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1.
J Immunother Cancer ; 9(10)2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34599021

RESUMO

BACKGROUND: Triple negative breast cancer (TNBC) is a subtype of breast cancers with poor prognosis and targeted drug therapies are limited. To develop novel and efficacious therapies for TNBC, we developed a bispecific antibody F7AK3 that recognizes both trophoblast cell surface antigen 2 (TROP2) and CD3 and evaluated its antitumor activities both in vitro and in vivo. METHODS: The binding affinities of F7AK3 to the two targets, TROP2 and CD3, were evaluated by surface plasmon resonance. Binding of F7AK3 to TNBC cells and T cells were evaluated by flow cytometry. Immunofluorescent staining was performed to demonstrate the interactions between T cells with TNBC cells. The cytotoxicity of T cells against TNBC cell lines and primary tumor cells mediated by F7AK3 were determined in vitro. In vivo antitumor activity of F7AK3 was investigated in a xenograft TNBC tumor model, using immunodeficient mice that were reconstituted with human peripheral blood mononuclear cells. RESULTS: We demonstrated that F7AK3 binds specifically to human TROP2 and CD3 antigens, as well as TNBC cell lines and primary tumor cells. Human T cells can only be activated by F7AK3 in the presence of target tumor cells. F7AK3 recruits T cells to TROP2+ tumor cells in vitro and into tumor tissues in vivo. Antitumor growth activity of F7AK3 is observed in a xenograft TNBC tumor model. CONCLUSION: This study showed the antitumor potential of an anti-TROP2xCD3 bispecific antibody F7AK3 to TNBC tumor cells both in vitro and in vivo. These data demonstrate that F7AK3 has the potential to treat TNBC patients, which warrants further preclinical and clinical evaluation of the F7AK3 in advanced or metastatic TNBC patients.

2.
Front Oncol ; 11: 708900, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34557409

RESUMO

Background: Kinesin superfamily of proteins (KIFs) has been broadly reported to play an indispensable role in the biological process. Recently, emerging evidence reveals its oncogenic role in various cancers. However, the prognostic, oncological, and immunological values of KIFs have not been comprehensively explored in pancreatic ductal adenocarcinoma (PDAC) patients. We aimed to illustrate the relationship between KIFs and pancreatic ductal adenocarcinoma by using bioinformatical analysis. Methods: We use GEPIA, Oncomine datasets, cBioPortal, LOGpc, TIMER, and STRING bioinformatics tools and web servers to investigate the aberrant expression, prognostic values, and oncogenic role of KIFs. The two-gene prognostic model and the correlation between KIFs and KRAS and TP53 mutation were performed using an R-based computational framework. Results: Our results demonstrated that KIFC1/2C/4A/11/14/15/18A/18B/20B/23 (we name it prognosis-related KIFs) were upregulated and associated with unfavorable clinical outcome in pancreatic cancer patients. KIF21B overexpression is associated with better clinical outcome. The KIFC1/2C/4A/11/14/15/18A/18B/20B/23 profiles were significantly increased compared to grade 1 and grade 2/3. Besides, KIFC1/2C/4A/11/14/15/18A/18B/20B/23 was significantly associated with the mutation status of KRAS and TP53.Notably, most prognosis-related KIFs have strong correlations with tumor growth and myeloid-derived suppressor cells infiltration (MDSCs). A prognostic signature based on KIF20B and KIF21B showed a reliable predictive performance. Receiver operating characteristic (ROC) curve was employed to assess the predictive power of two-gene signature. Consequently, the gene set enrichment analysis (GSEA) showed that KIF20B and KIF21B's overexpression was associated with the immunological and oncogenic pathway activation in pancreatic cancer. Finally, real-time quantitative PCR (RT-qPCR) was utilized to investigate the expression pattern of KIF20B and KIF21B in pancreatic cancer cell lines and normal pancreatic cell. Conclusions: Knowledge of the expression level of the KIFs may provide novel therapeutic molecular targets and potential prognostic biomarkers to pancreatic cancer patients.

3.
J Cell Mol Med ; 25(20): 9851-9862, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34523794

RESUMO

Adiponectin is an adipocyte-derived hormone, which is closely associated with the development of Alzheimer's disease (AD) and has potential preventive and therapeutic significance. In the present study, we explored the relationship between adiponectin and circadian rhythm disorder in AD, the effect of adiponectin on the abnormal expression of Bmal1 mRNA/protein induced by amyloid-ß protein 31-35 (Aß31-35), and the underlying mechanism of action. We found that adiponectin-knockout mice exhibited amyloid-ß deposition, circadian rhythm disorders and abnormal expression of Bmal1. Adiponectin ameliorated the abnormal expression of the Bmal1 mRNA/protein caused by Aß31-35 by inhibiting the activity of glycogen synthase kinase 3ß (GSK3ß). These results suggest that adiponectin deficiency could induce circadian rhythm disorders and abnormal expression of the Bmal1 mRNA/protein, whilst exogenous administration of adiponectin may improve Aß31-35-induced abnormal expression of Bmal1 by inhibiting the activity of GSK3ß, thus providing a novel idea for the treatment of AD.

4.
Front Pharmacol ; 12: 686133, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34349647

RESUMO

Zishen Yutai Pills (ZYP) is a safe and well quality-controlled TCM preparation with promising effects in many fields of reproduction, including prevention of miscarriage, increase of pregnancy rate during in vitro fertilization-embryo transfer (IVF-ET). The plasma of patients was collected from a clinical trial, namely, "Effect of Traditional Chinese Medicine vs placebo on live births among women undergoing in vitro fertilization, a multi-center randomized controlled trial." Plasma samples were analyzed with metabonomics method. UPLC-MS technology was used to establish the plasma metabolic fingerprint. Multivariate statistical analysis was applied for comparing the differences of plasma metabolites between ZYP group and placebo group, 44 potential metabolites were screen out and identified. Pathway analysis was conducted with database mining. Compared with placebo, chemicals were found to be significantly down-regulated on HCG trigger day and 14 days after embryo transplantation, including trihexosylceramide (d18:1/26:1), glucosylceramide(d18:1/26:0), TG(22:6/15:0/22:6), TG(22:4/20:4/18:4). Compared with placebo, some chemicals were found to be significantly up-regulated on HCG trigger day and 14 days after embryo transplantation, i.e., PIP3(16:0/16:1), PIP2(18:1/18:1), tauroursodeoxycholic acid, L-asparagine, L-glutamic acid, kynurenic acid, 11-deoxycorticosterone, melatonin glucuronide, hydroxytyrosol. These metabolites were highly enriched in pathways including sphingolipid metabolism, alanine, aspartic acid and glutamic acid metabolism, aminoacyl tRNA biosynthesis, taurine and hypotaurine metabolism. This study revealed metabolic differences between subjects administered with ZYP and placebo. Relating metabolites were identified and pathways were enriched, providing basis on the exploration on the underlying mechanisms of ZYP combined with IVF-ET in the treatment of infertility.

5.
J Cell Mol Med ; 25(17): 8464-8478, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34322993

RESUMO

Cardiomyocytes autophagy is essential for maintaining cardiac function. Our previous studies have found that ß1 -adrenergic receptor autoantibody (ß1 -AA) induced the decreased myocardial autophagic flux, which resulted in cardiomyocyte death and cardiac dysfunction. And other studies demonstrated that ß1 -AA induced the decrease of AMPK phosphorylation, the key hub of autophagy pathway, while adiponectin up-regulated autophagic flux mediated by AMPK. However, it is not clear whether adiponectin improves the inhibition of myocardial autophagic flux induced by ß1 -AA by up-regulating the level of AMPK phosphorylation. In this study, it has been confirmed that ß1 -AA induced the decrease of AMPK phosphorylation level in both vivo and vitro. Moreover, pretreatment of cardiomyocytes with AMPK inhibitor Compound C could further reduce the autophagic flux induced by ß1 -AA. Adiponectin deficiency could aggravate the decrease of myocardial AMPK phosphorylation level, autophagic flux and cardiac function induced by ß1 -AA. Further, exogenous adiponectin could reverse the decline of AMPK phosphorylation level and autophagic flux induced by ß1 -AA and even reduce cardiomyocyte death. While pretreated with the Compound C, the adiponectin treatment did not improve the decreased autophagosome formation, but still improved the decreased autophagosome clearance induced by ß1 -AA in cardiomyocytes. This study is the first time to confirm that ß1 -AA could inhibit myocardial autophagic flux by down-regulating AMPK phosphorylation level. Adiponectin could improve the inhibition of myocardial autophagic flux induced by ß1 -AA partly dependent on AMPK, so as to provide an experimental basis for the treatment of patients with ß1 -AA-positive cardiac dysfunction.

6.
Bioengineered ; 12(1): 1676-1688, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33960283

RESUMO

Colorectal cancer (CRC) is one of the most common tumors, ranking second in the global cause of death from cancer. The prognosis of advanced patients is still very poor. In this study, hub modules with the highest association with tumor-infiltrating immune cells were identified by weighted gene co-expression network analysis based on CRC expression data from the Gene Expression Omnibus database. Next, three hub genes (ADAM8, IL-1A, VAV3) related to infiltrating immune cells were identified by co-expression network and prognostic analysis. After analysis and verification of the TIMER database, ADAM8 was selected as a prognostic biomarker. Finally, the result of functional test showed that ADAM8 gene expression down-regulation partially reversed the immune tolerance of CRC cells to TILs. By bioinformatics analysis methods and the experimental techniques, we identified ADAM8 as a prognostic biomarker and clinical therapeutic target related to tumor-infiltrating immune cells in CRC.

7.
Cell Metab ; 33(5): 971-987.e6, 2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-33798471

RESUMO

Serine metabolism promotes tumor oncogenesis and regulates immune cell functions, but whether it also contributes to antiviral innate immunity is unknown. Here, we demonstrate that virus-infected macrophages display decreased expression of serine synthesis pathway (SSP) enzymes. Suppressing the SSP key enzyme phosphoglycerate dehydrogenase (PHGDH) by genetic approaches or by treatment with the pharmaceutical inhibitor CBR-5884 and by exogenous serine restriction enhanced IFN-ß-mediated antiviral innate immunity in vitro and in vivo. Mechanistic experiments showed that virus infection or serine metabolism deficiency increased the expression of the V-ATPase subunit ATP6V0d2 by inhibiting S-adenosyl methionine-dependent H3K27me3 occupancy at the promoter. ATP6V0d2 promoted YAP lysosomal degradation to relieve YAP-mediated blockade of the TBK1-IRF3 axis and, thus, enhance IFN-ß production. These findings implicate critical functions of PHGDH and the key immunometabolite serine in blunting antiviral innate immunity and also suggest manipulation of serine metabolism as a therapeutic strategy against virus infection.

8.
Int J Biol Macromol ; 179: 270-278, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33676982

RESUMO

Laccase, an important oxidoreductase, is widely distributed in various organisms. Termites are known to decompose lignocellulose efficiently with the aid of gut microorganisms. However, few laccases have been characterized from termite or its gut microbes. We aimed to screen the strain capable of degrading lignocellulose from fungus-growing termites. In this study, Bacillus stratosphericus BCMC2 with lignocellulolytic activity was firstly isolated from the hindgut of fungus-growing termite Macrotermes barneyi. The laccase gene (BaCotA) was cloned both from the BCMC2 strain and termite intestinal metagenomic DNA. BaCotA was overexpressed in E. coli, and the recombinant BaCotA showed high specific activity (554.1 U/mg). BaCotA was thermostable with an optimum temperature of 70 °C, pH 5.0. Furthermore, BaCotA was resistant to alkali and organic solvents. The enzyme remained more than 70% residual activity at pH 8.0 for 120 min; and the organic solvents such as methanol, ethanol and acetone (10%) had no inhibitory effect on laccase activity. Additionally, BaCotA exhibited efficient decolorization ability towards indigo and crystal violet. The multiple enzymatic properties suggested the presented laccase as a potential candidate for industrial applications. Moreover, this study highlighted that termite intestine is a good resource for either new strains or enzymes.


Assuntos
Bacillus/enzimologia , Microbioma Gastrointestinal , Isópteros/microbiologia , Lacase/química , Lignina/metabolismo , Animais , Estabilidade Enzimática , Concentração de Íons de Hidrogênio , Cinética , Proteínas Recombinantes/química , Temperatura
9.
J Am Soc Echocardiogr ; 34(6): 629-641, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33422666

RESUMO

BACKGROUND: Ultrafast ultrasound imaging has been demonstrated to be an effective method to evaluate carotid stiffness through carotid pulse-wave velocity (PWV) with high reproducibility, but a lack of reference values has precluded its widespread use in clinical practice. The aims of this study were to establish reference values of PWV for ultrafast ultrasound imaging in a prospective, multicenter, population-based cohort study and to investigate the main determinants of carotid PWV. METHODS: A total of 1,544 healthy Han Chinese volunteers (581 men [38%]; age range, 18-95 years) were enrolled from 32 collaborating laboratories in China. The participants were categorized by age, blood pressure (BP), and body mass index (BMI). Basic clinical parameters and carotid PWV at the beginning of systole (BS) and at end-systole (ES) were measured using ultrafast ultrasound imaging techniques. RESULTS: PWV at both BS and ES was significantly higher in the left carotid artery than in the right carotid artery. PWV at BS was significantly higher in men than in women; however, no significant difference was noted in PWV at ES between men and women. Multiple linear regression analyses revealed that age, BP, and BMI were independently correlated with PWV at both BS and ES. PWV at BS and ES progressively increased with increases in age, BP, and BMI. Furthermore, age- and sex-specific reference values of carotid PWV for ultrafast ultrasound imaging were established. CONCLUSIONS: Reference values of carotid PWV for ultrafast ultrasound imaging, stratified by sex and age, were determined for the first time. Age, BP, and BMI were the dominant determinants of carotid PWV for ultrafast ultrasound imaging, which should be considered in clinical practice for assessing arterial stiffness.


Assuntos
Análise de Onda de Pulso , Rigidez Vascular , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Pressão Sanguínea , Artérias Carótidas/diagnóstico por imagem , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Valores de Referência , Reprodutibilidade dos Testes , Adulto Jovem
10.
Genomics ; 113(1 Pt 2): 601-612, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33002624

RESUMO

Lepidoptera (moths and butterflies) and Trichoptera (caddisflies), belonging to the superorder Amphiesmenoptera, are the most diverse insect orders as representatives of the terrestrial and aquatic insects, respectively. The insects of the two orders possess different biological and behavioral characteristics, especially their larvae, presumably resulting in the differences of the ionotropic receptor (IR) genes in numbers, sequence characteristics or gene structure. Here, we employed genomics, transcriptomics, bioinformatics, phylogenetics and molecular biology strategies to characterize the IR gene repertoire in Lepidoptera and Trichoptera. Genome and transcriptome analyses with exhaustive homology-based searches and manual efforts, in 32 lepidopterans and five trichopterans, led to the identification of 1449 genes encoding IRs with 1170 full-length sequences, representing the most comprehensive set of chemoreceptor superfamilies across the Amphiesmenoptera. Analysis of gene gains and losses in orthologous groups implied that some IRs were lost in related species, and multiple gene copies occurred mainly in divergent IRs (D-IRs) by gene duplications. Phylogenetic analysis of 2442 IR proteins from 67 species revealed that Lepidoptera and Trichoptera IRs could be classified into three subfamilies, i.e., 14 antennal IRs (A-IRs), five Lepidoptera-specific IRs (LS-IRs) and four D-IRs. Of the three subfamilies, A-IRs and LS-IRs members within orthologous groups exhibited high conservation of gene structure, but D-IRs shared extremely low amino acid identities (below 30%). Expression profiles revealed functional diversities of IRs from Bombyx mori and Papilio xuthus involving smell, taste or reproduction, in which some genes displayed sex-biased expression in antennae associated with specific chemosensory behaviors of female or male adults. Our current study has provided insights into the evolution, conservation and divergence of IRs between/within Lepidoptera and Trichoptera, and allows for further experiments to investigate IR functions.

11.
J Pharm Biomed Anal ; 191: 113570, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-32905860

RESUMO

Zishen Yutai Pills (ZYP) is a well-known Chinese patent medicine which has been used to prevent recurrent miscarriage and treat threatened abortion in China. In this study, a comprehensive strategy combining ultrahigh performance liquid chromatography coupled with charged aerosol detector (UHPLC-CAD) fingerprint and multi-components quantitative analysis was developed and validated for quality evaluation of ZYP. For fingerprint analysis, a total of 52 characteristic peaks were selected to evaluate the similarities of 16 batches of ZYP. In addition, combining the chemical fingerprint profile with an advanced hybrid LTQ-Orbitrap mass spectrometer, 281 compounds were identified or tentatively identified in ZYP based on chemical standards, accurate mass and fragmentation information. Moreover, 18 chemical markers were simultaneously determined within 13 min by ultra-performance liquid chromatography couple to tandem mass spectrometry (UPLC-MS/MS) with positive-negative conversion multiple reaction monitor (+/-MRM) technique. This method has been validated and exhibited satisfactory sensitivity, precision, reproducibility and accuracy. The validated quantitative method was successfully applied to the analysis of 16 batches of ZYP samples. The combination of UHPLC-CAD fingerprint and multi-components quantification has been proved to be an efficient and reliable strategy for quality control of ZYP and could be considered as a reference for quality evaluation of Chinese patent medicine.


Assuntos
Medicamentos de Ervas Chinesas , Espectrometria de Massas em Tandem , China , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Medicamentos de Ervas Chinesas/análise , Medicamentos sem Prescrição , Controle de Qualidade , Reprodutibilidade dos Testes
12.
J Ethnopharmacol ; 260: 113045, 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-32504785

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Zishen Yutai Pills (ZYP), a famous traditional Chinese patent medicine, has been widely applied to avoid recurrent miscarriage and treat threatened abortion. Polysaccharides of ZYP (ZYPPs) play an essential role in the theraprutic effects of ZYP. However, the complex compositions of ZYP and the complicated structure of ZYPPs have posed great challenges and barriers to the quality evaluation of ZYP. AIM OF THE STUDY: To identify and characterize the ZYPPs for better quality control of ZYP, a reliable and valid quality control system was established in this study. MATERIALS AND METHODS: A multi-fingerprint profile strategy based on HPSEC-MALL-RID, FT-IR, and HPLC (complete acid digested fingerprint, partial acid digested fingerprint and enzymatically digested fingerprint) was established to identify and discriminate the chemical structure of ZYPPs. Besides, the purpose of revealing the relationships between structure and biological activity of ZYPPs, their chemical characteristics, in vitro antioxidant and anti-glycation activities were investigated and discussed. RESULTS: The similarity evaluation of ZYPPs indicated ZYPPs from different batches showed a high similarity based on the correlation coefficient values of multi-fingerprints. Furthermore, ZYPPs exhibited remarkable antioxidant and antiglycation properties, which might be attributed to their molecular weights and the content of uronic acids. CONCLUSIONS: These results indicated that the multiple fingerprint technique was reliable and effective for the improvement of quality control of ZYPPs, suggesting the multiple fingerprint technique could also be potentially applied as a valid and feasible strategy to control the quality of polysaccharide-enriched herbal medicines.


Assuntos
Antioxidantes/análise , Medicamentos de Ervas Chinesas/análise , Polissacarídeos/análise , Antioxidantes/farmacologia , Cromatografia em Gel , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/farmacologia , Produtos Finais de Glicação Avançada/efeitos dos fármacos , Hidrólise , Estrutura Molecular , Oxirredução , Polissacarídeos/farmacologia , Controle de Qualidade , Espectroscopia de Infravermelho com Transformada de Fourier , Relação Estrutura-Atividade , Comprimidos
13.
Medicine (Baltimore) ; 99(14): e19413, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32243360

RESUMO

The aim of this observational study was to test whether ABO blood type was a prognostic factor for pancreatic ductal adenocarcinoma (PDAC) patients and whether other risk factors could influence pancreatic cancer patients' survival. This study included 610 patients who were diagnosed as pancreatic cancer and had undergone radical surgery. Patients' characteristics included age, gender, tumor stage, tumor grade, adenosquamous carcinoma (ASC) status, preoperative serum carbohydrate antigen 19-9 (CA19-9) levels, preoperative serum carcinoembryonic antigen (CEA) levels, ABO blood type, smoking status, and drinking status were analyzed in this study. Cox proportional hazards regression model and Kaplan-Meier method were used to evaluate the role of prognostic factors. For pancreatic cancer patients undergoing radical surgery, the overall survival was worse for ASC patients than PDAC patients (Log-rank = 11.315, P < .001). Compared with ASC patients (Log-rank < 0.001, P = .996), PDAC patients can benefit from chemotherapy (Log-rank = 17.665, P < .001). For PDAC patients, O blood type had better overall survival than non-O blood type (Log-rank = 4.153, P = .042). Moreover, the group with higher serum levels of CA19-9 had poor prognosis compared to another group with low serum CA19-9 (Log-rank = 4.122, P = .042). Higher CEA levels indicated poor prognosis (Log-rank = 13.618, P < .001). In conclusion, ASC status was associated with overall survival of pancreatic cancer patients and cannot benefit from postoperative chemotherapy. Non-O blood type was a prognostic factor for PDAC patients.


Assuntos
Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Sistema ABO de Grupos Sanguíneos/sangue , Adulto , Fatores Etários , Idoso , Consumo de Bebidas Alcoólicas/epidemiologia , Antígeno CA-19-9/sangue , Antígeno Carcinoembrionário/sangue , Carcinoma Adenoescamoso/patologia , Carcinoma Ductal Pancreático/epidemiologia , Carcinoma Ductal Pancreático/cirurgia , Fumar Cigarros/epidemiologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/cirurgia , Modelos de Riscos Proporcionais , Fatores de Risco , Fatores Sexuais
14.
World J Gastroenterol ; 26(10): 1088-1097, 2020 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-32205999

RESUMO

BACKGROUND: Hepatopulmonary syndrome (HPS) is an arterial oxygenation defect induced by intrapulmonary vascular dilatation (IPVD) in the setting of liver disease and/or portal hypertension. This syndrome occurs most often in cirrhotic patients (4%-32%) and has been shown to be detrimental to functional status, quality of life, and survival. The diagnosis of HPS in the setting of liver disease and/or portal hypertension requires the demonstration of IPVD (i.e., diffuse or localized abnormally dilated pulmonary capillaries and pulmonary and pleural arteriovenous communications) and arterial oxygenation defects, preferably by contrast-enhanced echocardiography and measurement of the alveolar-arterial oxygen gradient, respectively. AIM: To compare brain and whole-body uptake of technetium for diagnosing HPS. METHODS: Sixty-nine patients with chronic liver disease and/or portal hypertension were prospectively included. Brain uptake and whole-body uptake were calculated using the geometric mean of technetium counts in the brain and lungs and in the entire body and lungs, respectively. RESULTS: Thirty-two (46%) patients had IPVD as detected by contrast-enhanced echocardiography. The demographics and clinical characteristics of the patients with and without IPVD were not significantly different with the exception of the creatinine level (0.71 ± 0.18 mg/dL vs 0.83 ± 0.23 mg/dL; P = 0.041), alveolar-arterial oxygen gradient (23.2 ± 13.3 mmHg vs 16.4 ± 14.1 mmHg; P = 0.043), and arterial partial pressure of oxygen (81.0 ± 12.1 mmHg vs 90.1 ± 12.8 mmHg; P = 0.004). Whole-body uptake was significantly higher in patients with IPVD than in patients without IPVD (48.0% ± 6.1% vs 40.1% ± 8.1%; P = 0.001). The area under the curve of whole-body uptake for detecting IPVD was significantly higher than that of brain uptake (0.75 vs 0.54; P = 0.025). The optimal cut-off values of brain uptake and whole-body uptake for detecting IPVD were 5.7% and 42.5%, respectively, based on Youden's index. The sensitivity, specificity, and accuracy of brain uptake > 5.7% and whole-body uptake > 42.5% for detecting IPVD were 23%, 89%, and 59% and 100%, 52%, and 74%, respectively. CONCLUSION: Whole-body uptake is superior to brain uptake for diagnosing HPS.


Assuntos
Síndrome Hepatopulmonar/diagnóstico , Imagem de Perfusão/métodos , Cintilografia/métodos , Compostos Radiofarmacêuticos/farmacocinética , Agregado de Albumina Marcado com Tecnécio Tc 99m/farmacocinética , Adulto , Gasometria , Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Dilatação Patológica/diagnóstico , Feminino , Síndrome Hepatopulmonar/etiologia , Humanos , Hipertensão Pulmonar/complicações , Hepatopatias/complicações , Pulmão/irrigação sanguínea , Pulmão/metabolismo , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Estudos Prospectivos , Doenças Vasculares/diagnóstico , Doenças Vasculares/etiologia
15.
CNS Neurosci Ther ; 26(3): 343-354, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31411808

RESUMO

INTRODUCTION: The occurrence of circadian rhythm disorder in patients with Alzheimer's disease (AD) is closely related to the abnormal deposition of amyloid-ß (Aß), and d-Ser2-oxyntomodulin (Oxy) is a protease-resistant oxyntomodulin analogue that has been shown to exert neuroprotective effects. AIMS: This study aimed to explore whether Oxy, a new GLP-1R/GCGR dual receptor agonist, can improve the Aß-induced disrupted circadian rhythm and the role of GLP-1R. METHODS: A mouse wheel-running experiment was performed to explore the circadian rhythm, and western blotting and real-time PCR were performed to assess the expression of the circadian clock genes Bmal1 and Per2. Furthermore, a lentivirus encoding an shGLP-1R-GFP-PURO was used to interfere with GLP-1R gene expression and so explore the role of GLP-1R. RESULTS: The present study has confirmed that Oxy could restore Aß31-35-induced circadian rhythm disorders and improve the abnormal expression of Bmal1 and Per2. After interfering the GLP-1R gene, we found that Oxy could not improve the Aß31-35-induced circadian rhythm disorder and abnormal expression of clock genes. CONCLUSION: This study demonstrated that Oxy could improve Aß31-35-induced circadian rhythm disorders, and GLP-1R plays a critical role. This study thus describes a novel target that may be potentially used in the treatment of AD.

16.
Oncol Lett ; 18(5): 5163-5172, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31612027

RESUMO

The aim of the present study was to evaluate the potential network of arsenic trioxide (ATO) target genes in pancreatic cancer. The DrugBank, STITCH, cBioPortal, Kaplan-Meier plotter and Oncomine websites were used to analyze the association of ATO and its target genes with pancreatic cancer. Initially, 19 ATO target genes were identified, along with their associated protein-protein interaction networks and Kyoto Encyclopedia of Genes and Genomes pathways. ATO was found to be associated with multiple types of cancer, and the most common solid cancer was pancreatic cancer. A total of 6 ATO target genes (namely AKT1, CCND1, CDKN2A, IKBKB, MAPK1 and MAPK3) were found to be associated with pancreatic cancer. Next, the mutation information of the 6 ATO target genes in pancreatic cancer was collected. A total of 20 ATO interacting genes were identified, which were mainly involved in hepatitis B, prostate cancer, pathways in cancer, glioma and chronic myeloid leukemia. Finally, the genes CCND1 and MAPK1 were detected to be prognostic factors in patients with pancreatic cancer. In conclusion, bioinformatics analysis may help elucidate the molecular mechanisms underlying the involvement of ATO in pancreatic cancer, enabling more effective treatment of this disease.

17.
Acta Biochim Biophys Sin (Shanghai) ; 51(10): 1016-1025, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31553425

RESUMO

Autophagy reduction has been confirmed as an important mechanism in apoptosis induction. Our previous study showed that decreased autophagy induced by ß1-adrenoceptor autoantibodies (ß1-AAs) enhanced cardiomyocyte apoptosis and contributed to heart failure progression. Endoplasmic reticulum stress (ERS) is known to be an important mechanism in intracellular homeostasis and is closely related to autophagy. However, ERS in ß1-AA-induced autophagy dysfunction of cardiomyocytes remains unclear. In this study, we used an active immunization rat model and H9c2 cardiomyocytes to study the role of ERS in ß1-AA-induced autophagy. Results showed that prolonged action of ß1-AAs significantly reduced the autophagy of myocardial tissues and H9c2 cardiomyocytes, and ERS and its related apoptotic pathways were significantly activated. Moreover, mRFP-GFP-LC3 double-labeled adenoviruses were used to detect cardiomyocyte autophagic flux to confirm that ß1-AAs caused a significant decrease in autophagic flux in H9c2 cardiomyocytes. The ERS inhibitor, 4-phenylbutyrate (4-PBA), partially attenuated the ß1-AA-induced reduction of cardiomyocyte autophagy, consistent with the effect of the mammalian target of rapamycin inhibitor rapamycin (Rapa). Compared to the pretreatment with 4-PBA or Rapa alone, pretreatment with the combination of 4-PBA and Rapa had a greater effect on attenuating the ß1-AA-induced decrease in autophagy and ß1-AA-induced apoptosis in cardiomyocytes. This study provides an experimental basis for the role of ß1-AAs in the homeostatic maintenance of cardiomyocytes in patients with heart failure with respect to autophagy and ERS.


Assuntos
Autoanticorpos/imunologia , Autofagia , Estresse do Retículo Endoplasmático , Miócitos Cardíacos/citologia , Receptores Adrenérgicos beta 1/imunologia , Animais , Apoptose , Linhagem Celular , Células Cultivadas , Masculino , Miócitos Cardíacos/imunologia , Ratos Sprague-Dawley
18.
Cell Death Discov ; 5: 101, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31231549

RESUMO

The SARS (severe acute respiratory syndrome) outbreak was caused by a coronavirus (CoV) named the SARS-CoV. SARS pathology is propagated both by direct cytotoxic effects of the virus and aberrant activation of the innate immune response. Here, we identify several mechanisms by which a SARS-CoV open reading frame (ORF) activates intracellular stress pathways and targets the innate immune response. We show that ORF8b forms insoluble intracellular aggregates dependent on a valine at residue 77. Aggregated ORF8b induces endoplasmic reticulum (ER) stress, lysosomal damage, and subsequent activation of the master regulator of the autophagy and lysosome machinery, Transcription factor EB (TFEB). ORF8b causes cell death in epithelial cells, which is partially rescued by reducing its ability to aggregate. In macrophages, ORF8b robustly activates the NLRP3 inflammasome by providing a potent signal 2 required for activation. Mechanistically, ORF8b interacts directly with the Leucine Rich Repeat domain of NLRP3 and localizes with NLRP3 and ASC in cytosolic dot-like structures. ORF8b triggers cell death consistent with pyroptotic cell death in macrophages. While in those cells lacking NLRP3 accumulating ORF8b cytosolic aggregates cause ER stress, mitochondrial dysfunction, and caspase-independent cell death.

19.
Inorg Chem ; 58(9): 6215-6221, 2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-31002240

RESUMO

Molecule-based solid-state materials with long lifetimes could enable longer migration distances for excitons, which are beneficial for vast applications in optoelectronic field. Herein, we report a hexanuclear zinc cluster based MOF exhibits highly enhanced phosphorescence about 2 orders of magnitude in comparison with the pristine phosphor ligand. The combination of both experimental and computational results suggest that the {Zn6} cluster is very important for adjusting molecular conformations, packing arrangement, and photophysical properties of the organic phosphor ligands within the MOF matrix. Optoelectronic measurements reveal that the MOF-modified electrode is catalytically active to hydrogen evolution under light irradiation in neutral solution. Thus, our study provide an effective way to achieve low-cost metal-based phosphorescence MOF, expanding its further optoelectronic applications.

20.
Mol Brain ; 12(1): 14, 2019 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-30744651

RESUMO

Studies have shown that a normal circadian rhythm is crucial to learning and memory. Circadian rhythm disturbances that occur at early stages of Alzheimer's disease (AD) aggravate the progression of the disease and further reduce learning and memory in AD patients. The novel, dual GLP-1R/GIPR agonist DA-JC1 has been found to exert a stronger hypoglycemic effect than a GLP-1R agonist alone and has been shown to exert neuroprotective effects. However, it is not clear whether DA-JC1 improves the Aß31-35-induced decline in learning and memory ability by restoring disrupted circadian rhythms. In the present study, we carried out a mouse wheel-running experiment and Morris water maze test (MWM) and found that DA-JC1 could effectively improve the decline of learning and memory and circadian rhythm disorders induced by Aß31-35. After downregulating Per2 expression via lentivirus-shPer2 in the hippocampus and the hippocampal HT22 cells, we found that circadian rhythm disorders occurred, and that DA-JC1 could not improve the impaired learning and memory. These results suggest that DA-JC1 improves damage to learning and memory by antagonizing circadian rhythm disorders induced by Aß31-35. The outcome of this ongoing study may provide a novel therapeutic intervention for AD in the future.


Assuntos
Peptídeos beta-Amiloides/toxicidade , Transtornos Cronobiológicos/fisiopatologia , Memória/efeitos dos fármacos , Fragmentos de Peptídeos/toxicidade , Peptídeos/farmacologia , Animais , Linhagem Celular , Ritmo Circadiano/efeitos dos fármacos , Proteína GAP-43/metabolismo , Inativação Gênica , Hipocampo/patologia , Lentivirus/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Proteínas Circadianas Period/metabolismo , Sinaptofisina/metabolismo
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