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3.
Cell Death Dis ; 11(5): 330, 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32382069

RESUMO

Quaking (QKI), an RNA-binding protein, has been reported to exhibit numerous biological functions, such as mRNA regulation, cancer suppression, and anti-inflammation. However, little known about the effects of QKI on bone metabolism. In this study, we used a monocyte/macrophage-specific QKI knockout transgenic mouse model to investigate the effects of QKI deficiency on receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis. The loss of QKI promoted the formation of multinucleated tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts (OCs) from bone marrow macrophages, and upregulated the expression of OC-specific markers, including TRAP (Acp5) and cathepsin K (Ctsk). The pro-osteoclastogenesis effect of QKI deficiency was achieved by amplifying the signaling cascades of the NF-κB and mitogen-activated protein kinase (MAPK) pathways; then, signaling upregulated the activation of nuclear factor of activated T cells c1 (NFATc1), which is considered to be the core transcription factor that regulates OC differentiation. In addition, QKI deficiency could inhibit osteoblast (OB) formation through the inflammatory microenvironment. Taken together, our data suggest that QKI deficiency promoted OC differentiation and disrupted bone metabolic balance, and eventually led to osteopenia under physiological conditions and aggravated the degree of osteoporosis under pathological conditions.

4.
J Mol Histol ; 2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32409849

RESUMO

Increasing evidence has indicated that circular RNAs (circRNAs) play a key role in the development and progression of diverse cancers, but their role in clear cell renal carcinoma (CCRCC) tumorigenesis is not well understood. In this study, we firstly performed comprehensive circRNA-seq from CCRCC tissues and pair-matched adjacent normal tissues. In total, 1184 circRNAs were dysregulated in human CCRCC tissues compared with those in adjacent normal tissues. We randomly selected four circRNAs, including circHIPK3 (circBase ID: hsa_circ_0000284), to test the circRNA-seq data in another 40 CCRCC tissues by quantitative real-time PCR (qRT-PCR). Furthermore, we found that circHIPK3 was downregulated in CCRCC tissues and cell lines. Overexpression of circHIPK3 effectively suppressed CCRCC cell invasion and migration in vitro, and inhibited CCRCC cell proliferation in vitro and in vivo. Moreover, bioinformatic analysis and luciferase reporter assay showed that circHIPK3 targeted miR-637 in CCRCC cells. Hence, CircHIPK3 may represent a tumor suppressor and target miR-637 in clear cell renal carcinoma.

5.
Liver Int ; 2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32410310

RESUMO

BACKGROUND & AIMS: Sedentariness and physical inactiveness are associated with deleterious health outcomes, but their associations with liver enzyme elevations remain uncertain. METHODS: In 10 385 US Hispanics/Latinos from the Hispanic Community Health Study/Study of Latinos, we examined associations of sedentary time and moderate-to-vigorous physical activity (MVPA) measured by accelerometers with liver enzyme elevations. Elevated alanine aminotransferase (ALT), aspartate aminotransferase, and γ-glutamyltransferase (GGT) were defined as the highest sex-specific deciles. Prevalence ratios (PRs) and 95% confidence intervals (CIs) were calculated using weighted Poisson regressions. RESULTS: After adjusting for demographic/socioeconomic factors and MVPA, increasing quartiles of sedentary time were associated with a higher prevalence of elevated ALT (PRs [95% CI] = 1.0, 1.17 [0.92-1.47], 1.21 [0.96, 1.53], and 1.51 [1.13-2.02]; P-trend=0.007) and elevated GGT (PRs [95% CI] =1.0, 1.06 [0.82-1.36], 1.35 [1.06-1.73], and 1.66 [1.27-2.16]; P-trend=0.0001). These associations were attenuated but remained significant after further adjustment for cardiometabolic traits including body-mass index, waist-hip-ratio, lipids, and homeostatic model assessment of insulin resistance. In contrast, increasing quartiles of MVPA were associated with a lower prevalence of elevated ALT (PRs [95% CI] =1.0, 0.97 [0.77-1.23], 0.84 [0.66-1.06], and 0.72 [0.54-0.96]; P-trend=0.01) after adjusting for demographic/socioeconomic factors and sedentary time, but this association became non-significant after further adjustment for cardiometabolic traits. Notably, the association of sedentary time with GGT elevation was significant both in individuals meeting the US Physical Activity Guidelines for Americans (MVPA≥150 minutes/week) and in those who did not (both P-trend≤0.003). CONCLUSIONS: Our findings suggest that objectively measured sedentary time is independently associated with elevated ALT and GGT in US Hispanics/Latinos.

6.
Inflammation ; 2020 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-32394287

RESUMO

Sepsis is a life-threatening condition. Polydatin (PD), a small natural compound from Polygonum cuspidatum, possesses antioxidant and anti-inflammatory properties. However, the protective mechanism of PD on sepsis-induced acute myocardial damage is still unclear. The aim of this study was to investigate the effect and mechanism of action of PD on lipopolysaccharide (LPS)-induced H9c2 cells and in a rat model of sepsis, and explored the role of PD-upregulated sirtuin (SIRT)6. LPS-induced H9c2 cells were used to simulate sepsis. Cecal ligation and puncture (CLP)-induced sepsis in rats were used to verify the protective effect of PD. ELISA, western blotting, immunofluorescence, immunohistochemistry, and flow cytometry were used to study the protective mechanism of PD against septic myocardial injury. PD pretreatment suppressed LPS-induced H9c2 cell apoptosis by promotion of SIRT6-mediated autophagy. Downregulation of SIRT6 or inhibition of autophagy reversed the protective effect of PD on LPS-induced apoptosis. PD pretreatment also suppressed LPS-induced inflammatory factor expression. CLP-induced sepsis in rats showed that PD pretreatment decreased CLP-induced myocardial apoptosis and serum tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6 expression. 3-Methyladenine (autophagy inhibitor) pretreatment prevented the protective effect of PD on septic cardiomyopathy. SIRT6 expression was increased with PD treatment, which confirmed that PD attenuates septic cardiomyopathy by promotion of SIRT6-mediated autophagy. All these results indicate that PD has potential therapeutic effects that alleviate septic myocardial injury by promotion of SIRT6-mediated autophagy.

7.
Stem Cell Res Ther ; 11(1): 188, 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32434593

RESUMO

An amendment to this paper has been published and can be accessed via the original article.

8.
Blood ; 2020 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-32396938

RESUMO

The connections between energy metabolism and stemness of hematopoietic stem cells (HSCs) at different developmental stages remain largely unknown. We herein generate a transgenic mouse line for the genetically encoded NADH/NAD+ sensor (SoNar) and demonstrate that there exist three distinct fetal liver hematopoietic cell populations according to the ratios of SoNar fluorescence. SoNar-low cells have an enhanced level of mitochondrial respiration, but similar glycolytic level to SoNar-high cells. Interestingly, 10% of SoNar-low cells are enriched for 65% of total immunophenotypical fetal liver HSCs (FL-HSCs) and contain approximately 5-fold greater functional HSCs than that of SoNar-high counterparts. SoNar can monitor sensitively the dynamic changes of energy metabolism in HSCs both in vitro and in vivo. Mechanistically, STAT3 transactivates MDH1 to sustain the malate-aspartate NADH shuttle activity and the HSC self-renewal and differentiation. We reveal an unexpected metabolic program of FL-HSCs and provide a powerful genetic tool for metabolic studies of HSCs or other types of stem cells.

9.
BMC Cancer ; 20(1): 421, 2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32410591

RESUMO

BACKGROUND: We aimed to assess whether disease-free survival (DFS) could serve as a reliable surrogate endpoint for overall survival (OS) in adjuvant trials of pancreatic cancer. METHODS: We systematically reviewed adjuvant randomized trials for non-metastatic pancreatic cancer after curative resection that reported a hazard ratio (HR) for DFS and OS. We assessed the correlation between treatment effect (HR) on DFS and OS, weighted by sample size or precision of hazard ratio estimate, assuming fixed and random effects, and calculated the surrogate threshold effect (STE). We also performed sensitivity analyses and a leave-one-out cross validation approach to evaluate the robustness of our findings. RESULTS: After screening 450 relevant articles, we identified a total of 20 qualifying trails comprising 5170 patients for quantitative analysis. We noted a strong correlation between the treatment effects for DFS and OS, with coefficient of determination of 0.82 in the random effect model, 0.82 in the fixed effect model, and 0.80 in the sample size weighting; the robustness of this finding was further verified by the leave-one-out cross-validation approach. Sensitivity analyses with restriction to phase 3 trials, large trials, trials with mature follow-up periods, and trials with adjuvant therapy versus adjuvant therapy strengthened the correlation (0.75 to 0.88) between DFS and OS. The STE was 0.96 for DFS. CONCLUSIONS: Therefore, DFS could be regarded as a surrogate endpoint for OS in adjuvant trials of pancreatic cancer. In future similar adjuvant trials, a hazard ratio for DFS of 0.96 or less would predict a treatment impact on OS.

10.
Int J Infect Dis ; 2020 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-32439540

RESUMO

OBJECTIVES: To better understand the spectrums of pathogens causing herpangina and circulation of Coxsackievirus A4 in Yancheng, China. METHODS: Stool samples from herpangina and HFMD cases were collected. Real Time PCR Kits was used to identify Enterovirus 71, CV-A16 and CV-A6, and nested reverse transcription PCR (nRT-PCR) to detect the other enterovirus types. Complete VP1 and genome sequence of CV-A4 were amplified by using nRT-PCR. Genetic, phylogenetic and recombination analysis were performed. RESULTS: Co-circulation of three recombinant CV-A4 groups, including one novel (C2 lineage), was identified in Yancheng, China, 2016 and 2018. One was the major causative agent of herpangina, and another two were responsible for HFMD. Phylogenetic and recombination analysis indicated that the non-structural region of their genome originated from the same ancestry and subsequently adaptation. C2 lineage of CV-A4 group may be introduced from countries outside China and its genome occurred recombination in China. CONCLUSION: Novel recombinant CV-A4 was mainly associated with herpanginain in Yancheng, 2018, China. C2 lineage of CV-A4 group with recombinant non-structural region was also identified in HFMD patients.

11.
J Chem Phys ; 152(18): 184107, 2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32414256

RESUMO

TURBOMOLE is a collaborative, multi-national software development project aiming to provide highly efficient and stable computational tools for quantum chemical simulations of molecules, clusters, periodic systems, and solutions. The TURBOMOLE software suite is optimized for widely available, inexpensive, and resource-efficient hardware such as multi-core workstations and small computer clusters. TURBOMOLE specializes in electronic structure methods with outstanding accuracy-cost ratio, such as density functional theory including local hybrids and the random phase approximation (RPA), GW-Bethe-Salpeter methods, second-order Møller-Plesset theory, and explicitly correlated coupled-cluster methods. TURBOMOLE is based on Gaussian basis sets and has been pivotal for the development of many fast and low-scaling algorithms in the past three decades, such as integral-direct methods, fast multipole methods, the resolution-of-the-identity approximation, imaginary frequency integration, Laplace transform, and pair natural orbital methods. This review focuses on recent additions to TURBOMOLE's functionality, including excited-state methods, RPA and Green's function methods, relativistic approaches, high-order molecular properties, solvation effects, and periodic systems. A variety of illustrative applications along with accuracy and timing data are discussed. Moreover, available interfaces to users as well as other software are summarized. TURBOMOLE's current licensing, distribution, and support model are discussed, and an overview of TURBOMOLE's development workflow is provided. Challenges such as communication and outreach, software infrastructure, and funding are highlighted.

12.
Technol Cancer Res Treat ; 19: 1533033820923427, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32419651

RESUMO

BACKGROUND: Gastric cancer is one of the most common malignancies worldwide with high mortality. Therefore, identifying cancer-related biomarkers for predicting prognosis and progression of gastric cancer is essential. This study aimed to investigate the clinical value and functional role of microRNA-3196 in gastric cancer. METHODS: The relative expression levels of microRNA-3196 in gastric cancer tissues and adjacent normal tissues were detected by quantitative reverse transcription-polymerase chain reaction. In this study, quantitative reverse transcription-polymerase chain reaction, cell proliferation assay, and Transwell migration and invasion assays were performed to explore microRNA-3196 expression level and its effects on cell proliferation, migration, and invasion in gastric cancer cells. The Kaplan-Meier method and multivariate Cox regression analyses were used to explore the prognostic significance of microRNA-3196 in gastric cancer. Dual-luciferase report assay was performed to validate the potential target gene regulated by microRNA-3196 in gastric cancer. RESULTS: The expression of microRNA-3196 was downregulated in gastric cancer tissues and cell lines. Downregulation of microRNA-3196 was associated with lymph node metastasis and Tumor Node Metastasis (TNM) stage. The Kaplan-Meier curve analysis indicated that patients with low expression of microRNA-3196 had a poor prognosis, and the Cox regression analysis results showed microRNA-3196 expression was an independent prognostic factor of gastric cancer. Moreover, overexpression of microRNA-3196 inhibited cell proliferation, migration, and invasion, while knockdown of microRNA-3196 promoted these cellular behaviors in AGS and MKN45 cells. OTX1 may be a potential target gene regulated by microRNA-3196 in gastric cancer. CONCLUSIONS: These results suggested that microRNA-3196 might not only a tumor suppressor in gastric cancer cells by modulating OTX1 but also might be an independent prognostic biomarker and therapeutic target of gastric cancer.

13.
Invest New Drugs ; 2020 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-32361788

RESUMO

A new drug, Caba-780, was synthesized by chemical coupling of the heptamethyl phthalocyanine near-infrared fluorescent (NIRF) dye IR-780 and the paclitaxel-based chemotherapeutic drug cabazitaxel. Then, the potential value of Caba-780 in the diagnosis and treatment of castration-resistant prostate cancer (CRPC) was evaluated. The CRPC cell lines DU145 and PC-3, as well as the normal human prostate stromal cell line WPMY-1, were used to evaluate the uptake of Caba-780 and its antitumor effect in vitro. The distribution, antitumor effect, and safety of Caba-780 were also evaluated in tumor-bearing mouse xenograft models. Our results showed that Caba-780 was efficiently absorbed by DU145 and PC-3 cells and that the cytotoxicity of Caba-780 was significantly stronger than that of IR-780 and cabazitaxel. In addition, Caba-780 inhibited the migration and invasion of DU145 and PC-3 cells and promoted apoptosis by prolonging the G2 phase of the cell cycle. Further analysis indicated that Caba-780 could be used to effectively image tumor xenografts. At the same time, this drug inhibited the growth of tumors in vivo. Therefore, the new synthetic drug Caba-780 has potential applications in the diagnosis and treatment of CRPC.

14.
Artigo em Inglês | MEDLINE | ID: mdl-32364293

RESUMO

Alkyne is a biologically significant moiety found in many natural products and a versatile functional group widely used in modern chemistry. Recent studies have revealed the biosynthesis of acetylenic bonds in fatty acids and amino acids. However, the molecular basis for the alkynyl moiety in acetylenic prenyl chains occurring in a number of meroterpenoids remains obscure. Here, we identify the biosynthetic gene cluster and characterize the biosynthetic pathway of an acetylenic meroterpenoid biscognienyne B based on heterologous expression, feeding experiments and in vitro assay. We discover that the alkyne moiety is constructed by an unprecedented cytochrome P450 enzyme BisI, which shows promiscuous activity towards C5 and C15 prenyl chains. This finding provides an opportunity for discovery of new compounds featured with acetylenic prenyl chains through genome mining, and expands the enzyme inventory for de novo biosynthesis of alkyne.

16.
J Hematol Oncol ; 13(1): 38, 2020 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-32299513

RESUMO

Rituximab in combination with chemotherapy has shown efficacy in patients with diffuse large B-cell lymphoma (DLBCL) for more than 15 years. HLX01 was developed as the rituximab biosimilar following a stepwise approach to demonstrate biosimilarity in analytical, pre-clinical, and clinical investigations to reference rituximab. With demonstrated pharmacokinetic similarity, a phase 3 multi-center, randomized, parallel, double-blind study (HLX01-NHL03) was subsequently conducted to compare efficacy and safety between HLX01 plus cyclophosphamide, doxorubicin, vincristine, and prednisone (H-CHOP) and reference rituximab plus CHOP (R-CHOP) in a total of 407 treatment-naïve, CD20-positive DLBCL patients aged 18-80 years. The primary efficacy endpoint was best overall response rate (ORR) within six cycles of treatment in the per-protocol set (PPS). Secondary endpoints included 1-year efficacy outcomes, safety, and immunogenicity profile. The results showed difference in ORRs [H-CHOP 94.1%; R-CHOP 92.8%] between two treatment groups was 1.4% (95% confidence interval [CI], - 3.59 to 6.32, p = 0.608) which falls within the pre-defined equivalence margin of ± 12%. The safety profile was comparable between the treatment groups, with a similar overall incidence of treatment-emergent adverse events (H-CHOP 99.5%, R-CHOP 99.0%, p = 1.000) and serious adverse events (H-CHOP 34.0%, R-CHOP 32.5%, p = 0.752). This study established bioequivalence in efficacy and safety between HLX01 and reference rituximab. The trial was registered at http://www.chinadrugtrials.org.cn on 26 August 2015 [#CTR20150583].

17.
Chem Commun (Camb) ; 2020 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-32323669

RESUMO

We report on a supramolecular sensor array using fluorogenic peptide probes and graphene oxide that can target glycoproteins on a viral caspid, facilitating the differentiation of ebola virus from marburg virus and receptor-extensive vesicular stomatitis virus using principal component analysis.

18.
Mol Carcinog ; 2020 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-32319143

RESUMO

Lactate dehydrogenase isozyme (LDH) is a tetramer constituted of two isoforms, LDHA and LDHB, the expression of which is associated with cell metabolism and cancer progression. Our previous study reveals that CC-chemokine ligand-18 (CCL18) is involved in progression of prostate cancer (PCa).This study aims to investigate how CCL18 regulates LDH isoform expression, and therefore, contributes to PCa progression. The data revealed that the expression of LDHA was upregulated and LDHB was downregulated in PCa cells by CCL18 at both messenger RNA and protein levels. The depletion of CCR8 reduced the ability of CCL18 to promote the proliferation, migration, and lactate production of PCa cells. Depletion of a CCR8 regulated transcription factor, ARNT, significantly reduced the expression of LDHA. In addition, The Cancer Genome Atlas dataset analyses revealed a positive correlation between CCR8 and ARNT expression. Two dimension difference gel electrophoresis revealed that the LDHA/LDHB ratio was increased in the prostatic fluid of patients with PCa and PCa tissues. Furthermore, increased LDHA/LDHB ratio was associated with poor clinical outcomes of patients with PCa. Together, our results indicate that the CCR8 pathway programs LDH isoform expression in an ARNT dependent manner and that the ratio of LDHA/LDHB has the potential to serve as biomarkers for PCa diagnosis and prognosis.

19.
Metab Eng ; 60: 119-127, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32315761

RESUMO

Halophilic Halomonas bluephagenesis (H. bluephagenesis), a chassis for cost-effective Next Generation Industrial Biotechnology (NGIB), was for the first time engineered to successfully produce L-threonine, one of the aspartic family amino acids (AFAAs). Five exogenous genes including thrA*BC, lysC* and rhtC encoding homoserine dehydrogenase mutant at G433R, homoserine kinase, L-threonine synthase, aspartokinase mutant at T344M, S345L and T352I, and export transporter of threonine, respectively, were grouped into two expression modules for transcriptional tuning on plasmid- and chromosome-based systems in H. bluephagenesis, respectively, after pathway tuning debugging. Combined with deletion of import transporter or/and L-threonine dehydrogenase encoded by sstT or/and thd, respectively, the resulting recombinant H. bluephagenesis TDHR3-42-p226 produced 7.5 g/L and 33 g/L L-threonine when grown under open unsterile conditions in shake flasks and in a 7 L bioreactor, respectively. Engineering H. bluephagenesis demonstrates strong potential for production of diverse metabolic chemicals.

20.
J Org Chem ; 85(10): 6252-6260, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32298579

RESUMO

A one-pot synthesis of 1,3-diyne-tethered trifluoromethylcyclopropanes starting from 2-CF3-3,5-diyne-1-enes and sulfur ylides via a sulfur ylide mediated cyclopropanation and a DBU-mediated epimerization sequence is described in this work. This process is highly diastereoselective with broad substrate scope. Moreover, a series of synthetic transformations based on the diyne moieties were conducted smoothly, affording cyclopropanes featuring trifluoromethyl-substituted all-carbon quaternary centers.

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