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1.
J Ethnopharmacol ; 264: 113021, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32479885

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Liver fibrosis is an outcome of many chronic liver diseases and often results in cirrhosis, liver failure, and even hepatocarcinoma. Xiaoyaosan decoction (XYS) as a classical Traditional Chinese Medicine (TCM) formula is used to liver fibrosis in clinical practice while its mechanism is unclear. AIM OF THE STUDY: The aim of this study was to investigate the anti-fibrosis effect of XYS and to explore the molecular mechanisms by combining network pharmacology and transcriptomic technologies. MATERIALS AND METHODS: The carbon tetrachloride (CCl4)-induced liver fibrosis rat were treated with three doses of XYS. The liver fibrosis and function were evaluated by histopathological examination and serum biochemical detection. The fibrosis related protein a-SMA and collagen I were assessed by Western blot. Different expressed genes (DEGs) between XYS-treated group and model group were analyzed. The herb-component-target network was constructed combined the network pharmacology. The predict targets and pathways were validated by in vitro and in vivo experiments. RESULTS: With XYS treatment, the liver function was significantly improved, and fibrotic changes were alleviated. The a-SMA and collagen I expression levels in the liver were also decreased in XYS-treated rats compared with CCl4 model rats. 108 active components and 42 targets from 8 herbs constituted herb-compound-target network by transcriptomics and network pharmacology analysis. The KEGG pathway and GO enrichment analyses showed that the FoxO, TGFß, AMPK, MAPK, PPAR, and hepatitis B and C pathways were involved in the anti-fibrosis effects of XYS. In the liver tissues, p-FoxO3a and p-Akt expression levels were significantly increased in the CCl4 model group but decreased in the XYS-treated group. The TGFß1/Smad pathway and Akt/FoxO3 pathway were verified in LX2 cells by inhibiting phosphorylation of Smad3 and Akt activity, respectively. CONCLUSIONS: Our findings suggested that XYS markedly alleviated CCl4-induced liver fibrosis in histopathological and serum liver function analyses, and this effect may occur via the TGFß1/Smad and Akt/FoxO signaling pathways.

2.
Aging (Albany NY) ; 12(14): 14949-14965, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32701483

RESUMO

Hepatitis B virus (HBV) infection is an important factor causing hepatocellular carcinoma (HCC). The aim of this study was to investigate the metabolic characteristics and related metabolic enzyme changes during the progression from chronic hepatitis B (CHB) to liver cirrhosis (LC) and, ultimately, to HCC. An untargeted metabolomics assay was performed in plasma from 50 healthy volunteers, 43 CHB patients, 67 LC patients, and 39 HCC patients. A total of 24 differential metabolites (DMs) were identified. Joint pathway analysis suggested striking changes in amino acid metabolism and lipid metabolism from CHB to HCC. The panel of L-serine, creatine and glycine distinguished LC from CHB, and L-serine, cystathionine, creatine and linoleic acid distinguished HCC from LC. Bioinformatic analysis of publicly available data showed that differential metabolite profile-associated enzyme genes, including alanine-glyoxylate aminotransferase-2 (AGXT2), D-amino-acid oxidase (DAO), and cystathionine gamma-lyase (CTH), were downregulated, while bisphosphoglycerate mutase (BPGM), cystathionine-ß-synthase (CBS), phosphoserine phosphatase (PSPH) and acyl-CoA thioesterase 7 (ACOT7) were upregulated, in HCC, all of which correlated with a poor prognosis for HCC patients. Our results indicated that serum metabolites and related enzymes are of considerable significance for the diagnosis and prognosis of HCC and can provide a theoretical basis and therapeutic index for future diagnosis and treatment.

3.
J Ethnopharmacol ; 253: 112689, 2020 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-32101775

RESUMO

ETHNOPHARMACOLOGICAL REVELVANCE: Tanshinone IIA (TIIA) is a major component extracted from the traditional herbal medicine salvia miltiorrhiza (Danshen), which activates blood circulation and treats chronic hepatitis and liver fibrosis. However, the underlying molecular mechanism of TIIA against hepatic fibrosis is still largely unknown. AIM OF THE STUDY: The present study aimed to evaluate the antifibrotic effects of TIIA in liver fibrosis and investigate its underlying mechanism through network pharmacology-based prediction and experimental verification. MATERIALS AND METHODS: In this study, a "TIIA-targets-liver fibrosis" network was constructed by combining the TIIA-specific and hepatic fibrosis-specific targets with protein-protein interactions (PPIS), and network pharmacology was applied to identify the potential targets and mechanisms of TIIA in the treatment of hepatic fibrosis. The antifibrotic effect of TIIA was investigated in CCl4-induced liver fibrosis in rats in vivo and in the human HSC line LX2 in vitro. RESULTS: We identified 75 potential targets of TIIA and 1382 targets of liver fibrosis. Subsequently, the 29 target proteins that overlapped between the potential TIIA targets and the liver fibrosis targets indicated that TIIA has potential antifibrotic effects through regulating multiple targets, including c-Jun, c-Myc, CCND1, MMP9 and P65. Pathway and functional enrichment analysis of these putative targets showed that TIIA could regulate the MAPK, PI3K/Akt and Wnt signaling pathways. Consistently, in vivo and in vitro experiments indicated that TIIA attenuated CCl4-induced liver injury and fibrosis and inhibited hepatic stellate cell (HSC) proliferation and activation; these findings were concomitant with the decreased expression of α-smooth muscle actin (α-SMA) and human α2 (I) collagen (COL1A2). Moreover, TIIA remarkably downregulated the expression of c-Jun, c-Myc, MMP9, PI3K and P38 proteins, which were upregulated in CCl4-induced hepatic fibrosis in vivo. TIIA significantly downregulated the expression of c-Jun, p-c-Jun, c-Myc, CCND1, MMP9, P65, P-P65, PI3K and P38 proteins, which were upregulated during HSC activation in vitro. CONCLUSION: Our study demonstrated that TIIA could significantly improve liver function, decrease liver injury, alleviate ECM accumulation, and attenuate HSC proliferation and activation, thus exerting an antifibrotic effect. The possible molecular mechanism involved MAPK, Wnt and PI3K/Akt signaling pathways via inhibiting c-Jun, p-c-Jun, c-Myc, CCND1, MMP9, P65, P-P65, PI3K and P38. Overall, our results suggest that TIIA could alleviate liver fibrosis through multiple targets and multiple signaling pathways and provide deep insight into the pharmacological mechanisms of TIIA in the treatment of hepatic fibrosis.

4.
Medicine (Baltimore) ; 98(37): e17143, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31517857

RESUMO

The aim of this study was to investigate the alterations of urinary microRNA (miRNA) expression and explore its clinical significance in patients with chronic hepatitis B (CHB).The expression levels of urinary miRNA were detected by miRNA microarray and quantitative reverse transcription polymerase chain reaction (qRT-PCR) from 106 CHB and 40 healthy controls (Ctrl) subjects. The correlation between the levels of miRNA expression and clinical characteristics were analyzed. Receiver-operator characteristic (ROC) curves were generated to determine the specificity and sensitivity of each individual miRNA. MiRNAs expression were further measured by PCR from exosomes, which were isolated from urine samples. LX2 cells were transfected with miRNA inhibitor and accumulation of cytoplasmic lipid droplets was analyzed by Oil Red O staining.miRNA expression profile analysis showed that 22 miRNAs were upregulated and 55 miRNAs were downregulated in CHB patients compared with Ctrl subjects (fold-change>1.5 and P < .05). miR-92b-3p, miR-770-5p, miR-5196-5p, and miR-7855-5p were significantly higher (P < .0001) in CHB subjects than in Ctrl subjects. ROC curve analysis showed that these four miRNAs were sensitive and specific enough to distinguish CHB and Ctrl subjects. The levels of miR-92b-3p expression were negatively correlated with total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and APOA-1. Moreover, in vitro experiments indicated that inhibition of miR-92b-3p increased lipid droplet formation in LX2 cells.Aberrant expression of miRNAs has been observed in urine of CHB patients. Our findings may provide novel insights into the pathogenesis of CHB and may assist in the diagnosis of patients with CHB.


Assuntos
Hepatite B Crônica/urina , MicroRNAs/urina , Adulto , Biomarcadores/urina , Linhagem Celular , Exossomos/metabolismo , Feminino , Expressão Gênica , Humanos , Gotículas Lipídicas/metabolismo , Masculino , Sensibilidade e Especificidade
5.
Virol Sin ; 34(5): 489-500, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31161555

RESUMO

The study was conducted to explore the mechanisms of sex differences in the response to chronic hepatitis B (CHB) in terms of DNA methylation, SNP genotype, and gene expression. Genomic DNA was isolated from peripheral blood mononuclear cells (PBMCs) of CHB patients and healthy controls and evaluated using the Human Methylation 450 K Assay. The DNA methylation level at hg37 chromosome (CHR) X: 7810800 was further validated using pyrosequencing. SNP genotypes, VCX mRNA expression of PBMCs, and plasma VCX protein concentration were further examined using SNaPshot, RT-qPCR, and Western blot, respectively. Results showed that a total of 5529 CpG loci were differentially methylated between male and female CHB patients. DNA methylation level and CC + CT frequency at CHR X: 7810800, VCX mRNA expression of PBMCs, and plasma VCX protein concentration were higher in female than in male CHB patients. The CHR X: 7810800 locus was hypermethylated in CHB patients with CC + CT genotypes in comparison with those with the TT genotype. In cases of CC + CT genotypes, VCX mRNA expression was negatively correlated with the DNA methylation level. CHB patients with higher levels of HBV DNA, AST, and GGT or higher GPRI scores exhibited lower VCX expression. In conclusion, SNPs and DNA methylation at the CHR X: 7810800 locus cooperatively regulate VCX expression in CHB. The upregulated VCX expression in female CHB patients might represent a mechanism of protection from more severe liver dysfunction and extensive fibrosis, as observed in male CHB patients.


Assuntos
Metilação de DNA , Hepatite B Crônica/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , Fatores Sexuais , Adulto , Feminino , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/sangue , Regiões Promotoras Genéticas , Regulação para Cima , Adulto Jovem
6.
Biomed Pharmacother ; 114: 108863, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30991286

RESUMO

Yinchenhao decoction (YCHD) is a classical Traditional Chinese Medicine (TCM) formula that has been widely used in the treatment of liver fibrosis caused by chronic hepatitis B and jaundice for more than 1800 years. The purpose of this study was to investigate the apoptosis regulation mechanisms of YCHD and its active components suppresses liver fibrosis. The active components and putative targets of YCHD were predicted by network pharmacology approach. Functional and pathway enrichment analysis were presented in the present study by using clusterProfiler. Further, experimental validation was done by using terminal deoxynucleotidyl transferase (TDT) dUTP nick end labelling (TUNEL) assay and western blotting in dimethylnitrosamine (DMN)-induced liver fibrosis rats, and cell proliferation assay, apoptosis assay, and western blotting in human hepatic L02 cells and LX2 cells. 45 active compounds in YCHD formula, 592 potential target proteins and 1191 liver fibrosis-related human genes were identified. Functional and pathway enrichment analysis indicated that YCHD obviously influenced TNF, PI3K-Akt signaling pathways. Further, In vivo experiment indicated that YCHD treatment not only attenuated the symptoms of liver fibrosis, but also decrease the apoptosis of hepatic parenchyma cells. Moreover, in vitro experiments showed that rhein, kaempferol and quercetin treatments remarkably decreased the protein levels of cleaved caspase-3 and increased p-ERK1/2, PI3K and Bcl-XL protein expression in TNF-α-stimulated L02 cells. On the contrary, rhein, kaempferol, aloe-emodin and quercetin inhibited the proliferation of LX2 cells and up-regulated the protein levels of Bax and cleaved caspase-8. In conclusion, 45 active components and 296 potential targets of YCHD against liver fibrosis were identified by the analysis of network pharmacology and transcriptomics combination. The mechanisms of YCHD against liver fibrosis were involved in the regulation of multiple targets, especially affecting the apoptosis-related signaling pathways.


Assuntos
Apoptose/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Cirrose Hepática/tratamento farmacológico , Animais , Caspase 3/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Perfilação da Expressão Gênica/métodos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Cirrose Hepática/metabolismo , Masculino , Medicina Tradicional Chinesa/métodos , Fosfatidilinositol 3-Quinases/metabolismo , Ratos , Ratos Wistar , Proteína bcl-X/metabolismo
7.
Artigo em Inglês | MEDLINE | ID: mdl-31015849

RESUMO

To investigate the mechanism of a Bushen-Jianpi decoction (BSJPD) in liver cancer (LC) treatment, we analyzed clinical therapy data, conducted network pharmacology analysis, and performed pharmacological experimental verification in vitro and in vivo. The univariate analysis of clinical therapy showed that the BSJPD was protective factor (p < 0.05). The network pharmacology analysis showed that 9 compounds were important nodes of BSJPD-LC therapy network. In experimental verification, the rate of apoptosis increased in the liver tumors of mice treated with the BSJPD (p < 0.05); drug serum with 20 % BSJPD inhibited cell viability (p < 0.05) and reduced the expression of PI3K, the Bcl-xL/BAD ratio, and the levels of p53 and p-Akt in HepG2 cells. Moreover, licochalcone A, alisol B, and hederagenin inhibited cell viability (p < 0.05), induced cell apoptosis (p < 0.01), reduced p-Akt levels, and increased cleaved-CASP3 (p < 0.05) and p53 expression levels in HepG2 cells. These data suggest that the BSJPD prolongs the survival of LC patients and induces apoptosis and that it may be associated with the regulation of PI3K, Akt, p53, CASP3, and Bcl-xL/BAD expression.

8.
J Ethnopharmacol ; 238: 111888, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31004725

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Fuzheng-Huayu formula (FZHY) is traditionally used to treat liver fibrosis in clinic. The study was conducted to investigate the metabolic mechanisms of FZHY against liver fibrosis in rats. MATERIALS AND METHODS: Rats with CCl4 -induced liver fibrosis were treated with FZHY and its components, including amygdalin, cordyceps polysaccharide and gypenoside, respecitively. Liver fibrosis and function were assesed by histopathological examination, Western blot and serum biochemical detection. Metabolic profiling of liver tissue, serum and urine in each group were detected by gas chromatography-mass spectrometry (GC-MS) and transcriptomic changes were tested by gene chip. RT-qPCR was used to validate levels of different expressed genes (DEGs) with statistical significance. Metabolic network together with DEGs was constructed based on KEGG database. RESULTS: FZHY effectively improved liver fibrosis better than the mixture or single use of gypenoside, cordyceps sinensis mycelia and amygdalin. FZHY treatment widely modulated the metabolic profiles perturbed by liver fibrosis, involving several important metabolic pathways, including glycolysis/gluconeogenesis, glucose-alanine cycle, citrate cycle, galactose metabolism, tryptophan metabolism, urea cycle, etc. It also increased alanine and decreased glucose levels in liver tissue and decreased both of them in serum and urine, which were dysregulated by CCl4 treatment. Additionally, FZHY also upregulated expression of metabolic enzymes including Hk2, Adh1 and Gpt increased, and downregulated Gs and Acss2. CONCLUSION: FZHY improved liver fibrosis in rats via altering the metabolic pathways and regulating gene expression of involved metabolic enzymes.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Cirrose Hepática/prevenção & controle , Animais , Intoxicação por Tetracloreto de Carbono , Cirrose Hepática/induzido quimicamente , Masculino , Ratos , Ratos Wistar
9.
Molecules ; 24(6)2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30901941

RESUMO

Metastasis is a major cause of death in patients with breast cancer. In the process of cancer development, epithelial-mesenchymal transition (EMT) is crucial to promoting the invasion and migration of tumor cells. In a previous study, the role of resveratrol in migration and metastasis was investigated in MDA-MB-231 (MDA231) human breast cancer cells and a xenograft-bearing mouse model. Additionally, the related mechanism was explored. In the present study, in vitro Transwell assays showed that resveratrol can inhibit the migration of transforming growth factor (TGF)-ß1-induced MDA231 cells in a concentration-dependent manner. An enzyme-linked immunosorbent assay (ELISA) showed that resveratrol can reduce the secretion of matrix metalloproteinase (MMP)-2 and MMP-9. Immunofluorescence was performed to confirm the expression of EMT-related markers. Immunofluorescence assays confirmed that resveratrol changed the expression of the EMT-related markers E-cadherin and vimentin. Western blot analysis demonstrated that resveratrol decreased the expression levels of MMP-2, MMP-9, Fibronectin, α-SMA, P-PI3K, P-AKT, Smad2, Smad3, P-Smad2, P-Smad3, vimentin, Snail1, and Slug, as well as increased the expression levels of E-cadherin in MDA231 cells. In vivo, resveratrol inhibited lung metastasis in a mouse model bearing MDA231 human breast cancer xenografts without marked changes in body weight or liver and kidney function. These results indicate that resveratrol inhibits the migration of MDA231 cells by reversing TGF-ß1-induced EMT and inhibits the lung metastasis of MDA231 human breast cancer in a xenograft-bearing mouse model.


Assuntos
Neoplasias da Mama/metabolismo , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Resveratrol/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Humanos , Metaloproteinases da Matriz/metabolismo , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Biomed Pharmacother ; 112: 108676, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30797157

RESUMO

Liver diseases cause serious public health problems because of their high global prevalence and poor long-term clinical outcomes. With its mild and broad therapeutic efficacy, traditional Chinese medicine (TCM) has played an important role in the prevention and treatment of liver diseases in China for hundreds of years. Tanshinone IIA (TIIA), a major component extracted from the traditional herbal medicine Salvia miltiorrhiza Bunge, has been broadly studied for its multiple biological activities, including antiangiogenic, antioxidant, anti-inflammatory and anticancer properties. In this article, we focus on the effects of TIIA on the development of liver diseases, including hepatic injury, fatty liver, hepatic fibrosis and hepatocellular carcinoma (HCC), as well as the mechanism underlying TIIA and its new formulations and carriers in order to provide a reference for its further study and clinical therapeutic use in liver diseases.


Assuntos
Abietanos/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Hepatopatias/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Abietanos/isolamento & purificação , Animais , Anti-Inflamatórios não Esteroides/isolamento & purificação , Antineoplásicos Fitogênicos/isolamento & purificação , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Humanos , Hepatopatias/metabolismo , Hepatopatias/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Extratos Vegetais/isolamento & purificação
11.
Molecules ; 24(2)2019 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-30669350

RESUMO

Fuzheng huayu formula (FZHY), an antifibrotic traditional Chinese medicine, is frequently used for the treatment of liver fibrosis. In this study, network analysis, transcriptomic analysis, assays of cell apoptosis, viability and protein expression were used for investigating the effects and mechanisms of compounds derived from FZHY on hepatic parenchymal cell (HPC) protection and hepatic stellate cell activation. Network pharmacology analysis found that 6 major compounds and 39 potential targets were important network nodes. Our analysis predicted that the active compounds of FZHY, including hederagenin, luteolin and tanshinone IIA inhibited cell apoptosis (p < 0.05), increased PI3K expression and reduced cleaved caspase 3 expression and the Bax/Bcl-w ratio (p < 0.05) in L02 cells that had apoptosis induced by TNF-α. Few significant changes caused by FZHY, hederagenin, luteolin and tanshinone IIA were observed in hepatic stellate Lx2 cells upon TGF-ß1 induction. These data suggest that FZHY is active against liver fibrosis, protects hepatic parenchymal cells from apoptosis, and recovers liver function, possibly through the effects of its active compounds hederagenin, luteolin and tanshinone IIA and is involved in the inhibition of apoptosis in HPCs, possibly through regulating the PI3K, ERK, cleaved caspase 3 and Bax/Bcl-w levels.


Assuntos
Apoptose/efeitos dos fármacos , Apoptose/genética , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Transcriptoma , Animais , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/farmacocinética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Ratos , Transdução de Sinais/efeitos dos fármacos
12.
Gene ; 687: 255-260, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30472375

RESUMO

Mounting evidence has shown that long noncoding RNAs (lncRNAs) can function as competing endogenous RNAs (ceRNAs) in distinct physiological and pathological states. The activation of hepatic stellate cells (HSCs) is a critical event in the development of hepatic fibrosis (HF). LncRNAs have recently been revealed to be involved in HSC activation as ceRNAs. CeRNA analysis tremendously expands the functional information of proteins, DNA and coding and noncoding RNA. In addition, many validated ceRNA networks, including the traditional ceRNA/mRNA/miRNA, participate in the initiation and progress of HF, and additional work is needed in elucidating the potential of ceRNAs in precancer diagnosis, prognosis and providing new therapeutic methods for HF reversion.


Assuntos
Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Cirrose Hepática/genética , Cirrose Hepática/terapia , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Animais , Humanos
13.
J Exp Clin Cancer Res ; 37(1): 243, 2018 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-30285892

RESUMO

BACKGROUND: Licorice is an herb extensively used for both culinary and medicinal purposes. Various constituents of licorice have been shown to exhibit anti-tumorigenic effect in diverse cancer types. However, majority of these studies focus on the aspect of their growth-suppressive role. In this study, we systematically analyzed known licorice's constituents on the goal of identifying component(s) that can effectively suppress both cell migration and growth. METHODS: Effect of licorice's constituents on cell growth was evaluated by MTT assay while cell migration was assessed by both wound-healing and Transwell assays. Cytoskeleton reorganization and focal adhesion assembly were visualized by immunofluorescence staining with labeled phalloidin and anti-paxillin antibody. Activity of Src in cells was judged by western blot using phosphor-Src416 antibody while Src kinase activity was measured using Promega Src kinase assay system. Anti-tumorigenic capabilities of isoliquiritigenin (ISL) and 2, 4, 2', 4'-Tetrahydroxychalcone (THC) were investigated using lung cancer xenograft model. RESULTS: Using a panel of lung cancer cell lines, ISL was identified as the only licorice's constituent capable of inhibiting both cell migration and growth. ISL-led inhibition in cell migration resulted from impaired cytoskeleton reorganization and focal adhesion assembly. Assessing the phosphorylation of 141 cytoskeleton dynamics-associated proteins revealed that ISL reduced the abundance of Tyr421-phosphorylation of cortactin, Tyr925- and Tyr861-phosphorylation of FAK, indicating the involvement of Src because these sites are known to be phosphorylated by Src. Enigmatically, ISL inhibited Src in cells while displayed no effect on Src activity in cell-free system. The discrepancy was explained by the observation that THC, one of the major ISL metabolite identified in lung cancer cells abrogated Src activity both in cells and cell-free system. Similar to ISL, THC deterred cell migration and abolished cytoskeleton reorganization/focal adhesion assembly. Furthermore, we showed both ISL and THC suppressed in vitro lung cancer cell invasion and in vivo tumor progression. CONCLUSION: Our study suggests that ISL inhibits lung cancer cell migration and tumorigenesis by interfering with Src through its metabolite THC. As licorice is safely used for culinary purposes, our study suggests that ISL or THC may be safely used as a Src inhibitor.


Assuntos
Chalconas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Actinas/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Citoesqueleto/efeitos dos fármacos , Citoesqueleto/metabolismo , Progressão da Doença , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/farmacologia , Adesões Focais/efeitos dos fármacos , Glycyrrhiza/química , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Extratos Vegetais/farmacologia , Distribuição Aleatória , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases da Família src/metabolismo
14.
Sci Rep ; 8(1): 15367, 2018 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-30337590

RESUMO

Yinchenhao decoction (YCHD), comprising Yinchenhao (Artemisiae Scopariae Herba), Zhizi (Gardeniae Fructus) and Dahuang (Radix Rhei et Rhizoma), is widely used for treating various diseases. We aimed to investigate the bile acid metabolic mechanism of YCHD in dimethylnitrosamine (DMN)-induced liver fibrosis model. Rats received DMN (10 mg/kg, intraperitoneally) for four successive weeks for liver fibrosis induction and were treated with YCHD for the last 2 weeks. Histopathological analysis showed that YCHD prevented DMN-induced histopathological changes in liver tissues. Serum liver function in YCHD group improved. Ultraperformance liquid chromatography-mass spectrometry analysis showed that YCHD significantly restored both free and conjugated bile acid levels increased by DMN, to normal levels. RT-qPCR results showed that YCHD treatment upregulated the expression of genes related to bile acid synthesis, reabsorption, and excretion. Western blotting analysis showed that YCHD downregulated α-SMA, TGF-ß1, p-Smad3, and p-ERK1/2 expression in chenodeoxycholic acid (CDCA)-activated hepatic stellate cells (HSCs). The viability of CDCA-activated HSCs significantly increased after treatment with YCHD and PD98059 (an ERK inhibitor) compared to YCHD treatment alone. Our findings suggest that YCHD alleviated DMN-induced liver fibrosis by regulating enzymes responsible for bile acid metabolism. Additionally, it inhibits CDCA-induced HSC proliferation and activation via TGF-ß1/Smad/ERK signalling pathway.


Assuntos
Ácidos e Sais Biliares/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática/prevenção & controle , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Perfilação da Expressão Gênica , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Ratos , Ratos Wistar , Proteínas Smad/genética , Fator de Crescimento Transformador beta1/genética
15.
Complement Ther Med ; 36: 14-19, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29458921

RESUMO

OBJECTIVES: This study aims to investigate the metabolic profiles of postoperative colorectal cancer (PCRC) patients with different traditional Chinese medicine (TCM) syndromes and to discuss the metabolic mechanism under PCRC progression and TCM syndrome classification. METHODS: Fifty healthy controls (HC) and 70 PCRC patients, including 10 Dampness and heat syndrome (DHS), 33 Spleen deficiency syndrome (SDS), 19 Liver and kidney Yin deficiency syndrome (LKYDS) and 8 with non-TCM syndrome (NS) were enrolled. Plasma metabolic profiles were detected by Gas chromatography-mass spectrometry (GC-MS) and analyzed by principal component analysis (PCA) and partial least squares-discriminate analysis (PLS-DA). Furthermore, pathway enrichment was analyzed based on KEGG and DAVID databases and metabolic network was constructed via metaboanalyst and cytoscape. RESULTS: The top-3 metabolites with higher abundance in PCRC compared with HC were terephthalic acid (165.417-fold), ornithine (24.484-fold) and aminomalonic acid (21.346-fold). And the cholesterol (0.588-fold) level was decreased in PCRC. l-Alanine, 1, 2-ethanediamine, urea, glycerol, glycine, aminomalonic acid, creatinine and palmitic acid were specifically altered in the DHS, while d-tryptophan was exclusively changed in SDS, and l-proline, 1, 2, 3-propanetricarboxylic acid, d-galactose and 2-indolecarboxylic acids in LKYDS. CONCLUSIONS: The plasma metabolic profiles were perturbed in PCRC patients. Increased levels of terephthalic acid might indicate high risk of relapse and elevated ornithine may contribute to the post-operational recovery or may raise the susceptibility to PCRC recurrence. The metabolic profiles of DHS, SDS, LKYDS and NS were almost separately clustered, indicating the possibility of explaining TCM syndromes classification using metabolomics. Furthermore, creatinine and aminomalonic acid alternation might correlate with the formation of DHS, while d-tryptophan may associate with SDS and d-galactose and 1, 2, 3-propanetricarboxylic acid may relate to LKYDS. As numbers of patients in each TCM syndrome are small, further study is needed to verify those results.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Colorretais , Medicina Tradicional Chinesa , Metaboloma/fisiologia , Deficiência da Energia Yin/sangue , Estudos de Casos e Controles , Neoplasias Colorretais/sangue , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/cirurgia , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Metabolômica , Período Pós-Operatório , Deficiência da Energia Yin/metabolismo
16.
Oncotarget ; 9(1): 1075-1090, 2018 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-29416678

RESUMO

Circulating microRNAs (miRNAs) can be employed as biomarkers to diagnose liver and other diseases. Noninvasive approaches are needed to complement and improve the current strategies for screening for biomarkers liver cirrhosis. We determined whether the serum levels of miRNAs can distinguish between chronic hepatitis B (CHB) and CHB-induced cirrhosis (HBC) and investigated the potential mechanisms involved. We found that serum miR-27a was significantly up-regulated in HBC, distinguishing HBC from CHB and healthy controls (Ctrl) (P<0.0001, the area of under the curve (AUC) =0.82 and 0.87, respectively). Specifically, when miR-27a was combined with miR-122, HBC was differentiated from CHB with an AUC=0.94. The serum miR-27a level in HBC patients with hepatic decompensation was significantly higher than that in patients with compensated HBC (P=0.0009). MiR-27a was also significantly up-regulated in the serum of rats with DMN-induced liver cirrhosis compared to that in saline-treated rats (P<0.0001). Furthermore, the down-regulation of miR-27a inhibited the proliferation and overexpression of miR-27a in activated hepatic stellate cells (HSCs) through the up-regulation of α-SMA and COL1A2 expression by targeting PPARγ, FOXO1, APC, P53 and RXRα. Our study demonstrated that circulating miR-27a can be used as a predictor for the activation of HSCs and the occurrence and development of HBC.

17.
Chin Med ; 13: 65, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30619503

RESUMO

Systems biology is an academic field that attempts to integrate different levels of information to understand how biological systems function. It is the study of the composition of all components of a biological system and their interactions under specific conditions. The core of systems biology is holistic and systematic research, which is different from the manner of thinking and research of all other branches of biology to date. Chinese herbal formulae (CHF) are the main form of Chinese medicine and are composed of single Chinese herbal medicines (CHMs) with pharmacological and pharmacodynamic compatibility. When single CHMs are combined into CHF, the result is different from the original effect of a single drug and can be better adapted to more diseases with complex symptoms. CHF represent a complex system with multiple components, targets and effects. Therefore, the use of systems biology is conducive to revealing the complex characteristics of CHF. With the rapid development of omics technologies, systems biology has been widely and increasingly applied to the study of the basis of the pharmacological substances, action targets and mechanisms of CHF. To meet the challenges of multiomics synthesis-intensive studies and system dynamics research in CHF, this paper reviews the common techniques of genomics, transcriptomics, proteomics, metabolomics, and metagenomics and their applications in research on CHF.

18.
Acta Pharmacol Sin ; 39(6): 942-951, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29072258

RESUMO

Fuzheng-Huayu formula (FZHY), a Chinese herbal mixture prescription, has been proven effective in treating liver fibrosis and cirrhosis in both clinical trials and animal experiments. In this study we assessed the metabolic mechanisms of traditional Chinese medicine (TCM) syndrome-based FZHY treatment in liver cirrhosis (LC). A total of 113 participants, including 50 healthy controls and 63 LC patients, were recruited. According to the diagnosis and differentiation of the TCM syndromes, the LC patients were classified into 5 TCM syndrome groups including the liver stagnation syndrome (LSS), spleen deficiency and damp overabundance syndrome (SDDOS), damp-heat accumulation syndrome (DHAS), liver-kidney Yin deficiency syndrome (LKYDS), and blood stagnation syndrome (BSS), and administered FZHY for 6 months. FZHY treatment significantly decreased serum levels of hyaluronic acid (HA), a biochemical marker for LC, as well as TCM syndrome scores (the TCM syndrome scores were decreased in all the groups with significant decreases in the LSS and LKYDS groups). Furthermore, FZHY treatment gradually shifted the metabolic profiles of LC patients from a pathologic state to a healthy state, especially in LC patients with LSS and LKYDS. Twenty-two differently altered metabolites (DAMs) were identified, including carbohydrates, amino acids, fatty acids, etc with 9 DAMs in LSS patients, 9 in LKYDS patients, and 4 in other patients. The metabolic pathways involved in the conversion of amino acids and the body's detoxification process were regulated first, followed by the pathways involved in the body's energy supply process. In conclusion, the evaluation of the effect of TCM syndrome-based FZHY treatment show that FZHY has a better effect on LKYDS and LSS than on the other TCM syndromes, and the metabolic mechanisms might be involved in the increased detoxification function in LKYDS and the improvement of energy supply in LSS, which provides important evidence for the clinical application of TCM syndrome-based treatment.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Metabolismo Energético/efeitos dos fármacos , Cirrose Hepática/tratamento farmacológico , Medicina Tradicional Chinesa/métodos , Metabolômica/métodos , Biomarcadores/sangue , Estudos de Casos e Controles , China , Medicamentos de Ervas Chinesas/efeitos adversos , Humanos , Cirrose Hepática/sangue , Cirrose Hepática/diagnóstico , Fatores de Tempo , Resultado do Tratamento
19.
Acta Pharmacol Sin ; 39(6): 930-941, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29094729

RESUMO

Liver fibrosis is a consequence of chronic liver disease that can progress to liver cirrhosis or even hepatocarcinoma. Fuzheng Huayu (FZHY), a Chinese herbal formula, has been shown to exert anti-fibrotic effects. To better understand the molecular mechanisms underlying the anti-fibrotic effects of FZHY, we analyzed transcriptomic and proteomic combination profiles in CCl4-induced liver fibrosis in rats, which were treated with extracted FZHY powder (0.35 g·kg-1·d-1, ig) for 3 weeks. We showed that FZHY administration significantly improved liver function, alleviated hepatic inflammatory and fibrotic changes, and decreased the hydroxyproline content in the livers of CCl4-treated rats. When their liver tissues were examined using microarray and iTRAQ, we found 255 differentially expressed genes (fold change ≥1.5, P<0.05) and 499 differentially expressed proteins (fold change ≥1.2, P<0.05) in the FZHY and model groups. Functional annotation with DAVID (The Database for Annotation, Visualization and Integrated Discovery) showed that 15 enriched gene ontology terms, including drug metabolic process, response to extracellular stimulus, response to vitamins, arachidonic acid metabolic process, response to wounding, and oxidation reduction might be involved in the anti-fibrotic effects of FZHY; whereas KEGG pathway analysis revealed that eight enriched pathways, including arachidonic acid metabolism, retinol metabolism, metabolism of xenobiotics by cytochrome P450, and drug metabolism might also be involved. Moreover, the protein-protein interaction network demonstrated that 10 core genes/proteins overlapped, with Ugt2a3, Cyp2b1 and Cyp3a18 in retinol metabolism pathway overlapped to a higher degree. Compared to the model rats, the livers of FZHY-treated rats had significantly higher mRNA and protein expression levels of Ugt2a3, Cyp2b1 and Cyp3a18. Furthermore, the concentration of retinoic acid was significantly higher in the FZHY-treated rats compared with the model rats. The results suggest that the anti-fibrotic effects of FZHY emerge through multiple targets, multiple functions, and multiple pathways, including FZHY-regulated retinol metabolism, xenobiotic metabolism by cytochrome P450, and drug metabolism through up-regulated Ugt2a3, Cyp2b1, and Cyp3a18. These genes may play important anti-fibrotic roles in FZHY-treated rats.


Assuntos
Tetracloreto de Carbono , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Medicamentos de Ervas Chinesas/farmacologia , Perfilação da Expressão Gênica/métodos , Cirrose Hepática Experimental/prevenção & controle , Fígado/efeitos dos fármacos , Proteômica/métodos , Animais , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Citocromo P-450 CYP2B1/genética , Citocromo P-450 CYP2B1/metabolismo , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática Experimental/genética , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática Experimental/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Proteoma , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Transcriptoma
20.
Anticancer Res ; 37(11): 6141-6151, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29061795

RESUMO

BACKGROUND/AIM: The synergistic combinations of natural products have long been the basis of Traditional Chinese herbal Medicine formulas. In this study, we investigated the synergistic effects of a combination of berberine and evodiamine against human breast cancer MCF-7 cells in vitro and in vivo, and explored its mechanism. MATERIALS AND METHODS: Cell survival was measured using the MTT assay. Apoptosis-related proteins were observed using western blot analysis. Apoptosis was detected with flow cytometric analysis and by Hoechst 33258 staining. Tumor xenografts were used in vivo. RESULTS: Compared to berberine or evodiamine treatments alone, the combination treatment of berberine (25 µM) and evodiamine (15 µM) synergistically inhibited the proliferation of MCF-7 cells in a time-dependent manner and resulted in the G0/G1 phase accumulation of cells that exhibited increased expression levels of the CDK inhibitors p21 and p27 with a concomitant reduction in the expression levels of cell-cycle checkpoint proteins cyclin D1, cyclin E, CDK4, and CDK6. Furthermore, the combination treatment induced apoptosis that was accompanied by increased expression levels of p53 and Bax, reduced expression levels of Bcl-2, activation of caspase-7, and caspase-9, and the cleavage of PARP. The combination of berberine and evodiamine synergistically inhibited tumor growth in vivo in MCF-7 human breast cancer xenografts. CONCLUSION: Combination of berberine and evodiamine acts synergistically to suppress the proliferation of MCF-7 cells by inducing cell cycle arrest and apoptosis, illustrating the potential synergistic and combinatorial application of bioactive natural products.


Assuntos
Apoptose/efeitos dos fármacos , Berberina/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quinazolinas/farmacologia , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Neoplasias da Mama/metabolismo , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
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