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1.
Respir Res ; 21(1): 62, 2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32111211

RESUMO

BACKGROUND: This study was to investigate of the mechanism by which histone deacetylase (HDAC) 8 inhibitor ameliorated airway hyperresponsiveness (AHR) and allergic airway inflammation. METHODS: Mice were sensitized and then treated with budesonide (BUD) or PCI-34051 (PCI) prior to exposing to normal saline (NS) or ovalbumin (OVA). The raw264.7 cells were treated with interleukin (IL)-4 and PCI or shRNA alone. Repetitive measurements of enhanced pause (Penh) were executed by increasing concentrations of acetyl-ß-methacholine chloride (0 - 50 mg/ml). Cells in bronchoalveolar lavage fluid (BALF) and pathological changes of lungs were examined, respectively. The expression levels of HDAC8, Galecitn (Gal)-3, CD68, CD86, CD163, Arg1 and NOS2 in lungs were measured. Co-regulation of HDAC8 and Gal-3 proteins was observed by immunofluorescence staining and co-immunoprecipitation assay (Co-IP). RESULTS: Significant increases in Penh and IL-4 level were detected with a large inflammatory infiltrate, comprised predominantly of macrophages and eosinophils, into the BALF in OVA-exposed lungs. HDAC8, Gal-3, CD68, CD86, CD163, Arg1 and NOS2 proteins were over-expressed with the significant changes in the Arg1 and NOS2 mRNA levels in the lungs and the IL-4-treated cells. PCI intervention obviously reduced the counts of CD163+ cells. Furthermore, Gal-3 knockdown suppressed Arg1 expression in the cells. Immunofluorescence staining displayed simultaneous changes in HDAC8 and Gal-3 expression in the investigated samples. Treatment with PCI resulted in synchronous reduction of HDAC8 and Gal-3 expression in the Co-IP complexes. CONCLUSIONS: The HDAC8 inhibitor ameliorates AHR and airway inflammation in animal model of allergic asthma through reducing HDAC8-Gal-3 interaction and M2 macrophage polarization.

2.
Adv Ther ; 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32152869

RESUMO

INTRODUCTION: This pre-specified subgroup analysis evaluated the efficacy and safety of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI) triple therapy versus corresponding dual therapies in the China subgroup of the phase III, double-blind KRONOS study in patients with moderate to very severe chronic obstructive pulmonary disease (COPD). METHODS: Patients were randomized 2:2:1:1 to BGF MDI 320/18/9.6 µg, glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6 µg, budesonide/formoterol fumarate (BFF) MDI 320/9.6 µg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 400/12 µg twice daily for 24 weeks. The primary endpoint was change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) over weeks 12-24. Secondary endpoints included symptoms, health-related quality of life, and safety. Rate of moderate/severe COPD exacerbations was an additional efficacy endpoint. RESULTS: In the China subgroup (n = 432; 22.7% of the KRONOS population), BGF MDI demonstrated nominally significant improvements in the primary endpoint versus BFF MDI (least squares mean (LSM) difference 68 mL; P = 0.0035) and BUD/FORM DPI (LSM difference 78 mL; P = 0.0010) but not GFF MDI (LSM difference - 4 mL; P = 0.8316). BGF MDI demonstrated at least numerical improvements versus comparators in secondary lung function and symptom endpoints. BGF MDI reduced the rate of moderate/severe COPD exacerbations versus GFF MDI (rate ratio 0.41; P = 0.0030), with numerical benefits versus BFF MDI and BUD/FORM DPI. All treatments were well tolerated. CONCLUSIONS: Results demonstrated that BGF MDI showed benefits on lung function (vs inhaled corticosteroid/long-acting ß2-agonist), as well as symptoms and exacerbations relative to dual therapies. Findings support BGF MDI use in Chinese patients with moderate to very severe COPD. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02497001.

3.
Int J Biol Macromol ; 154: 634-643, 2020 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-32156541

RESUMO

The point mutation in myostatin (MSTN) can produce the Texel sheep double muscle phenotype. However, whether other species have the same mode of action as MSTN and whether breeding materials can be obtained through cross-species genetic editing remain unclear. The mutation in the mouse MSTN 3'UTR could create a target site for mmu-miR-1/206, as verified by the dual luciferase reporter system. A C2C12 cell model with the mutation in MSTN 3'UTR was constructed using CRISPR/Cas9 gene editing. Then, the mRNA and protein expression of MSTN was analyzed in the mutant C2C12 cell model. Results revealed that the mutation blocked the translational level of MSTN. By inhibiting mmu-mir-206, low expression of MSTN protein in mutant C2C12 cell can be rescued. Furthermore, the proliferation and differentiation abilities of the mutant C2C12 cell model were tested by RT-PCR, CCK8 analysis, EDU (5-ethynyl-2'-deoxyuridine) proliferation analysis, immunofluorescence analysis, Western blot, and myotube fusion statistics. This study may serve as a reference for elucidating the function and molecular mechanism of MSTN and as a foundation for accurate breeding improvement.

4.
Mech Ageing Dev ; 187: 111229, 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32171687

RESUMO

Oncogene-induced senescence (OIS) is a powerful intrinsic tumor-suppressive mechanism, arresting cell cycle progression upon oncogene-activating genomic alterations. The discovery and characterization of the senescence-associated secretome unveiled a rich additional complexity to the senescence phenotype, including extrinsic impacts on the microenvironment and engagement of the immune response. Emerging evidence suggests that senescence phenotypes vary depending on the oncogenic stimulus. Therefore, understanding the mechanisms underlying OIS and how they are subverted in cancer will provide invaluable opportunities to identify alternative strategies for treating oncogene-driven cancers. In this review, we primarily discuss the key mechanisms governing OIS driven by the RAS/MAPK and PI3K/AKT pathways and how understanding the biology of senescent cells has uncovered new therapeutic possibilities to target cancer.

5.
Medicine (Baltimore) ; 99(11): e19501, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32176092

RESUMO

BACKGROUND: Clinical and basic research supports that blood glucose fluctuation is an important predictor of diabetic vascular disease and an etiology of lower extremity atherosclerosis, which is an important pathological basis for lower extremity vascular diseases. Previous Chinese National Natural Science Foundation trials (No. 81503566) have reported that the traditional Chinese medicine Shenqi compound can reduce blood glucose fluctuation and low-grade inflammation, and protect blood vessels; however, there are no high-quality clinical evidences available to support the same. This multicenter randomized controlled trial aims to obtain more clinical evidence to confirm the efficacy and safety of Shenqi compound in type 2 diabetes with lower extremity atherosclerosis. METHODS: A multicenter RCT will be implemented in this study for a 32-week study period (8 weeks for intervention and 24 weeks for follow-up). Participants will be recruited from the Teaching Hospital of Chengdu University of TCM, Mianyang Hospital of TCM, and Shuangliu Hospital of TCM. Sixty participants will be randomly divided into a treatment group (basic treatment combined with traditional Chinese medicine Shenqi Compound) or a control group (basic treatment combined with Chinese medicine placebo) with 30 participants in each group. Patients will be selected considering the following inclusion criteria: age between 35 and 65 years, and a positive diagnosis for type 2 diabetes with lower extremity atherosclerosis and TCM syndromes. Primary outcome indicator is an arterial color Doppler ultrasound. Secondary outcome indicators include: blood glucose fluctuation indicators (MBG, SDBG, LAGE), islet ß-cell function evaluation indicators (Homa-IR, Homa-islet, SG, SCP), inflammation indicators (NLR, CRP, IL-6), blood lipids, and HbA1c. Safety index includes vital signs (T, P, R, BP), blood, urine, stool routine, liver and renal function, electrocardiogram, and adverse event records. The endpoint event is defined as the presence of gangrene in the lower limbs. DISCUSSION: Explore the clinical effect of traditional Chinese medicine "Shenqi Compound" to reduce blood glucose fluctuation and use HOMA-IR, the area under the glucose curve, and the area under the C-peptide curve to evaluate the effect of protecting islet ß cell function. TRIAL REGISTRATION: Chinese clinical trial registry (ChiCTR-1900027693). Registered on November 23, 2019. http://www.chictr.org.cn.


Assuntos
Aterosclerose/tratamento farmacológico , Diabetes Mellitus Tipo 2 , Angiopatias Diabéticas/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Hipoglicemiantes/uso terapêutico , Extremidade Inferior/irrigação sanguínea , Medicina Tradicional Chinesa , Aterosclerose/sangue , Aterosclerose/fisiopatologia , Glicemia , China , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/fisiopatologia , Medicamentos de Ervas Chinesas/administração & dosagem , Humanos , Hipoglicemiantes/administração & dosagem , Fitoterapia , Fluxo Pulsátil , Ensaios Clínicos Controlados Aleatórios como Assunto , Fluxo Sanguíneo Regional , Projetos de Pesquisa
6.
Artif Cells Nanomed Biotechnol ; 48(1): 627-638, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32054316

RESUMO

We aimed to evaluate the therapeutic effects of exosomes, which were collected from human neuroepithelial stem cells (HNESCs) treated by miR-29b mimics, on the treatment of spinal cord injury (SCI). Computational analysis, real-time PCR, Western blot analysis and TUNEL assay, a BBB score system, the Nissl staining and IHC assay were conducted to explore the molecular signalling pathway underlying the function of exosomes in SCI. Exosomes isolated from cells treated with HNESC exhibited the strongest inhibitory effect on cell apoptosis while exhibiting the highest level of miR-29b expression and the lowest levels of PTEN and caspase-3 expression. Moreover, PTEN and caspase-3 were identified as the direct target genes of miR-29b. The exosomes isolated from the groups of HNESC and HNESC + miR-29b mimics exhibited in vivo therapeutic effects by restoring the BBB score and apoptosis index of post-SCI neuron cells to those of normal neuron cells, with the exosomes collected from the group of HNESC + miR-29b mimics showing the strongest effect. We suggested that the exosomes derived from the group of HNESC + miR-29b mimics exerted therapeutic effects on SCI by down-regulating the expression of PTEN/caspase-3 and subsequently suppressing the apoptosis of neuron cells.

7.
Medicine (Baltimore) ; 99(8): e19067, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32080080

RESUMO

Unplanned resection of soft-tissue sarcomas (STS) predispose the patients to recurrences and metastases, secondary wide resection is usually warranted.To investigate the outcomes of re-excision of STS after unplanned initial resection.The records of 39 patients undergoing re-excision of STS after unplanned initial resection from January 2006 through December 2015 were retrospectively investigated.There were 17 males and 22 females, the mean age was 45.7 years. Most initial unplanned resections were performed in rural hospitals by surgeons from general surgery department, dermatology department, plastic surgery department, and orthopedic department. Thirty-five patients underwent secondary wide resections in our department. Histopathological findings indicated positive margins after primary surgeries in 18 patients. Until the conclusion of 37.2-month follow-up, 7 patients developed metastasis, 3 had local recurrence, and 7 were dead. Positive margins were associated with increased metastases and lower survival rates (P < .05). There was no significant difference in recurrences between the 2 groups.Unplanned initial resection of STS often lead to unfavorable prognosis. Primary wide resections are warranted for this disease entity.


Assuntos
Reoperação/estatística & dados numéricos , Sarcoma/mortalidade , Sarcoma/cirurgia , Adolescente , Adulto , Idoso , Feminino , Seguimentos , Hospitais Rurais/estatística & dados numéricos , Humanos , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Metástase Neoplásica/patologia , Recidiva Local de Neoplasia/patologia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Prognóstico , Reoperação/mortalidade , Estudos Retrospectivos , Sarcoma/diagnóstico por imagem , Sarcoma/patologia , Taxa de Sobrevida , Adulto Jovem
8.
Nanotechnology ; 31(24): 245703, 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32084658

RESUMO

Fluorochromic materials that change their emission properties in response to their environment are of interest for the development of sensors, optical data storage and light-emitting materials. A thermally fluorochromic elastic polymer film that exhibits remarkable fluorochromism (from red to yellow) and enhancement of fluorescence intensity after thermal treatment (>120 °C) is designed by the incorporation of silver nanoclusters. The thermal treatment also leads to a significant increase of quantum yield and fluorescence lifetime. It is found that the thermo-induced etching on larger silver nanoclusters generates smaller silver nanoclusters. This simple and efficient size-tuning process in solid state is responsible for the thermo-fluorochromism and enhancement of fluorescence emission from silver nanoclusters. Such a thermo-fluorochromic polymer material is finally demonstrated to be useful for thermo-printing. This material illustrates a new way to make smart optical materials, particularly for potential applications in optical data storage and soft OLED display.

9.
J Cell Physiol ; 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32020624

RESUMO

Abnormal expression of KDM6A and SOX9 is a key factor in the pathogenesis of osteoarthritis (OA). Cellular treatments of OA with articular cartilage chondrocytes (ACCs) and bone marrow mesenchymal stem cells (BMSCs) are promising, but their underlying mechanisms remain to be explored. The pellet size, weight and sulfated glycosaminoglycan/DNA content of ACCs were measured to evaluate the effect of BMSCs on the chondrogenic differentiation of SCCs. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to analyze the proliferation of ACCs cultured along or cocultured with BMSCs. Quantitative polymerase chain reaction (qPCR) was performed to evaluate the messenger RNA expression of KDM6A, SOX9, type2 collagen, and Aggrecan in ACCs and OA rats. Western blot and immunohistochemistry were performed to analyze the expression of KDM6A and SOX9 proteins. Bisulfite sequencing PCR was performed to assess the DNA methylation level of the SOX9 promoter. Flow cytometry was used to evaluate the apoptotic status of ACCs. The chondrogenic differentiation of ACCs was significantly enhanced by coculturing with BMSCs, especially under a hypoxic condition. The expression of KDM6A, SOX9, type2 collagen, and Aggrecan was remarkably elevated in ACCs cocultured with BMSCs. Also, the DNA methylation of SOX9 promoter was decreased in ACCs cocultured with BMSCs, along with notably reduced apoptosis. Moreover, ACCs cocultured with BMSCs could repair cartilage lesions and prevent the abnormal expression of KDM6A, SOX9, type2 collagen, and Aggrecan in OA rats. In this study, we cocultured ACCs with BMSCs and used them to treat OA rats. Our findings presented a mechanistic basis for explaining the therapeutic effect of BMSCs on OA treatment.

10.
Sci Total Environ ; 711: 134571, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32000311

RESUMO

Introducing pleasant natural sounds to mask urban noises is an important soundscape design strategy to improve acoustic comfort. This study investigates the effects of signal-to-noise ratio (SNR) between natural sounds (signal) and the target noises (noise) and their temporal characteristics on the perceived loudness of noise (PLN) and overall soundscape quality (OSQ) through a laboratory experiment. Two types of urban noise sources (hydraulic breaker and traffic noises) were set to A-weighted equivalent sound pressure levels (SPL) of 55, 65, and 75 dB and then augmented with two types of natural sounds (birdsong and stream), across a range of SNRs. Each acoustic stimulus was a combination of noise and natural sound at SNRs from -6 to 6 dB. Averaged across all cases, the subjective assessment of PLN showed that augmenting urban noise separately with the two natural sounds reduced the PLN by 17.9%, with no significant differences found between the birdsong and stream sounds. Adding natural sounds increased the OSQ by on average 18.3% across the cases, but their effects gradually decreased as the noise level increased. The OSQ of the birdsong and stream sounds were similar for traffic noise, whereas the stream sound was rated higher than the birdsong for the breaker noise. The results suggest that increasing the dissimilarity in temporal structure between the target noise and natural sounds could enhance the soundscape quality. Appropriate SNRs were explored considering both PLN and OSQ. The results showed that the SNR of -6 dB was desirable when the A-weighted SPL of the noise rose to 75 dB.

11.
J Acoust Soc Am ; 147(1): 206, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32007025

RESUMO

Noise acceptance is an aspect of indoor soundscape research. While staying or walking in a transport hub, sequential sounds form sequence sounds sessions, which are referred to as an acoustic sequence. The basic phenomenon and effects of acoustic sequences on acceptance evaluations have been explored. A total of 209 sections of 30 s acoustic units were extracted before performing acceptance evaluations. The acoustic units were divided into strong, medium, and weak levels, and compiled into 37 pieces of acoustic sequences, which were then subjected to four tests for acceptance evaluation: sound content, acceptance level, and effects of weak and strong acceptance units. One piece of an acoustic sequence consists of 20 acoustic units. The results show that all acoustic sequences exhibit "attenuation effects"-as for any acoustic unit that makes up the sequence, general acceptance decreases with time. The lower the acceptance, the faster the decay in score. High acceptance units have an "enhancement effect," and the acceptance increases after a high acceptance unit. Low acceptance units have a "boost effect," and the acceptance increases after a low-level acceptance. Both enhancement and boost effects could improve the acceptance evaluation of acoustic sequences and sound experiences in transport hubs.

12.
In Vitro Cell Dev Biol Anim ; 56(2): 154-164, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31898012

RESUMO

Cigarette smoke exposure is one of the main etiologies for chronic obstructive pulmonary disease. Moreover, cigarette smoke participates in disease progression by inducing abnormal macrophage polarization; however, the effects of cigarette smoke on M1/M2 macrophage polarization have not been established. The aim of the current study was to determine the effects of cigarette smoke extract (CSE) on M1/M2 macrophage polarization in alveolar and peritoneal macrophages (AM and PM, respectively) at different concentrations and exposure times. Rat AM and PM were cultured with CSE at different concentrations. CCK-8 was used as an indicator of cell viability, and mRNA expression of M1 (iNOS, TNF-α, and IL-1ß) and M2 markers (arg-1, CD206, and TGF-ß1) were measured at 3, 6, 9, 12, and 24 h using qPCR. Expressions of CD86 and CD206 proteins at 12 h were determined using flow cytometry, and the iNOS/arg-1 ratio was used to determine the polarization dominance of M1 and M2. M2 subtypes were detected at 12 h using qPCR and flow cytometry. CSE increased the expression of iNOS, TNF-α, and IL-1ß mRNA, and the proportion of CD86-positive cells in AM and PM promoted M1 polarization, and M1 polarization was continuously enhanced as exposure time and concentration increased. CSE reduced the expression of arg-1, CD206, and TGF-ß1 mRNA and the proportion of CD206-positive cells in AM and PM and inhibited M2 polarization. At 9-24 h of CSE exposure, the expression of arg-1 in AM and PM gradually increased, showing tendency towards activation of M2 polarization. Besides, CSE might induce M2b and M2d polarization at 12 h. After 12 h of CSE exposure, transformation from M1 to M2 polarization dominance was shown in AM; however, M1 polarization was continuously enhanced in PM within 24 h of CSE exposure. CSE promoted M1 polarization in macrophages, exhibiting dynamic regulatory effects on M2 polarization, first as a suppressor and then as a promoter. The polarization change induced by CSE on AM was more sensitive than PM.

13.
BMC Pulm Med ; 20(1): 11, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31931767

RESUMO

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is the fifth leading cause of death in China with a reported prevalence of 8.2% people aged ≥40 years. It is recommended that Chinese physicians follow Global Initiative for Chronic Obstructive Lung Disease (GOLD) and national guidelines, yet many patients with COPD in China remain undiagnosed. Furthermore, missed diagnoses and a lack of standardized diagnosis and treatment remain significant problems. The situation is further complicated by a lack of large-scale, long-term, prospective studies of real-world outcomes, including exacerbation rates, disease severity, efficacy of treatment, and compliance of COPD patients in China. METHODS/DESIGN: The REALizing and improving management of stable COPD in China (REAL) study is a 52-week multi-center, prospective, observational trial. REAL aims to recruit approximately 5000 outpatients aged ≥40 years with a clinical diagnosis of COPD per GOLD 2016. Outpatients will be consecutively recruited from approximately 50 tertiary and secondary hospitals randomly selected across six geographic regions to provide a representative population. Patients will receive conventional medical care as determined by their treating physicians. The primary objective is to evaluate COPD patient outcomes including lung function, health status, exacerbations, hospitalization rate, and dyspnea following 1 year of current clinical practice. Secondary objectives are to assess disease severity, treatment patterns, adherence to medication, and associated risk factors. Data will be collected at two study visits, at patients' usual care visits, and by telephone interview every 3 months. DISCUSSION: Knowledge of COPD among physicians in China is poor. The REAL study will provide reliable information on COPD management, outcomes, and risk factors that may help improve the standard of care in China. Patient recruitment began on 30 June 2017 and the estimated primary completion date is 30 July 2019. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03131362. Registered on 20 March 2017.

14.
J Addict Med ; 14(1): 69-77, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31658113

RESUMO

OBJECTIVE: To evaluate the efficacy in smoking cessation and safety of 2 and 4 mg nicotine mint lozenges in Chinese adult smokers. METHODS: This was a multicenter, randomized, stratified, double-blind, placebo-controlled, parallel-group study. The low-dependence stratum included 483 smokers (241 randomized to active 2 mg nicotine lozenge and 242 to placebo lozenge). The high-dependence stratum included 240 smokers (120 randomized to active 4 mg nicotine lozenge and 120 to placebo lozenge). The primary endpoint was successful smoking cessation at 6 weeks postquit, defined as continuous abstinence from smoking for the 28-day period up to and including the 6-week visit (verified by CO measurement). Cochran-Mantel-Haenszel tests were performed to compare quit rates between active nicotine and placebo separately for the high-dependence and low-dependence strata. RESULTS: The primary analysis showed that in the low-dependence (2 mg) stratum, 59 subjects (24.5%) of 241 in the active nicotine group and 52 subjects (21.5%) of 242 in the placebo group were successful quitters (P = .3851). In the high-dependence (4 mg) stratum, 37 subjects (30.8%) of 120 in the active nicotine group and 24 subjects (20.2%) of 119 in the placebo group were successful quitters (P = .0565). CONCLUSIONS: The 4 mg nicotine lozenge provided a directionally significant improvement in smoking cessation rates compared with placebo in Chinese adult smokers with high nicotine dependence for the primary endpoint. The 2 mg nicotine lozenge provided higher, but nonsignificant, smoking cessation rates than placebo. Both nicotine lozenges were generally well tolerated in Chinese adult smokers.

15.
Reproduction ; 159(1): 91-104, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31721723

RESUMO

Coactivator-associated arginine methyltransferase 1 (CARM1) is a type I arginine methyltransferase that methylates the arginine residues of histone and nonhistone. Carm1 regulates various cellular processes, including transcriptional regulation, mRNA processing, cellular proliferation, and differentiation. Blastomeres with high Carm1 expression levels show cleavage tendency to inner cell mass (ICM) in mouse embryos. However, details about the factors for CARM1 distribution in mouse early embryos and the role of Carm1 in blastocyst development remain unclear. Here, the endonuclear distribution of CARM1 protein was heterogeneous between blastomeres from the late four-cell stage to the blastocyst stage. The heterogeneity of CARM1 distribution in blastomeres at the late four-cell stage was randomly obtained from two-cell stage embryos. From the four-cell stage to morula, CARM1 in individual blastomere remained heterogeneous. In the blastocyst stage, CARM1 protein level in ICM was much higher than that in trophoblast. We found that microRNA (miRNA) miR-181a is an important regulator for Carm1 distribution at the late four-cell stage. The ratio of heterogeneous embryos was reduced in all the embryos when miR-181a was inhibited. CARM1 inhibition reduced the level of symmetrical histone H3 arginine-26 dimethylation and impaired blastocyst development. Silencing Carm1 reduced cell number and increased cell apoptosis at the blastocyst stage. These results show a CARM1 heterogeneous distribution from the four-cell embryos to the blastocysts. miR-181a regulates the control of CARM1 heterogeneous distribution in the four-cell-stage embryos, and CARM1 is an important protein in regulating blastocyst development.

16.
Per Med ; 17(1): 15-22, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31797717

RESUMO

Aim: This study investigated the association between voriconazole-induced liver injury and gene polymorphisms of CYP2C19 and UGT1A4. Materials & methods: Thirty-eight adult patients who received voriconazole therapy were included in the study. Genotype of CYP2C19 was detected using gene chip hybrid analysis. The UGT1A4 142T>G was genotyped using PCR-RFLP analysis. Results: Ten patients (26.3%) had voriconazole-induced liver injury and were considered as the case group There was no significant difference between the two groups in genotype and allele frequencies of CYP2C19*2 and UGT1A4 142T>G (p > 0.05), however, the GA frequency of CYP2C19 *3 in the drug-induced liver injury case group was higher than that in the control group (p < 0.05). Compared with patients carrying *1/*1 or *1/*2, there was no significant difference in voriconazole trough concentration of the patients with *1/*3 (p > 0.05). Conclusion: There was no significant correlation between voriconazole-induced liver injury and gene polymorphisms of CYP2C19 and UGT1A4.

17.
Sci Total Environ ; 705: 135794, 2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-31806297

RESUMO

Chinese college students reside primarily in four-person bedrooms and even six-person bedrooms, where the sound from roommates may affect their sleep. Therefore, the purpose of the present study is to investigate the effects of different sound sources and sound levels on sleep for college students in China. Based on sleep quality measurements, acoustic environment measurements, and a questionnaire survey with 90 participants in a typical residence hall in Harbin city, China, the results are as following: First, 68.89% of college students experienced sleep deprivation, and indoor noise was the most influential environmental factor among 15 disruptors that disturbed 50% of college students. Second, the number of occupants per room was a significant factor affecting the background sound level of sleep, which was highest when the number of occupants was two, and lowest when the number was five. Third, deep sleep time and rapid eye movements (REM) sleep time decreased 1.7 min and 1.4 min per 1 dBA (decibel with A-weight), with R2 = 0.352 and 0.332, respectively (p < .001). In terms of the effect of sound sources on sleep, sleep was mostly disturbed by roommate conversation (77.42%), and noise caused by roommate sleep-related activities was the most common source of activities (67.74%). The present study can provide guidelines to help enhance the sleep quality of Chinese college students through improvements in the sound environment.

18.
Biochem Biophys Res Commun ; 522(4): 826-831, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-31791586

RESUMO

It has remained a mystery why cells maintain ATP concentrations of 2-12 mM, much higher than required for its known functions, until ATP is decoded to act as a hydrotrope to non-specifically control protein homeostasis above 5 mM. Unexpectedly, our NMR studies further reveal that by specific binding, ATP also mediates liquid-liquid phase separation in a two-stage style and inhibits fibrillation of RRM domains of FUS and TDP-43, implying that ATP might have a second category of functions previously unknown. So can ATP also bind nucleic-acid-binding proteins without RRM fold? Here we characterized the interaction between ATP and SYNCRIP acidic domain (AcD), a non-canonical RNA-binding domain with no similarity to RRM fold in sequence and structure. The results reveal that ATP does bind AcD at physiologically-relevant concentrations with the affinity determinants generally underlying protein-nucleic acid interactions. Therefore, at concentrations above mM, ATP might bind most, if not all, nucleic-acid-binding proteins.

19.
Biochem Biophys Res Commun ; 522(1): 247-253, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31759630

RESUMO

ATP is the universal energy currency for all cells but has cellular concentrations of 2-12 mM, much higher than required for its classic functions. RNA-recognition motif (RRM) constitutes one of the most abundant domains in eukaryotes and most heterogeneous nuclear ribonucleoproteins (hnRNP) contain RRM domains which not only mediate direct interactions with nucleic acids, but whose aggregation/fibrillation is the pathological hallmark of various human diseases. Here, by NMR and molecular docking, ATP has been decoded to bind TDP-43 two tandem RRM domains with distinctive types of interactions, thus resulting in diverse affinities. Most strikingly, the binding of ATP enhances thermodynamic stability of TDP-43 RRM domains and inhibits ALS-/AD-associated fibrillation. Together, ATP is a cryptic binder of RRM-containing proteins which generally safeguards functional phase separation from transforming into pathological aggregation/fibrillation associated with various diseases and ageing. Our study thus reveals a mechanism of ATP to control protein homeostasis by specific binding.

20.
Cell Death Differ ; 27(2): 725-741, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31285545

RESUMO

Exquisite regulation of PI3K/AKT/mTORC1 signaling is essential for homeostatic control of cell growth, proliferation, and survival. Aberrant activation of this signaling network is an early driver of many sporadic human cancers. Paradoxically, sustained hyperactivation of the PI3K/AKT/mTORC1 pathway in nontransformed cells results in cellular senescence, which is a tumor-suppressive mechanism that must be overcome to promote malignant transformation. While oncogene-induced senescence (OIS) driven by excessive RAS/ERK signaling has been well studied, little is known about the mechanisms underpinning the AKT-induced senescence (AIS) response. Here, we utilize a combination of transcriptome and metabolic profiling to identify key signatures required to maintain AIS. We also employ a whole protein-coding genome RNAi screen for AIS escape, validating a subset of novel mediators and demonstrating their preferential specificity for AIS as compared with OIS. As proof of concept of the potential to exploit the AIS network, we show that neurofibromin 1 (NF1) is upregulated during AIS and its ability to suppress RAS/ERK signaling facilitates AIS maintenance. Furthermore, depletion of NF1 enhances transformation of p53-mutant epithelial cells expressing activated AKT, while its overexpression blocks transformation by inducing a senescent-like phenotype. Together, our findings reveal novel mechanistic insights into the control of AIS and identify putative senescence regulators that can potentially be targeted, with implications for new therapeutic options to treat PI3K/AKT/mTORC1-driven cancers.

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