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1.
Free Radic Biol Med ; 2020 Jan 13.
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 mice livers with concanavalin A (ConA) -induced AIH. The dramatically upregulated gene indoleamine 2, 3-dioxygenase 1 (IDO1) after AIH was identified, 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 was 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 following 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 in vivo results, 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 included nitrative stress in ConA-induced liver injury, and also identify IDO1-dependent ferroptosis as a potential target for the treatment of AIH.

3.
FEBS Open Bio ; 9(3): 468-477, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30868055

RESUMO

Dengue fever (DF) and dengue hemorrhagic fever (DHF) are recurrent diseases that are widespread in the tropics. Here, we identified candidate genes associated with these diseases by performing integrated analyses of DF (GSE51808) and DHF (GSE18090) microarray datasets in the Gene Expression Omnibus (GEO). In all, we identified 7635 differentially expressed genes (DEGs) in DF and 8147 DEGs in DHF as compared to healthy controls (P < 0.05). In addition, we discovered 215 differentially expressed long non-coding RNAs (DElncRNAs) in DF and 225 DElncRNAs in DHF. There were 1256 common DEGs and eight common DElncRNAs in DHF vs DF, DHF vs normal control, and DF vs normal control groups. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that signal transduction (false discovery rate = 8.33E-10), 'toxoplasmosis', and 'protein processing in endoplasmic reticulum' were significantly enriched pathways for common DEGs. We conclude that the MAGED1,STAT1, and IL12A genes may play crucial roles in DF and DHF, and suggest that our findings may facilitate the identification of biomarkers and the development of new drug design strategies for DF and DHF treatment.

4.
Neuropathology ; 39(2): 85-96, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30834629

RESUMO

The aim of this study is to explore the macroscale neural mechanisms of the antidepressant effects of Xiaoyaosan, a traditional Chinese herbal formula. We analyzed blood oxygen level-dependent (BOLD) functional magnetic resonance imaging signals. To further minimize the hemodynamic variations of BOLD signals and analyze the intra-region neural activity or temporal coherence, we employed the newly developed regional homogeneity (ReHo) approach to determine aberrant functional connectivity using the chronic unpredictable mild stress (CUMS) mouse model of depression and to also explore the brain-region rescue effect of modified Xiaoyaosan (MXYS) in such mice. We found the aberrant ReHo in CUMS mice replicated previous discoveries in patients with depression. Intriguingly, MXYS only normalized several limbic regions, which suggests the essential roles of these regions in mediating the antidepressant effects of MXYS. Our results provide a reliable framework for the use of ReHo analysis with animal models of depression and further suggest a new perspective to elucidate the antidepressant effects of MXYS.


Assuntos
Antidepressivos/administração & dosagem , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Depressão/tratamento farmacológico , Depressão/fisiopatologia , Medicamentos de Ervas Chinesas/administração & dosagem , Animais , Mapeamento Encefálico , Modelos Animais de Doenças , Imagem por Ressonância Magnética , Masculino , Camundongos Endogâmicos C57BL
5.
Biomed Pharmacother ; 111: 1057-1065, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30841419

RESUMO

Major depressive disorder (MDD) affects ˜16% of the world population. Chronic stressors contribute to reduced hippocampal volumes and increase the risk of developing MDD. Our previous work showed that XYS ameliorates social isolation and chronic unpredictable mild stress (CUMS) induced depressive-like behaviors in rats by regulating hypothalamic-pituitary-adrenal hyperactivation, locus coeruleus -norepinephrine activity and kynurenine/5-hydroxytryptamin balance. Here, we report that CUMS & isolation-treated mice exhibit depressive-like behaviors and show a phenotype of mixed apoptosis/autophagy characteristic in mice hippocampus in vivo. Modified Xiaoyao San (MXS) significantly ameliorates CUMS & social isolation-induced anhedonia, loss of interests, psychomotor retardation and behavioral despair. It suppresses the apoptosis by downregulaing condensation of heterochromatin and reducing hippocampal TdT-mediated dUTP Nick-End Labeling (TUNEL)-positive cells. MSX significantly inhibits mitochondrial outer membrane permeabilization (MOMP) reduces the release of cytochrome C and the shift of apoptosis inducing factor (AIF) from mitochondria to nucleus. Further, it stimulates the formation of autophagosomes and activates the expression of Atg5 and LC3II. Combined silencing of Atg5 and Atg7 dampens MOMP and impaired the anti-apoptotic effects of MXS. In conclusion, MXS ameliorates depressive-like behaviors by triggering autophagy to alleviate neuronal apoptosis. MXS is an effective supplement for MDD treatment, and can be harnessed to enhance autophagy and synergize with antidepressant action.


Assuntos
Antidepressivos/farmacologia , Apoptose/efeitos dos fármacos , Autofagossomos/efeitos dos fármacos , Depressão/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Neurônios/efeitos dos fármacos , Animais , Fator de Indução de Apoptose/metabolismo , Autofagossomos/metabolismo , Autofagia/efeitos dos fármacos , Depressão/metabolismo , Transtorno Depressivo Maior/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neurônios/metabolismo , Permeabilidade/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo
6.
J Nat Med ; 73(1): 179-189, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30377904

RESUMO

The present study was designed to investigate the effects of betulinic acid on human hepatic stellate cells in vitro and C57BL/6 mice in vivo, as well as the signaling pathways involved. In this study, we explored the effects of betulinic acid on expression of alpha smooth muscle actin and autophagy-related proteins. Betulinic acid reduced pathological damage associated with liver fibrosis, as well as serum platelet-derived growth factor and serum hydroxyproline levels. Furthermore, betulinic acid downregulated the expression of alpha smooth muscle actin and type I collagen in mouse liver and upregulated the expression of microtubule-associated protein light chain 3B and autophagy-related gene 7 at the gene and protein levels. LC3II expression was increased and alpha smooth muscle actin expression was decreased in betulinic acid-treated hepatic stellate cells. Interventions with bafilomycin A1 and mCherry-GFP-LC3 adenoviruses promoted the formation of autophagosomes in hepatic stellate cells and the development of autophagic flow. Our study found that mitogen-activated protein kinase/extracellular signal-regulated kinase may be involved in the effects of betulinic acid on liver fibrosis. The present study suggests that betulinic acid has anti-hepatic fibrosis activity by inducing autophagy and could serve as a promising new agent for treating hepatic fibrosis.


Assuntos
Cirrose Hepática/tratamento farmacológico , Triterpenos/uso terapêutico , Animais , Autofagia , MAP Quinases Reguladas por Sinal Extracelular/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Cirrose Hepática/patologia , Camundongos Endogâmicos C57BL , Triterpenos/farmacologia
7.
Psychol Med ; 49(15): 2608-2616, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30520409

RESUMO

BACKGROUND: We hypothesize that the tumor necrosis factor-α (TNF-α) may play a role in disturbing the effect of selective serotonin reuptake inhibitor (SSRI) on the striatal connectivity in patients with major depressive disorder (MDD). METHODS: We performed a longitudinal observation by combining resting-state functional magnetic resonance imaging (rs-fMRI) and biochemical analyses to identify the abnormal striatal connectivity in MDD patients, and to evaluate the effect of TNF-α level on these abnormal connectivities during SSRI treatment. Eighty-five rs-fMRI scans were collected from 25 MDD patients and 35 healthy controls, and the scans were repeated for all the patients before and after a 6-week SSRI treatment. Whole-brain voxel-wise functional connectivity (FC) was calculated by correlating the rs-fMRI time courses between each voxel and the striatal seeds (i.e. spherical regions placed at the striatums). The level of TNF-α in serum was evaluated by Milliplex assay. Factorial analysis was performed to assess the interaction effects of 'TNF-α × treatment' in the regions with between-group FC difference. RESULTS: Compared with controls, MDD patients showed significantly higher striatal FC in the medial prefrontal cortex (MPFC) and bilateral middle/superior temporal cortices before SSRI treatment (p < 0.001, uncorrected). Moreover, a significant interaction effect of 'TNF-α × treatment' was found in MPFC-striatum FC in MDD patients (p = 0.002), and the significance remained after adjusted for age, gender, head motion, and episode of disease. CONCLUSION: These findings provide evidence that treatment-related brain connectivity change is dependent on the TNF-α level in MDD patients, and the MPFC-striatum connectivities possibly serve as an important target in the brain.

8.
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
10.
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.

12.
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
13.
Biomed Res Int ; 2018: 2653497, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29967769

RESUMO

Purpose: To compare the dosimetric differences between volumetric modulated arc therapy (VMAT) and helical tomotherapy (HT) in treating early T-stage nasopharyngeal carcinoma (NPC). Method: Ten patients with early T-stage NPC who received tomotherapy using simultaneously integrated boost (SIB) strategies were replanned with VMAT (RapidArc of Varian, dual-arc). Dosimetric comparisons between the RapidArc plan and the HT plan included the following: (1) D98, homogeneity, and conformity of PTVs; (2) sparing of organs at risk (OARs); (3) delivery time and monitor units (MUs). Results: (1) Compared with RapidArc, HT achieved better dose conformity (CI of PGTVnx + nd: 0.861 versus 0.818, P = 0.004). (2) In terms of OAR protection, RapidArc exhibited significant superiority in sparing ipsilateral optic nerve (Dmax: 27.5Gy versus 49.1Gy, P < 0.001; D2: 23.5Gy versus 48.2Gy, P < 0.001), contralateral optic nerve (Dmax: 30.4Gy versus 49.2Gy, P < 0.001; D2: 26.2Gy versus 48.1Gy, P < 0.001), and optic chiasm (Dmax: 32.8Gy versus 48.3Gy, P < 0.001; D2: 30Gy versus 47.6Gy, P < 0.001). HT demonstrated a superior ability to protect the brain stem (D1cc: 43.0Gy versus 45.2Gy, P = 0.012), ipsilateral temporal lobe (Dmax 64.5Gy versus 66.4 Gy, P = 0.015), contralateral temporal lobe (Dmax: 62.8Gy versus 65.1Gy, P = 0.001), ipsilateral lens (Dmax: 4.27Gy versus 5.24Gy, P = 0.009; D2: 4.00Gy versus 5.05Gy, P = 0.002; Dmean: 2.99Gy versus 4.31Gy, P < 0.001), contralateral lens (Dmax: 4.25Gy versus 5.09Gy, P = 0.047; D2: 3.91Gy versus 4.92Gy, P = 0.005; Dmean: 2.91Gy versus 4.18Gy, P < 0.001), ipsilateral parotid (Dmean: 36.4Gy versus 41.1Gy, P = 0.002; V30Gy: 54.8% versus 70.4%, P = 0.009), and contralateral parotid (Dmean: 33.4Gy versus 39.1Gy, P < 0.001; V30Gy: 48.2% versus 67.3%, P = 0.005). There were no statistically significant differences in spinal cord or pituitary protection between the RapidArc plan and the HT plan. (3) RapidArc achieved a much shorter delivery time (3.8 min versus 7.5 min, P < 0.001) and a lower MU (618MUs versus 5646MUs, P < 0.001). Conclusion: Our results show that RapidArc and HT are comparable in D98, dose homogeneity, and protection of the spinal cord and pituitary gland. RapidArc performs better in shortening delivery time, lowering MUs, and sparing the optic nerve and optic chiasm. HT is superior in dose conformity and protection of the brain stem, temporal lobe, lens, and parotid.


Assuntos
Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/radioterapia , Radioterapia de Intensidade Modulada , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Órgãos em Risco , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador
14.
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 , Imagem 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
15.
Brain Res Bull ; 139: 197-202, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29253606

RESUMO

BACKGROUND AND OBJECTIVE: Xiao Yao San (XYS) is a traditional Chinese medicine used to treat depression; however, the mechanism underlying its antidepressant properties remains unclear. The objective of the present study was to investigate the effects and action mechanisms of XYS on interferon-α-induced depression in mice. METHOD: Mice were divided into six groups: control; model; low-, medium-, and high-dose XYS; and escitalopram-treated group. Except for the control mice, all groups of mice were injected with interferon (IFN)-α to establish the depression model. XYS and escitalopram were then administered to the respective mice daily for 21 days. Sucrose preference test (SPT), forced swim test (FST), and tail suspension test (TST) were used to measure behavioral indices. High-performance liquid chromatography (HPLC) was used to measure serotonin (5-HT) concentrations, while western blots were used to examine indoleamine-2,3-dioxygenase 1 (IDO1) expression in the dorsal raphe nucleus (DRN). The number of microglia in the DRN was observed using immunofluorescence. RESULTS: Compared with that of the control group, the model group showed a significant decrease in sucrose consumption (P < 0.05) and significant increase in the duration of immobility in the FST and TST (P  < 0.05). These parameters improved significantly after XYS or escitalopram treatment. There was also a significantly higher and lower expression of IDO1 protein and 5-HT in the mouse DRN, respectively, which were reversed by administering XYS and escitalopram (P < 0.05). Moreover, the number of microglia in the mouse DRN increased significantly and was reduced by XYS and escitalopram (P < 0.05). CONCLUSION: XYS reduced the number of microglia and expression of IDO1, which increased the levels of 5-HT in the mouse DRN and, thereby, improved the depressive behavior of mice. This may explain, at least in part, the antidepressant properties of XYS in patients.


Assuntos
Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Citalopram/farmacologia , Citalopram/uso terapêutico , Depressão/induzido quimicamente , Depressão/patologia , Modelos Animais de Doenças , Núcleo Dorsal da Rafe/efeitos dos fármacos , Núcleo Dorsal da Rafe/metabolismo , Preferências Alimentares/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Elevação dos Membros Posteriores/psicologia , Fatores Imunológicos/toxicidade , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Interferon-alfa/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/metabolismo , Microglia/efeitos dos fármacos , Microglia/patologia , Serotonina/metabolismo , Sacarose/administração & dosagem , Natação/psicologia
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.
Mol Med Rep ; 16(3): 2411-2416, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28656273

RESUMO

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer­associated mortality worldwide. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are two common risk factors for HCC. The majority of patients with HCC present at an advanced stage and are refractory to therapy. It is important to identify a method for efficient diagnosis at early stage. In the present study gene expression profile data, generated from microarray data, were pretreated according to the annotation files. The genes were mapped to pathways of Ingenuity Pathways Analysis. Dysregulated pathways and dysregulated pathway pairs were identified and constructed into individual networks, and a main network was constructed from individual networks with several edges. Random Forest (RF) classification was introduced to calculate the area under the curve (AUC) value of this network. Subsequently, 50 runs of Monte Carlo cross­validation were used to screen the optimal main network. The results indicated that a total of 4,929 genes were identified in the pathways and gene expression profile. By combining dysregulated pathways with Z<0.05 and dysregulated pathway pairs with Z<0.2, individual networks were constructed. The optimal main network with the highest AUC value was identified. In the HCV group, the network was identified with an AUC value of 0.98, including 41 pairs of pathways, and in the HBV group, the network was identified with an AUC value of 0.94, including eight pairs of pathways. In addition, four pairs were identified in both groups. In conclusion, the optimal networks of HCV and HBV groups were identified with the highest AUC values. The use of these networks is expected to assist in diagnosing patients effectively at an early stage.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/virologia , Redes Reguladoras de Genes , Hepatite B/complicações , Hepatite C/complicações , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virologia , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/etiologia , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Hepacivirus/isolamento & purificação , Vírus da Hepatite B/isolamento & purificação , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/etiologia , Método de Monte Carlo , Transcriptoma
18.
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.

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
20.
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 , Imagem por Ressonância Magnética/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Neuroquímica , Oxigênio/sangue , Oxigênio/metabolismo , Corrida/psicologia , Estresse Psicológico/fisiopatologia
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