RESUMO
Neuromodulation techniques have shown promising efficacy on memory function and understanding the epigenetic mechanisms contributing to these processes would shed light on the molecular outcomes essential for cognition. In this review, we highlight some epigenetic mechanisms underlying neuromodulation and regulatory effects of neuronal activity-induced DNA methylation on genes that are highly involved in memory formation. Next, we examine the evidence to support DNA methyltransferase 3a, methyl-CpG binding protein 2, and DNA demethylase as possible memory modulation targets. Finally, we report the recent developments in the field of neuromodulation and explore the potential of these techniques for future neuroepigenetic research.
Assuntos
Metilação de DNA/fisiologia , Terapia por Estimulação Elétrica , Epigênese Genética/fisiologia , Hipocampo/fisiologia , Memória/fisiologia , Animais , DNA Metiltransferase 3A , Hipocampo/metabolismo , HumanosRESUMO
Depression is a common and severe neuropsychiatric disorder that is one of the leading causes of global disease burden. Although various anti-depressants are currently available, their efficacies are barely adequate and many have side effects. Hericium erinaceus, also known as Lion's mane mushroom, has been shown to have various health benefits, including antioxidative, antidiabetic, anticancer, anti-inflammatory, antimicrobial, antihyperglycemic, and hypolipidemic effects. It has been used to treat cognitive impairment, Parkinson's disease, and Alzheimer's disease. Bioactive compounds extracted from the mycelia and fruiting bodies of H. erinaceus have been found to promote the expression of neurotrophic factors that are associated with cell proliferation such as nerve growth factors. Although antidepressant effects of H. erinaceus have not been validated and compared to the conventional antidepressants, based on the neurotrophic and neurogenic pathophysiology of depression, H. erinaceus may be a potential alternative medicine for the treatment of depression. This article critically reviews the current literature on the potential benefits of H. erinaceus as a treatment for depressive disorder as well as its mechanisms underlying the antidepressant-like activities.
Assuntos
Basidiomycota/química , Produtos Biológicos/uso terapêutico , Transtorno Depressivo/tratamento farmacológico , Basidiomycota/metabolismo , Produtos Biológicos/química , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Ensaios Clínicos como Assunto , Transtorno Depressivo/patologia , Diterpenos/química , Diterpenos/isolamento & purificação , Diterpenos/uso terapêutico , Humanos , Indóis/química , Indóis/isolamento & purificação , Indóis/uso terapêutico , Micélio/química , Micélio/metabolismo , Fatores de Crescimento Neural/metabolismoRESUMO
Chronic intermittent hypoxia (CIH) is a hallmark of obstructive sleep apnea (OSA), which induces hippocampal injuries mediated by oxidative stress. This study aims to examine the neuroprotective mechanism of Lycium barbarum polysaccharides (LBP) against CIH-induced spatial memory deficits. Adult Sprague-Dawley rats were exposed to hypoxic treatment resembling a severe OSA condition for a week. The animals were orally fed with LBP solution (1 mg/kg) daily 2 hours prior to hypoxia or in air for the control. The effect of LBP on the spatial memory and levels of oxidative stress, inflammation, endoplasmic reticulum (ER) stress, apoptosis and neurogenesis in the hippocampus was examined. There was a significant deficit in the spatial memory and an elevated level of malondialdehyde with a decreased expression of antioxidant enzymes (SOD, GPx-1) in the hypoxic group when compared with the normoxic control. In addition, redox-sensitive nuclear factor kappa B (NFÐB) canonical pathway was activated with a translocation of NFÐB members (p65, p50) and increased expression levels of NFÐB-dependent inflammatory cytokines and mediator (TNFα, IL-1ß, COX-2); also, a significantly elevated level of ER stress (GRP78/Bip, PERK, CHOP) and autophagic flux in the hypoxic group, leading to neuronal apoptosis in hippocampal subfields (DG, CA1, CA3). Remarkably, LBP administration normalized the elevated level of oxidative stress, neuroinflammation, ER stress, autophagic flux and apoptosis induced by hypoxia. Moreover, LBP significantly mitigated both the caspase-dependent intrinsic (Bax, Bcl2, cytochrome C, cleaved caspase-3) and extrinsic (FADD, cleaved caspase-8, Bid) signaling apoptotic cascades. Furthermore, LBP administration prevented the spatial memory deficit and enhanced the hippocampal neurogenesis induced by hypoxia. Our results suggest that LBP is neuroprotective against CIH-induced hippocampal-dependent spatial memory deficits by promoting hippocampal neurogenesis and negatively modulating the apoptotic signaling cascades activated by oxidative stress and inflammation.
Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Hipocampo/efeitos dos fármacos , Transtornos da Memória/etiologia , Fármacos Neuroprotetores/farmacologia , Memória Espacial/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático , Hipocampo/metabolismo , Hipocampo/patologia , Hipóxia/metabolismo , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , NF-kappa B/metabolismo , Neurogênese/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Antígeno Nuclear de Célula em Proliferação/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/metabolismoRESUMO
This study aimed to investigate the possible therapeutic effects and active components of Lycium barbarum polysaccharides (LBP) on a high fat diet-induced NASH rat model. We induced NASH in a rat model by voluntary oral feeding with a high-fat diet ad libitum for 8 weeks. After 8 weeks, 1â mg/kg LBP was orally administered for another 4 weeks with a high-fat diet. When compared with NASH rats treated for 12 weeks, therapeutic LBP treatment for 4 weeks during 12 weeks of NASH induction showed ameliorative effects on: (1) increased body and wet liver weights; (2) insulin resistance and glucose metabolic dysfunction; (3) elevated level of serum aminotransferases; (4) fat accumulation in the liver and increased serum free fatty acid (FFA) level; (5) hepatic fibrosis; (6) hepatic oxidative stress; (7) hepatic inflammatory response; and (8) hepatic apoptosis. These improvements were partially through the modulation of transcription factor NF-κB, MAPK pathways and the autophagic process. In a palmitate acid-induced rat hepatocyte steatosis cell-based model, we also demonstrated that l-arabinose and ß-carotene partially accounted for the beneficial effects of LBP on the hepatocytes. In conclusion, LBP possesses a variety of hepato-protective properties which make it a potent supplementary therapeutic agent against NASH in future clinical trials.
Assuntos
Fármacos Antiobesidade/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Hepatócitos/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Apoptose , Arabinose/farmacologia , Autofagia , Sobrevivência Celular , Células Cultivadas , Dieta Hiperlipídica/efeitos adversos , Feminino , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/patologia , Sistema de Sinalização das MAP Quinases , Hepatopatia Gordurosa não Alcoólica/etiologia , Obesidade/tratamento farmacológico , Estresse Oxidativo , Ratos Sprague-Dawley , beta Caroteno/farmacologiaRESUMO
In the current study, the therapeutic effects of zeaxanthin dipalmitate (ZD) on a rat alcoholic fatty liver disease (AFLD) model were evaluated. After-treatment with ZD from the 5th week to the 10th week in a 10-week ethanol intragastric administration in rats significantly alleviated the typical AFLD symptoms, including reduction in rat body weight, accumulation of hepatic fat droplets, occurrence of oxidative stress, inflammation, chemoattractive responses and hepatic apoptosis in the liver. The reduction of liver function abnormalities by ZD was partly through lower expression level of cytochrome P450 2E1 (CYP2E1), diminished activity of nuclear factor kappa B (NF-κB) through the restoration of its inhibitor kappa B alpha (IκBα), and the modulation of MAPK pathways including p38 MAPK, JNK and ERK. ZD treatment alone did not pose obvious adverse effect on the healthy rat. In the cellular AFLD model, we also confirmed the inhibition of p38 MAPK and ERK abolished the beneficial effects of ZD. These results provide a scientific rationale for the use of zeaxanthin and its derivatives as new complementary agents for the prevention and treatment of alcoholic liver diseases.
Assuntos
Antioxidantes/farmacologia , Etanol/administração & dosagem , Fígado Gorduroso Alcoólico/tratamento farmacológico , Palmitatos/farmacologia , Substâncias Protetoras/farmacologia , Xantofilas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Apoptose/efeitos dos fármacos , Citocromo P-450 CYP2E1/genética , Citocromo P-450 CYP2E1/metabolismo , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fígado Gorduroso Alcoólico/genética , Fígado Gorduroso Alcoólico/metabolismo , Fígado Gorduroso Alcoólico/patologia , Feminino , Regulação da Expressão Gênica , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/metabolismo , Inibidor de NF-kappaB alfa , NF-kappa B/genética , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Redução de Peso/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/genéticaRESUMO
PURPOSE: To investigate the protective mechanisms of an 85 % pure extract of (-) epigallocatechin gallate (EGCG) in the development of fibrosis, oxidative stress and inflammation in a recently developed dietary-induced animal model of non-alcoholic fatty liver disease (NAFLD). METHODS: Female Sprague-Dawley rats were fed with either normal rat diet or high-fat diet for 8 weeks to develop NAFLD. For both treatments, rats were treated with or without EGCG (50 mg/kg, i.p. injection, 3 times per week). At the end, blood and liver tissue samples were obtained for histology, molecular, and biochemical analyses. RESULTS: Non-alcoholic fatty liver disease (NAFLD) rats showed significant amount of fatty infiltration, necrosis, fibrosis, and inflammation. This was accompanied by a significant expressional increase in markers for fibrosis, oxidative stress, and inflammation. TGF/SMAD, PI3 K/Akt/FoxO1, and NF-κB pathways were also activated. Treatment with EGCG improved hepatic histology (decreased number of fatty score, necrosis, and inflammatory foci), reduced liver injury (from ~0.5 to ~0.3 of ALT/AST ratio), attenuated hepatic changes including fibrosis (reduction in Sirius Red and synaptophysin-positive stain) with down-regulation in the expressions of key pathological oxidative (e.g. nitrotyrosine formation) and pro-inflammatory markers (e.g. iNOS, COX-2, and TNF-α). EGCG treatment also counteracted the activity of TGF/SMAD, PI3 K/Akt/FoxO1, and NF-κB pathways. Treatment with EGCG did not affect the healthy rats. CONCLUSIONS: Epigallocatechin gallate (EGCG) reduced the severity of liver injury in an experimental model of NAFLD associated with lower concentration of pro-fibrogenic, oxidative stress, and pro-inflammatory mediators partly through modulating the activities of TGF/SMAD, PI3 K/Akt/FoxO1, and NF-κB pathways. Therefore, green tea polyphenols and EGCG are useful supplements in the prevention of NAFLD.
Assuntos
Antioxidantes/farmacologia , Catequina/análogos & derivados , Fígado Gorduroso/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Catequina/farmacologia , Ciclo-Oxigenase 2/metabolismo , Dieta Hiperlipídica , Regulação para Baixo , Fígado Gorduroso/patologia , Feminino , Fibrose , Fatores de Transcrição Forkhead/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , NF-kappa B/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Hepatopatia Gordurosa não Alcoólica , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Smad/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Our previous study demonstrated that administration of garlic-derived antioxidant S-allylmercaptocysteine (SAMC) ameliorated hepatic injury in a nonalcoholic fatty liver disease (NAFLD) rat model. Our present study aimed to investigate the mechanism of SAMC on NAFLD-induced hepatic apoptosis and autophagy. Adult female rats were fed with a high-fat diet for 8 weeks to develop NAFLD with or without intraperitoneal injection of 200 mg/kg SAMC for three times per week. During NAFLD development, increased apoptotic cells and caspase-3 activation were observed in the liver. Increased apoptosis was modulated through both intrinsic and extrinsic apoptotic pathways. NAFLD treatment also enhanced the expression of key autophagic markers in the liver with reduced activity of LKB1/AMPK and PI3K/Akt pathways. Increased expression of proapoptotic regulator p53 and decreased activity of antiautophagic regulator mTOR were also observed. Administration of SAMC reduced the number of apoptotic cells through downregulation of both intrinsic and extrinsic apoptotic mechanisms. SAMC also counteracted the effects of NAFLD on LKB1/AMPK and PI3K/Akt pathways. Treatment with SAMC further enhanced hepatic autophagy by regulating autophagic markers and mTOR activity. In conclusion, administration of SAMC during NAFLD development in rats protects the liver from chronic injury by reducing apoptosis and enhancing autophagy.
RESUMO
PURPOSE: To investigate the hepato-protective properties and underlying mechanisms of SAMC in a non-alcoholic fatty liver disease (NAFLD) rat model. METHODS: Female rats were fed with a diet comprising highly unsaturated fat diet (30% fish oil) for 8 weeks to develop NAFLD with or without an intraperitoneal injection of 200 mg/kg SAMC three times per week. After euthanasia, blood and liver samples of rats were collected for histological and biochemical analyses. RESULTS: Co-treatment of SAMC attenuated NAFLD-induced liver injury, fat accumulation, collagen formation and free fatty acids (FFAs). At the molecular level, SAMC decreased the lipogenesis marker and restored the lipolysis marker. SAMC also reduced the expression levels of pro-fibrogenic factors and diminished liver oxidative stress partly through the inhibition in the activity of cytochrome P450 2E1-dependent pathway. NAFLD-induced inflammation was also partially mitigated by SAMC treatment via reduction in the pro-inflammatory mediators, chemokines and suppressor of cytokine signaling. The protective effect of SAMC is also shown partly through the restoration of altered phosphorylation status of FFAs-dependent MAP kinase pathways and diminished in the nuclear transcription factors (NF-κB and AP-1) activity during NAFLD development. CONCLUSIONS: SAMC is a novel hepato-protective agent against NAFLD caused by abnormal liver functions. Garlic or garlic derivatives could be considered as a potent food supplement in the prevention of fatty liver disease.
Assuntos
Cisteína/análogos & derivados , Fígado Gorduroso/tratamento farmacológico , Alho/química , Fígado/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Western Blotting , Cisteína/farmacologia , Citocromo P-450 CYP2E1/genética , Citocromo P-450 CYP2E1/metabolismo , Inibidores do Citocromo P-450 CYP2E1 , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Inflamação/tratamento farmacológico , Inflamação/patologia , Lipogênese/efeitos dos fármacos , Fígado/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/genética , NF-kappa B/metabolismo , Hepatopatia Gordurosa não Alcoólica , Estresse Oxidativo/efeitos dos fármacos , Fosforilação , Ratos , Ratos Sprague-Dawley , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismoRESUMO
PURPOSE: To study the protective effects and underlying molecular mechanisms of SAMC on carbon tetrachloride (CCl4)-induced acute hepatotoxicity in the mouse model. METHODS: Mice were intraperitoneally injected with CCl4 (50 µl/kg; single dose) to induce acute hepatotoxicity with or without a 2-h pre-treatment of SAMC intraperitoneal injection (200 mg/kg; single dose). After 8 h, the blood serum and liver samples of mice were collected and subjected to measurements of histological and molecular parameters of hepatotoxicity. RESULTS: SAMC reduced CCl4-triggered cellular necrosis and inflammation in the liver under histological analysis. Since co-treatment of SAMC and CCl4 enhanced the expressions of antioxidant enzymes, reduced the nitric oxide (NO)-dependent oxidative stress, and inhibited lipid peroxidation induced by CCl4. SAMC played an essential antioxidative role during CCl4-induced hepatotoxicity. Administration of SAMC also ameliorated hepatic inflammation induced by CCl4 via inhibiting the activity of NF-κB subunits p50 and p65, thus reducing the expressions of pro-inflammatory cytokines, mediators, and chemokines, as well as promoting pro-regenerative factors at both transcriptional and translational levels. CONCLUSIONS: Our results indicate that SAMC mitigates cellular damage, oxidative stress, and inflammation in CCl4-induced acute hepatotoxicity mouse model through regulation of NF-κB. Garlic or garlic derivatives may therefore be a potential food supplement in the prevention of liver damage.
Assuntos
Tetracloreto de Carbono/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/patologia , Cisteína/análogos & derivados , Inflamação/prevenção & controle , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Alanina Transaminase/sangue , Animais , Antioxidantes/farmacologia , Cisteína/farmacologia , Feminino , Inflamação/induzido quimicamente , Inflamação/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Malondialdeído/sangue , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Lycium barbarum has been used as a traditional Chinese medicine to nourish liver, kidneys and the eyes. AIM OF THE STUDY: We investigated the protective mechanisms of Wolfberry, Lycium barbarum polysaccharides (LBP) in carbon tetrachloride (CCl(4))-induced acute liver injury. MATERIALS AND METHODS: Mice were intraperitoneally injected with a 50 µl/kg CCl(4) to induce acute hepatotoxicity (8h) and were orally fed with LBP 2 h before the CCl(4) injection. There were six experimental groups of mice (n=7-8 per group), namely: control mice (vehicle only; 1 mg/kg LBP or 10 mg/kg LBP), CCl(4)-treated mice and CCl(4)+LBP treated mice (1 mg/kg LBP or 10 mg/kg LBP). RESULTS: Pre-treatment with LBP effectively reduced the hepatic necrosis and the serum ALT level induced by CCl(4) intoxication. LBP remarkably inhibited cytochrome P450 2E1 expression and restored the expression levels of antioxidant enzymes. It also decreased the level of nitric oxide metabolism and lipid peroxidation induced by CCl(4). LBP attenuated hepatic inflammation via down-regulation of proinflammatory mediators and chemokines. Furthermore, LBP promoted liver regeneration after CCl(4) treatment. The protective effects of LBP against hepatotoxicity were partly through the down-regulation of nuclear factor kappa-B activity. CONCLUSION: LBP is effective in reducing necroinflammation and oxidative stress induced by a chemical toxin, thus it has a great potential use as a food supplement in the prevention of hepatic diseases.
Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Tetracloreto de Carbono , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Medicamentos de Ervas Chinesas/farmacologia , Fígado/efeitos dos fármacos , Lycium , Estresse Oxidativo/efeitos dos fármacos , Alanina Transaminase/sangue , Animais , Anti-Inflamatórios/isolamento & purificação , Antioxidantes/isolamento & purificação , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Citocromo P-450 CYP2E1/metabolismo , Inibidores do Citocromo P-450 CYP2E1 , Citocinas/genética , Citocinas/metabolismo , Citoproteção , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/isolamento & purificação , Inibidores Enzimáticos/farmacologia , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Lycium/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Necrose , Óxido Nítrico/metabolismo , Plantas MedicinaisRESUMO
Our review aims to examine the cellular and molecular mechanisms of cardiovascular protection of green tea polyphenols, particularly epigallocatechin gallate (EGCG), which focuses on the anti-oxidative and anti-inflammatory effects. EGCG is the major and the most active component in green tea. Studies have shown that EGCG protects cellular damage by inhibiting DNA damage and oxidation of LDL. One of the protective properties of EGCG is its ability to scavenge free radicals. EGCG can also reduce the inflammatory response associated with local tissue injuries such as the hepatocellular necrosis in acute liver injury induced by carbon tetrachloride. The protective effect of EGCG is due to its ability to decrease lipid peroxidation, oxidative stress and the production of nitric oxide (NO) radicals by inhibiting the expression of iNOS. EGCG also ameliorates the overproduction of pro-inflammatory cytokines and mediators, reduces the activity of NF-kappaB and AP-1 and the subsequent formation of peroxynitrite with NO and reactive oxygen species. Thus, EGCG effectively mitigates cellular damage by lowering the inflammatory reaction and reducing the lipid peroxidation and NO generated radicals leading to the oxidative stress. Green tea is proposed to be a dietary supplement in the prevention of cardiovascular diseases in which oxidative stress and proinflammation are the principal causes.