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1.
Brain Behav ; : e02098, 2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33655641

RESUMO

INTRODUCTION: We conducted a two-sample Mendelian randomization study to determine the associations of modifiable risk factors with epilepsy. METHODS: Fourteen potential risk factors for epilepsy were selected based on a systematic review of risk factors for epilepsy. Single-nucleotide polymorphisms associated with each exposure at the genome-wide significance threshold (p < 5×10-8 ) were proposed as instrumental variables from corresponding genome-wide association studies. Summary-level data for epilepsy were obtained from the FinnGen consortium (4,588 cases and 144 780 noncases). Potential causal associations (p < .05) were attempted for replication using UK Biobank data (901 cases and 395 209 controls). RESULTS: Among 14 potential risk factors, 4 showed significant associations with epilepsy in FinnGen. All associations were directionally similar in UK Biobank and associated with epilepsy at p ≤ .004 in meta-analyses of FinnGen and UK Biobank data. The odds ratios of epilepsy were 1.46 (95% CI, 1.18, 1.82) for one unit increase in log odds ratio of having depression, 1.44 (95% CI, 1.13, 1.85) for one standard deviation increase in serum ferritin, 1.12 (95% CI, 1.04, 1.21) for one standard deviation increase in transferrin saturation, and 1.25 (95% CI, 1.09, 1.43) for one standard deviation increase in the prevalence of smoking initiation. There were suggestive associations of serum iron and magnesium with epilepsy. No association was observed for insomnia, blood pressure, alcohol consumption, or serum vitamin B12, 25-hydroxyvitamin D and calcium levels. CONCLUSION: This MR study identified several modifiable risk factors for adulthood epilepsy. Reducing prevalence of depression and smoking initiation should be considered as primary prevention strategies for epilepsy.

2.
J Cell Mol Med ; 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33608980

RESUMO

The immunophenotype of bladder cancer plays a pivotal role in the prognosis of cancer, but the effect of different epigenetic factors on different immunophenotypes in bladder tumours remains unclear. This study used multi-omics data analysis to provide molecular basis support for different immune phenotypes. Unsupervised cluster analysis revealed distinct subclusters with higher (subcluster B2) or lower cytotoxic immune phenotypes (subcluster A1) related to PD-L1 and IFNG expression. Mutational landscape analyses showed that the mutation level of TP53 in subcluster B1 was highest than other subclusters, and subcluster B1 had a lower frequency of concurrent mutation than subcluster A2. A total of 2364 differentially expressed genes were identified between subclusters A2 and B1, and the main functions of the up-regulated genes in subcluster B1 were enriched in the activation of T cells and other related pathways. We found that STAT1 was a key gene in a gene regulatory network related to immune phenotypes in bladder cancer. Finally, we constructed a prognostic prediction model by LASSO Cox regression which could distinguish high-risk and low-risk cases significantly. In conclusion, the present study addressed a field synopsis between genetic and epigenetic events in immune phenotypes of bladder cancer.

3.
Circ Res ; 2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33550812

RESUMO

Rationale: Previously, we identified the human cardiac long non-coding RNAs (lncRNAs) profile in dilated cardiomyopathy (DCM) patients, among which ZNF593-AS, also named as RP11-96L14.7 and ENST00000448923.2, showed good conservation among species. Objective: We aim to elucidate the mechanism underlying lncRNA in DCM and DCM that lead to heart failure, which might provide new insights into the mechanisms of DCM and possible treatment strategies in the future. Methods and Results: lncRNA expression was measured by real-time PCR and in situ hybridization assays. Coding potential was verified by bioinformatic and biologic assays. Recombinant adeno-associated virus with cardiac specific promoter was used to deliver lncRNA in vivo, while cardiac structure and functions were assessed by echocardiography and catheter. Sarcomere shortening, calcium imaging, gene expression profiling, and pull-down assays were performed to investigate the underlying mechanisms. ZNF593-AS, which mainly localized in the cytoplasm of cardiomyocytes, was robustly decreased in the failing heart of DCM patients, as well as in phenylephrine-treated human cardiomyocytes. Overexpression of mmu-ZNF593-AS significantly improved transverse aortic constriction (TAC)-induced cardiac dysfunction in mice. Moreover, ZNF593-AS overexpression restored the aberrant Ca2+ handling and contractility of cardiomyocytes from TAC-treated mice. Further, we found that ZNF593-AS acted as a guide RNA scaffold and recruited HNRNPC to ryanodine receptor type 2 (RYR2) mRNA, which in turn facilitated RYR2 mRNA stability, contributed to the improvement of cardiac Ca2+ handling and contractile function in DCM. Conclusions: Our findings suggested that lncRNA-based therapeutics may protect against DCM.

4.
Adv Mater ; : e2006120, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33586281

RESUMO

The synthesis of a new molecule, SFIC-Cl, is reported, which features enhanced π-electron delocalization by spiroconjugation and narrowed bandgap by chlorination. SFIC-Cl is integrated into a single-crystal transistor (OFET) and organic light-emitting diode (OLED). The material demonstrates remarkable transport abilities across various solution-processed OFETs and retains efficient radiance in a near-infrared OLED emitting light at 700 nm. Furthermore, the intermolecular multi-dimensional connection of SFIC-Cl enables the fabrication of a single-component large-area (2 × 2 cm2 ) near-infrared OLED by spin-coating. The SFIC-Cl-acceptor-based solar cell shows excellent power conversion efficiency of 10.16% resulting from the broadened and strong absorption and well-matched energy levels. The study demonstrates that chlorinated spiroconjugated fused systems offer a novel direction toward the development of high-performance organic semiconductor materials for hybrid organic electronic devices.

5.
Signal Transduct Target Ther ; 6(1): 69, 2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33597502

RESUMO

MicroRNAs (miRNAs) are aberrantly expressed in the pathophysiologic process of heart failure (HF). However, the functions of a certain miRNA in different cardiac cell types during HF are scarcely reported, which might be covered by the globe effects of it on the heart. In the current study, Langendorff system was applied to isolate cardiomyocytes (CMs) and cardiac fibroblasts (CFs) from transverse aortic constriction (TAC)-induced mice. Slight increase of miR-320 expression was observed in the whole heart tissue of TAC mice. Interestingly, miR-320 was significantly elevated in CMs but decreased in CFs from TAC mice at different time points. Then, recombinant adeno-associated virus 9 with cell-type-specific promoters were used to manipulate miR-320 expressions in vivo. Both in vitro and in vivo experiments showed the miR-320 overexpression in CMs exacerbated cardiac dysfunction, whereas overexpression of miR-320 in CFs alleviated cardiac fibrosis and hypertrophy. Mechanically, downstream signaling pathway analyses revealed that miR-320 might induce various effects via targeting PLEKHM3 and IFITM1 in CMs and CFs, respectively. Moreover, miR-320 mediated effects could be abolished by PLEKHM3 re-expression in CMs or IFITM1 re-expression in CFs. Interestingly, miR-320 treated CFs were able to indirectly affect CMs function, but not vice versa. Meanwhile, upstream signaling pathway analyses showed that miR-320 expression and decay rate were rigorously manipulated by Ago2, which was regulated by a cluster of cell-type-specific TFs distinctively expressed in CMs and CFs, respectively. Together, we demonstrated that miR-320 functioned differently in various cell types of the heart during the progression of HF.

6.
Clin Nutr ; 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33593662

RESUMO

BACKGROUND & AIMS: Epidemiological evidence on the associations of egg, cholesterol and protein intake with risk of type 2 diabetes is inconsistent. Therefore, we conducted this study to explore these associations among Chinese adults. METHODS: Data from 4 waves (2004, 2006, 2009 and 2011) of the China Health and Nutrition Survey were used. A multistage random-cluster sampling method was employed to recruit the participants in both rural and urban areas. We included individuals who participated in 2004 and any waves afterwards. Those 1) below 18 years of age; 2) with diabetes at baseline; or 3) with extreme energy intake (men: <800 kcal or >6000 kcal; women: <600 kcal or >4000 kcal) were excluded. Respondents were classified into four groups according to quartiles of egg, cholesterol and protein intake per day. Numbers of eggs per day were calculated by dividing egg intake in grams by 50 g. Diagnosis of type 2 diabetes was self-reported. Logistic generalized estimation equation models were employed. RESULTS: There were 7312 individuals included in 2004, 6390 in 2006, 4826 in 2009 and 4963 in 2011. The mean age of participants at baseline was 48.3 years and 47.2% were men. Over an average of 5.8-y follow-up, 209 developed type 2 diabetes. After adjustment for demographic, lifestyle and dietary confounders, the odds ratio of type 2 diabetes for those in the highest compared with the lowest protein intake quartile was 2.38 (95% CI: 1.43, 3.98). The odds ratio of individuals with ≥3 eggs/day versus none was 3.76 (95% CI, 2.05, 6.90). Cholesterol intake was not associated with type 2 diabetes. CONCLUSIONS: Individuals with the highest protein intake had over a 2-fold increased risk of type 2 diabetes compared with those with the lowest protein intake. A high intake of egg, but not dietary cholesterol, was associated with type 2 diabetes. This association warrants further investigation.

7.
Sci Rep ; 11(1): 4296, 2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-33619316

RESUMO

A deeper understanding of the causal links from education level to health outcomes may shed a light for disease prevention. In the present Mendelian randomization study, we found that genetically higher education level was associated with lower risk of major mental disorders and most somatic diseases, independent of intelligence. Higher education level adjusted for intelligence was associated with lower risk of suicide attempts, insomnia, major depressive disorder, heart failure, stroke, coronary artery disease, lung cancer, breast cancer, type 2 diabetes and rheumatoid arthritis but with higher risk of obsessive-compulsive disorder, anorexia nervosa, anxiety, bipolar disorder and prostate cancer. Higher education level was associated with reduced obesity and smoking, which mediated quite an extent of the associations between education level and health outcomes. These findings emphasize the importance of education to reduce the burden of common diseases.

8.
Artigo em Inglês | MEDLINE | ID: mdl-33462619

RESUMO

CONTEXT: The associations of circulating insulin-like growth factor-1 (IGF-1) levels with bone mineral density and fracture risk are inconclusive in observational studies. OBJECTIVE: We conducted a mendelian randomization study to assess the associations of serum IGF-1 levels with estimated bone mineral density (eBMD) and fracture. METHODS: Genetic instruments for IGF-1 were selected at the genome-wide significance level (P < 5 × 10-8) from a genome-wide association study including 358 072 individuals of European ancestry. Summary-level data for eBMD (426 824 individuals) and fracture (53 184 fracture cases and 373 611 noncases) were obtained from the UK Biobank study. Univariable and multivariable mendelian randomization analyses methods were used to estimate the associations of IGF-1 with eBMD and fracture. The main outcome measure included the change of eBMD and odds ratio of fracture per genetically predicted 1-SD increase of serum IGF-1 levels. RESULTS: For 1-SD increase in IGF-1, the change of eBMD levels was 0.04 g/cm2 (95% CI, 0.01-0.07; P = .011) and the odds ratio of fracture was 0.94 (95% CI, 0.91-0.98; P = .003). The associations persisted with similar magnitude after adjustment for height. The association was consistent for fracture but not for eBMD after excluding genetic instruments that might directly influence these outcomes. The association between IGF-1 and fracture was somewhat attenuated after adjustment for eBMD (odds ratio 0.96; 95% CI, 0.92-0.99; P = .012). CONCLUSION: The present study supports a role for IGF-1 in preventing fracture, possibly and partly mediated by greater bone mineral density.

9.
Artigo em Inglês | MEDLINE | ID: mdl-33418132

RESUMO

BACKGROUND & AIMS: Obesity, type 2 diabetes, and lifestyle factors (cigarette smoking, alcohol drinking, and coffee consumption) have been associated with the risk of developing gallstone disease in observational studies, but whether these associations are causal is undetermined. We conducted a Mendelian randomization study to assess these associations. METHODS: Genetic instruments associated with the exposures at the genome-wide significance (p < 5×10-8) level were selected from corresponding genome-wide associations studies (n=224 459 to 1 232 091 individuals). Summary-level data for gallstone disease were obtained from the UK Biobank (10 520 cases and 350 674 non-cases) and FinnGen consortium (11 675 cases and 121 348 non-cases). Univariable and multivariable Mendelian randomization analyses were conducted. Results from UK Biobank and FinnGen were combined using fixed-effects meta-analysis. RESULTS: The odds ratios were 1.63 (95% confidence interval (CI), 1.49, 1.79) for one standard deviation (SD) increase in body mass index, 1.81 (95% CI, 1.60, 2.05) for one SD increase in waist circumference, 1.13 (95% CI, 1.09, 1.17) for one unit increase in the log-odds ratio of type 2 diabetes and 1.25 (95% CI, 1.16, 1.34) for one SD increase in prevalence of smoking initiation. The associations for body mass index and type 2 diabetes persisted after mutual adjustment. Genetically predicted coffee consumption was inversely associated with gallstone disease after adjustment for body mass index and smoking (odds ratio per 50% increase 0.44, 95% CI, 0.21, 0.91). There was no association with alcohol consumption. CONCLUSIONS: This study supports independent causal roles of obesity, type 2 diabetes, and smoking in gallstone disease.

10.
ACS Appl Mater Interfaces ; 13(5): 6615-6630, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33507059

RESUMO

The control of surface wettability through a combination of surface roughness, chemical composition, and structural modification has attracted significant attention for antifogging and antibacterial applications. Herein, a two-step spin-coating method for amphiphilic organic-inorganic hybrid materials with incorporated transition metal ions is presented. The coating solution was prepared via photochemical thiol-ene click reaction between the mercapto functional group in trimethylolpropane tris(3-mercaptopropionate) and the vinyl functionalized silica precursor 3-(trimethoxysilyl)propyl methacrylate. In the first step of coating, a glass substrate was coated using a solution of metal nitrate hydrates and subsequently showed hydrophobic properties. As the second step, the spin-coated glass substrate was further coated with silica nanoparticles (SiO2 NPs) and polycaprolactone triol (PCT) suspension, where the contents of SiO2 NPs were fixed at 0.1 wt %, unless otherwise noted. The coated substrate exhibited hydrophilic properties. For comparison, the coating was also formulated with the SiO2 NPs/PCT suspension without SiO2 NPs and with 0.5 wt % SiO2 NPs as well as by adjusting different coating layer thicknesses. The surface morphology and chemical compositions of the obtained coating materials were analyzed by field emission scanning electron microscopy with energy-dispersive X-ray spectroscopy and X-ray photoelectron spectroscopy. The transparency and static contact angle of coated samples were measured by UV-visible spectrophotometry and drop shape analysis, respectively. It was concluded that our novel hybrid coating materials exhibited excellent antibacterial and antifogging properties with extremely high scratch resistance and transparency.

11.
J Hazard Mater ; 404(Pt B): 124067, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33086183

RESUMO

Recycling iron tailings is significant for environmental security and resource recovery, as they contain iron-rich minerals. Given the complex composition of iron minerals and the low grade of iron present in the tailings, innovative suspension roasting-magnetic separation (SRMS) technology was proposed to treat iron tailings that would separate out the iron minerals for recovery. In this study, the reduction kinetics, phase transformation, and structure evolution of the iron tailings were investigated to explain the mechanism behind magnetite production from iron tailings. These studies were conducted using chemical analyses, X-ray diffraction, Brunauer-Emmett-Teller specific surface area, and scanning electron microscopy. The results showed that high temperatures during the suspension reduction process were conducive to improving the reduction rate of the iron tailings. The best kinetics model for this reduction reaction of iron tailings is the P1 model, which demonstrated a linear increase in the conversion degree with the extension of the reaction time. The corresponding mechanism function was f(α) = 1, the apparent activation energy (Eα) was 51.56 kJ/mol, and the kinetics equation was k = 3.14exp(- 51.56/RT). Using the SRMS technology, magnetite gradually formed from hematite, starting at the outer particle layers and moving inward toward the core. The microcracks and pores in the surface of the particles increased, which promoted CO penetration into the particles where it reacted with the hematite. Our results provide important insight into the efficient and clean recycling of iron tailings.

12.
Br J Haematol ; 192(4): 769-777, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33326595

RESUMO

In sickle cell disease (SCD), cerebral oxygen delivery is dependent on the cerebral vasculature's ability to increase blood flow and volume through relaxation of the smooth muscle that lines intracranial arteries. We hypothesised that anaemia extent and/or circulating markers of inflammation lead to concentric macrovascular arterial wall thickening, visible on intracranial vessel wall magnetic resonance imaging (VW-MRI). Adult and pediatric SCD (n = 69; age = 19.9 ± 8.6 years) participants and age- and sex-matched control participants (n = 38; age = 22.2 ± 8.9 years) underwent 3-Tesla VW-MRI; two raters measured basilar and bilateral supraclinoid internal carotid artery (ICA) wall thickness independently. Mean wall thickness was compared with demographic, cerebrovascular and haematological variables. Mean vessel wall thickness was elevated (P < 0·001) in SCD (1·07 ± 0·19 mm) compared to controls (0·97 ± 0·07 mm) after controlling for age and sex. Vessel wall thickness was higher in participants on chronic transfusions (P = 0·013). No significant relationship between vessel wall thickness and flow velocity, haematocrit, white blood cell count or platelet count was observed; however, trends (P < 0·10) for wall thickness increasing with decreasing haematocrit and increasing white blood cell count were noted. Findings are discussed in the context of how anaemia and circulating inflammatory markers may impact arterial wall morphology.

13.
J Cell Mol Med ; 25(2): 1263-1273, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33336936

RESUMO

To determine whether pre-hospitalization use of aspirin is associated with all-cause mortality in coronavirus disease 2019 (COVID-19) patients with coronary artery disease (CAD). We recruited 183 adult patients with CAD diagnosed with COVID-19, including 52 taking low-dose aspirin (mean [SD] age, 69.7 [1.1] years; 59.6% men) and 131 without using aspirin (mean [SD] age, 71.8 [0.9] years; 51.9% men), who were admitted in the Tongji hospital in Wuhan, China from January 10, 2020 to March 30, 2020. There was no difference on in-hospital mortality between aspirin group and non-aspirin group (21.2% vs. 22.1%, P = .885). Similarly, for critically severe COVID-19 patients, the mortality in aspirin group was close to that in non-aspirin group (44% vs. 45.9%, P = .872). Moreover, the percentage of patients with CAD taking low-dose aspirin did not differ between those survivors and non-survivors (28.7% vs. 27.5%, P = .885). Meanwhile, the usage of aspirin was not correlated with all-cause mortality in multivariate analysis (OR = 0.944, 95% CI: 0.411-2.172, P = .893). Collectively, our study suggested that the pre-hospitalization use of low-dose aspirin was not associated with the clinical outcome of patients with CAD hospitalized with COVID-19 infections.

14.
Psychol Health Med ; : 1-9, 2020 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-33297726

RESUMO

The study aimed to investigate the individual and combined association of health-risk behaviors with mental health among Chinese children. A cross-sectional study was conducted in Wuhan, China, from May to June 2018. Participants self-reported the information on physical activity (PA), screen time (ST), fruit and vegetable (FV) intake, and sleep duration. Mental health, including depression, social anxiety and self-esteem, was assessed using standard questionnaires. A total of 1296 children (704 males and 592 females) aged 9.2 ± 0.4 years were included in the present study. The prevalence of low PA, high ST, low FV intake, and inadequate sleep duration was 45.6%, 18.0%, 69.7%, and 64.7%, respectively. Overall, significant associations were found between individual health-risk behavior and increased risks of mental health. Furthermore, children with three or four health-risk behaviors showed significantly increased risks of anxiety (OR: 3.18, 95%CI: 1.63-6.21), depression (OR: 4.55, 95%CI: 2.28-9.09) and low self-esteem (OR: 3.59, 95%CI: 2.20-5.88) compared with those without health-risk behavior. Results of this study revealed a high prevalence of health-risk behaviors among Chinese children. Furthermore, the clustering of health-risk behavior was associated with significantly increased risks of mental health in this population. Considering these findings, it is important to perform early interventions to reduce children's health-risk behavior and prevent mental health problems.

15.
iScience ; 23(12): 101788, 2020 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-33294796

RESUMO

It has been unclear whether the elevated levels of the circulating miR-320a in patients with coronary artery disease is due to environmental influence or genetic basis. By recombinant adeno-associated virus (rAAV)-mediated loss- and gain-of-function studies in the mouse liver, we revealed that elevated miR-320a is sufficient to aggravate diet-induced hyperlipidemia and hepatic steatosis. Then, we analyzed the data from published genome-wide association studies and identified the rs12541335 associated with hyperlipidemia. We demonstrated that the rs13282783 T allele indeed obligated the silencer activity by preventing the repressor ZFP161 and co-repressor HDAC2 from binding to DNA that led to miR-320a upregulation. We further confirmed this genetic connection on an independent population and through direct genome editing in liver cells. Besides environmental (diet) influence, we established a genetic component in the regulation of miR-320a expression, which suggest a potential therapeutic avenue to treat coronary artery disease by blocking miR-320a in patient liver.

16.
Arterioscler Thromb Vasc Biol ; : ATVBAHA120315081, 2020 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-33267657

RESUMO

OBJECTIVE: Chronic hemolysis is a hallmark of sickle cell disease (SCD) and a driver of vasculopathy; however, the mechanisms contributing to hemolysis remain incompletely understood. Although XO (xanthine oxidase) activity has been shown to be elevated in SCD, its role remains unknown. XO binds endothelium and generates oxidants as a byproduct of hypoxanthine and xanthine catabolism. We hypothesized that XO inhibition decreases oxidant production leading to less hemolysis. Approach and Results: Wild-type mice were bone marrow transplanted with control (AA) or sickle (SS) Townes bone marrow. After 12 weeks, mice were treated with 10 mg/kg per day of febuxostat (Uloric), Food and Drug Administration-approved XO inhibitor, for 10 weeks. Hematologic analysis demonstrated increased hematocrit, cellular hemoglobin, and red blood cells, with no change in reticulocyte percentage. Significant decreases in cell-free hemoglobin and increases in haptoglobin suggest XO inhibition decreased hemolysis. Myographic studies demonstrated improved pulmonary vascular dilation and blunted constriction, indicating improved pulmonary vasoreactivity, whereas pulmonary pressure and cardiac function were unaffected. The role of hepatic XO in SCD was evaluated by bone marrow transplanting hepatocyte-specific XO knockout mice with SS Townes bone marrow. However, hepatocyte-specific XO knockout, which results in >50% diminution in circulating XO, did not affect hemolysis levels or vascular function, suggesting hepatocyte-derived elevation of circulating XO is not the driver of hemolysis in SCD. CONCLUSIONS: Ten weeks of febuxostat treatment significantly decreased hemolysis and improved pulmonary vasoreactivity in a mouse model of SCD. Although hepatic XO accounts for >50% of circulating XO, it is not the source of XO driving hemolysis in SCD.

17.
Nanotechnology ; 2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33352536

RESUMO

We demonstrate the use of a photonic crystal structure to improve the performance of a germanium avalanche photodetector by simultaneously manipulating the distribution of the optical and electric fields. The photonic crystal is fabricated at the top center of the vertical germanium avalanche photodetector. For a 14-µm-diameter device, the 1550 nm responsivity increases from 0.2 to 0.6 A/W at unity gain, owing to the resonance-enhanced absorption. Moreover, the structure separates the absorption and multiplication regions of the device, resulting in an increase of the avalanche gain and the gain-bandwidth product. Under -10 dBm input optical power, a 3-dB bandwidth of 34 GHz before avalanche and a clear 40 Gbps eye diagram under avalanche demonstrates good high-speed performance of the device.

18.
Drug Des Devel Ther ; 14: 5419-5430, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33324039

RESUMO

Background: Neohesperidin (NH) and lncRNA HOTAIR (HOTAIR) could regulate osteoclastic and osteogenic differentiation. This study aimed to explore whether HOTAIR-mediated osteogenic differentiation was regulated by NH. Methods: Steroid-induced osteonecrosis of the femoral head (SONFH) mice model was established. Histopathological changes in mouse osteonecrosis tissues were detected by hematoxylin-eosin staining. Bone marrow stromal cells (BMSCs) were isolated from healthy mice bone marrow samples by Ficoll density gradient and identified by flow cytometry. After treating the BMSCs with NH and dexamethasone or transfecting with HOTAIR overexpression plasmids and siHOTAIR, histone modification of HOTAIR, the cell viability, osteogenic differentiation, and adipogenic differentiation were detected by chromatin immunoprecipitation, MTT, Alizarin Red and Oil Red O staining, respectively. The expressions of HOTAIR and differentiation-related factors in the BMSCs were detected by RT-qPCR and Western blot. Results: HOTAIR was highly expressed in SONFH model mice. NH ameliorated histopathological changes in the model mice, but the effect was reversed by overexpressed HOTAIR. NH increased viability of BMSCs and the H3K27me3 occupancy of HOTAIR, but decreased the expression and the H3K4me3 occupancy of HOTAIR. HOTAIR expression was down-regulated in BMSCs after osteogenic differentiation but was up-regulated after adipogenic differentiation. HOTAIR overexpression inhibited osteogenic differentiation and the expressions of RUNX2, OCN, and ALP, but increased adipogenic differentiation and the expressions of LPL and PPARr in BMSCs; moreover, the opposite results were observed in siHOTAIR. Conclusion: NH ameliorated SONFH by inhibiting the histone modifications of HOTAIR.

19.
Aging (Albany NY) ; 12(21): 22019-22045, 2020 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-33186123

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder worldwide. Multiple metabolic disorders, such as hyperlipidemia, hyperglycemia, insulin resistance and obesity, have been reportedly associated with NAFLD, but little is known about the detailed mechanisms. METHODS AND RESULTS: Here, we explored the effects of multiple metabolic disorders, especially hyperglycemia on lipid accumulation in liver using several well-established animal models. We found that liver lipid deposition was increased in both type 1 diabetes and high-fat diet (HFD) induced hyperlipidemia models, suggesting that either hyperglycemia or hyperlipidemia alone or together was able to trigger NAFLD. Moreover, we tested whether miR-320, a miRNA promoting lipid accumulation in heart revealed by our previous study, also participated in NAFLD. Though miR-320 treatment further increased liver lipid deposition in type 1 diabetes and HFD-feeding mice, it showed no effect in leptin-receptor deficient db/db mice. Interestingly, miR-320 affected different target genes in cytosol and nucleus, respectively, which collectively led to liver lipid overload. CONCLUSIONS: Our findings illustrated the complex roles of miRNAs in subcellular fractions including nucleus and cytoplasm, which may lead to new insights into the mechanisms and treatment strategies for NAFLD in the future.

20.
Mol Cell ; 2020 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-33188728

RESUMO

The causative virus of the COVID-19 pandemic, SARS-CoV-2, uses its nonstructural protein 1 (Nsp1) to suppress cellular, but not viral, protein synthesis through yet unknown mechanisms. We show here that among all viral proteins, Nsp1 has the largest impact on host viability in the cells of human lung origin. Differential expression analysis of mRNA-seq data revealed that Nsp1 broadly alters the cellular transcriptome. Our cryo-EM structure of the Nsp1-40S ribosome complex shows that Nsp1 inhibits translation by plugging the mRNA entry channel of the 40S. We also determined the structure of the 48S preinitiation complex formed by Nsp1, 40S, and the cricket paralysis virus internal ribosome entry site (IRES) RNA, which shows that it is nonfunctional because of the incorrect position of the mRNA 3' region. Our results elucidate the mechanism of host translation inhibition by SARS-CoV-2 and advance understanding of the impacts from a major pathogenicity factor of SARS-CoV-2.

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