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1.
Clin Transl Med ; 11(10): e541, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34709765

RESUMO

More and more evidence show that major depressive disorder (MDD) is closely related to inflammation caused by chronic stress, which seriously affects human physical and mental health. However, the inflammatory mechanism of depression and its effect on brain function have not been clarified. Based on resting-state functional magnetic resonance imaging (rs-fMRI), we investigated change of brain functional imaging and the inflammatory mechanism of damage-related molecular patterns (DAMPs)-receptor of advanced glycation protein end product (RAGE) in MDD patients and depressive-like cynomolgus monkeys and mice models induced by chronic stress. The regional homogeneity (ReHo) and functional connectivity (FC) were analyzed using MATLAB and SPM12 software. We detected the expression of DAMPs-RAGE pathway-related proteins and mRNA in MDD peripheral blood and in serum and brain tissue of cynomolgus monkeys and mice. Meanwhile, RAGE gene knockout mice, RAGE inhibitor, and overexpression of AVV9RAGE adeno-associated virus were used to verify that RAGE is a reliable potential biomarker of depression. The results showed that the ReHo value of prefrontal cortex (PFC) in MDD patients and depressive-like cynomolgus monkeys was decreased. Then, the PFC was used as a seed point, the FC of ipsilateral and contralateral PFC were weakened in depressive-like mice. At the same time, qPCR showed that RAGE and HMGB1 mRNA were upregulated and S100ß mRNA was downregulated. The expression of RAGE-related inflammatory protein in PFC of depressive-like monkeys and mice were consistent with that in peripheral blood of MDD patients. Moreover, the results were confirmed in RAGE-/- mice, injection of FPS-ZM1, and overexpression of AAV9RAGE in mice. To sum up, our findings enhance the evidence that chronic stress-PFC-RAGE are associated with depression. These results attempt to establish the links between brain functional imaging, and molecular targets among different species will help to reveal the pathophysiological mechanism of depression from multiple perspectives.

2.
J Cardiovasc Pharmacol ; 78(2): 269-279, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34554678

RESUMO

ABSTRACT: Coronary artery disease (CAD) is a common cardiovascular disease, mainly due to vascular endothelial cell (VEC) injury caused by atherosclerosis. Circular RNA has been shown to be involved in the regulation of various diseases. However, the role and mechanism of circ_0004104 in CAD are still unclear. Oxidized low-density lipoprotein (ox-LDL) was used to construct the VEC injury model in vitro. The expression levels of circ_0004104 and miR-100 were measured by quantitative real-time polymerase chain reaction. The proliferation of VECs was determined using 3-(45)-dimethylthiahiazo (-z-y1)-35-di-phenytetrazoliumromide assay and 5-ethynyl-2'-deoxyuridine staining assay. VEC apoptosis rate was assessed using flow cytometry, and caspase-3 activity was measured using a Caspase-3 Assay Kit. The protein expression levels of Ki-67, cleaved-caspase3, and tumor necrosis factor-α-induced protein 8 (TNFAIP8) were detected by western blot analysis. Furthermore, enzyme-linked immunosorbent assay was performed to assess the concentrations of inflammatory cytokines. In addition, the relationship between miR-100 and circ_0004104 or TNFAIP8 was confirmed by dual-luciferase reporter assay and biotin-labeled RNA pull-down assay. Our results revealed that circ_0004104 was upregulated and miR-100 was downregulated in patients with CAD and ox-LDL-induced VECs. Ox-LDL could inhibit the proliferation and promote the apoptosis and inflammation of VECs to induce VEC injury. However, silenced circ_0004104 could alleviate VEC injury induced by ox-LDL. Moreover, we found that circ_0004104 could sponge miR-100 and a miR-100 inhibitor could reverse the inhibition effect of circ_0004104 knockdown on ox-LDL-induced VEC injury. In addition, TNFAIP8 was a target of miR-100, and miR-100 alleviated ox-LDL-induced VEC injury by targeting TNFAIP8. Our data suggested that circ_0004104 promoted ox-LDL-induced VEC injury by the miR-100/TNFAIP8 axis, indicating that circ_0004104 might be a potential biomarker for CAD treatment.

3.
Front Pharmacol ; 12: 703965, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34557092

RESUMO

Xiaoyaosan (XYS), as a classic Chinese medicine compound, has been proven to have antidepressant effect in many studies, but its mechanism has not been clarified. In our previous studies, we found that chronic stress can induce depressive-like behavior and lead to emotion-related cingulate gyrus (Cg) dysfunction, as well as the decrease of neurotrophic factors and the increase of inflammatory-related proteins. Therefore, we speculated that XYS may play an antidepressant role by regulating the inflammation-related receptor of advanced glycation protein end product (RAGE) to affect the functional connectivity (FC) signal of the Cg and improve the depressive-like behavior. In order to verify this hypothesis, we analyzed the FC and RAGE expression in the Cg of depressive-like mice induced by chronic unpredictable mild stress (CUMS) and verified it with RAGE knockout mice. At the same time, we detected the effect of XYS on the depressive-like behavior, expression of RAGE, and the FC of the Cg of mice. The results showed that the FC of the Cg of depressive-like mice induced by CUMS was weakened, and the expression of RAGE was upregulated. The antidepressant effect of XYS is similar to that of fluoxetine hydrochloride, which can significantly reduce the depressive-like behavior of mice and inhibit the expression of the RAGE protein and mRNA in the Cg, and increase the FC of the Cg in mice. In conclusion, XYS may play an antidepressant role by downregulating the expression of RAGE in the Cg of depressive-like mice induced by CUMS, thereby affecting the functional signal and improving the depressive-like behavior.

5.
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
6.
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.

7.
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
8.
Aging (Albany NY) ; 13(4): 5875-5891, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33591947

RESUMO

Indoleamine 2, 3-dioxygenase 1 (IDO1) has been implicated in the pathogenesis of depression, though its molecular mechanism is still poorly understood. We investigated the molecular mechanism of IDO1 in depression by using the chronic unpredictable mild stress (CUMS) model in Ido1-/- mice and WT mice. The brain blood oxygen level dependent (BOLD) signals in mice were collected by functional magnetic resonance imaging (fMRI) technology. IDO1 inhibitor INCB024360 was intervened in dorsal raphe nucleus (DRN) through stereotactic injection. We found an elevation of serum IDO1 activity and decreased 5-HT in CUMS mice, and the serum IDO1 activity was negatively correlated with 5-HT level. Consistently, IDO1 was increased in hippocampus and DRN regions, accompanied by a reduction of hippocampal BDNF levels in mice with CUMS. Specifically, pharmacological inhibition of IDO1 activity in the DRN alleviated depressive-like behaviour with improving hippocampal BDNF expression and neurogenesis in CUMS mice. Furthermore, ablation of Ido1 exerted stress resistance and decreased the sensitivity of depression in CUMS mice with the stable BOLD signals, BDNF expression and neurogenesis in hippocampus. Thus, IDO1 hyperactivity played crucial roles in modulating 5-HT metabolism and BDNF function thereby impacting outcomes of hippocampal neurogenesis and BOLD signals in depressive disorder.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/metabolismo , Hipocampo/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Triptofano/metabolismo , Animais , Depressão/diagnóstico por imagem , Depressão/tratamento farmacológico , Depressão/etiologia , Núcleo Dorsal da Rafe/metabolismo , Avaliação Pré-Clínica de Medicamentos , Hipocampo/diagnóstico por imagem , Hipocampo/efeitos dos fármacos , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Imageamento por Ressonância Magnética , Camundongos Endogâmicos C57BL , Neurogênese/efeitos dos fármacos , Oximas/farmacologia , Oximas/uso terapêutico , Estresse Psicológico/complicações , Estresse Psicológico/metabolismo , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Triptofano Hidroxilase/metabolismo
9.
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
10.
J Colloid Interface Sci ; 584: 174-181, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33069017

RESUMO

Photocatalytic nitrogen fixation has been considered to be a safe, green, eco-friendly, and sustainable technology. However, photoinduced activation of inert dinitrogen is an important factor hindering the development of this technology. Herein, in-situ Fe3+ doped flower-like BiOCl with highly active sites exposure was prepared by a solvent thermal method, which has excellent performance of N2 photofixation. Compared with virgin BiOCl with no nitrogen fixation activity, Fe-BiOCl reached 30 µmol·L-1·h-1 ammonia evolution rate under simulated sunlight without any sacrificial reagent. Characterization results demonstrated that the enhancement of N2 photofixation capacity was mainly attributed to the in-situ doped Fe3+ in BiOCl, the doped Fe3+ not only acts as a reaction center for N2 activation also as an "electron transfer bridge" trapping and migrating electrons from BiOCl to N2 molecules. Furthermore, the transformation of crystal facets from virgin BiOCl (001) to Fe-BiOCl (110) and (102) is more conducive for the exposure and accessibility of iron reactive sites. This work developed a potential strategy by in-situ introducing Fe3+ active sites in BiOCl semiconductor substrate, which establishes a good basis for the application of semiconductor catalysts in nitrogen fixation.

11.
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
12.
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
13.
Turk J Chem ; 44(2): 393-408, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33488165

RESUMO

A series of alkylorganotin-based catalysts (Sn-g-C3N4 /AC) was prepared by wet impregnation in ethanol using different g-C3N4 precursors and alkylorganotin compounds. The structure, texture, surface composition, and adsorption properties of the as-prepared catalysts were extensively characterized. Then, the obtained samples were evaluated for their catalytic performance in hydrochlorination of acetylene. The results provided by the X-ray photoelectron spectroscopy, acetylene temperature-programmed desorption, and HCl adsorption confirmed the nature of the active sites (i.e. Sn-Nx) involved in the reactant adsorption, and hence in the improved catalytic performance. These active sites were also related to the improved lifetime of alkylorganotin-based catalysts in the hydrochlorination of acetylene. At a constant reaction temperature of 200 °C with an acetylene gas hourly space velocity (C2H2 -GHSV) of 30 h-1 , Sn-g1 -C3N4 /AC-550 exhibited the highest acetylene conversion (~98.0%) and selectivity toward the vinyl chloride monomer (>98.0%). From the catalytic test results, it was reasonably concluded that the hexamethylenetetramine is the most suitable N precursor, as compared to the dicyandiamide and urea, to prepare high-performance catalysts. From the BET specific surface area of fresh and used catalysts, it was suggested that, in contrast to dicyandiamide and urea, hexamethylenetetramine could delay the deposition of coke on alkylorganotin-based catalysts, which is reflected by the extended lifetime.

14.
Acta Chim Slov ; 67(1): 336-347, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33558943

RESUMO

Cobaltosic oxide has been used as catalysts in dehydrogenation for tail chlorine due to the advantages of low price and security. The Co3O4/ZSM-5 was synthesized by the volume impregnation method. The catalytic dehydrogenation performance of Co3O4/ZSM-5 was investigated, the catalytic reaction of hydrogen with oxygen and chlorine was carried out in a fixed-bed, and the mixed reactant gases were prepared according to the composition and content of tail chlorine in industry: Cl2(65%-80%), N2(6-16%), O2(8%-10%) and H2(1.5%-4%). The catalytic efficiency and stability of Co3O4/ZSM-5 in dehydrogenation for tail chlorine were better than that of Co3O4. After the calcination on 300°C, the Co3O4/ZSM-5 with 1 %wt. Co3O4 shown excellent catalytic performance at 50°C, and the average conversion of hydrogen can reach up to 99.59%.

16.
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
17.
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 , Imageamento por Ressonância Magnética , Masculino , Camundongos Endogâmicos C57BL
18.
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.


Assuntos
Dengue/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Dengue Grave/genética , Biomarcadores/análise , Perfilação da Expressão Gênica , Humanos
19.
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.

20.
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
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