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2.
Int Immunopharmacol ; 96: 107639, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34162128

RESUMO

Sepsis-induced myocardial dysfunction (SIMD) represents one of the serious complications secondary to sepsis, which is a leading cause of the high mortality rate among septic cases. Subsequent cardiomyocyte apoptosis, together with the uncontrolled inflammatory response, has been suggested to be closely related to SIMD. Piceatannol (PIC) is verified with potent anti-apoptotic and anti-inflammatory effects, but its function and molecular mechanism in SIMD remain unknown so far. This study aimed to explore the potential role and mechanism of action of PIC in resisting SIMD. The interaction of PIC with JAK2 proteins was evaluated by molecular docking, molecular dynamics (MD) simulation and surface plasmon resonance imaging (SPRi). The cecal ligation and puncture-induced septicemia mice and the LPS-stimulated H9C2 cardiomyocytes were prepared as the models in vivo and in vitro, separately. Molecular docking showed that JAK2-PIC complex had the -8.279 kcal/mol binding energy. MD simulations showed that JAK2-PIC binding was stable. SPRi analysis also showed that PIC has a strong binding affinity to JAK2. PIC treatment significantly ameliorated the cardiac function, attenuated the sepsis-induced myocardial loss, and suppressed the myocardial inflammatory responses both in vivo and in vitro. Further detection revealed that PIC inhibited the activation of the JAK2/STAT3 signaling, which was tightly associated with apoptosis and inflammation. Importantly, pre-incubation with a JAK2 inhibitor (AG490) partially blocked the cardioprotective effects of PIC. Collectively, the findings demonstrated that PIC restored the impaired cardiac function by attenuating the sepsis-induced apoptosis and inflammation via suppressing the JAK2/STAT3 pathway both in septic mice and H9C2 cardiomyocytes.

3.
Phytomedicine ; 84: 153524, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33667840

RESUMO

BACKGROUND: Indoleamine 2,3-dioxygenase 1 (IDO1) has been reported as a hallmark of hepatic fibrosis. Ginseng Rg1(G-Rg1) is a characterized bioactive component isolated from a traditional Chinese medicinal herb Panax ginseng C. A. Meyer (Ginseng) that used in China widely. However, the anti-hepatic fibrosis property of G-Rg1 and the underlying mechanisms of action are poorly reported. PURPOSE: Here, we researched the effect of G-Rg1 on experimental liver fibrosis in vivo and in vitro. STUDY DESIGN AND METHODS: We applied a CCL4-induced liver fibrosis in mice (wild-type and those overexpressing IDO1 by in vivo AAV9 vector) and HSC-T6 cells to detect the anti-hepatic fibrosis effect of G-Rg1 in vivo and in vitro. RESULTS: We found that G-Rg1 reduced serum levels of AST and ALT markedly. Histologic examination indicated that G-Rg1 dramatically improved the extent of liver fibrosis and suppressed the hepatic levels of fibrotic marker α-SMA in vivo and in vitro. The proliferation of HSC-T6 was significantly inhibited by G-Rg1 in vitro. Both TUNEL staining and flow cytometry demonstrated that G-Rg1 attenuated the levels of hepatocyte apoptosis in fibrotic mice. Additionally, G-Rg1 up-regulated the maturation of hepatic DCs via reducing the expression level of hepatic IDO1, which played an inverse role in the maturation of DCs. Furthermore, oral administration of G-Rg1 ameliorated IDO1 overexpression-induced worsen liver fibrosis as well as IDO1 overexpression-mediated more apparent inhibition of maturation of DCs. CONCLUSION: These results suggest that G-Rg1, which exerts its antifibrotic properties via alleviating IDO1-mediated the inhibition of DCs maturation, may be a potential therapeutic drug in treating liver fibrosis.


Assuntos
Células Dendríticas/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Ginsenosídeos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Cirrose Hepática/prevenção & controle , Actinas/metabolismo , Animais , Células Dendríticas/fisiologia , Células Estreladas do Fígado/efeitos dos fármacos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Camundongos Endogâmicos C57BL , Panax/química , Substâncias Protetoras/farmacologia , Ratos
4.
Front Pharmacol ; 12: 616409, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33716743

RESUMO

Alcoholic liver disease (ALD) has become a heavy burden on health worldwide. Ginsenoside Rb1 (GRb1), extracted from Panax quinquefolium L., has protective effects on many diseases, but the effect and mechanisms of GRb1 on ALD remain unknown. This study aimed to investigate the protective effects of GRb1 on ALD and to discover the potential mechanisms. Zebrafish larvae were exposed to 350 mM ethanol for 32 h to establish a model of acute alcoholic liver injury, and the larvae were then treated with 6.25, 12.5, or 25 µM GRb1 for 48 h. The human hepatocyte cell line was stimulated by 100 mM ethanol and meanwhile incubated with 6.25, 12.5, and 25 µM GRb1 for 24 h. The lipid changes were detected by Oil Red O staining, Nile Red staining, and triglyceride determination. The antioxidant capacity was assessed by fluorescent probes in vivo, and the expression levels of inflammatory cytokines were detected by immunohistochemistry, immunofluorescence, and quantitative real-time PCR. The results showed that GRb1 alleviated lipid deposition in hepatocytes at an optimal concentration of 12.5 µM in vivo. GRb1 reversed the reactive oxygen species accumulation caused by alcohol consumption and partially restored the level of glutathione. Furthermore, GRb1 ameliorated liver inflammation by inhibiting neutrophil infiltration in the liver parenchyma and downregulating the expression of nuclear factor-kappa B pathway-associated proinflammatory cytokines, including tumor necrosis factor-α and interleukin-1ß. This study revealed that GRb1 has a protective effect on alcohol-induced liver injury due to its resistance to lipid deposition as well as antioxidant and anti-inflammatory actions. These findings suggest that GRb1 may be a promising candidate against ALD.

5.
Aging (Albany NY) ; 13(5): 6592-6605, 2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33707345

RESUMO

Acute hepatic damage is a severe condition characterized by inflammation and oxidative stress, which is a serious threat to people's life and health. But there are few effective treatments for acute liver injury. Therefore, safe and effective therapeutic approaches for preventing acute liver damage are urgently needed. Lupeol is a natural compound, which has significant antioxidant and anti-inflammatory properties in liver disease. However, the protective mechanism of lupeol against acute liver injury remains unclear. Here, zebrafish and mutant mice were utilized to investigate the protective effects of lupeol against lipopolysaccharide (LPS)/ D-galactosamine(D-GalN) -induced liver injury and the underlying mechanisms. We found that pretreatment with lupeol attenuated the LPS/D-GalN-induced liver injury by decreasing the infiltration of inflammatory cells and reducing pro-inflammatory cytokines. We also demonstrated that lupeol could protect injured liver from oxidative stress by downregulating the expression of TGFß1 and upregulating Nrf2. Notably, our experimental results provided the support that lupeol effectively protected against LPS/D-GalN-induced acute liver injury via suppression of inflammation response and oxidative stress, which were largely dependent on the upregulation of the Nrf2 pathway via downregulating TGFß1.


Assuntos
Anti-Inflamatórios/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Fator 2 Relacionado a NF-E2/metabolismo , Triterpenos Pentacíclicos/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Animais , Modelos Animais de Doenças , Regulação para Baixo , Galactosamina/toxicidade , Inflamação/prevenção & controle , Lipopolissacarídeos/toxicidade , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Regulação para Cima , Peixe-Zebra
6.
Cell Death Dis ; 12(1): 16, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33414436

RESUMO

Liver fibrosis is a course of chronic liver dysfunction, can develop into cirrhosis and hepatocellular carcinoma. Inflammatory insult owing to pathogenic factors plays a crucial role in the pathogenesis of liver fibrosis. Indoleamine 2,3-dioxygenase 1 (IDO1) can affect the infiltration of immune cells in many pathology processes of diseases, but its role in liver fibrosis has not been elucidated completely. Here, the markedly elevated protein IDO1 in livers was identified, and dendritic cells (DCs) immune-phenotypes were significantly altered after BDL challenge. A distinct hepatic population of CD11c+DCs was decreased and presented an immature immune-phenotype, reflected by lower expression levels of co-stimulatory molecules (CD40, MHCII). Frequencies of CD11c+CD80+, CD11c+CD86+, CD11c+MHCII+, and CD11c+CD40+ cells in splenic leukocytes were reduced significantly. Notably, IDO1 overexpression inhibited hepatic, splenic CD11c+DCs maturation, mature DCs-mediated T-cell proliferation and worsened liver fibrosis, whereas above pathological phenomena were reversed in IDO1-/- mice. Our data demonstrate that IDO1 affects the process of immune cells recruitment via inhibiting DCs maturation and subsequent T cells proliferation, resulting in the promotion of hepatic fibrosis. Thus, amelioration of immune responses in hepatic and splenic microenvironment by targeting IDO1 might be essential for the therapeutic effects on liver fibrosis.


Assuntos
Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Cirrose Hepática/enzimologia , Cirrose Hepática/patologia , Animais , Ductos Biliares/enzimologia , Ductos Biliares/patologia , Ductos Biliares/cirurgia , Diferenciação Celular/fisiologia , Hepatócitos/enzimologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
7.
Free Radic Biol Med ; 160: 178-190, 2020 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-32771520

RESUMO

Liver fibrosis can develop into liver cirrhosis and hepatocellular carcinoma substantially without effective available treatment currently due to rarely characterized molecular pathogenesis. Indoleamine 2,3-dioxygenase 1(IDO1) can be detected on antigen-presenting cells (APCs) and modulates various immune responses. However, the role of IDO1 in the regulation of dendritic cells (DCs) during liver fibrosis is rarely reported. Here, we found that hepatic IDO1 was up-regulated during CCL4-induced liver fibrosis, which accompanied by a significant decrease in the frequencies of CD11c+CD80+, CD11c+CD86+, CD11c+CD40+ and CD11c+MHCII+ cells and a reduction in the subsequent T cell proliferation rate, whereas these changes were reversed significantly in IDO1-/- mice. Overexpressing IDO1 by adeno-associated viral vector serotype 9 (AAV9) significantly inhibited the maturation status of DCs, worsened fibrosis. In vitro studies showed that significantly elevated CD80, CD86, CD40 and MHCII expression were observed in BMDCs derived from IDO1-/- mice. Moreover, the maturation of BMDCs derived from WT mice were significantly increased after stimulated with IDO1 inhibitor (1-methyl- D -tryptophan). Nuclear factor E2-related factor 2 (Nrf2), a key regulator of the cellular adaptive response to oxidative insults and inflammation, exhibited a markedly decrease in the liver of WT fibrotic mice, nevertheless, knockout of IDO1 enhanced the protein level of Nrf2. Moreover, the expression of IDO1 and Nrf2 exhibited inverse colocalization pattern suggesting that ectopically expressed IDO1 down-regulated Nrf2. Additionally, up-regulation of IDO1 was also observed in the livers of Nrf2-/- fibrotic mice. Taken together, these data uncovered mutual antagonism between IDO1 and Nrf2 on the maturation status of DCs during hepatic fibrosis.


Assuntos
Indolamina-Pirrol 2,3,-Dioxigenase , Cirrose Hepática , Fator 2 Relacionado a NF-E2 , Animais , Células Dendríticas , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Cirrose Hepática/genética , Camundongos , Fator 2 Relacionado a NF-E2/genética , Triptofano
8.
Free Radic Biol Med ; 152: 668-679, 2020 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-31945497

RESUMO

Ferroptosis is a recently recognized form of regulated cell death that is characterized by lipid peroxidation. However, the molecular mechanisms of ferroptosis in acute immune hepatitis (AIH) are largely unknown. In this study, we investigated the classical ferroptotic events in the livers of mice with concanavalin A (ConA) to induce AIH. The dramatically upregulated gene indoleamine 2, 3-dioxygenase 1 (IDO1) was identified with AIH, and its role in generation of ferroptosis and reactive nitrogen species (RNS) was assessed both in vitro and in vivo by genetic deletion or pharmacologic inhibition of IDO1. We observed that ferroptosis contributed to the ConA-induced hepatic damage, which was confirmed by the therapeutical effects of ferroptosis inhibitor (ferrostatin-1). Noteworthy, upregulation of hepatic IDO1 and nitrative stress in ConA-induced hepatic damage were also remarkably inhibited by the ferroptosis abolishment. Additionally, IDO1 deficiency contributed to ferroptosis resistance by activating solute carrier family 7 member 11 (SLC7A11; also known as xCT) expression, accompanied with the reductions of murine liver lesions and RNS. Meanwhile, IDO inhibitor 1-methyl tryptophan alleviated murine liver damage with the reduction of inducible nitric oxide synthase and 3-nitrotyrosine expression. Consistent with the results in vivo, hepatocytes-specific knockdown of IDO1 led to ferroptosis resistance upon exposure to ferroptosis-inducing compound (Erastin) in vitro, whereas IDO1 overexpression aggravated the classical ferroptotic events, and the RNS stress. Overall, these results revealed a novel molecular mechanism of ferroptosis with the key feature of nitrative stress in ConA-induced liver injury, and also identified IDO1-dependent ferroptosis as a potential target for the treatment of AIH.


Assuntos
Ferroptose , Hepatite , Animais , Hepatócitos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Camundongos
10.
Front Pharmacol ; 10: 1594, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32047433

RESUMO

Alcoholic liver disease (ALD), which is recognized as an important health problem worldwide, is a direct consequence of alcohol consumption, which can induce alcoholic fatty liver, alcoholic steatohepatitis, fibrosis and cirrhosis. P-Hydroxyacetophenone (p-HAP) is mainly used as a choleretic and hepatoprotective compound and has anti-hepatitis B, antioxidative and anti-inflammatory effects. However, no experimental report has focused on p-HAP in ALD, and the effect and mechanism of p-HAP in ALD remain unknown. In addition, there is no research on p-HAP in the treatment of ALD. The potential molecular mechanisms of p-HAP against acute alcoholic liver injury remain unknown. In this study, we aimed to investigate whether p-HAP alleviates ALD and to clarify the potential molecular mechanisms. Zebrafish larvae were soaked in 350 mmol/l ethanol for 32 h at 4 days post fertilization (dpf) and then treated with p-HAP for 48 h. We chose various outcome measures, such as liver histomorphological changes, antioxidation and antiapoptosis capability and expression of inflammation-related proteins, to elucidate the essential mechanism of p-HAP in the treatment of alcohol-induced liver damage. Subsequently, we applied pathological hematoxylin and eosin (H&E) staining, Nile red staining and oil red O staining to detect the histomorphological and lipid changes in liver tissues. We also used TUNEL staining, immunochemistry and Western blot analysis to reveal the changes in apoptosis- and inflammation-related proteins. In particular, we used a variety of fluorescent probes to detect the antioxidant capacity of p-HAP in live zebrafish larvae in vivo. In addition, we discovered that p-HAP treatment relieved alcoholic hepatic steatosis in a dose-dependent manner and that the 50 µM dose had the best therapeutic effect. Generally, this research indicated that p-HAP might reduce oxidative stress and cell apoptosis in vivo and in vitro via the NF-κB signaling pathway.

11.
Life Sci ; 216: 305-312, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30031061

RESUMO

AIMS: Alcoholic liver disease (ALD) is a leading health risk worldwide, which can induce hepatic steatosis, progressive fibrosis, cirrhosis and even carcinoma. As a potential therapeutic drug for ALD, naringin, an abundant flavanone in grapefruit, could improve resistance to oxidative stress and inflammation and protects against multiple organ injury. However, the specific mechanisms responsible for protection against alcoholic injury remain not fully understood. In this study, we aim to investigate the effect and the regulatory mechanisms of naringin in the liver and whole body after alcohol exposure under zebrafish larvae system. MAIN METHODS: At 96 h post fertilization (hpf), larvae from wild-type (WT) and transgenic zebrafish, with liver-specific eGFP expression (Tg(lfabp10α:eGFP)), were exposed to 2% ethanol for 32 h to establish an ALD model. Different endpoints, such as morphological changes in liver shape and size, histological changes, oxidative stress-related free radical levels, apoptosis and the expression of certain genes, were chosen to verify the essential impact of naringin in alcohol-induced liver lesions. KEY FINDINGS: Subsequent experiments, including Oil red O, Nile red, pathological hematoxylin and eosin (H&E), and TUNEL staining and qPCR, revealed that naringin treatment reduced alcoholic hepatic steatosis, and this inhibitory effect was dose dependent. Specifically, a 25 mg/L dose resulted in an almost normal response. SIGNIFICANCE: This finding suggested that naringin may inhibit alcoholic-induced liver steatosis and injury by attenuating lipid accumulation and reducing oxidative stress and apoptosis.


Assuntos
Fígado Gorduroso Alcoólico/prevenção & controle , Flavanonas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Hepatopatias Alcoólicas/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Animais , Animais Geneticamente Modificados , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Etanol/efeitos adversos , Flavanonas/administração & dosagem , Proteínas de Fluorescência Verde/genética , Marcação In Situ das Extremidades Cortadas , Larva , Reação em Cadeia da Polimerase em Tempo Real , Peixe-Zebra
13.
Front Pharmacol ; 9: 1098, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30323763

RESUMO

As the traditional Chinese herbal formula, Xiaoyaosan and its modified formula have been described in many previous studies with definite anti-depressive effects, but its underlying mechanism remains mystery. Previous work in our lab has demonstrated that depression induced by chronic stress could generate brain blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) signals disorder, accompanied by the impairment of hippocampal neuronal plasticity, decrease of brain-derived neurotrophic factor, and reduction of the number and complexity of adult neurons in the dentate gyrus. We hypothesized that herbal formula based on Xiaoyaosan could exert anti-depressive effects through restoring these neurobiological dysfunctions and rectifying BOLD-fMRI signals. To test this hypothesis, we examined the effect of modified Xiaoyaosan (MXYS) on depressive-like behaviors, as well as hippocampal neurogenesis and BOLD signals in a mice model of chronic unpredictable mild stress (CUMS)-induced depression. MXYS exerted anti-depressant effects on CUMS-induced depression that were similar to the effects of classical antidepressants drug (fluoxetine hydrochloride), with a significant alleviation of depressive-like behaviors, an improvement of hippocampal neurogenesis, and a reversal of activation of BOLD in the limbic system, particularly in the hippocampus. These results suggested that MXYS attenuated CUMS-induced depressive behaviors by rectifying the BOLD signals in the mice hippocampus. These novel results demonstrated that MXYS had anti-depressive effects accompanied by improving BOLD signals and hippocampal neurogenesis, which suggested that BOLD-fMRI signals in brain regions could be a key component for the evaluation of novel antidepressant drugs.

14.
J Pharmacol Sci ; 138(1): 46-53, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30245287

RESUMO

Hepatic steatosis is the early stage of alcoholic liver disease (ALD), may progress to steatohepatitis, fibrosis even cirrhosis. Polydatin, the primary active component of Polygonum cuspidatum Sieb. et Zucc, has been recognized to possess hepatoprotective and anti-inflammatory properties. To investigate whether polydatin alleviates ethanol induced liver injury and to elucidate the underlying molecular mechanisms, zebrafish larvae at 4 days post-fertilization (dpf) were exposed to 350 mmol/L of ethanol for 32 h, then treated with polydatin for 48 h. Oil red O, Nile Red and H&E staining were used to analyze the pathological changes in liver. The mRNA levels were measured by quantitative PCR and the antioxidant capacity was detected using H2O2-specific fluorescent probe. Here, polydatin strongly alleviated hepatic steatosis and decreased the expression levels of alcohol and lipid metabolism-related genes, including CYP2Y3, CYP3A65, HMGCRa, HMGCRb and FASN. Additionally, polydatin inhibited oxidative stress in the liver according to fluorescent probe. Moreover, significantly up-regulated expression of DNA damage-related genes (CHOP, GADD45αa) revealed that polydatin attenuated hepatic apoptosis in larvae. In conclusion, polydatin may improve the liver function of zebrafish with acute alcoholic liver injury through attenuating hepatic fat accumulation, ameliorating lipid and ethanol metabolism and reducing oxidative stress and DNA damage.


Assuntos
Anti-Inflamatórios , Antioxidantes , Glucosídeos/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Hepatopatias Alcoólicas/tratamento farmacológico , Hepatopatias Alcoólicas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fitoterapia , Estilbenos/farmacologia , Peixe-Zebra , Animais , Hidrocarboneto de Aril Hidroxilases/genética , Hidrocarboneto de Aril Hidroxilases/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Família 3 do Citocromo P450/genética , Família 3 do Citocromo P450/metabolismo , Dano ao DNA/genética , Fallopia japonica/química , Expressão Gênica/efeitos dos fármacos , Glucosídeos/isolamento & purificação , Glucosídeos/uso terapêutico , Metabolismo dos Lipídeos/genética , Hepatopatias Alcoólicas/genética , Hepatopatias Alcoólicas/patologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Oxirredutases N-Desmetilantes/genética , Oxirredutases N-Desmetilantes/metabolismo , Estilbenos/isolamento & purificação , Estilbenos/uso terapêutico , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
15.
Brain Res Bull ; 142: 107-115, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29969645

RESUMO

BACKGROUND: Depression is a heterogeneous disorder, but the exact neuronal mechanisms causing the disease have not yet been discovered. METHODS/MATERIALS: We have established a chronic unpredictable mild stress (CUMS) mouse model to explore the blood oxygen level-dependent (BOLD) activity in the hippocampus, prefrontal cortex (PFC), and basolateral amygdala (BLA) using amplitude of low-frequency fluctuations (ALFF) in functional magnetic resonance imaging (fMRI). We initially studied the relationship between brain-derived neurotrophic factor (BDNF) expression and BOLD activity using BDNFtm1Krj/J mice. RESULTS: We found that CUMS induced depressive-like behaviours and stimulated changes in brain regions expressing a different BDNF level, which was decreased in the hippocampus and PFC but increased in the BLA. In contrast, the BOLD activity was elevated in the hippocampus and PFC but reduced in the BLA after CUMS exposure, indicating that the BDNF level negatively correlated with the BOLD activity in the WT CUMS-exposed mice. Moreover, the depressive-like behaviours and region-specific BOLD activity in BDNFtm1Krj/J mice were consistent with those in WT CUMS-exposed mice. CONCLUSION: We surmised that critical neural circuitry connects the hippocampus, PFC and BLA in mice, which was regulated by BDNF to protect against depression. These findings suggested a potential central role of BDNF expression in functional changes in the brain.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Transtorno Depressivo/diagnóstico por imagem , Transtorno Depressivo/fisiopatologia , Animais , Mapeamento Encefálico , Circulação Cerebrovascular/fisiologia , Modelos Animais de Doenças , Expressão Gênica , Imageamento por Ressonância Magnética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiopatologia , Neurogênese/fisiologia , Oxigênio/sangue , Distribuição Aleatória , Estresse Psicológico/diagnóstico por imagem , Estresse Psicológico/fisiopatologia
16.
Oncol Rep ; 38(5): 2877-2884, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29048675

RESUMO

Alcoholic liver disease (ALD) includes a spectrum of hepatic abnormalities that range from isolated alcoholic steatosis to steatohepatitis and cirrhosis. Naringenin, a predominant flavanone in grapefruit, increases resistance to oxidative stress and inflammation and protects against multiple organ injury in various animal models. However, the specific mechanisms responsible for protection against alcoholic injury are poorly understood. In the present study, we aimed to investigate the effect of naringenin on alcoholic events and the molecular regulatory mechanisms of naringenin in the liver and whole body of zebrafish larvae following exposure to 350 mmol/l ethanol for 32 h. Zebrafish larvae {4 days post­fertilization (dpf); wild-type (WT) and a transgenic line with liver-specific eGFP expression [Tg(lfabp10α-eGFP)]} were used to establish an alcoholic fatty liver model in order to evaluate the effects of naringenin treatment on anti-alcoholic injury. Naringenin significantly reduced alcoholic liver morphological phenotypes and the expression of alcohol and lipid metabolism-related genes, including cyp2y3, cyp3a65, hmgcra, hmgcrb, fasn, fabp10α, fads2 and echs1, in zebrafish larvae. Naringenin also attenuated hepatic apoptosis in larvae as detected by TUNEL staining, consistent with the expression of critical biomarkers of endoplasmic reticulum stress and of DNA damage genes (chop, gadd45αa and edem1). The present study showed that naringenin inhibited alcohol-induced liver steatosis and injury in zebrafish larvae by reducing apoptosis and DNA damage and by harmonizing alcohol and lipid metabolism.


Assuntos
Proteínas de Ciclo Celular/genética , Flavanonas/administração & dosagem , Hepatopatias Alcoólicas/tratamento farmacológico , Proteínas de Membrana/genética , Proteínas Nucleares/genética , Fator de Transcrição CHOP/genética , Proteínas de Peixe-Zebra/genética , Animais , Apoptose/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Etanol/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Larva/efeitos dos fármacos , Larva/genética , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/lesões , Fígado/patologia , Hepatopatias Alcoólicas/genética , Hepatopatias Alcoólicas/patologia , Estresse Oxidativo/efeitos dos fármacos , Peixe-Zebra/genética
17.
Artigo em Inglês | MEDLINE | ID: mdl-28596796

RESUMO

Alcoholic liver disease (ALD) is a series of abnormalities of liver function, including alcoholic steatosis, steatohepatitis, and cirrhosis. Hesperidin, the major constituent of flavanone in grapefruit, is proved to play a role in antioxidation, anti-inflammation, and reducing multiple organs damage in various animal experiments. However, the underlying mechanism of resistance to alcoholic liver injury is still unclear. Thus, we aimed to investigate the protective effects of hesperidin against ALD and its molecular mechanism in this study. We established an ALD zebrafish larvae model induced by 350 mM ethanol for 32 hours, using wild-type and transgenic line with liver-specific eGFP expression Tg (lfabp10α:eGFP) zebrafish larvae (4 dpf). The results revealed that hesperidin dramatically reduced the hepatic morphological damage and the expressions of alcohol and lipid metabolism related genes, including cyp2y3, cyp3a65, hmgcra, hmgcrb, fasn, and fads2 compared with ALD model. Moreover, the findings demonstrated that hesperidin alleviated hepatic damage as well, which is reflected by the expressions of endoplasmic reticulum stress and DNA damage related genes (chop, gadd45αa, and edem1). In conclusion, this study revealed that hesperidin can inhibit alcoholic damage to liver of zebrafish larvae by reducing endoplasmic reticulum stress and DNA damage, regulating alcohol and lipid metabolism.

18.
Behav Brain Res ; 330: 17-24, 2017 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-28527694

RESUMO

BACKGROUND: Physical exercise has been long recognized for its therapeutic effects on depressive disorders, but the underlying mechanisms remain largely unknown. In the study, we investigated whether the physical exercise by voluntary wheel running (VWR) alters depression-like behaviors and its impact on brain blood oxygen level-dependent (BOLD) signals in mice. METHODS: Adult male C57BL/6 mice were assigned to one of the following groups; (1) no exercise control (noEx), housed in a standard cage; (2) exercise (Ex), 2h/day in a running wheel apparatus; (3) chronic unpredictable mild stress (CUMS), which was imitating adult stress; and (4) CUMS+Ex. The differences in functional brain changes were determined by BOLD functional magnetic resonance imaging (fMRI). RESULTS: The results showed that VWR exercise significantly reversed the CUMS-induced behavioral abnormalities. Base on the fMRI amplitude of low-frequency fluctuation (ALFF) analysis, we found that VWR exercise could restore the CUMS-induced excessive BOLD activation in parts of limbic system, such as cortex, hippocampus and corpus callosum. Furthermore, CUMS-induced BOLD suppressive regions were also partially attenuated by VWR exercise, such as amygdala, cerebellum anterior lobe, thalamus, midbrain, and pontine. Most of these regions are involved in mood-regulating circuit, suggesting dysfunction of the circuit in CUMS model of depression, and VWR exercise could adjust the mood-regulating circuit. CONCLUSIONS: These results suggested that VWR exercise ameliorated depression-like behaviors and brain BOLD signals in CUMS induced depression mice.


Assuntos
Depressão/terapia , Condicionamento Físico Animal/psicologia , Afeto , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/fisiopatologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Doença Crônica , Depressão/diagnóstico por imagem , Depressão/psicologia , Transtorno Depressivo/fisiopatologia , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Imageamento por Ressonância Magnética/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Neuroquímica , Oxigênio/sangue , Oxigênio/metabolismo , Corrida/psicologia , Estresse Psicológico/fisiopatologia
19.
Oncotarget ; 8(25): 40486-40500, 2017 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-28465467

RESUMO

Indoleamine 2,3-dioxygenase 1 (IDO1) is an intracellular rate-limiting enzyme in the metabolism of tryptophan along the kynurenine pathway, subsequently mediating the immune response; however, the role of IDO1 in liver fibrosis and cirrhosis is still unclear. In this study, we investigated the role of IDO1 in the development of hepatic fibrosis and cirrhosis. Patients with hepatitis B virus-induced cirrhosis and healthy volunteers were enrolled. For animals, carbon tetrachloride (CCl4) was used to establish liver fibrosis in wild-type and IDO1 knockout mice. Additionally, an IDO1 inhibitor (1-methyl-D-tryptophan) was administered to WT fibrosis mice. Liver lesions were positively correlated with serum IDO1 levels in both the clinical subjects and hepatic fibrosis mice. A positive correlation between serum IDO1 levels and liver stiffness values was found in the cirrhosis patients. Notably, IDO1 knockout mice were protected from CCl4-induced liver fibrosis, as reflected by unchanged serum alanine transaminase and aspartate transaminase levels and lower collagen deposition, α-smooth muscle actin expression and apoptotic cell death rates. On the other hand, tryptophan 2,3-dioxygenase (TDO), another systemic tryptophan metabolism enzyme, exhibited a compensatory increase as a result of IDO1 deficiency. Moreover, hepatic interleukin-17a, a characteristic cytokine of T helper 17 (Th17) cells, and downstream cytokines' mRNA levels showed lower expression in the IDO1-/- model mice. IDO1 appears to be a potential hallmark of liver lesions, and its deficiency protects mice from CCl4-induced fibrosis mediated by Th17 cells down-regulation and TDO compensation.


Assuntos
Regulação para Baixo , Indolamina-Pirrol 2,3,-Dioxigenase/deficiência , Cirrose Hepática/metabolismo , Células Th17/metabolismo , Triptofano Oxigenase/metabolismo , Adulto , Animais , Tetracloreto de Carbono , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Hepatite B/genética , Hepatite B/metabolismo , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/sangue , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Interleucina-17/genética , Interleucina-17/metabolismo , Fígado/metabolismo , Fígado/patologia , Fígado/virologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/genética , Masculino , Camundongos Knockout , Pessoa de Meia-Idade , Triptofano Oxigenase/genética
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