque Cardiogênico/induzido quimicamente , Animais , Pressão Arterial/efeitos dos fármacos , Pressão Arterial/fisiologia , Débito Cardíaco/efeitos dos fármacos , Débito Cardíaco/fisiologia , Circulação Coronária/efeitos dos fármacos , Circulação Coronária/fisiologia , Vasos Coronários/efeitos dos fármacos , Etanol/toxicidade , Feminino , Humanos , Reprodutibilidade dos Testes , Ovinos , Choque Cardiogênico/mortalidade , Choque Cardiogênico/fisiopatologia , Taxa de Sobrevida , Função Ventricular Esquerda/efeitos dos fármacos , Função Ventricular Esquerda/fisiologia
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