Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 77
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
BMC Ophthalmol ; 20(1): 92, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32143590

RESUMO

BACKGROUND: Retinoblastoma (RB) is the most frequent pediatric retinal tumor. In the present study, to elucidate chemoresistance mechanisms and identify potential biomarkers in RB, we utilized RNA sequencing (RNAseq) technological platforms to reveal transcriptome profiles and identify any differentially expressed genes (DEGs) between an etoposide drug-resistant subline (Y79/EDR) and parental Y79 cells. METHODS: To test whether Y79/EDR cells showed resistance to antineoplastic agents for RB, we treated the cells with etoposide, carboplatin and vincristine and analyzed them with a Cell Counting Kit-8 (CCK-8). Y79/EDR and parental Y79 cells were used for RNAseq and bioinformatics analysis to enable a genome-wide review of DEGs between the two lines using the DESeq R package (1.10.1). Then, DEG enrichment in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways was analyzed with KOBAS software. Next, real-time quantitative reverse transcription polymerase chain reaction (real time QRT-PCR) and cytotoxicity assays were performed to experimentally and functionally validate the identified candidate biomarkers. RESULTS: Y79/EDR cells showed resistance to etoposide, carboplatin and vincristine at different concentrations. In total, 524 transcripts were differentially expressed in Y79/EDR cells based on analysis of fragments per kilobase of transcript per million fragments mapped (FPKM); among these, 57 genes were downregulated and 467 genes were upregulated in Y79/EDR cells compared to parental Y79 cells. We selected candidate DEGs, including ARHGAP9, HIST1H4H, RELN, DDIT4, HK2, STC1 and PFKFB4, for mRNA expression validation with real time QRT-PCR assays and found that the expression levels determined by real time QRT-PCR were consistent with the RNAseq data. Further studies involving downregulation of ARHGAP9 with a specific siRNA showed that ARHGAP9 altered the cellular sensitivity of Y79 cells to etoposide and carboplatin. CONCLUSION: Our initial findings provided a genomic view of the transcription profiles of etoposide-induced acquired resistance in RB. Follow-up studies indicated that ARHGAP9 might be a chemoresistance biomarker in RB, providing insight into potential therapeutic targets for overcoming acquired chemoresistance in RB. These findings can aid in understanding and overcoming chemoresistance during treatment of RB in the clinic.

2.
Acta Pharmacol Sin ; 41(5): 661-669, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31932644

RESUMO

Chronic tissue injury with fibrosis results in the disruption of tissue architecture, organ dysfunction, and eventual organ failure. Therefore, the development of effective antifibrotic drugs is urgently required. IMB-S7 is novel biphenyl compound derived from bifendate (biphenyldicarboxylate) that is used for the treatment of chronic hepatitis in China. In the current study we investigated the potential of IMB-S7 as an antihepatic fibrosis agent. In bile duct ligation (BDL) rat model, oral administration of IMB-S7 (400 mg· kg-1· d-1, for 14 days) significantly ameliorated BDL-induced liver necrosis, bile duct proliferation, and collagen accumulation. We then showed that IMB-S7 treatment markedly suppressed the TGF-ß/Smad pathway in human hepatic stellate cell line LX2 and mouse primary HSCs, as well as in liver samples of BDL rats, thus inhibiting the transcription of most fibrogenesis-associated genes, including TGF-ß1, COL1A1, and ACTA2. Furthermore, IMB-S7 treatment significantly suppressed the expression of integrin αv at the mRNA and protein levels in TGF-ß-treated LX2 cells and liver samples of BDL rats. Using integrin αv overexpression and silencing, we demonstrated that integrin αv activity correlated positively with the activation of TGF-ß/Smad pathway. Based on dual luciferase assay and DNA affinity precipitation assay, we revealed that IMB-S7 inactivated integrin αv through competitively inhibiting the binding of Sp1, a transcription factor, to the integrin αv (ITGAV) promoter (-173/-163 bp). These results suggest that IMB-S7 inhibits HSCs activation and liver fibrosis through Sp1-integrin αv signaling, and IMB-S7 may be a promising candidate to combat hepatic fibrosis in the future.

3.
Acta Pharmacol Sin ; 41(5): 686-697, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31932645

RESUMO

Sophoridine is a quinolizidine natural product and the exploration of its derivatives has been carried out, and the potent anticancer compound IMB-HDC was acquired. Although previous studies have revealed that some sophoridine derivatives could induce DNA breakage, the underlying mechanisms of inhibition of DNA damage repair (ATR inactivation) and the apoptosis independent of p53, have not been elucidated. Our research reveals a novel DNA response mechanism different from general DNA-damaging agents, and that sophoridine derivate inhibits the phosphorylation of Tyr694 and Ser780 of STAT5a to induce the lessened shuttle from the cytoplasm to the nucleus, and leads to the decreased nuclear STAT5a and subsequently inhibits the expression of STAT5a target gene RAD51 that contributes to the checkpoint activation, thus inhibiting ATR activation. Meanwhile, IMB-HDC that induced the diminished expression of STAT5a target gene contributes to proliferation and leads to apoptosis. More importantly, we give the first evidence that promoting the effect of Tyr694 phosphorylation on nuclear location and subsequent STAT5a target gene transcription depends on Ser780 increased or unchanged phosphorylation and was not correlated with Ser726 phosphorylation.

4.
Br J Pharmacol ; 177(2): 372-387, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31621893

RESUMO

BACKGROUND AND PURPOSE: This study investigates the antifibrotic activities and potential mechanisms of costunolide (COS), a natural sesquiterpene compound. EXPERIMENTAL APPROACH: Rats subjected to bile duct ligation and mice challenged with CCl4 were used to study the antifibrotic effects of COS in vivo. Mouse primary hepatic stellate cells (pHSCs) and human HSC line LX-2 also served as an in vitro liver fibrosis models. The expression of fibrogenic genes and signaling proteins in the neurogenic locus notch homologue protein 3 (Notch3)-hairy/enhancer of split-1 (HES1) pathway was examined using western blot and/or real-time PCR. Notch3 degradation was analysed using immunofluorescence and coimmunoprecipitation. KEY RESULTS: In animals, COS administration attenuated hepatic histopathological injury and collagen accumulation and reduced the expression of fibrogenic genes. COS time- and dose-dependently suppressed the levels of fibrotic markers in LX-2 cells and mouse pHSCs. Mechanistic studies showed COS destabilized Notch3 and subsequently inhibited the Notch3-HES1 pathway, thus inhibiting HSC activation. Furthermore, COS blocked the WW domain-containing protein 2 (WWP2)/protein phosphatase 1G (PPM1G) interaction and enhanced the effect of WWP2 on Notch3 degradation. CONCLUSIONS AND IMPLICATIONS: COS exerted potent antifibrotic effects in vitro and in vivo by disrupting the WWP2/PPM1G complex, promoting Notch3 degradation and inhibiting the Notch3/HES1 pathway. This indicates that COS may be a potential therapeutic candidate for the treatment of liver fibrosis.

5.
J Drug Target ; 28(1): 23-32, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31094236

RESUMO

Src family kinases (SFKs) are non-receptor tyrosine kinases and are involved in various cellular functions (proliferation, differentiation, migration, survival and invasion) by regulating downstream pathways. Considerable evidence suggests that co- and post-translational modifications are highly related to the activation of SFKs and their downstream signals. How SFKs are activated and how their subsequent cascades were regulated has been reviewed in previous reports. However, the contribution of co- and post-translational modification to SFKs activation has not been fully elucidated. This review focuses on the effect of these modifications on SFKs activity according to structural and biochemical studies and uncovers the significance of co-and post-translational modifications in the regulation of SFKs activity.

6.
J Drug Target ; 28(1): 1-10, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31244351

RESUMO

In recent years, the rate of colorectal cancer has sharply increased, especially in China, where it ranks second for the number of cancer fatalities. Currently, the treatment of colorectal cancer patients involves the combination of resection surgery and treatment with postoperative anticancer drugs such as 5-FU and oxaliplatin. However, recurrence and metastasis after treatment are still the dominant reasons for the low survival rate. Colorectal cancer stem cells (CSCs) are regarded as the key contributors to tumour recurrence and metastasis due to their resistance to chemotherapy drugs and their extremely high tumourigenicity. Once CSCs overcome chemotherapy treatment, they continue to survive and reinitiate proliferation to form tumours, leading to recurrence. The dominant reason for CSC resistance is that most anticancer drugs are aimed at inhibiting proliferative pathways in cancer cells that differ from those in CSCs. Therefore, studies on the characteristics of CSCs and their intracellular molecular pathways are essential for the exploration of CSC-targeted drugs. In this report, we review recent advances in the research of CSCs and, in particular, review the important intracellular molecular pathways, such as HOXA5-catenin, STRAP-NOTCH and YAP/TAZ, related to the maintenance and differentiation of stem cells to generate a theoretical basis for the exploration of CSC-targeted drugs.

7.
Biochem Pharmacol ; 164: 152-164, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30978324

RESUMO

The conversion of cholesterol to bile acids (BAs) contributes to the elimination of total cholesterol from the body. In addition, manipulating BA homeostasis by modulating cholesterol 7α-hydroxylase (CYP7A1) may affect the metabolic processing of cholesterol, exerting therapeutic effects on hypercholesterolemia and cardiovascular diseases. Multiple mechanisms (such as various nuclear receptors and regulatory factors) are involved in CYP7A1 modulation. Recently, microRNAs, protein degradation pathways, and the gut microbiota have been identified to participate in these sophisticated networks. In this review, research progress on the regulatory mechanism of CYP7A1 is summarized.


Assuntos
Colesterol 7-alfa-Hidroxilase/metabolismo , Colesterol/metabolismo , Microbioma Gastrointestinal/fisiologia , Homeostase/fisiologia , Animais , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/metabolismo
8.
Acta Pharmacol Sin ; 40(7): 895-907, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30573812

RESUMO

The manipulation of bile acid (BA) homeostasis by blocking the ileal apical Na+-dependent bile salt transporter (ASBT/SLC10A2) may have therapeutic effects in nonalcoholic fatty liver disease. We developed a novel ASBT inhibitor, an N-(3,4-o-dichlorophenyl)-2-(3-trifluoromethoxy) benzamide derivative referred to as IMB17-15, and investigated its therapeutic effects and the molecular mechanisms underlying the effects. Syrian golden hamsters were challenged with high-fat diet (HFD) to induce NAFLD and were subsequently administered 400 mg/kg IMB17-15 by gavage daily for 21 days. Serum, liver, and fecal samples were collected for further analysis. Plasma concentration-time profiles of IMB17-15 were also constructed. The human hepatocyte cell line HL-7702 was treated with Oleic acid (OA) with or without IMB17-15. Western blotting and real-time PCR were used to study the molecular mechanisms of IMB17-15. We found that IMB17-15 inhibited ASBT and subsequently suppressed ileal farnesoid X receptor (FXR) and FXR-activated fibroblast growth factor15/19 (FGF15/19) expression, which reduced the hepatic phosphorylated extracellular regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) levels and upregulated the cholesterol 7α-hydroxylase (CYP7A1) activity. Additionally, IMB17-15 stimulated adenosine monophosphate (AMP)-activated protein kinase (AMPKα) phosphorylation and enhanced peroxisome proliferator activated receptor α (PPARα) expression and thus promoted triglyceride (TG) oxidation and high-density lipoprotein cholesterol (HDL-c) metabolism through an ASBT-independent mechanism. In conclusion, a novel ASBT inhibitor known as IMB17-15 protected hamsters against HFD-induced NFALD by manipulating BA and lipid homeostasis. IMB17-15 also reduced lipid deposition in human hepatic cell lines, indicating that it may be useful as a therapy for NAFLD patients.


Assuntos
Benzamidas/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Sulfonamidas/uso terapêutico , Simportadores/antagonistas & inibidores , Animais , Benzamidas/farmacocinética , Benzamidas/toxicidade , Linhagem Celular , Citocinas/metabolismo , Dieta Hiperlipídica , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Fígado/patologia , Masculino , Mesocricetus , Camundongos , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Sulfonamidas/farmacocinética , Sulfonamidas/toxicidade
9.
Bioconjug Chem ; 29(9): 3104-3112, 2018 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-30105903

RESUMO

Depending on increasing extracellular protein utilization and altering metabolic programs, cancer cells could proliferate and survive without restricion by ingesting human serum albumin (HSA) to serve as nutritional amino acids. Here, we hypothesize that the consumption of albumin by cancer cells could be utilized as an efficient approach to targeted drug delivery. Lidamycin (LDM), an antitumor antibiotic with extremely potent cytotoxicity to cultured cancer cells, consists of an apoprotein (LDP) and an active enediyne chromophore (AE). In the present study, a novel albumin-lidamycin conjugate was prepared by DNA recombination and molecular reconstitution. Results show that the IC50 values of albumin-lidamycin conjugate (HSA-LDP-AE) for a variety of tested cancer cells were at subnanomolar levels. At tolerated doses, the albumin-lidamycin conjugate significantly inhibited the growth of lung carcinoma PG-BE1 xenografts by 97.8%. The therapeutic efficacy of the albumin-lidamycin conjugate was much stronger than that of free lidamycin. Meanwhile, the images of albumin-lidamycin conjugate showed obvious and lasting tumor localization and fluorescence enrichment and there was no detectable signal in nontumor locations. Taken together, albumin-lidamycin conjugate, a new format of lidamycin, could be a promising antitumor therapeutic agent and albumin-integration might be a feasible approach to targeted antitumor drug delivery.


Assuntos
Albuminas/química , Aminoglicosídeos/química , Aminoglicosídeos/uso terapêutico , Antibióticos Antineoplásicos/uso terapêutico , Enedi-Inos/química , Enedi-Inos/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Antibióticos Antineoplásicos/química , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Imagem Óptica , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Acta Pharmacol Sin ; 39(8): 1347-1358, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29283175

RESUMO

c-Myc, a key activator of cell proliferation and angiogenesis, promotes the development and progression of breast cancer. Ezrin-radixin-moesin-binding phosphoprotein-50 (EBP50) is a multifunctional scaffold protein that suppresses the proliferation of breast cancer cells. In this study we investigated whether the cancer-suppressing effects of EBP50 resulted from its regulation of c-Myc signaling in human breast cancer MCF-7 cells in vitro and in vivo. We first found a significant correlation between EBP50 and c-Myc expression levels in breast cancer tissue, and demonstrated that EBP50 suppressed cell proliferation through decreasing the expression of c-Myc and its downstream proteins cyclin A, E and Cdc25A in MCF-7 cells. We further showed that EBP50 did not regulate c-Myc mRNA expression, but it promoted the degradation of c-Myc through the autophagic lysosomal pathway. Moreover, EBP50 promoted integration between c-Myc and p62, an autophagic cargo protein, triggering the autophagic lysosomal degradation of c-Myc. In EBP50-silenced MCF-7 cells, activation of autophagy by Beclin-1 promoted the degradation of c-Myc and inhibited cell proliferation. These results demonstrate that the EBP50/Beclin-1/p62/c-Myc signaling pathway plays a role in the proliferation in MCF-7 breast cancer cells: EBP50 stimulates the autophagic lysosomal degradation of c-Myc, thereby inhibits the proliferation of MCF-7 cells. Based on our results, promoting the lysosomal degradation of c-Myc might be a promising new strategy for treating breast cancer.


Assuntos
Proteína Beclina-1/metabolismo , Proliferação de Células/fisiologia , Lisossomos/metabolismo , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteína Sequestossoma-1/metabolismo , Trocadores de Sódio-Hidrogênio/metabolismo , Animais , Feminino , Técnicas de Silenciamento de Genes , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosfoproteínas/genética , Transdução de Sinais/fisiologia , Trocadores de Sódio-Hidrogênio/genética
11.
Acta Pharmacol Sin ; 39(2): 213-221, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28748913

RESUMO

Cholestatic liver diseases are important causes of liver cirrhosis and liver transplantation, but few drugs are available for treatment. D-chiro-inositol (DCI), an isomer of inositol found in many Leguminosae plants and in animal viscera, is used clinically for the treatment of polycystic ovary syndrome (PCOS) and diabetes mellitus. In this study, we investigated whether DCI exerted an anti-cholestatic effect and its underlying mechanisms. A cholestatic rat model was established via bile duct ligation (BDL). After the surgery, the rats were given DCI (150 mg·kg-1·d-1) in drinking water for 2 weeks. Oral administration of DCI significantly decreased the serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and attenuated bile duct proliferation, parenchymal necrosis and fibrosis in BDL rats. Furthermore, DCI treatment significantly increased the serum and bile levels of total bile acid (TBA), and decreased TBA levels in the liver. Moreover, DCI treatment significantly increased expression of the genes encoding bile acid transporters BSEP (Abcb11) and MRP2 (Abcc2) in liver tissues. DCI treatment also markedly decreased hepatic CD68 and NF-kappaB (NF-κB) levels, significantly decreased the serum and hepatic MDA levels, markedly increased superoxide dismutase activity in both serum and liver tissues. Using whole-genome oligonucleotide microarray, we revealed that DCI treatment altered the expression profiles of oxidation reduction-related genes in liver tissues. Collectively, DCI effectively attenuates BDL-induced hepatic bile acid accumulation and decreases the severity of injury and fibrosis by improving bile acid secretion, repressing inflammation and decreasing oxidative stress. The results suggest that DCI might be beneficial for patients with cholestatic disorders.


Assuntos
Ácidos e Sais Biliares/metabolismo , Colestase/prevenção & controle , Inositol/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Alanina Transaminase/sangue , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Aspartato Aminotransferases/sangue , Ductos Biliares/cirurgia , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Inositol/administração & dosagem , Ligadura , Fígado/patologia , Cirrose Hepática/prevenção & controle , Masculino , NF-kappa B/metabolismo , Substâncias Protetoras/administração & dosagem , Ratos Sprague-Dawley , Estereoisomerismo , Superóxido Dismutase/metabolismo
12.
Autophagy ; 13(5): 900-913, 2017 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-28521610

RESUMO

SPHK1 (sphingosine kinase 1), a regulator of sphingolipid metabolites, plays a causal role in the development of hepatocellular carcinoma (HCC) through augmenting HCC invasion and metastasis. However, the mechanism by which SPHK1 signaling promotes invasion and metastasis in HCC remains to be clarified. Here, we reported that SPHK1 induced the epithelial-mesenchymal transition (EMT) by accelerating CDH1/E-cadherin lysosomal degradation and facilitating the invasion and metastasis of HepG2 cells. Initially, we found that SPHK1 promoted cell migration and invasion and induced the EMT process through decreasing the expression of CDH1, which is an epithelial marker. Furthermore, SPHK1 accelerated the lysosomal degradation of CDH1 to induce EMT, which depended on TRAF2 (TNF receptor associated factor 2)-mediated macroautophagy/autophagy activation. In addition, the inhibition of autophagy recovered CDH1 expression and reduced cell migration and invasion through delaying the degradation of CDH1 in SPHK1-overexpressing cells. Moreover, the overexpression of SPHK1 produced intracellular sphingosine-1-phosphate (S1P). In response to S1P stimulation, TRAF2 bound to BECN1/Beclin 1 and catalyzed the lysine 63-linked ubiquitination of BECN1 for triggering autophagy. The deletion of the RING domain of TRAF2 inhibited autophagy and the interaction of BECN1 and TRAF2. Our findings define a novel mechanism responsible for the regulation of the EMT via SPHK1-TRAF2-BECN1-CDH1 signal cascades in HCC cells. Our work indicates that the blockage of SPHK1 activity to attenuate autophagy may be a promising strategy for the prevention and treatment of HCC.


Assuntos
Autofagia/fisiologia , Caderinas/metabolismo , Carcinoma Hepatocelular/metabolismo , Transição Epitelial-Mesenquimal , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Antígenos CD , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Transição Epitelial-Mesenquimal/fisiologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Neoplasias Hepáticas/metabolismo
13.
Br J Pharmacol ; 174(10): 1147-1160, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28257144

RESUMO

BACKGROUND AND PURPOSE: Dihydrotanshinone I (DHI), a lipophilic component of traditional Chinese medicine Salvia miltiorrhiza Bunge, has various therapeutic effects. We investigated the anti-fibrotic effect of DHI and its underlying mechanisms in vitro and in vivo. EXPERIMENTAL APPROACH: Rats subjected to bile duct ligation (BDL) were treated with DHI (25 mg·kg-1 ·day-1 , i.p.) for 14 days. Serum biochemical and liver tissue morphological analyses were performed. The human hepatic stellate cell line LX-2 served as a liver fibrosis model in vitro. Liver fibrogenic genes, yes-associated protein (YAP) downstream genes and autophagy markers were examined using western blot and real-time PCR analyses. Similar analyses were done in rat primary hepatic stellate cells (pHSCs). Autophagy flux was assessed by immunofluorescence. KEY RESULTS: In BDL rats, DHI administration attenuated liver necrosis, bile duct proliferation and collagen accumulation and reduced the expression of genes associated with fibrogenesis, including Tgfb1, Mmp-2, Acta2 and Col1a1. DHI (1, 5, 10 µmol·L-1 ) time- and dose-dependently suppressed the protein level of COL1A1, TGFß1 and α-SMA in LX-2 cells and rat pHSCs. Furthermore, DHI blocked the nuclear translocation of YAP, which inhibited the YAP/TEAD2 interaction and its downstream fibrogenic genes, connective tissue growth factor, SOX4 and survivin. This stimulated autophagic flux and accelerated the degradation of liver collagen. CONCLUSIONS AND IMPLICATIONS: DHI exerts anti-fibrotic effects in BDL rats, LX-2 cells and rat pHSCs by inhibiting the YAP and TEAD2 complex and stimulating autophagy. These findings indicate that DHI may be a potential therapeutic for the treatment of liver fibrosis.


Assuntos
Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Autofagia/efeitos dos fármacos , Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática/tratamento farmacológico , Fenantrenos/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Ductos Biliares/patologia , Ductos Biliares/cirurgia , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Ligadura , Cirrose Hepática/genética , Cirrose Hepática/patologia , Masculino , Estrutura Molecular , Fenantrenos/administração & dosagem , Fenantrenos/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
14.
J Asian Nat Prod Res ; 19(2): 109-113, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28133978

RESUMO

Hepatic fibrosis is a wound-healing response to chronic liver injury caused by various pathogenesis, such as hepatitis virus infection, drugs toxicity and autoimmune imbalances. Autophagy, a cellular process degrading damaged organelles or aggregative proteins, participates in multiple human diseases including hepatic fibrosis. However, the precise role of autophagy in the pathogenesis of hepatic fibrosis is yet to be elucidated. Accumulated evidences indicate that several nature compounds exhibit anti-fibrotic potential through modulating autophagy activity. For a better understanding of the relationships among autophagy, hepatic fibrosis, and autophagy-regulating nature compounds, this review highlights the recent advancement of nature compounds treating hepatic fibrosis through regulating autophagy.


Assuntos
Autofagia , Cirrose Hepática/tratamento farmacológico , Animais , Humanos , Fígado/metabolismo , Estrutura Molecular , Transdução de Sinais
15.
Oncol Lett ; 14(6): 7889-7895, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29344233

RESUMO

Cluster of differentiation (CD)133 is considered a molecular marker of cancer stem cells in hepatocellular carcinoma. In the present study, the effect of lidamycin (LDM) on CD133 expression in hepatocellular carcinoma (Huh7 cells) was evaluated and the potential molecular mechanism was investigated. Flow cytometry analysis, as well as sorting, sphere formation and western-blot assays, were performed in vitro to explore the effects of LDM on CD133 expression. A subcutaneous tumor model in nude mice was used to observe the effects of LDM on tumor volume and CD133 protein in vivo. To investigate the potential underlying molecular mechanism, Notch signaling pathway activity was detected by western blot analysis and reverse transcription-quantitative polymerase chain reaction. The proportion of CD133+ cells and the expression of CD133 protein were revealed to be downregulated by LDM. Sphere formation of sorted CD133+ cells was suppressed 7 days after LDM treatment. In addition, LDM inhibited tumor volume formed from sorted CD133+ cells and CD133 protein level in vivo. LDM decreased the mRNA level of NOTCH1, Hes1 (Hes family BHLH transcription factor 1) and Hey1 (Hes-related family BHLH transcription factor with YRPW motif 1) genes; consequently, the protein expression of NOTCH1, Notch intracellular domain, Hes1 and Hey1 was decreased by LDM. Downregulation of the Notch signaling pathway by LDM was enhanced through combination with N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester. In brief, these data suggest that LDM suppresses CD133 expression via the Notch signaling pathway, indicating the potential mechanism of LDM on CD133 and the benefits for further clinical application.

16.
Yao Xue Xue Bao ; 52(2): 189-97, 2017 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-29979499

RESUMO

Bile acids play critical roles in the regulation of metabolism and absorption of lipids. The ileal apical sodium-dependent bile acid transporter (ASBT) located at the enterocyte brush border is responsible for the reuptake of bile acids and the maintenance of bile acid homeostasis. Recently, a number of investigations have been made concerning the regulation and control of ASBT and the relationship between ASBT and intestinal inflammation, tumorigenesis, diabetes mellitus and hyperlipemia, which suggests ASBT as a potential therapeutic target of these diseases. In this review, advances in the study of above-mentioned issues were summarized.


Assuntos
Ácidos e Sais Biliares/fisiologia , Íleo/fisiologia , Transportadores de Ânions Orgânicos Dependentes de Sódio/fisiologia , Simportadores/fisiologia , Transporte Biológico , Homeostase , Humanos , Intestinos/fisiopatologia
17.
Cell Death Dis ; 7(11): e2486, 2016 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-27882937

RESUMO

Lidamycin (LDM) is a novel member of the enediyne antibiotics identified in China with potent antitumor activity. However, it remains unclear whether LDM has potential molecular targets that may affect its antitumor activity. Enhancer of zeste homolog 2 (EZH2) functions as a histone lysine methyltransferase and mediates trimethylation on histone 3 lysine 27 (H3K27me3). High EZH2 level is found to be positively correlated with the aggressiveness, metastasis and poor prognosis of cancer. Here, we aim to study the role of EZH2 in LDM-induced senescence, as well as in the cytotoxicity of LDM in human colon cancer cells. LDM is found to be relatively more potent in inhibiting the colon cancer cells harboring high EZH2 level and induces irreversible cellular senescence at IC50 dose range, as evidenced by senescence-associated ß-galactosidase staining, cell cycle arrest and molecular changes of senescence regulators including p21 in HCT116 and SW620 cells. More importantly, LDM is found to markedly inhibit EZH2 expression at both protein and mRNA levels upon the induction of p21 and cellular senescence. LDM also selectively inhibits EZH2 expression as compared with other histone lysine methyltransferases. Knockdown of p21 with siRNAs abolishes LDM-induced senescence, whereas EZH2 knockdown markedly increases p21 expression and causes senescent phenotype. Enrichment of both EZH2 and H3K27me3 levels in the p21 promoter region is reduced by LDM. Moreover, EZH2 overexpression reduces cellular senescence, p21 expression and DNA damage response upon LDM exposure. LDM also demonstrates potent antitumor efficacy in xenografted animal models. Collectively, our work provides first demonstration that EZH2 may mediate, at least partially, the senescence-inducing effects of LDM by regulating p21 expression and DNA damage effect. Thus, EZH2 may serve as a potential target and biomarker to indicate the clinical efficacy of the potent enediyne antitumor drug.


Assuntos
Aminoglicosídeos/farmacologia , Senescência Celular/efeitos dos fármacos , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Inibidor de Quinase Dependente de Ciclina p21/genética , Enedi-Inos/farmacologia , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Antineoplásicos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Dano ao DNA , Relação Dose-Resposta a Droga , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Células HCT116 , Células HT29 , Humanos , Concentração Inibidora 50 , Gradação de Tumores , Regiões Promotoras Genéticas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Yao Xue Xue Bao ; 51(1): 23-8, 2016 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-27405157

RESUMO

Autophagy is a classical regulatory mechanism of energy metabolism and self-update system in the maintenance of the intracellular homeostasis and cell development. Autophagy has been recently found to play a role in tumor development. Autophagy regulates tumor formation, proliferation, metastasis, and metabolism. At the same time, the anticancer drugs formed with autophagic mediators have been used in the treatment, which suggested that improving autophagy activity to inhibit tumor has become a new way for cancer treatment of cancer patients. This article gives an overview of the regulatory mechanism of autophagy, the relationship between autophagy and tumor, and tumor therapy by targeting autophagy.


Assuntos
Autofagia , Neoplasias/fisiopatologia , Antineoplásicos , Humanos
19.
Life Sci ; 151: 23-29, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-26944438

RESUMO

AIM: Sphingosine 1-phosphate (S1P) promotes cell growth, proliferation and survival. Sphingosine kinase 1 (SphK1), which converts sphingosine to S1P, is a key promoter in cancer. We previously found that the SphK1 inhibitor II (SKI II), suppresses the cell growth and induces apoptosis in human hepatoma HepG2 cells. However, the precise regulatory mechanism and signaling pathway on SKI II inhibiting tumor growth remains unknown. MAIN METHODS: The expressions of ß-catenin and related molecules of Wnt/ß-catenin signal were detected by western blot in HepG2 cells. And the mRNA expression of ß-catenin was detected by RT-PCR. The Wnt5A gene was silenced by siRNA. The colony formation was determined by staining with crystal violet. And the cell growth was examined by SRB assay and BrdU assay. KEY FINDINGS: We found that SKI II decreased the expression of ß-catenin and the downstream molecules of ß-catenin signal pathway and promotes the ß-catenin degradation. In addition, SKI II induced the expression of Wnt5A, and then triggered ß-catenin degradation. Furthermore, silencing Wnt5A decreased the anti-tumor effects of SKI II through recovering the expressions of ß-catenin and downstream molecules of ß-catenin signal pathway. SIGNIFICANCE: SKI II-induced downregulation of HepG2 cell proliferation was associated with Wnt signaling pathway through Wnt5A-mediated ß-catenin degradation. Our study revealed that a novel signal pathway was involved in SKI II-inhibited cell proliferation in human hepatoma cells.


Assuntos
Proliferação de Células/efeitos dos fármacos , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Proteína Wnt-5a/antagonistas & inibidores , beta Catenina/antagonistas & inibidores , Animais , Carcinoma Hepatocelular/patologia , Sobrevivência Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas Experimentais/patologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Interferente Pequeno/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Proteína Wnt-5a/metabolismo , beta Catenina/metabolismo
20.
Food Chem Toxicol ; 86: 202-7, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26498411

RESUMO

Gastrodin has been showed to possess many beneficial physiological functions, including protection against inflammation and oxidation and apoptosis. Studies showed inflammation and oxidation play important roles in producing liver damage and initiating hepatic fibrogenesis. However, it has not been reported whether gastrodin has a protective effect against hepatic fibrosis or not. This is first ever made attempts to test gastrodin against liver fibrosis in bile duct ligation (BDL) rats. The aim of the present study is to evaluate the effect of gastrodin on BDL-induced hepatic fibrosis in rats. BDL rats were divided into two groups, BDL alone group, and BDL-gastrodin group treated with gastrodin (5 mg/ml in drinking water). The effects of gastrodin on BDL-induced hepatic injury and fibrosis in rats were estimated by assessing serum, urine, bile and liver tissue biochemistry followed by liver histopathology (using hematoxylin & eosin and sirius red stain) and hydroxyproline content measurement. The results showed that gastrodin treatment significantly reduced collagen content, bile duct proliferation and parenchymal necrosis after BDL. The serum alanine aminotransferase (ALT) and serum aspartate aminotransferase (AST) decreased with gastrodin treatment by 15.1 and 23.6 percent respectively in comparison to BDL group did not receive gastrodin. Gastrodin also significantly increased the level of serum high density lipoprotein (HDL) by 62.5 percent and down-regulated the elevated urine total bilirubin (TBIL) by 56.5 percent, but had no effect on total bile acid (TBA) in serum, bile and liver tissues. The immunohistochemical assay showed gastrodin remarkably reduced the expressions of CD68 and NF-κB in BDL rats. Hepatic SOD levels, depressed by BDL, were also increased by gastrodin by 8.4 percent. In addition, the increases of hepatic MDA and NO levels in BDL rats were attenuated by gastrodin by 31.3 and 38.7 percent separately. Our results indicate that gastrodin significantly attenuated the severity of BDL-induced hepatic injury and fibrosis by attenuating oxidative stress and inflammation. Taken together, these findings suggest that gastrodin might be an effective antifibrotic drug in cholestatic liver disease.


Assuntos
Álcoois Benzílicos/farmacologia , Colestase/complicações , Glucosídeos/farmacologia , Cirrose Hepática/prevenção & controle , Animais , Bile/química , Análise Química do Sangue , Colestase/sangue , Ligadura , Fígado/química , Fígado/metabolismo , Cirrose Hepática/etiologia , Ratos , Urinálise
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA