The in Vivo Deleterious Effects of Ethanol

Oxidative stress, which is defined as an imbalance between pro-oxidants and antioxidants, has been demonstrated to mediate the pathogenesis of ethanol-induced injury. Senescence-accelerated mice prone P8 (SAMP8) is considered an excellent model for rode

Protective and therapeutic effects of Chamomilla Recutita extract on subacute ethanol intoxication in white albino rats

Medicinal plants may provide an effective remedy for the enormous health burden posed by alcohol abuse. The aim of this study was to investigate putative protective and therapeutic effects of an aqueous extract of Chamomilla recutita (CHR) on alcohol-induced hepato-nephrotoxicity and pancytopenia in rats. Rats fed only alcohol developed hepato-nephrotoxicity as indicated by significant increases in the levels of all hepatic enzyme markers [alanine amino transferase (ALT), aspartate amino transferase (AST), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GTT)], significantly decreased levels of total protein and increased levels of serum creatinine and urea. Ethanol administered rats also developed pancytopeniawithdecreased levels of total red blood cells (RBC's), white blood cells (WBC's) and platelets and macrocytic, hypochromic anemia. Oral administration of CHR extract for 28 days to normal rats confirmed its safe use with all the above biochemical and hematological parameters remaining within their normal levels. Pre-treatment or post-treatment with CHR to ethanol administered rats ameliorated the deleterious effects of ethanol on all biochemical and hematological parameters. CHR effect was more potent in pretreated- than in post-treated group. The results also show that a diminution of oxidative stress is one mechanism by which CHR extract exerts potent protective and mild therapeutic effects against alcohol-induced hepato-nephrotoxicity and pancytopenia.Keywords: Chamomilla, alcohol, liver, kidney, hematology, protection, therapyAfrican Journal of Biotechnology Vol. 12(18), pp. 2378-238

ETHANOL-INDUCED ALTERATIONS IN CARDIAC ENZYMES–AMELIORATIVE EFFECT OF THESPESIA POPULNEA LEAF EXTRACT

Objective: This study covers the estimation of changes in cardiac enzymes such as ATPases and antioxidant enzymes following ethanol-administration in rats, and the possible ameliorative effect of leaf extract of the plant Thespesia populnea (TP) on these changes.Methods: Male adult Wistar rats were divided into 10 groups of six rats each. Vehicle controls received 5% gum acacia. Experimental groups received ethanol (20%, 2g/kg); or TP leaf extract (200 mg/kg and 400 mg/kg respectively); or vitamin E (25 mg/kg); or carvedilol (1 mg/kg) per orally every morning for 6 w, individually as well as in combination with ethanol. Following this, changes in the activities of Na+ ATPase, Ca2+ATPase, Mg2+ATPase, and antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) were determined in the heart tissue and compared with those in vehicle control.Results: Ethanol (20%, 2g/kg) treatment caused a reduction from the vehicle control in activities of all the examined enzymes, with minimal reduction in Mg2+ ATPase activity (29.26%) and maximal reduction in CAT activity (71.05%). With TP leaf extracts of 200 and 400 mg/kg, vitamin E and carvedilol individually, the vehicle controls showed percent changes in enzyme activities ranging from ‒8.24% for Mg2+ ATPase activity to+109.39% for Na+ ATPase activity caused by carvedilol. When administered along with ethanol, TP leaf extracts, vitamin E and carvedilol reversed the effect of ethanol to various degrees and brought back the enzyme activities to near vehicle control levels. While recovery with 200 mg Thespesia leaf extract was less, ranging from 24.1% for Mg2+ATPase activity to 190.91% for CAT activity, 400 mg Thespesia extract effected a greater recovery, with a minimum of 48.19% for Mg2+ ATPase activity and a maximum of 222.73% for CAT activity, as compared with ethanol-treated rats as controls. These effects could be interpreted in terms of the adverse effects of ethanol on cardiac function and the ameliorative effects, primarily the antioxidant potential, of TP leaf extracts, vitamin E and carvedilol.Conclusion: The restoration of enzyme activities with TP leaf extract may promote recovery of cardiac tissue from oxidative damage. Results from the current study indicate that treatment with TP leaf extract reduces ethanol-induced oxidative stress in rat heart and hence may help prevent cardiac damage.Â

Hepatoprotective Effects of Chinese Medicinal Herbs: A Focus on Anti-Inflammatory and Anti-Oxidative Activities

published_or_final_versio

The Mechanistic Role and Therapeutic Potential of microRNA-122 in Alcoholic Liver Disease: A Dissertation

Chronic alcohol use results in accelerated liver injury, leading to alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. However, due to the complex nature of this disease process, a central, druggable mechanism has remained elusive. microRNAs are potent post-transcriptional regulators of gene expression. A single miRNA has the ability to regulate hundreds of pathways simultaneously, defining cellular fate and function. microRNA-122 (miR-122), the most abundant miRNA in hepatocytes, has a demonstrated role as an tumor suppressor, regulator of hepatocyte metabolism, and hepatic differentiation. In this dissertation I demonstrate the role of miR-122 on alcoholic liver disease (ALD) pathogenesis over four parts. In chapter II, I will demonstrate chronic alcoholic patients, free of neoplastic changes, have a reduction of miR-122 and that this miRNA regulates HIF-1α, a determinant of ALD pathogenesis. In chapter III, using hepatocytetropic adeno-associated virus 8 (AAV8) vector, I demonstrate that miR-122 inhibition mimics ALD pathogenesis, and furthermore, using hepatocyte-specific HIF-1α-null (HIF1hepKO) mice that this phenomenon is HIF-1α dependent. Given this finding, in chapter IV, I demonstrate that ectopic expression of miR-122 in vivo can reverse alcoholinduced liver damage, steatosis, and inflammation by directly targeting HIF-1α. Finally, in chapter V, I present evidence that alcohol-induced dysregulation of grainyhead-like proteins 1 and 2 (GRHL2), mediate the inhibition of miR-122 at the transcriptional level. These findings dissect a novel mechanistic regulatory axis of miR-122 and indicate a potential opportunity for restoration of miR-122 as a therapy in early ALD

Avaliação farmacológica dos efeitos hepáticos e gástricos da Baccharis trimera em lesões induzidas por etanol

Orientadoar : Profª. Drª. Alexandra AccoTese (doutorado) - Universidade Federal do Paraná, Setor de Ciências Biológicas, Programa de Pós-Graduação em Farmacologia. Defesa: Curitiba, 12/02/2016Inclui referênciasResumo: Estima-se que 2 bilhões de pessoas consumam o etanol em todo o mundo, e destas 76,3 milhões apresentam doenças relacionadas ao seu consumo. Dentre elas, a esteatose hepática alcoólica (EHA), estágio inicial das doenças hepáticas alcoólicas, destaca-se como uma enfermidade diretamente relacionada ao estresse oxidativo e a desarmonia da homeostase lipídica. Já a úlcera gástrica é uma doença multifatorial que decorre do desequilíbrio entre fatores agressivos e protetores. Tais lesões merecem atenção especial devido à ausência de tratamento preconizado, ou ainda, à vasta quantidade de efeitos colaterais observados. Buscando uma nova alternativa de tratamento, investigamos o potencial farmacológico da Baccharis trimera ("carqueja"), planta popularmente utilizada para tratar distúrbios gastrointestinais, em modelos de lesão gástrica e EHA. O extrato hidroetanólico (HEBT) foi obtido das partes aéreas da planta e caracterizado por cromatografia líquida de alta eficiência. Para investigar a atividade farmacológica do HEBT frente à EHA, submetemos camundongos à ingestão de etanol a 10% e dieta hipoprotéica por 6 semanas. Nas duas últimas semanas os animais foram tratados diariamente com o HEBT (30 mg.kg-1, via oral). O estresse oxidativo induzido pelo etanol foi revertido pelo HEBT, que normalizou os níveis de LPO, ROS total e GSH, bem como a atividade das enzimas SOD, Cat, GPx e GST. Além disso, o HEBT corrigiu os níveis de colesterol (CHO) e triglicerídeos (TG), HDL e LDL plasmáticos, normalizou os níveis de TG, HDL e LDL hepáticos e aumentou a excreção fecal de TG. O HEBT também reverteu alterações histológicas e ultraestruturais induzidas pelo etanol e normalizou a expressão dos genes Cyp2e1, Nrf2 e Scd1. Adicionalmente, úlceras induzidas por uso agudo ou crônico de etanol e por ácido acético, ligadura do piloro e motilidade gastrointestinal foram avaliados em ratos e camundongos a fim de examinar a atividade gastroprotetora do HEBT. O extrato preveniu a ulceração aguda e crônica, diminuindo significativamente a área da lesão induzida por etanol e ácido acético, mas não protegeu contra a depleção de muco. Além disso, o HEBT não alterou o volume e acidez gástricos. Histologicamente, o tratamento acelerou a cicatrização, refletida pela contração da base da úlcera. A atividade antiulcerogênica do HEBT pode ser atribuída, em partes, à inibição da geração de radicais livres e consequente prevenção da lipoperoxidação, promovida pelos ácidos cafeilquínicos, componentes principais do extrato. Nenhum sinal de toxicidade foi observado. Nossos resultados indicam que o HEBT possui efeitos hepato- e gastroprotetores e que pode ser uma terapia promissora para o tratamento de doenças hepáticas e gástricas decorrentes do consumo do etanol.Abstract: An estimated 2 billion people consume ethanol worldwide, and 76.3 million have ethanol-related disorders. Among them, alcoholic fatty liver disease (AFLD), early stages of alcoholic liver diseases, is directly related to oxidative stress and lipogenesis disruption. Regarding gastric ulcer, it is a multifactorial process that occurs through an imbalance between aggressive and protective factors. These injuries deserve special attention due the absence of preconized treatment, or even the vast amount of side effects observed. Searching for a new alternative treatment, we investigated the pharmacologic activity of Baccharis trimera ("carqueja"), a plant popularly used for gastrointestinal disorders, in gastric lesions models and AFLD. The hydroethanolic extract (HEBT) was obtained from the plant aerial parts and characterized by high-performance liquid chromatography. To investigate the pharmacologic HEBT activity against AFLD, we submitted mice to 10% ethanol ingestion and low-protein diet, during 6 weeks. In the last 2 weeks, mice were treated with HEBT (30 mg.kg-1, p.o.). The oxidative stress induced by ethanol was reversed by HEBT, which normalized LPO, total ROS and GSH levels, as well as SOD, Cat, GPx and GST activity. Beside this, HEBT corrected plasmatic cholesterol (CHO), triglycerides (TG), HDL and LDL levels, normalized hepatic TG, HDL and LDL levels and increased fecal TG excretion. HEBT also reverted histologic and ultrastructural alterations induced by ethanol and normalized Cyp2e1, Nrf2 e Scd1 gene expression. Additionally, gastric ulcers induced by acute or chronic ethanol or acetic acid consumption, pylorus ligature and gastrointestinal motility were evaluated in mice and rats to examine HEBT gastrointestinal protective effects. HEBT prevented acute and chronic gastric ulceration, decreasing significantly the lesion area induced by ethanol and acetic acid but not protect against mucus depletion. Besides this, HEBT did not altered gastric volume and acidity. Histologically, HEBT accelerated the healing, reflected by contractions of the ulcer base. HEBT antiulcerogenic activity may be partially attributable to the inhibition of free radical generation and subsequent prevention of lipid peroxidation, promoted by caffeoylquinic acids, the major components of extract. No signs of toxicity were observed. Our results indicate that HEBT have hepatic and gastroprotective effects and may be a promising therapy for hepatic and gastric disorders, due to ethanol consumption

Antioxidents or reduced oxygen tension as a defense system in T cells ex vivo and in vitro

Age-related deterioration and dysregulation of T cell function, termed ‘immunosenescence’, may lead to increased mortality and morbidity in humans through greater susceptibility to infections and disease. Previous research from the group of Barnett, suggested that oxidative stress may play a role in the immunosenescence process, through resultant genomic instability, cell cycle delay and arrest. The aim of this research programme was to investigate the effect of the antioxidants, ebselen, NAcetyl L- Cysteine (NAC) or mitoQ or reduced oxygen (O2) tension on markers of T cell function and integrity using CD4+ T cell clones and ex vivo polyclonal human peripheral blood derived mononuclear cells or CD4+ T cells derived from healthy young and older aged donors. The results of this investigation revealed that 30μM ebselen or 7.5mM NAC supplementation significantly increased the lifespan and reduced levels of oxidative DNA damage in clones supplemented from a young in vitro age and in human peripheral blood mononuclear cells and CD4+ T cells ex vivo derived from either age group. The GSH:GSSG ratio was also significantly higher in supplemented clones and cells ex vivo. Ebselen or NAC were not able to bring about such biological effects in clones when supplemented from the midpoint of their in vitro lifespan. In this latter situation, age related changes in T cell physiology example: reduced DNA repair capacity, heat shock response and an accumulation of biomolecule damage may have contributed to these findings