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1.
Zhongguo Zhong Yao Za Zhi ; 46(16): 4061-4068, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34467715

RESUMO

Reverse prediction and molecular docking techniques were employed to evaluate the feasibility of reniformin A(RA) as an anti-tumor leading compound. Based on the reverse prediction, network pharmacology was used to construct a "disease-compound-target-pathway" network. Thirty-nine tumor-related targets of RA were predicted, which participated in the regulation of multiple cellular activities such as apoptosis, cell cycle, and tumor metastasis, and regulated estrogen signal transduction and inflammatory response. Discovery Studio 2020 was adopted for molecular docking and toxicity prediction(TOPKAT). As revealed by the results, the binding affinity of RA with the tumor-related targets ABL1, ESR1, SRC and BCL-XL was stronger than that of oridonin(OD), while its mutagenicity, rodent carcinogenesis, and oral LD_(50) in rats were all inferior to that of OD. Furthermore, in vitro experiments were performed to confirm the anti-tumor activity of RA, and the mechanism was preliminarily discussed. The results demonstrated that RA was superior to OD in cytotoxicity, inhibition of cell colony formation, and induction of apoptosis. RA, possessing potent anti-tumor activity, is expected to be a new anti-tumor leading compound.


Assuntos
Medicamentos de Ervas Chinesas , Neoplasias , Animais , Medicamentos de Ervas Chinesas/farmacologia , Chumbo , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/genética , Ratos , Transdução de Sinais
2.
Acta Pharmacol Sin ; 2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34349236

RESUMO

An epidemic of pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spreading worldwide. SARS-CoV-2 relies on its spike protein to invade host cells by interacting with the human receptor protein Angiotensin-Converting Enzymes 2 (ACE2). Therefore, designing an antibody or small-molecular entry blockers is of great significance for virus prevention and treatment. This study identified five potential small molecular anti-virus blockers via targeting SARS-CoV-2 spike protein by combining in silico technologies with in vitro experimental methods. The five molecules were natural products that binding to the RBD domain of SARS-CoV-2 was qualitatively and quantitively validated by both native Mass Spectrometry (MS) and Surface Plasmon Resonance (SPR). Anti-viral activity assays showed that the optimal molecule, H69C2, had a strong binding affinity (dissociation constant KD) of 0.0947 µM and anti-virus IC50 of 85.75 µM.

3.
Acta Pharmacol Sin ; 2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33907306

RESUMO

The COVID-19, caused by SARS-CoV-2, is threatening public health, and there is no effective treatment. In this study, we have implemented a multi-targeted anti-viral drug design strategy to discover highly potent SARS-CoV-2 inhibitors, which simultaneously act on the host ribosome, viral RNA as well as RNA-dependent RNA polymerases, and nucleocapsid protein of the virus, to impair viral translation, frameshifting, replication, and assembly. Driven by this strategy, three alkaloids, including lycorine, emetine, and cephaeline, were discovered to inhibit SARS-CoV-2 with EC50 values of low nanomolar levels potently. The findings in this work demonstrate the feasibility of this multi-targeting drug design strategy and provide a rationale for designing more potent anti-virus drugs.

4.
Abdom Radiol (NY) ; 46(7): 3456-3463, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33630127

RESUMO

OBJECTIVE: To evaluate the clinical efficacy and long-term outcomes associated with the treatment of hepatic vein (HV)-type Budd-Chiari syndrome (BCS) via accessory HV (AHV) recanalization. METHODS: In total, 26 HV-type BCS patients underwent AHV recanalization between July 2014 and December 2019 at our hospital, while 73 HV-type BCS patients without compensatory AHV underwent main HV (MHV) recanalization and served as controls in the present study. Short- and long-term clinical outcomes were compared. RESULTS: AHV and MHV recanalization approaches were both associated with 100% technical success rates, with one recanalization procedure being performed per patient. Respective clinical success rates for the AHV and MHV recanalization approaches were 96.2% and 94.5% (P = 0.744). Re-obstruction rates were comparable between these two approaches at 20% and 34.8%, respectively (P = 0.17). Primary cumulative 1-, 2-, and 5-year patency rates in the AHV group were 96.0%, 91.6%, and 76.3%, respectively, whereas in the MHV group, these three respective rates were 87.0%, 78.6%, and 58.6% (P = 0.048). Secondary cumulative 1-, 2-, and 5-year patency rates in the AHV group were 96.0%, 96.0%, and 96.0%, respectively, whereas in the MHV group, they were 97.1%, 97.1%, and 81.8%, respectively (P = 0.289). Cumulative 1-, 2-, and 5-year survival rates for AHV group patients were 96.0%, 96.0%, and 96.0%, respectively, while for the MHV group, these respective rates were 98.6%, 95.2%, and 89.7% (P = 0.462). CONCLUSION: HV-type BCS can be safely and effectively treated via AHV recanalization, which may achieve longer patency relative to MHV recanalization.


Assuntos
Síndrome de Budd-Chiari , Síndrome de Budd-Chiari/diagnóstico por imagem , Síndrome de Budd-Chiari/terapia , Veias Hepáticas/diagnóstico por imagem , Humanos , Estudos Retrospectivos , Resultado do Tratamento
5.
Toxicol Appl Pharmacol ; 412: 115389, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33385404

RESUMO

Cytochrome P450 (CYP) gene expression exhibits large interindividual variation attributable to diverse regulatory factors including microRNAs (miRNAs) and hepatic transcription factors (TFs). We used real-time qPCR with 106 human liver samples to measure the expression and interindividual variation of seven miRNAs and four TFs that have been reported to regulate the expression of CYPs; we also identified factors that influence their expression. The results show that expression of the seven miRNAs and the four TFs exhibits a non-normal distribution and the expression variability is high (89- to 618-fold for miRNA and 12- to 85-fold for TFs). Age contributed to the interindividual variation for miR-148a, miR-27b and miR-34a, whereas cigarette smoking and alcohol consumption significantly reduced HNF4α mRNA levels. Association analysis showed significant correlations among the seven miRNAs as well as the four TFs. Furthermore, we systematically evaluated the impact of the seven miRNAs and four TFs on protein content, mRNA levels, translation efficiency and activity of 10 CYPs. The results show that numerous associations (positive and negative) are present between the seven miRNAs or the four TFs and the 10 CYP phenotypes (as indicated by mRNA, protein and activity); specifically, miR-27b, miR-34a and all four TFs played key roles in the interindividual variation of CYPs. Our results extend previous findings and suggest that miR-27b and miR-34a may be potential direct or indirect master regulators of CYP expression and thereby contribute to the interindividual variations in CYP-mediated drug metabolism.


Assuntos
Variação Biológica da População , Sistema Enzimático do Citocromo P-450/genética , Fígado/enzimologia , MicroRNAs/genética , Fatores de Transcrição/genética , Fatores Etários , Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Feminino , Regulação Enzimológica da Expressão Gênica , Heterogeneidade Genética , Fator 4 Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/metabolismo , Humanos , Isoenzimas , Masculino , MicroRNAs/metabolismo , Fenótipo , Fumar/genética , Fumar/metabolismo , Fatores de Transcrição/metabolismo
6.
Int J Biol Sci ; 17(1): 107-118, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33390837

RESUMO

Aerobic glycolysis, also known as the Warburg effect, is emerged as a hallmark of most cancer cells. Increased aerobic glycolysis is closely associated with tumor aggressiveness and predicts a poor prognosis. Pancreatic ductal adenocarcinoma (PDAC) is characterized by prominent genomic aberrations and increased glycolytic phenotype. However, the detailed molecular events implicated in aerobic glycolysis of PDAC are not well understood. In this study, we performed a comprehensive molecular characterization using multidimensional ''omic'' data from The Cancer Genome Atlas (TCGA). Detailed analysis of 89 informative PDAC tumors identified substantial copy number variations (MYC, GATA6, FGFR1, IDO1, and SMAD4) and mutations (KRAS, SMAD4, and RNF43) related to aerobic glycolysis. Moreover, integrated analysis of transcriptional profiles revealed many differentially expressed long non-coding RNAs involved in PDAC aerobic glycolysis. Loss-of-function studies showed that LINC01559 and UNC5B-AS1 knockdown significantly inhibited the glycolytic capacity of PDAC cells as revealed by reduced glucose uptake, lactate production, and extracellular acidification rate. Moreover, genetic silencing of LINC01559 and UNC5B-AS1 suppressed tumor growth and resulted in alterations in several signaling pathways, such as TNF signaling pathway, IL-17 signaling pathway, and transcriptional misregulation in cancer. Notably, high expression of LINC01559 and UNC5B-AS1 predicted poor patient prognosis and correlated with the maximum standard uptakevalue (SUVmax) in PDAC patients who received preoperative 18F-FDG PET/CT. Taken together, our results decipher the glycolysis-associated copy number variations, mutations, and lncRNA landscapes in PDAC. These findings improve our knowledge of the molecular mechanism of PDAC aerobic glycolysis and may have practical implications for precision cancer therapy.

7.
Medicine (Baltimore) ; 99(30): e21082, 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32791681

RESUMO

INTRODUCTION: Cerebral palsy is the most common motor disability of childhood. Spastic cerebral palsy accounts for 60% to 70% of cases. Research has shown that acupuncture can improve the quality of life of children with cerebral palsy, but the mechanism of action remains unclear. This study aims to determine the effectiveness of acupuncture for treatment of children with spastic cerebral palsy and to assess the value of multimodal magnetic resonance imaging (MRI) and ambulatory electroencephalogram (EEG) for evaluation of treatment effect. METHODS AND ANALYSIS: This randomized controlled trial will enroll a total of 72 children with CP from 2 hospitals-Jiangsu Province Hospital of Chinese Medicine and Nanjing State Hospital of Pediatric-with 36 participants from each hospital. Patients will be randomly assigned (1:1 ratio) to receive "Tonifying Kidney and Invigorating Brain" acupuncture treatment plus standardized physical rehabilitation treatment (treatment group) or only standardized physical rehabilitation (control group). All participants will receive 3 treatment sessions per week for 3 consecutive months; they will then be followed up for another 3 months. The primary outcome measures will include multimodal magnetic resonance imaging (MRI), ambulatory electroencephalogram (EEG), and Gesell Developmental Diagnostic Schedules. The secondary outcome measures will include Gross Motor Function Classification System (GMFCS), Gross Motor Function Measure (GMFM), Functional Independence Measure (WeeFIM), and Modified Ashworth Scale score. Outcome measures (including primary and secondary outcome measures) were collected at the baseline, 3 months and 6 months prior to the intervention.Ethics and dissemination PATIENTS CONSENT:: Obtained. ETHICS APPROVAL: The central independent ethics committee of Jiangsu Province Hospital of Traditional Chinese Medicine approved the protocol (2017NL-115-02). SAFETY CONSIDERATIONS: Routine blood tests and liver and kidney function tests will be conducted to exclude patients with severe heart, liver, or kidney diseases. The same examinations will be performed again at the end of the study to detect any possible side effects. Possible acupuncture-related adverse events (e.g., fainting, needle stick injury, local infection, subcutaneous hematoma, and low-grade fever) will be documented. Serious adverse events will be reported to the principal investigator immediately. All unexpected and unintended responses, even those not necessarily related to the acupuncture intervention, will be documented as adverse events. CASE DROPOUT MANAGEMENT: Participants have a right to withdraw from the study at any time if they feel uncomfortable upon receiving the treatments or being diagnosed with serious complications or diseases. They will then be referred to the preferred department for further treatment and management. If cases of dropout, the researcher need to contact the participant to reason the problem out, collect and record all the necessary assessments on the last visit as well as the date of last visit. All data available until the date of withdrawal will be stored for further statistical analysis. DISCUSSION: This research is being conducted to assess the value of acupuncture as an intervention for rehabilitation of children with spastic cerebral palsy and also to evaluate the usefulness of multimodal MRI and ambulatory EEG for identifying changes in brain function. TRIAL REGISTRATION: This trial is registered with Chinese Clinical Trials Register, ChiCTR 1900024546 (registered 15 July 2019; retrospective registration, http://www.chictr.org.cn/showproj.aspx?proj=35763).


Assuntos
Acupuntura , Paralisia Cerebral/fisiopatologia , Paralisia Cerebral/terapia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Paralisia Cerebral/diagnóstico por imagem , Paralisia Cerebral/reabilitação , Criança , Desenvolvimento Infantil , Eletroencefalografia , Humanos , Rim , Imageamento por Ressonância Magnética , Destreza Motora , Ensaios Clínicos Controlados Aleatórios como Assunto
8.
Zhen Ci Yan Jiu ; 45(6): 504-7, 2020 Jun 25.
Artigo em Chinês | MEDLINE | ID: mdl-32643889

RESUMO

A literature review was performed to investigate the possible mechanism of scalp acupuncture in stimulating the skin, fascia, muscle, and periosteum and thus affecting cerebral cortex function. The results of literature research show that the effect of scalp acupuncture on cerebral cortex function may be achieved by the stimulation of specific anatomical structures. Stimulation of the skin, fascia, muscle and periosteum can activate the functional areas of the cerebral cortex through the midbrain, thalamus, and brainstem. In addition, different depths of stimulation may affect the deep and shallow sensation of the brain, self-monitoring of the fascia, subcortical central compensation, and cortical discharge. Therefore, exploration of the specific rules and differences in the effect of stimulating different anatomical structures on brain function is the future focus of the clinical and basic research on scalp acupuncture.


Assuntos
Terapia por Acupuntura , Córtex Cerebral , Couro Cabeludo
10.
Chem Commun (Camb) ; 56(20): 2979-2982, 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32077882

RESUMO

A N2-selective ß-selenoalkylation of 1,2,3-triazoles with alkenes mediated by diamines has been developed. The reaction proceeds presumably via the interaction of diamines with both the triazole moiety and selenium/alkene complex to construct a U-shaped reaction intermediate. This activation mode will block the N1 position on triazoles and thus favor the N2-selective selenoamination. This stereospecific anti-addition method enables an efficient N2-selective ß-selenoalkylation of 1,2,3-triazoles under mild and open-air conditions and might find applications in the synthesis of biologically active molecules.

11.
Eur J Pharmacol ; 876: 172946, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31996320

RESUMO

Liver fibrosis is involved in the progression of most chronic liver diseases. Even though we have made a huge progress in order to understand the pathogenesis of liver fibrosis, however, there is still a lack of productive treatments. Being a traditional Chinese medicine, Platycodin D (PD), an oleanane kind of triterpenoid saponin has been put to extensive use for treating different kinds of illnesses that include not just anti-nociceptive, but also antiviral, anti-inflammatory, and anti-cancer for thousands of years. Nonetheless, there has been no clarification made for its effects on the progression of liver fibrosis. In this manner, we carried out in vitro studies for the purpose of investigating the anti-fibrosis impact of PD. Activation of hepatic stellate cells was evaluated by means of the detection of the proliferation of HSCs and the expression of specific proteins. We discovered the fact that PD had the potential of activating HSCs. Thereafter, we detected the apoptosis and autophagy of the HSCs; as the results suggested, PD induced apoptosis and autophagy of the HSCs. It augmented the expression level of apoptotic proteins that included Bax, Cytochrome C (cyto-c), cleaved caspase3 and cleaved caspase9, in addition to the autophagy relevant proteins, for instance, LC3II, beclin1, Atg5 and Atg9. Further research was carried out for the investigation of the underlying molecular mechanism, and discovered that PD promoted the phosphorylation of JNK and c-Jun. Treating the JNK inhibitor P600125 inhibited the effect of PD, confirming the impact of PD on the regulation of JNK/c-Jun pathway. Thus, we speculated that PD alleviates liver fibrosis and activation of hepatic stellate via promoting phosphorylation of JNK and c-Jun and further altering the autophagy along with apoptosis of HSCs.


Assuntos
Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática/prevenção & controle , Fígado/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Saponinas/farmacologia , Triterpenos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Autofagia/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Humanos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Saponinas/administração & dosagem , Saponinas/uso terapêutico , Triterpenos/administração & dosagem , Triterpenos/uso terapêutico
12.
FASEB J ; 34(3): 3943-3955, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31944405

RESUMO

Mangrove-derived actinobacteria strains are well-known for producing novel secondary metabolites. The polycyclic tetramate macrolactam (PTM), ikarugamycin (IKA) isolated from Streptomyces xiamenensis 318, exhibits antiproliferative activities against pancreatic ductal adenocarcinoma (PDAC) in vitro. However, the protein target for bioactive IKA is unclear. In this study, whole transcriptome-based profiling revealed that the glycolysis pathway is significantly affected by IKA. Metabolomic studies demonstrated that IKA treatment induces a significant drop in glucose-6-phosphate and a slight increase in intracellular glucose level. Analysis of glucose consumption, lactate production, and the extracellular acidification rate confirmed the inhibitory role of IKA on the glycolytic flux in PDAC cells. Surface plasmon resonance (SPR) experiments and docking studies identified the key enzyme of glycolysis, hexokinase 2 (HK2), as a molecular target of IKA. Moreover, IKA reduced tumor size without overt cytotoxicity in mice with PDAC xenografts and increased chemotherapy response to gemcitabine in PDAC cells in vitro. Taken together, IKA can block glycolysis in pancreatic cancer by targeting HK2, which may be a potential drug candidate for PDAC treatment.


Assuntos
Hexoquinase/metabolismo , Lactamas/farmacologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Glucose/metabolismo , Glicólise/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Ácido Láctico/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Reação em Cadeia da Polimerase em Tempo Real , Ressonância de Plasmônio de Superfície
13.
Huan Jing Ke Xue ; 40(12): 5191-5201, 2019 Dec 08.
Artigo em Chinês | MEDLINE | ID: mdl-31854589

RESUMO

This paper discusses the concentration characteristics of PM2.5, as well as its relationship with meteorological factors in autumn and winter (from September to the following February), from 2013 to 2018 in the Beijing-Tianjin-Hebei (BTH) region. The accuracy and uncertainty of the air quality forecast models NAQPMS(nested air quality prediction modeling system), CMAQ(community multiscale air quality modeling system), and CAMx (comprehensive air quality model with extensions) were analyzed based on the model-predicted and measured PM2.5 concentration in autumn and winter from 2015 to 2018. The accuracy of NAQPMS, CMAQ, and CAMx during typical heavy air pollution was also tested. Moreover, methods to improve the accuracy of the model forecast were discussed. The results showed that the mean concentrations of PM2.5 in the BTH region were 122, 98, 82, 99, and 65 µg·m-3 in the five autumn and winter periods, respectively. When the air quality index (AQI) exceeded 150 during each autumn and winter, it reached 229, 198, 210, 204, and 180 µg·m-3, respectively. There were 64 occurrences of heavy regional PM2.5 air pollution in autumn and winter from 2013 to 2018. The average duration was longest in the 2013 to 2014 period, and shortest in the 2017 to 2018 period. The peak concentration and average concentration of PM2.5 decreased year on year, except for the period from 2016 to 2017. In autumn and winter, PM2.5 concentration had a relatively close relationship with relative humidity, wind and sunshine duration, compared with a weak relationship with temperature and air pressure. Regional heavy air pollution always happened under the condition of low wind speed(less than 2 m·s-1),higher relative humidity(greater than 65%),and southwest and northeast wind direction. In addition, the heavy air pollution of PM2.5 in BTH in autumn and winter can be effectively forecasted by NAQPMS, CMAQ, and CAMx. The predicted and measured PM2.5 concentration showed a close relationship. The models performed well in forecasting Zhangjiakou, Chengde, and Qinhuangdao, but by contrast overestimated in Tangshan, Shijiazhuang, Baoding, Beijing, and Tianjin. The uncertainty of emission sources, measured and predicted meteorological data, and the atmospheric chemical reaction mechanism may be the main reasons for the overestimate.

14.
Chin J Nat Med ; 17(7): 535-544, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31514985

RESUMO

The aim of this study is to investigate the protective effects of a small molecular fraction (SMF) of Polygoni multiflori Radix Praeparata (PMRP) in a cyclophosphamide (CTX) induced anemia mouse model. Small molecular fraction of PMRP was prepared and identified by high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (HPLC-Q-TOF-MS). In pharmacology, we examined the peripheral hemogram and thymus and spleen index. The content of granulocyte-macrophage colony-stimulating factor (GM-CSF) in serum was mensurated by enzyme-linked immunosorbent assay (ELISA); The level of superoxide dismutase (SOD), catalase (CAT), total antioxidant capacity (T-AOC), and malondialdehyde (MDA) in serum and spleen tissue homogenate were detected, and glutathione peroxidase (GSH-PX) was assayed in spleen. The results show that SMF can significantly accelerate the recovery of peripheral hemogram, increase the activity of antioxidant enzymes and GM-CSF in serum and spleen. SMF also increases the number of spleen cells, improves bone marrow pathology. In conclusion, the SMF of PMRP promoted the recovery of hematopoietic function in a CTX-induced anemia mouse, which can support SMF to be used as an adjunct to chemotherapy to counteract its side effects.


Assuntos
Anemia/tratamento farmacológico , Ciclofosfamida/toxicidade , Hematopoese/efeitos dos fármacos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Polygonum/química , Anemia/induzido quimicamente , Animais , Antioxidantes/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/sangue , Masculino , Camundongos Endogâmicos ICR , Estrutura Molecular , Fitoterapia , Extratos Vegetais/química , Raízes de Plantas/química , Baço/efeitos dos fármacos , Baço/metabolismo , Baço/patologia , Timo/efeitos dos fármacos , Timo/metabolismo
15.
J Exp Clin Cancer Res ; 38(1): 214, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31118109

RESUMO

BACKGROUND: Gastric cancer is one of the deadliest malignant tumours, with a high incidence in China, and is regulated by aberrantly overexpressed oncogenes. However, existing therapies are insufficient to meet patients' needs; thus, the identification of additional therapeutic targets and exploration of the underlying mechanism are urgently needed. GPAA1 is the subunit of the GPI transamidase that transfers the GPI anchor to proteins within the ER. The functional impacts of increased expression levels of GPAA1 in human cancers are not well understood. METHODS: Data mining was performed to determine the pattern of GPAA1 expression and the reason for its overexpression in tumour and adjacent normal tissues. In vitro and in vivo experiments evaluating proliferation and metastasis were performed using cells with stable deletion or overexpression of GPAA1. A tissue microarray established by the Ren Ji Hospital was utilized to analyse the expression profile of GPAA1 and its correlation with prognosis. Western blotting, an in situ proximity ligation assay, and co-immunoprecipitation (co-IP) were performed to reveal the mechanism of GPAA1 in gastric cancer. RESULTS: GPAA1 was a markedly upregulated oncogene in gastric cancer due to chromosomal amplification. GPAA1 overexpression was confirmed in specimens from the Ren Ji cohort and was associated with ERBB2 expression, predicting unsatisfactory patient outcomes. Aberrantly upregulated GPAA1 dramatically contributed to cancer growth and metastasis in in vitro and in vivo studies. Mechanistically, GPAA1 enhanced the levels of metastasis-associated GPI-anchored proteins to increase tumour metastasis and intensified lipid raft formation, which consequently promoted the interaction between EGFR and ERBB2 as well as downstream pro-proliferative signalling. CONCLUSIONS: GPAA1 facilitates the expression of cancer-related GPI-anchored proteins and supplies a more robust platform-the lipid raft-to promote EGFR-ERBB2 dimerization, which further contributes to tumour growth and metastasis and to cancer progression. GPAA1 could be a promising diagnostic biomarker and therapeutic target for gastric cancer.


Assuntos
Proteínas Ligadas por GPI/genética , Glicoproteínas de Membrana/genética , Receptor ErbB-2/genética , Neoplasias Gástricas/genética , Aciltransferases/genética , Idoso , Animais , Proliferação de Células/genética , Progressão da Doença , Intervalo Livre de Doença , Receptores ErbB/química , Receptores ErbB/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Xenoenxertos , Humanos , Masculino , Glicoproteínas de Membrana/química , Microdomínios da Membrana/genética , Camundongos , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Multimerização Proteica/genética , Receptor ErbB-2/química , Transdução de Sinais/genética , Neoplasias Gástricas/patologia , Análise Serial de Tecidos
16.
Gut ; 68(11): 1994-2006, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-30826748

RESUMO

BACKGROUND AND AIMS: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death worldwide. Neurotransmitter-initiated signalling pathway is profoundly implicated in tumour initiation and progression. Here, we investigated whether dysregulated neurotransmitter receptors play a role during pancreatic tumourigenesis. METHODS: The Cancer Genome Atlas and Gene Expression Omnibus datasets were used to identify differentially expressed neurotransmitter receptors. The expression pattern of gamma-aminobutyric acid type A receptor pi subunit (GABRP) in human and mouse PDAC tissues and cells was studied by immunohistochemistry and western blot analysis. The in vivo implications of GABRP in PDAC were tested by subcutaneous xenograft model and lung metastasis model. Bioinformatics analysis, transwell experiment and orthotopic xenograft model were used to identify the in vitro and in vivo effects of GABRP on macrophages in PDAC. ELISA, co-immunoprecipitation, proximity ligation assay, electrophysiology, promoter luciferase activity and quantitative real-time PCR analyses were used to identify molecular mechanism. RESULTS: GABRP expression was remarkably increased in PDAC tissues and associated with poor prognosis, contributed to tumour growth and metastasis. GABRP was correlated with macrophage infiltration in PDAC and pharmacological deletion of macrophages largely abrogated the oncogenic functions of GABRP in PDAC. Mechanistically, GABRP interacted with KCNN4 to induce Ca2+ entry, which leads to activation of nuclear factor κB signalling and ultimately facilitates macrophage infiltration by inducing CXCL5 and CCL20 expression. CONCLUSIONS: Overexpressed GABRP exhibits an immunomodulatory role in PDAC in a neurotransmitter-independent manner. Targeting GABRP or its interaction partner KCNN4 may be an effective therapeutic strategy for PDAC.


Assuntos
Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Receptores de GABA-A/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Quimiocinas/metabolismo , Modelos Animais de Doenças , Humanos , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/metabolismo , Macrófagos/fisiologia , Camundongos , Transdução de Sinais/fisiologia
17.
Exp Ther Med ; 17(4): 2603-2613, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30906452

RESUMO

Previous studies on the correlation between positive autologous serum skin test (ASST) responses and the clinical features of patients with chronic spontaneous urticaria (CSU) have provided conflicting results. To evaluate the significance of ASST responses in CSU, a variety of databases were searched from inception to March 2018 to identify relevant studies on CSU. Data were analyzed with use of the Cochrane Collaboration's Review Manager 5.2. Multiple relevant factors of CSU were evaluated by calculating the weighted mean difference, odds ratio and 95% confidence interval. The results indicated that CSU cases with positive ASST responses had higher urticaria activity scores and higher levels of total serum immunoglobulin E than CSU cases with negative responses in the ASST. In addition, a positive ASST response was more likely to be accompanied with the presence of thyroid autoantibodies and angioedema. An increased prevalence of CSU was identified in females, who were more likely to have a positive response in the ASST. It was also indicated that a greater incidence of positive ASST responses was present in CSU patients as compared with that in healthy controls. No statistically significant differences were obtained between positive and negative ASST responses with regard to age and duration of disease. Based on these results, it was concluded that the ASST provides an effective means of predicting urticaria activity and recurrence in CSU patients.

18.
J Nat Med ; 73(2): 388-396, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30617707

RESUMO

To investigate if andrographolide impairs cholestatic liver injury. All rats were randomly divided into six groups-(1) control (n = 6), (2) control + 200 mg/kg andrographolide (n = 6), (3) alpha-naphthylisothiocyanate (ANIT)-control (n = 6), (4) ANIT + 50 mg/kg andrographolide (n = 6), (5) ANIT + 100 mg/kg andrographolide (n = 6), and (6) ANIT + 200 mg/kg andrographolide (n = 6). We gavaged 50 mg/kg ANIT to mimic cholestatic liver injury in rats. Seven days after treatment, all the rats were killed. Serum biochemistry and hepatic histopathological assays were performed to evaluate liver injury. We observed that 200 mg/kg andrographolide significantly decreased the level of alanine transaminase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyltranspeptidase, total bilirubin, and total bile acid in the blood. It also markedly decreased hepatic interleukin-6 and tumor necrosis factor α. Furthermore, 200 mg/kg andrographolide significantly decreased malondialdehyde but increased superoxide dismutase, glutathione, and erythrocyte glutathione peroxidase. Moreover, 200 mg/kg andrographolide effectively increased the accumulation of sirtuin 1 and nuclear erythroid 2-related factor-2. It also attenuated the level of nuclear factor kappa-light-chain-enhancer of activated B and cyclooxygenase-2. These data suggest that andrographolide may impair cholestatic liver injury via anti-inflammatory and anti-oxidative stress.


Assuntos
Colestase/tratamento farmacológico , Diterpenos/uso terapêutico , Fígado/efeitos dos fármacos , 1-Naftilisotiocianato , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Bilirrubina/sangue , Colestase/sangue , Colestase/induzido quimicamente , Diterpenos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Medicamentos de Ervas Chinesas , Inflamação/prevenção & controle , Fígado/metabolismo , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Sirtuína 1/metabolismo
19.
Clin Cancer Res ; 25(4): 1318-1330, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30420446

RESUMO

PURPOSE: Extensive research has reported that the tumor microenvironment components play crucial roles in tumor progression. Thus, blocking the supports of tumor microenvironment is a promising approach to prevent cancer progression. We aimed to determine whether blocking extracellular ATP-P2RY2 axis could be a potential therapeutic approach for PDAC treatment. EXPERIMENTAL DESIGN: Expression of P2RY2 was determined in 264 human PDAC samples and correlated to patient survival. P2RY2 was inhibited in human PDAC cell lines by antagonist and shRNA, respectively, and cell viability, clonogenicity, and glycolysis were determined. RNA sequencing of PDAC cell line was applied to reveal underlying molecular mechanisms. Multiple PDAC mouse models were used to assess the effects of the P2RY2 inhibition on PDAC progression. RESULTS: P2RY2 was upregulated and associated with poor prognosis in PDAC. Activated P2RY2 by increased extracellular ATP in tumor microenvironment promoted PDAC growth and glycolysis. Further studies showed that the agonist-activated P2RY2 triggered PI3K/AKT-mTOR signaling by crosstalk with PDGFR mediated by Yes1, resulting in elevated expression of c-Myc and HIF1α, which subsequently enhanced cancer cell glycolysis. Genetic and pharmacologic inhibition of P2RY2 impaired tumor cell growth in subcutaneous and orthotopic xenograft model, as well as delayed tumor progression in inflammation-driven PDAC model. In addition, synergy was observed when AR-C118925XX, the selective antagonist of P2RY2 receptor, and gemcitabine were combined, resulting in prolonged survival of xenografted PDAC mice. CONCLUSIONS: These findings reveal the roles of the P2RY2 in PDAC metabolic reprogramming, suggesting that P2RY2 might be a potential metabolic therapeutic target for PDAC.


Assuntos
Adenocarcinoma/tratamento farmacológico , Carcinoma Ductal Pancreático/tratamento farmacológico , Glicólise/genética , Receptores Purinérgicos P2Y2/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Trifosfato de Adenosina/genética , Animais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Evolução Clonal/genética , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Elafina/genética , Glicólise/efeitos dos fármacos , Xenoenxertos , Humanos , Camundongos , Proteína Oncogênica v-akt/genética , Antagonistas do Receptor Purinérgico P2Y , RNA Interferente Pequeno/farmacologia , Análise de Sequência de RNA , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/genética , Microambiente Tumoral/efeitos dos fármacos
20.
Huan Jing Ke Xue ; 39(10): 4422-4429, 2018 Oct 08.
Artigo em Chinês | MEDLINE | ID: mdl-30229587

RESUMO

Primary pollutants of air quality in Beijing, Baoding, Shijiazhuang, Xingtai, and Handan cities along the Taihang Mountains were analyzed to investigate their spatial distribution characteristics and temporal variation trends during 2014-2016. The results showed that the primary pollutants were ranked as PM2.5, O3-8h, NO2 and PM10 from most to least important in Beijing, and PM2.5, PM10, O3-8h, NO2, SO2 and CO in the other four cities. Three-year average percentages of days with PM2.5 as the primary pollutant in each city were similar (53.3%-58.1%), however, percentages of days with PM10 as primary pollutant increased, while percentages of O3-8h decreased basically, from north to south. Except for Handan with a significant descending trend, percentages of days with PM2.5 as primary pollutant varied slightly in the other four cities during the study period, and percentages of O3-8h of Shijiazhuang, Xingtai and Handan increased significantly in 2016. Percentages of NO2 slightly declined year by year in Beijing, and the other four cities mainly showed the opposite trend. Monthly variation curves of days with PM2.5 and O3-8h as primary pollutants showed "W" and "inverted U" types respectively, while the high value interval of days with PM10 as primary pollutant occurred between March and May. With the exception of Beijing, peak of monthly variation curves for days with NO2 as the primary pollutant was occurred in October in the other four cities. From "moderate" to "hazardous" levels for air quality, the percentages of days with PM2.5 and/or PM10 as primary pollutants increased level by level, with percentages of PM10 trending downwards and PM2.5 upwards. Meanwhile, days with O3-8h as the primary pollutant mostly appeared in the range between "moderate" and "unhealthy" levels, and NO2 was only prominent in "moderate" level.

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