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1.
Int J Antimicrob Agents ; : 106332, 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33798705

RESUMO

Among the 10 reported mcr genes, mcr-9 was firstly identified in Salmonella enterica Serotype Typhimurium, which was a leading cause of foodborne illness worldwide. But information about the prevalence and genetic features of mcr-9 is still lacking, especially among food samples. In this study, we found that mcr-9 had emerged in raw milk samples from China at a low prevalence rate of 0.83% (1/120). The mcr-9 was located on a transferable plasmid, and it was stable in wild-type S. enterica, however, it caused biological fitness cost when transfered to E. coli recipient. WGS revealed that the mcr-9 was located on IncHI2A-type plasmid, and surrounded by IS903B and IS26 in its flanking regions. The mcr-9-carrying S. enterica 19SE belonged to ST26 and presented multi-drug resistance phenotype. It was confirmed that mcr-9 did not mediate colistin resistance in our study, indicating its transfer may not facilitate the dissemination of colistin resistance.

2.
Environ Sci Technol ; 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33825446

RESUMO

Schwertmannite effectively sorbs chromate (Cr(VI)), yet the sorption mechanisms remain elusive. We determined the Cr(VI) sorption mechanisms on schwertmannite at pH 3.2 and 5 using combined macroscopic sorption experiments with molecular-scale characterization and by comparing them to arsenate (As(V)) sorption. Cr(VI) adsorbs as bidentate-binuclear (BB) inner-sphere complexes through exchanging more sulfate and less >Fe-OH/OH2, with 0.59-0.71 sulfate released per Cr(VI) sorbed. While As(V) also forms BB complexes, it exchanges sulfate and >Fe-OH/OH2 equally with 0.49-0.52 sulfate released per As(V) sorbed. At high As(V) loadings, As(V) precipitates as amorphous FeAsO4, particularly at low pH. The abovementioned differences between Cr(VI) and As(V) can be related to their different ionic radii and binding strength. Moreover, Cr(VI) and As(V) preferentially exchange sulfate inner-sphere complexes, increasing the proportion of sulfate outer-sphere complexes in schwertmannite. In turn, the concentration of sulfate outer-sphere complexes increases and then decreases with increasing Cr(VI) loading. Results suggest that an oxyanion, which would form inner-sphere complexes on a mineral surface, preferentially exchanges inner-spherically bound oxyanions than outer-spherically bound ones on the surface, even though both are exchanged. This study improves our understanding of the sorption of oxyanions on schwertmannite and their capabilities to template schwertmannite formation and stabilize its structure.

3.
Int J Mol Sci ; 22(7)2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33807157

RESUMO

Alzheimer's disease (AD) is a growing concern in modern society, and effective drugs for its treatment are lacking. Uncaria rhynchophylla (UR) and its main alkaloids have been studied to treat neurodegenerative diseases such as AD. This study aimed to uncover the key components and mechanism of the anti-AD effect of UR alkaloids through a network pharmacology approach. The analysis identified 10 alkaloids from UR based on HPLC that corresponded to 90 anti-AD targets. A potential alkaloid target-AD target network indicated that corynoxine, corynantheine, isorhynchophylline, dihydrocorynatheine, and isocorynoxeine are likely to become key components for AD treatment. KEGG pathway enrichment analysis revealed the Alzheimers disease (hsa05010) was the pathway most significantly enriched in alkaloids against AD. Further analysis revealed that 28 out of 90 targets were significantly correlated with Aß and tau pathology. These targets were validated using a Gene Expression Omnibus (GEO) dataset. Molecular docking studies were carried out to verify the binding of corynoxine and corynantheine to core targets related to Aß and tau pathology. In addition, the cholinergic synapse (hsa04725) and dopaminergic synapse (hsa04728) pathways were significantly enriched. Our findings indicate that UR alkaloids directly exert an AD treatment effect by acting on multiple pathological processes in AD.

4.
Anal Chim Acta ; 1154: 338310, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33736798

RESUMO

Novel coronavirus disease (COVID-19) caused by SARS-CoV-2 is an ongoing global pandemic associated with high rates of morbidity and mortality. RT-qPCR has become the diagnostic standard for the testing of SARS-CoV-2 in most countries. COVID-19 diagnosis generally relies upon RT-qPCR-mediated identification of SARS-CoV-2 viral RNA, which is costly, labor-extensive, and requires specialized training and equipment. Herein, we established a novel one-tube rapid diagnostic approach based upon formamide and colorimetric RT-LAMP (One-Pot RT-LAMP) that can be used to diagnose COVID-19 without the extraction of specific viral RNA. The technique could visually detect SARS-CoV-2 within 45 min with a limit of detection of 5 copies per reaction in extracted RNA, and about 7.66 virus copies per µL in viral transport medium. The One-Pot RT-LAMP test showed a high specificity without cross-reactivity with 12 viruses including SARS-CoV, MERS-CoV, and human infectious influenza virus (H1N1/H3N2 of influenza A and B virus, ect. We validated this One-Pot RT-LAMP approach by its successful use for the analysis of 45 clinical nasopharyngeal swab samples, yielding results identical to those of traditional RT-qPCR analyses, while achieving good selectivity and sensitivity relative to a commercial RT-qPCR approach. As such, this One-Pot RT-LAMP technology may be a valid means of conducting high-sensitivity, low-cost and rapid SARS-CoV-2 identification without the extraction of viral RNA.


Assuntos
/métodos , /diagnóstico , /virologia , Primers do DNA/química , Primers do DNA/metabolismo , Humanos , Limite de Detecção , Técnicas de Diagnóstico Molecular , Nasofaringe/virologia , Técnicas de Amplificação de Ácido Nucleico , RNA Viral/análise , RNA Viral/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , /isolamento & purificação , Fatores de Tempo
5.
Blood ; 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33728465

RESUMO

Venetoclax, a Bcl-2 inhibitor, in combination with the hypomethylating agent, Azacytidine, achieves complete response with or without count recovery in approximately 70% of treatment-naïve elderly patients unfit for conventional intensive chemotherapy. However, the mechanism of action of this drug combination is not fully understood. We discovered that Venetoclax directly activated T cells to increase their cytotoxicity against AML in vitro and in vivo. Venetoclax enhanced T cell effector function by increasing ROS generation through inhibition of respiratory chain supercomplexes formation. In addition, Azacytidine induced a viral-mimicry response in AML cells by activating the STING/cGAS pathway, thereby rendering the AML cells more susceptible to T-cell mediated cytotoxicity. Similar findings were seen in patients treated with Venetoclax as this treatment increased ROS generation and activated T cells. Collectively, this study demonstrates a new immune mediated mechanism of action for Venetoclax and Azacytidine in the treatment of AML and highlights a potential combination of Venetoclax and adoptive cell therapy for patients with AML.

6.
Chem Commun (Camb) ; 2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33729261

RESUMO

The new oxonitridosilicates Ln4-xSr2+xSi5N12-xOx (Ln = La, Ce) were synthesized by high temperature solid-state reactions. The crystal structures were solved and refined from both single-crystal and powder X-ray diffraction data. These oxonitridosilicate compounds crystallize in the monoclinic space group P21/n (no. 14) and exhibit a double-layer structure made up of corner-sharing Si(O/N)4 tetrahedra. When excited with near-UV and blue light, the Pr3+ doped La2.31Sr3.69Si5N10.31O1.69 phosphor shows a narrow-band red emission peaking at 625 nm with a full width at half-maximum of 40 nm.

7.
Sci Total Environ ; 776: 145911, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33647655

RESUMO

Dissolved organic carbon (DOC) and nitrogen (N) play essential roles in global C and N cycles. To address the possible role of DOC and N in precipitation and enrich the related global database, the characteristics of DOC and N in precipitation were investigated in a typical remote permafrost region (upper Heihe River Basin) of the northern Tibetan Plateau (TP) from February 2019 to March 2020. The results demonstrated that the average DOC and total dissolved N (TDN) concentrations in the precipitation were 1.41 ± 1.09 µg mL-1 and 0.84 ± 0.48 µg mL-1, respectively, with relatively lower concentrations in the summer. The annual DOC and TDN fluxes were estimated to be 6.42 kg ha-1 yr-1 and 3.39 kg ha-1 yr-1, respectively, indicating that precipitation was a significant factor in C and N deposition. The light-absorbing properties of precipitation DOC from the SUVA254 and spectral slope revealed that precipitation DOC containing more aromatic components and lower molecular weights mostly was present during the summer; the mass cross-section (at the wavelength of 365 nm) ranged 0.26-1.84 m2 g-1, suggesting the potential impact of DOC on climatic forcing in the area. The principal component analysis combined with air mass backward trajectories indicated that the air masses from west Siberia, Central Asia, and northwestern China most significantly influenced the precipitation C and N in the study area. The WRF-Chem simulations and aerosol vertical distributions further illustrated the air mass transport pathways, demonstrating that dust and anthropogenic emissions could be transported over the studied area by westerlies and monsoonal winds. In the study basin, the precipitation deposition of DOC and N contributed largely to the riverine DOC and N exportation during the summer and had potential ecological effects. These results highlight the importance of DOC and N deposition from precipitation in the northern TP.

9.
Int Immunopharmacol ; 93: 107447, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33601247

RESUMO

BACKGROUND: Long-acting muscarinic antagonist/long-acting ß2-agonist (LAMA/LABA, also known as dual bronchodilator) and inhaled corticosteroid/LABA (ICS/LABA) are the cornerstone of maintenance treatment for stable chronic obstructive pulmonary disease (COPD) patients. We aimed to comprehensively compare the efficacy and safety of the two maintenance treatment in COPD patients. METHODS: We searched the database Embase, Cochrane Library, PubMed, and Clinical Trials.gov systematically (from inception until September 2020). Randomized controlled trials (RCTs) comparing dual bronchodilator with ICS/LABA in the treatment of COPD were included. Efficacy and safety endpoints were pooled as mean differences (MDs) and risk ratios (RRs) with 95% confidence intervals (CIs). This meta-analysis was registered with PROSPERO prospectively # CRD42020203314). RESULTS: Fourteen RCTs including 21,496 patients were included. Dual bronchodilator showed a greater improvement in both trough FEV1 (MD = 0.06 L, 95% CI: 0.04-0.07, P < 0.001) and FVC (FVC: MD = 0.12 L, 95% CI: 0.07-0.16, P < 0.001), and a lower risk of pneumonia (RR = 0.62, 95% CI: 0.53-0.72, P < 0.001) in patients with COPD. There were no significant differences neither in the improvement of exacerbations, symptoms, and quality of life, nor in the incidence of cardiovascular events, serious adverse events, all-cause mortality, and withdrawals due to adverse events of treatment between these two maintenance treatments. CONCLUSIONS: Dual bronchodilator is superior to ICS/LABA in improving lung function and is associated with a lower risk of pneumonia in patients with COPD. There are no significant differences in other efficacy and safety profiles between these two maintenance treatments.

10.
Am J Trop Med Hyg ; 2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33556042

RESUMO

Malaria risk factor assessment is a critical step in determining cost-effective intervention strategies and operational plans in a regional setting. We develop a multi-indicator multistep approach to model the malaria risks at the population level in western Kenya. We used a combination of cross-sectional seasonal malaria infection prevalence, vector density, and cohort surveillance of malaria incidence at the village level to classify villages into malaria risk groups through unsupervised classification. Generalized boosted multinomial logistics regression analysis was performed to determine village-level risk factors using environmental, biological, socioeconomic, and climatic features. Thirty-six villages in western Kenya were first classified into two to five operational groups based on different combinations of malaria risk indicators. Risk assessment indicated that altitude accounted for 45-65% of all importance value relative to all other factors; all other variable importance values were < 6% in all models. After adjusting by altitude, villages were classified into three groups within distinct geographic areas regardless of the combination of risk indicators. Risk analysis based on altitude-adjusted classification indicated that factors related to larval habitat abundance accounted for 63% of all importance value, followed by geographic features related to the ponding effect (17%), vegetation cover or greenness (15%), and the number of bed nets combined with February temperature (5%). These results suggest that altitude is the intrinsic factor in determining malaria transmission risk in western Kenya. Malaria vector larval habitat management, such as habitat reduction and larviciding, may be an important supplement to the current first-line vector control tools in the study area.

11.
Vet Microbiol ; 254: 109009, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33640677

RESUMO

Macrolide and tetracycline resistance in streptococci is mainly caused by acquisition of integrative and conjugative elements (ICEs) of the ICESa2603 family carrying erm(B) and tet(O). But the characteristics about the transferability and physiological consequences of ICEs with triplet serine integrases are still rare. This study tested the transferability of ICESsuYZDH1_SSU0877, a novel erm(B)- and tet(O)-carrying ICESa2603 family-like ICE with triplet serine integrases, and evaluated the physiological consequences after ICE transferred and integrated into recipient. The prevalence of ICESsuYZDH1-like ICEs in S. suis was analyzed based on 1334 genomic sequences available in GenBank and examined in 330 clinical isolates in China. Nonconservative transfer was observed by integrating of ICESsuYZDH1 into SSU1797 gene besides the primary SSU0877 site. Imperfect direct repeats of 2-/4-nt (5'-TC-3'/5'-TCCC-3') and (5'-GC-3'/5'-TCCC-3') were observed at SSU0877 and SSU1797 sites, respectively. The transconjugant suffered a weak fitness cost with stunted growth and less competition with recipient strain. Successive passages indicate the ICESsuYZDH1 could be persist and endued stable resistant phenotype. Comprehensive analysis of the ICESsuYZDH1-like ICEs from both public genome database and our clinical isolates revealed the widespread and diversity of the ICEs by integration at the sites of SSU0877, SSU0468, SSU1262, and SSU1797. The ICESsuYZDH1-like ICEs could stably co-exist within the host chromosome at more than one attachment sites, which is probably mediated by the triplet serine integrases. Nonconservative integration and diversity of the ICESsuYZDH1 family of ICEs might have contributed to the evolution of ICEs and the dissemination of macrolide and tetracycline resistance in S. suis.

12.
Clin Cancer Res ; 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33547200

RESUMO

PURPOSE: Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma that can be divided into two classes: virus-positive (VP) MCC, associated with oncogenic Merkel cell polyomavirus (MCPyV); and virus-negative (VN) MCC, associated with photodamage. EXPERIMENTAL DESIGN: We classified 346 MCC tumors from 300 patients for MCPyV using a combination of IHC, ISH, and qPCR assays. In a subset of tumors, we profiled mutation status and expression of cancer-relevant genes. MCPyV and molecular profiling results were correlated with disease-specific outcomes. Potential prognostic biomarkers were further validated by IHC. RESULTS: A total of 177 tumors were classified as VP-MCC, 151 tumors were VN-MCC, and 17 tumors were indeterminate. MCPyV positivity in primary tumors was associated with longer disease-specific and recurrence-free survival in univariate analysis, and in multivariate analysis incorporating age, sex, immune status, and stage at presentation. Prioritized oncogene or tumor suppressor mutations were frequent in VN-MCC but rare in VP-MCC. TP53 mutation developed with recurrence in one VP-MCC case. Importantly, for the first time we find that VP-MCC and VN-MCC display distinct sets of prognostic molecular biomarkers. For VP-MCC, shorter survival was associated with decreased expression of immune markers including granzyme and IDO1. For VN-MCC, shorter survival correlated with high expression of several genes including UBE2C. CONCLUSIONS: MCPyV status is an independent prognostic factor for MCC. Features of the tumor genome, transcriptome, and microenvironment may modify prognosis in a manner specific to viral status. MCPyV status has clinicopathologic significance and allows for identification of additional prognostic subgroups.

14.
Med Oncol ; 38(3): 26, 2021 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-33586037

RESUMO

Neuroendocrine transdifferentiation of high-grade prostate cancer (PCA-NT) comprises a morphologic and immunophenotypic transition from conventional adenocarcinoma towards high-grade neuroendocrine/small cell carcinoma. This phenomenon is frequently observed post androgen deprivation and/or radiotherapy, but de novo instances are increasingly recognized. Herein, we report a series of de novo PCA-NT focusing on characteristic morphologic, immunophenotypic and clinical features. Treatment naïve PCA-NT were identified. IHC for PSA, NKX3.1, Chromogranin, Synaptophysin, Cyclin D1, RB and Ki67 were performed. Radiology, treatment and follow-up data were reviewed. Sixteen patients were included. Apart from focal areas of high-grade prostate cancer with acinar features (reminiscent of Grade Group 5 disease), extensive areas with sheets of cells with deep amphophilic/basophilic cytoplasm, enlarged, hyperchromatic nuclei with granular chromatin and inconspicuous to prominent nucleoli with high mitotic activity were identified. Immunohistochemistry showed patchy NKX3.1, patchy PSA, variable Synaptophysin and Chromogranin; RB and CyclinD1 showed loss of expression. Ki67 showed high proliferative index, in most cases. Adverse radiologic findings and metastases were documented in most cases. Two patients died of disease. De novo PCA-NT exhibits high-grade nuclei, high mitotic activity, reduced PSA expression with high Ki67 and functional inactivation of RB1 pathway, suggesting transition from androgen-driven to proliferation-driven phenotype. Most cases presented at advanced stage with adverse radiological findings, metastasis at time of diagnosis, and high mortality. In light of their prognostic and therapeutic implications, pathologists may need to maintain a sensitive threshold for performing immunostains-in particular, Ki67 and CyclinD1-when presented with such cases in their day to day clinical practice.

15.
Artigo em Inglês | MEDLINE | ID: mdl-33547605

RESUMO

How to satisfy food production sustainably in the rapid urbanizing process is a vital problem for major grain-producing areas. Taking two national grain-producing regions in China, Shandong and Dongting Lake Region as examples, this study uses step-by-step prediction and a double-objective linear programming model to analyze the dilemma of land scarcity, food demand, and environmental load. It is found that food demand by 2030 will induce partial regional cropland deficiency and heterogeneous agro-environmental risk among cities. The double-objective linear programming model finds possible solutions in different scenarios: on the premise of keeping the current cropland area unchanged, the upper threshold of crop yield by 2030 will be 2539.06 × 104 t in Dongting and 7175.13 × 104 t in Shandong, respectively. On the condition of guaranteeing food self-sufficiency and minimizing the environmental load, the lower threshold of arable land area should be 99.47 × 104 ha in Dongting and 436.85 × 104 ha in Shandong. Pollutant reduction will be realized by reallocation of agro-production task and optimized practices. The food carbon impact can be reduced by up to 1.27 kg CO2 eq/kg. This study contributes to feasible pathways towards adequate agro-production, lessened land scarcity, and minimal environmental risk for rapid urbanizing cities in a sustainable way.

16.
Sci Rep ; 11(1): 3865, 2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33594140

RESUMO

Cleft palate repair is a challenging procedure for cleft surgeons to teach, and in research, it can be difficult to evaluate different techniques and develop new treatments. In this study, a congenital cleft palate New Zealand rabbit model has been described and could be beneficial in future studies concerning cleft palate repair. Pregnant New Zealand rabbits received 1.0 mg dexamethasone injection intramuscularly once a day from the 13th gestation day (GD13) to GD16. On GD31. Newborn rabbits were delivered by cesarean sections, fed with a standardized gastric tube feeding method, and divided into two groups. The rate of survival and the incidence of cleft palate was calculated. Weight, appearance, behavior, maxillary occlusal view, and regional anatomic and histological comparisons were recorded within 1 month after birth. Infants from the two groups with similar physiological conditions were selected for continuous maxillofacial and mandibular Micro-CT scan and three-dimensional reconstruction analysis. Ten pregnant rabbits gave birth to 48 live infants. The survival and cleft palate rates were 65.6% and 60.4% respectively. Both groups survived over 1 month with no difference in weight, appearance, and behavior. The cleft type was stable, and anatomical defects, histological characteristics, and nasal-maxillary abnormalities of the cleft were similar to those of humans. There was no statistically significant difference in maxillary and mandible development between the two groups within one month after birth. This congenital cleft palate model is considered to have more research possibilities with efficient cleft induction, reliable feeding methods, stable anatomical defects, and maxillofacial development similar to those seen in humans.

17.
Nucl Med Commun ; 42(5): 528-534, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33481504

RESUMO

OBJECTIVE: The aim of this study was to investigate the expression of TP53-inducible glycolysis and apoptosis regulator (TIGAR) and its relationship with clinical pathology and prognosis; and to analyze the correlation between TIGAR expression and 18F-labeled fluoro-2-deoxyglucose (18F-FDG) PET/computed tomography (CT) parameters in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: We retrospectively analyzed the data of 23 patients who underwent preoperative 18F-FDG PET/CT examinations and were confirmed to have PDAC by postoperative pathology. TIGAR was detected using immunohistochemistry. The relationships between TIGAR expression and clinicopathology and its value in predicting the prognosis of patients with PDAC were analyzed. The correlations between TIGAR expression and 18F-FDG PET/CT parameters [standard uptake value (SUV) max, SUVmean, SUVpeak, metabolic tumor volume (MTV), and total lesion glycolysis (TLG)] were analyzed. RESULTS: The expression of TIGAR was low in 34.8% of patients and high in 65.2% of patients. There was no correlation between TIGAR expression and clinicopathology. The overall survival of patients with high TIGAR expression was significantly shorter than that of patients with low TIGAR expression (11.2 vs. 35.4 months). The 18F-FDG PET/CT parameters: SUVmax, SUVmean, SUVpeak, MTV, and TLG were positively correlated with TIGAR expression, but only the MTV correlation with TIGAR expression was statistically significant. CONCLUSION: TIGAR is highly expressed in PDAC. Its expression is independent of clinicopathological data and can be used as an independent prognostic factor. TIGAR expression was significantly positively correlated with the 18F-FDG PET/CT parameter MTV.

18.
Free Radic Biol Med ; 165: 191-202, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33515753

RESUMO

Cardiac hypertrophy, an important cause of heart failure, is characterized by an increase in heart weight, the ventricular wall, and cardiomyocyte volume. The volume regulatory anion channel (VRAC) is an important regulator of cell volume. However, its role in cardiac hypertrophy remains unclear. The purpose of this study was to investigate the effect of leucine-rich repeat-containing 8A (LRRC8A), an essential component of the VRAC, on angiotensin II (AngII)-induced cardiac hypertrophy. Our results showed that LRRC8A expression, NADPH oxidase activity, and reactive oxygen species (ROS) production were increased in AngII-induced hypertrophic neonatal mouse cardiomyocytes and the myocardium of C57/BL/6 mice. In addition, AngII activated VRAC currents in cardiomyocytes. The delivery of adeno-associated viral (AAV9) bearing siRNA against mouse LRRC8A into the left ventricular wall inhibited AngII-induced cardiac hypertrophy and fibrosis. Accordingly, the knockdown of LRRC8A attenuated AngII-induced cardiomyocyte hypertrophy and VRAC currents in vitro. Furthermore, knockdown of LRRC8A suppressed AngII-induced ROS production, NADPH oxidase activity, the expression of NADPH oxidase membrane-bound subunits Nox2, Nox4, and p22phox, and the translocation of NADPH oxidase cytosolic subunits p47phox and p67phox. Immunofluorescent staining showed that LRRC8A co-localized with NADPH oxidase membrane subunits Nox2, Nox4, and p22phox. Co-immunoprecipitation and analysis of a C-terminal leucine-rich repeat domain (LRRD) mutant showed that LRRC8A physically interacts with Nox2, Nox4, and p22phox via the LRRD. Taken together, the results of this study suggested that LRRC8A might play an important role in promoting AngII-induced cardiac hypertrophy by interacting with NADPH oxidases via the LRRD.

19.
Theranostics ; 11(5): 2108-2122, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33500714

RESUMO

Rationale: Protein kinases are critical therapeutic targets for curing hepatocellular carcinoma (HCC). As a serine/threonine kinase, the potential roles of serine/threonine kinase 39 (STK39) in HCC remain to be explored. Methods: The expression of STK39 was examined by RT-qPCR, western blotting and immunohistochemistry. Cell proliferation and apoptosis were detected by CCK8 and TUNEL kit. Cell migration and invasion assays were performed using a transwell system with or without Matrigel. RNA-seq, mass spectrometry and luciferase reporter assays were used to identify STK39 binding proteins. Results: Here, we firstly report that STK39 was highly overexpressed in clinical HCC tissues compared with adjacent tissues, high expression of STK39 was induced by transcription factor SP1 and correlated with poor patient survival. Gain and loss of function assays revealed that overexpression of STK39 promoted HCC cell proliferation, migration and invasion. In contrast, the depletion of STK39 attenuated the growth and metastasis of HCC cells. Moreover, knockdown of STK39 induced the HCC cell cycle arrested in the G2/M phase and promoted apoptosis. In mechanistic studies, RNA-seq revealed that STK39 positively regulated the ERK signaling pathway. Mass spectrometry identified that STK39 bound to PLK1 and STK39 promoted HCC progression and activated ERK signaling pathway dependent on PLK1. Conclusions: Thus, our study uncovers a novel role of STK39/PLK1/ERK signaling axis in the progress of HCC and suggests STK39 as an indicator for prognosis and a potential drug target of HCC.

20.
Artigo em Inglês | MEDLINE | ID: mdl-33486611

RESUMO

BACKGROUND: LncRNAs play an important role in the regulation of the killing effect of cytotoxic CD8 + T cells in various cancers. However, the role and underlying mechanisms of UCA1 in the killing effect of cytotoxic CD8 + T cells in anaplastic thyroid carcinoma (ATC) are not clear. METHODS: UCA1, miR-148a, and PD-L1 expression were detected by quantitative real-time PCR and/or Western blot. The ratio of PD-L1+ATC cells/ATC cells was determined using flow cytometry. The ability of CD8 + T cells to kill target ATC cells was detected by Chromium-51 (51Cr) release assay. The targeted relationship between UCA1 and miR-148a was confirmed by dual-luciferase reporter gene assay. RESULTS: UCA1 and PD-L1 expression levels were elevated in ATC tissues and cells. Silencing UCA1 and PD-L1 enhanced the killing effect of cytotoxic CD8 + T cells on ATC cells. UCA1 negatively regulated the expression of miR-148a, and miR-148a targeted PD-L1 to down-regulate its expression. Besides, we found that UCA1 attenuated the killing effect of cytotoxic CD8 + T cells and reduced cytokine secretion through PD-L1 and miR-148a. Finally, silencing UCA1 or PD-L1 in ATC cells restored the suppression of the killing effect of CD8 + T cells in vivo. CONCLUSION: UCA1 attenuated the killing effect of cytotoxic CD8 + T cells on ATC cells through the miR-148a/PD-L1 pathway.

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