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1.
Front Immunol ; 14: 1223650, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37575248

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant and lethal human cancers in the world due to its high metastatic potential, and patients with PDAC have a poor prognosis, yet quite little is understood regarding the underlying biological mechanisms of its high metastatic capacity. Baicalein has a dramatic anti-tumor function in the treatment of different types of cancer. However, the therapeutic effects of baicalein on human PDAC and its mechanisms of action have not been extensively understood. In order to explore the biological characteristic, molecular mechanisms, and potential clinical value of baicalein in inhibiting the metastatic capacity of PDAC. We performed several in vitro, in vivo, and in silico studies. We first examined the potential regulation of baicalein in the metastatic capacity of PDAC cells. We showed that baicalein could dramatically suppress liver metastasis of PDAC cells with highly metastatic potential in mice model. The high-throughput sequencing analysis was employed to explore the biological roles of baicalein in PDAC cells. We found that baicalein might be involved in the infiltration of Cancer-Associated Fibroblasts (CAF) in PDAC. Moreover, a baicalein-related risk model and a lncRNA-related model were built by Cox analysis according to the data set of PDAC from TCGA database which suggested a clinical value of baicalein. Finally, we revealed a potential downstream target of baicalein in PDAC, we proposed that baicalein might contribute to the infiltration of CAF via FGFBP1. Thus, we uncovered a novel role for baicalein in regulation of PDAC liver metastasis that may contribute to its anti-cancer effect. We proposed that baicalein might suppress PDAC liver metastasis via regulation of FGFBP1-mediated CAF infiltration. Our results provide a new perspective on clinical utility of baicalein and open new avenues for the inhibition of liver-metastasis of PDAC.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Hepáticas , Neoplasias Pancreáticas , Camundongos , Animais , Humanos , Prognóstico , Microambiente Tumoral , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Pancreáticas
2.
J Clin Pharmacol ; 63(4): 455-465, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36433675

RESUMO

This systematic review and meta-analysis aimed to reveal the efficacy and safety of zoledronic acid compared with alendronate in patients with primary osteoporosis. The PubMed, Embase, and the Cochrane Library databases were searched from the establishment of each database to April 2022 for comparative studies on the topic, including randomized controlled trials (RCTs) and cohort studies, and 2 authors individually extracted information and data concerning study design, baseline characteristics, bone mineral density (BMD), bone turnover markers, and adverse events (AEs). We identified 8 eligible trials, including 1863 participants. Pooled estimates demonstrated that, compared with alendronate, zoledronic acid showed no significant difference in increasing the BMD of the lumbar spine after 1 year (SMD = -0.03, 95%CI -0.15 to 0.09, I2  = 0.41%) or after 2 years (SMD = 0.16, 95%CI -0.12 to 0.43, I2  = 63%), and the BMD of the total hip after 1 year (SMD = -0.08, 95%CI -0.31 to 0.14, I2  = 64%) or after 2 years (SMD = 0.05, 95%CI -0.21 to 0.32, I2  = 61%). No significant difference in improving bone turnover markers, including serum C-terminal cross-linking telopeptide of type-1 collagen, urine N-terminal cross-linking telopeptide of type-1 collagen, and serum procollagen type-1 N-terminal propeptide, were found, whereas significantly higher total AE rates (RR = 2.27, 95%CI 1.60 to 3.21, I2  = 75%) were recorded within 3 days of infusion, but some lower AE rates, particularly of gastrointestinal AEs (RR = 0.6, 95%CI 0.44 to 0.83, I2  = 37%), were noted after 3 days of infusion. Compared with alendronate, zoledronic acid has achieved comparable therapeutic results in the treatment of primary osteoporosis in increasing BMD and reducing bone turnover marker levels. Zoledronic acid showed a better safety profile than alendronate with long-term use, especially with regards to gastrointestinal-related AEs.


Assuntos
Conservadores da Densidade Óssea , Osteoporose Pós-Menopausa , Osteoporose , Humanos , Feminino , Alendronato/efeitos adversos , Ácido Zoledrônico/uso terapêutico , Difosfonatos/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Densidade Óssea , Osteoporose/tratamento farmacológico , Osteoporose Pós-Menopausa/tratamento farmacológico
3.
Front Cell Infect Microbiol ; 12: 935205, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35846746

RESUMO

Viral oncogenes may drive cellular metabolic reprogramming to modulate the normal epithelia cell malignant transformation. Understanding the viral oncogene-mediated signaling transduction dysregulation that involves in metabolic reprogramming may provide new therapeutic targets for virus-associated cancer treatment. Latent EBV infection and expression of viral oncogenes, including latent membrane proteins 1 and 2 (LMP1/2), and EBV-encoded BamH I-A rightward transcripts (BART) microRNAs (miR-BARTs), have been demonstrated to play fundamental roles in altering host cell metabolism to support nasopharyngeal carcinoma (NPC) pathogenesis. Yet, how do EBV infection and its encoded oncogenes facilitated the metabolic shifting and their roles in NPC carcinogenesis remains unclear. In this review, we will focus on delineating how EBV infection and its encoded oncoproteins altered the metabolic reprograming of infected cells to support their malignances. Furthermore, based on the understanding of the host's metabolic signaling alterations induced by EBV, we will provide a new perspective on the interplay between EBV infection and these metabolic pathways and offering a potential therapeutic intervention strategy in the treatment of EBV-associated malignant diseases.


Assuntos
Infecções por Vírus Epstein-Barr , Neoplasias Nasofaríngeas , Carcinogênese , Transformação Celular Neoplásica/genética , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/metabolismo , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/metabolismo , Humanos , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia
4.
Int Immunopharmacol ; 98: 107897, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34182243

RESUMO

Alcoholism represents a predisposing factor for liver-related morbidity and mortality worldwide. Pogostemon cablin has been widely used in China for the treatment of digestive system diseases. Patchouli oil, the major active fraction of Pogostemon cablin, can ameliorate alcohol-induced acute liver injury (ALI). However, patchouli alcohol (PA),a principal bioactive ingredient of PO, exerts a protection against ALI remains elusive. Thepresentwork focused on the hepatoprotection of PA against acute ethanol-induced hepatotoxicity in rats. In this study, male Wistar rats orally received PA (10, 20, or 40 mg/kg), PO (400 mg/kg) and silymarin (200 mg/kg) for ten days. On the 8th day, the rats orally received 65% ethanol (10 mL/kg, 6.5 g/kg) every 12 h for 3 days. Results showed that PA wasfound to reduce alcohol-induced ALI, as evidenced bysignificantly alleviated histopathologicalalterations, decreased the elevation ofALT and AST levels, and enhancedthe alcoholdehydrogenase(ADH) andaldehyde dehydrogenase (ALDH) activities. Additionally, PA markedly suppressed ROS levels and increased antioxidant enzyme activities via the CYP2E1/ROS/Nrf2/HO-1 pathway. PA regulated lipid accumulation by markedly inhibiting the expression of lipogenesis-related genes and stimulating that of lipolysis-relatedgenes, which were associated with the activation of theAMPKpathway. What's more, PA pretreatment also restored acute alcohol-inducedalterationsin gut barrier function, colonic histopathology, and gut microbiota richness and evenness. PA pretreatment alleviated gut-origin LPS-inducedinflammation by inhibiting the MyD88/TLR4/NF-κB signal pathway. In general, PA ameliorates ethanol-induced ALI via restoration of CYP2E1/ROS/Nrf2/HO-1-mediatedoxidativestressand AMPK-mediated fat accumulation, as well as alleviation of gut-LPS-leakage-induced inflammation regulated by the MyD88/TLR4/NF-κB signaling pathway.


Assuntos
Microbioma Gastrointestinal/imunologia , Mucosa Intestinal/efeitos dos fármacos , Falência Hepática Aguda/tratamento farmacológico , Fígado/efeitos dos fármacos , Sesquiterpenos/farmacologia , Animais , Modelos Animais de Doenças , Humanos , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Lipogênese/efeitos dos fármacos , Lipogênese/imunologia , Lipólise/efeitos dos fármacos , Lipólise/imunologia , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/metabolismo , Fígado/imunologia , Fígado/patologia , Falência Hepática Aguda/imunologia , Falência Hepática Aguda/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/imunologia , Ratos , Espécies Reativas de Oxigênio/metabolismo , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
5.
Planta Med ; 86(4): 255-266, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31975362

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. Nevertheless, no first-line therapy exists. Hepatic steatosis is the earliest stage of NAFLD, which is characterized by an accumulation of hepatic lipids. Patchouli oil (PO), which is isolated from the well-known Chinese herb named Pogostemon cablin (Blanco) Benth. (Lamiaceae), inhibits hepatic lipid accumulation effectively. However, its potential ability for the treatment of NAFLD had not been reported before. Thus, the objective of this study was to investigate the effectiveness of PO against hepatic steatosis and its underlying mechanisms. We used a high fat diet (HFD)-induced hepatic steatosis model of rats to estimate the effect of PO against NAFLD. Hematoxylin-eosin and oil red O staining were used to analyze the hepatic histopathological changes. ELISA, RT-qPCR, and Western blotting analysis were applied to evaluate the parameters for hepatic steatosis. Our results showed that PO significantly attenuated the lipid profiles and the serum enzymes, evidenced by quantitative and histopathological analyses. It also markedly down-regulated the expression of sterol regulatory element-binding protein 1 (SREPB-1c) with its downstream factors in de novo lipogenesis. And, likewise, in lipid export by very low-density lipoproteins (VLDL), related molecules were dramatically improved. Furthermore, PO observably normalized the aberrant peroxisome proliferator-activated receptor α (PPAR-α) signal in fatty acids oxidation. In conclusion, PO exerted a preventing effect against HFD-induced steatosis and might be due to decrease de novo lipogenesis, promote export of lipids, as well as owing to improve fatty acids oxidation.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Animais , Dieta Hiperlipídica , Lipogênese , Fígado , Pogostemon , Ratos
6.
Neurochem Res ; 43(8): 1519-1528, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29855846

RESUMO

Honokiol (HNK), the main active component of Magnolia officinalis, has shown a variety of pharmacological activities. In the present study, we measured the antidepressant-like effects of HNK in a rat model of chronic unpredictable mild stress (CUMS) and explored its possible mechanisms. The antidepressant-like effects of HNK were assessed in rats by an open field test (OFT), sucrose preference test (SPT) and forced swimming test (FST). Then, serum levels of corticotrophin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and corticosterone (CORT) and hippocampal brain-derived neurotrophic factor (BDNF) and glucocorticoid receptor α (GRα) levels were assessed to explore the possible mechanisms. We identified that HNK treatment (2, 4, and 8 mg/kg) alleviated the CUMS-induced behavioural deficits. Treatment with HNK also normalized the CUMS-induced hyperactivity of the limbic hypothalamic-pituitary-adrenal (HPA) axis, as indicated by reduced CRH, ACTH and CORT serum levels. In addition, HNK increased the expression of GRα (mRNA and protein) and BDNF (mRNA and protein) in the hippocampus. These data confirmed the antidepressant-like effects of HNK, which may be related to its normalizing the function of the HPA axis and increasing the BDNF level in the hippocampus.


Assuntos
Antidepressivos/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Lignanas/uso terapêutico , Sistema Hipófise-Suprarrenal/metabolismo , Estresse Psicológico/metabolismo , Animais , Compostos de Bifenilo/farmacologia , Doença Crônica , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Lignanas/farmacologia , Masculino , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Ratos , Ratos Wistar , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/psicologia , Resultado do Tratamento
7.
Biomed Chromatogr ; 32(6): e4192, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29349799

RESUMO

In this study, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to simultaneously determine the anticancer drugs etoposide and paclitaxel in mouse plasma and tissues including liver, kidney, lung, heart, spleen and brain. The analytes were extracted from the matrices of interest by liquid-liquid extraction using methyl tert-butyl ether-dichloromethane (1:1, v/v). Chromatographic separation was achieved on an Ultimate XB-C18 column (100 × 2.1 mm, 3 µm) at 40°C and the total run time was 4 min under a gradient elution. Ionization was conducted using electrospray ionization in the positive mode. Stable isotope etoposide-d3 and docetaxel were used as the internal standards. The lower limit of quantitation (LLOQ) of etoposide was 1 ng/g tissue for all tissues and 0.5 ng/mL for plasma. The LLOQ of paclitaxel was 0.4 ng/g tissue and 0.2 ng/mL for all tissues and plasma, respectively. The coefficients of correlation for all of the analytes in the tissues and plasma were >0.99. Both intra- and inter-day accuracy and precision were satisfactory. This method was successfully applied to measure plasma and tissue drug concentrations in mice treated with etoposide and paclitaxel-loaded self-microemulsifying drug-delivery systems.


Assuntos
Cromatografia Líquida/métodos , Sistemas de Liberação de Medicamentos/métodos , Etoposídeo/análise , Paclitaxel/análise , Espectrometria de Massas em Tandem/métodos , Administração Oral , Animais , Estabilidade de Medicamentos , Emulsões/administração & dosagem , Etoposídeo/química , Etoposídeo/farmacocinética , Modelos Lineares , Masculino , Camundongos , Paclitaxel/química , Paclitaxel/farmacocinética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Distribuição Tecidual
8.
Int J Mol Med ; 40(3): 661-672, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28677722

RESUMO

All-trans retinoic acid (atRA), which is mainly generated endogenously via two steps of oxidation from vitamin A (retinol), plays an indispensible role in the development of the kidney and many other organs. Enzymes that catalyze the oxidation of retinol to generate atRA, including aldehyde dehydrogenase 1 family (ALDH1)A1, ALDH1A2 and ALDH1A3, exhibit complex expression patterns at different stages of renal development. However, molecular triggers that control these differential expression levels are poorly understood. In this study, we provide in vitro evidence to demonstrate that Wilms' tumor 1 (WT1) negatively regulates the expression of the atRA synthetic enzymes, ALDH1A1, ALDH1A2 and ALDH1A3, in the 293 cell line, leading to significant blockage of atRA production. Furthermore, we demonstrate that the suppression of ALDH1A1 by WT1 can be markedly attenuated by histone deacetylase inhibitors (HDACis). Taken together, we provide evidence to indicate that WT1 and HDACs are strong regulators of endogenous retinoic acid synthetic enzymes in 293 cells, indicating that they may be involved in the regulation of atRA synthesis.


Assuntos
Aldeído Desidrogenase/biossíntese , Aldeído Oxirredutases/biossíntese , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Retinal Desidrogenase/biossíntese , Tretinoína/metabolismo , Proteínas WT1/metabolismo , Família Aldeído Desidrogenase 1 , Linhagem Celular Transformada , Humanos
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