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1.
ACS Chem Neurosci ; 13(7): 959-977, 2022 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-35298129

RESUMO

Allosteric modulators (AMs) that bind allosteric sites can exhibit greater selectivity than the orthosteric ligands and can either enhance agonist-induced receptor activity (termed positive allosteric modulator or PAM), inhibit agonist-induced activity (negative AM or NAM), or have no effect on activity (silent AM or SAM). Until now, it is not clear what the exact effects of AMs are on the orthosteric active site or the allosteric binding pocket(s). In the present work, we collected both the three-dimensional (3D) structures of receptor-orthosteric ligand and receptor-orthosteric ligand-AM complexes of a specific target protein. Using our novel algorithm toolset, molecular complex characterizing system (MCCS), we were able to quantify the key residues in both the orthosteric and allosteric binding sites along with potential changes of the binding pockets. After analyzing 21 pairs of 3D crystal or cryo-electron microscopy (cryo-EM) complexes, including 4 pairs of GPCRs, 5 pairs of ion channels, 11 pairs of enzymes, and 1 pair of transcription factors, we found that the binding of AMs had little impact on both the orthosteric and allosteric binding pockets. In return, given the accurately predicted allosteric binding pocket(s) of a drug target of medicinal interest, we can confidently conduct the virtual screening or lead optimization without concern that the huge conformational change of the pocket could lead to the low accuracy of virtual screening.


Assuntos
Regulação Alostérica , Sítio Alostérico , Sítios de Ligação , Microscopia Crioeletrônica , Ligantes
2.
Cells ; 11(5)2022 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-35269537

RESUMO

Design and generation of high-quality target- and scaffold-specific small molecules is an important strategy for the discovery of unique and potent bioactive drug molecules. To achieve this goal, authors have developed the deep-learning molecule generation model (DeepMGM) and applied it for the de novo molecular generation of scaffold-focused small-molecule libraries. In this study, a recurrent neural network (RNN) using long short-term memory (LSTM) units was trained with drug-like molecules to result in a general model (g-DeepMGM). Sampling practices on indole and purine scaffolds illustrate the feasibility of creating scaffold-focused chemical libraries based on machine intelligence. Subsequently, a target-specific model (t-DeepMGM) for cannabinoid receptor 2 (CB2) was constructed following the transfer learning process of known CB2 ligands. Sampling outcomes can present similar properties to the reported active molecules. Finally, a discriminator was trained and attached to the DeepMGM to result in an in silico molecular design-test circle. Medicinal chemistry synthesis and biological validation was performed to further investigate the generation outcome, showing that XIE9137 was identified as a potential allosteric modulator of CB2. This study demonstrates how recent progress in deep learning intelligence can benefit drug discovery, especially in de novo molecular design and chemical library generation.


Assuntos
Canabinoides , Aprendizado Profundo , Inteligência Artificial , Desenho de Fármacos , Redes Neurais de Computação , Bibliotecas de Moléculas Pequenas/farmacologia
3.
Front Cardiovasc Med ; 9: 726025, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35252370

RESUMO

BACKGROUND: The hemoglobin level and red cell distribution width (RDW) have been linked to the prognosis of coronary atherosclerotic heart disease (CAHD). However, the relationship between the ratio of hemoglobin to the RDW (HRR) and clinical outcomes after percutaneous coronary intervention (PCI) is not known. Here, we explored the impact of the HRR on clinical outcomes after PCI. METHODS: In our study, we selected 6,046 CAHD patients with PCI hospitalized in the First Affiliated Hospital of Xinjiang Medical University from 2008 to 2016. The patients were grouped according to their HRR ratio: group A (HRR < 10.25, n = 2,344) and group B (HRR ≥ 10.25, n = 3,702). The difference in clinical outcomes between the two groups was compared. Patients were followed up for 35.9 ± 22.6 months. RESULTS: Three hundred nine patients died during follow-up. These included 166 patients (7.1%) in the HRR < 10.25 group and 143 patients (3.9%) in the HRR ≥ 10.25 group (P < 0.001). The incidences of cardiogenic death (5.7 vs. 3.2%) and major cardiovascular adverse events (16.5 vs. 12.9%) also differed significantly between the groups (both Ps < 0.001). Analysis using the multivariate Cox proportional hazard model found a significant association between a decreased HRR and post-PCI mortality (all-cause death, adjusted HR: 1.479, 95% CI: 1.156-1.893, p = 0.002; cardiac death, adjusted HR: 1.470, 95% CI: 1.116-1.936, p = 0.006). CONCLUSION: The HRR is predictive of post-PCI mortality among CAHD patients.

5.
Molecules ; 27(2)2022 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-35056767

RESUMO

Although the 3D structures of active and inactive cannabinoid receptors type 2 (CB2) are available, neither the X-ray crystal nor the cryo-EM structure of CB2-orthosteric ligand-modulator has been resolved, prohibiting the drug discovery and development of CB2 allosteric modulators (AMs). In the present work, we mainly focused on investigating the potential allosteric binding site(s) of CB2. We applied different algorithms or tools to predict the potential allosteric binding sites of CB2 with the existing agonists. Seven potential allosteric sites can be observed for either CB2-CP55940 or CB2-WIN 55,212-2 complex, among which sites B, C, G and K are supported by the reported 3D structures of Class A GPCRs coupled with AMs. Applying our novel algorithm toolset-MCCS, we docked three known AMs of CB2 including Ec2la (C-2), trans-ß-caryophyllene (TBC) and cannabidiol (CBD) to each site for further comparisons and quantified the potential binding residues in each allosteric binding site. Sequentially, we selected the most promising binding pose of C-2 in five allosteric sites to conduct the molecular dynamics (MD) simulations. Based on the results of docking studies and MD simulations, we suggest that site H is the most promising allosteric binding site. We plan to conduct bio-assay validations in the future.


Assuntos
Sítio Alostérico , Sítios de Ligação , Moduladores de Receptores de Canabinoides/química , Desenho de Fármacos , Modelos Moleculares , Receptor CB2 de Canabinoide/química , Regulação Alostérica , Moduladores de Receptores de Canabinoides/farmacologia , Humanos , Ligantes , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Receptor CB2 de Canabinoide/metabolismo
6.
ACS Omega ; 7(2): 1628-1638, 2022 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-35071858

RESUMO

Introduction: Smoking affects the occurrence and development of many diseases. We attempt to study the structure of intestinal flora in the middle-aged and elderly population as well as how smoking affects the intestinal flora. Methods: We collected population information, biochemical indicators, and patient feces from 188 middle-aged and elderly male patients, and their feces were tested for the 16S rRNA gene of intestinal flora. Results: We performed a cluster analysis on the intestinal structure of the included population and found that there was a significant difference in the number of smokers between each group (p = 0.011). Subsequently, the microbiological diversity analysis of current smokers and nonsmokers was carried out. The results indicated that there was a significant difference in species composition between the two groups (p = 0.029). Through the analysis on LEfSe differential bacteria, it was found that in current smoking patients, the abundances of the genus Bifidobacterium and the genus Coprobacillus were less, while the abundances of the genera Shigella, Paraprevotella, Burkholderia, Sutterella, Megamonas, and p-75-a5 under the family level of Erysipelotrichaceae were slightly high. We analyzed the correlation between the abundances of these eight different bacteria and clinical indicators. The results revealed the following: the abundance of the genus Bifidobacterium was negatively correlated with fasting blood glucose (r = -0.198, p = 0.006) and positively correlated with uric acid (r = 0.207, p = 0.004) and total bilirubin (r = 0.175, p = 0.017); Shigella bacteria were positively correlated with fasting blood glucose (r = 0.160, p = 0.028) and uric acid (r = 0.153, p = 0.036) levels; the genus Paraprevotella and BMI (r = -0.172, p = 0.018) are negatively correlated; the abundance of the genus Burkholderia was positively correlated with γ-glutamyltransferase (r = 0.146, p = 0.045) levels; Sutterella was correlated with fasting blood glucose (r = 0.143, p = 0.05) and creatinine level (r = -0.16, p = 0.027), which was positively correlated with fasting blood glucose and negatively correlated with creatinine. Conclusions: In middle-aged and elderly patients with cardiovascular disease, smoking can reduce the abundance of Bifidobacterium, while the abundances of some negative bacteria such as Burkholderia, Sutterella, and Megamonas increase.

8.
Sleep Med ; 89: 141-146, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34983016

RESUMO

OBJECTIVE: To evaluate the association between restless legs syndrome (RLS) and hypertension in men and women based on a community-based cohort of middle-aged and elderly participants. METHODS: This cross-sectional observational study enrolled 4080 participants from the Sleep Heart Health study (SHHS). RLS was defined by positive responses on a self-administered questionnaire assessing the four diagnostic criteria, with symptoms occurring at least five times per month and associated with at least moderate distress. Hypertension was defined as SBP ≥140 mmHg, DBP ≥90 mmHg, or current use of antihypertensive medication. Propensity score-matched (PSM) inverse probability treatment weighting (IPTW) analyses and multivariable logistic regression were used to examine the relationship between RLS and hypertension. RESULTS: RLS was present in 6.8% of women (n = 152) and 3.2% of men (n = 59). In the primary cohort analysis, the odds ratio (OR) for hypertension was 1.60 [95% confidence interval (CI) 1.19-2.16, p < 0.001] for participants with RLS compared to those without RLS. In the PSM analyses, the OR for hypertension was 1.66 (95% CI 1.09-2.54, p = 0.019) for participants with RLS compared to those without RLS. In sex subgroup analyses, the association between RLS and hypertension persisted in women. In the PSM cohort, the ORs for hypertension were 1.67 (95% CI 1.01-2.81, p = 0.048) and 1.85 (95% CI 0.75-4.75, p = 0.191) in women and men, respectively. Similar results were found in IPTW cohort. CONCLUSIONS: This study revealed a positive association between RLS and hypertension in a community-based population; in sex subgroup analyses, the association persisted in women.


Assuntos
Hipertensão , Síndrome das Pernas Inquietas , Idoso , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Hipertensão/complicações , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Pontuação de Propensão , Síndrome das Pernas Inquietas/diagnóstico
9.
Drug Discov Today ; 27(1): 362-370, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34592447

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is characterized by heightened autophagy and systemic immune dysfunction. Modest improvements in clinical outcomes have been demonstrated in completed clinical trials targeting autophagy with combination hydroxychloroquine (HCQ) and chemotherapy. Recent mechanistic insights into the role of autophagy-dependent immune evasion have prompted the need for more precise and druggable targets of autophagy inhibition. Sequestosome-1 (SQSTM-1) is a multidomain scaffold protein with well-established roles in autophagy, tumor necrosis factor alpha (TNFα)- and NF-κB-related signaling pathways. SQSTM1 overexpression is frequently observed in PDAC, correlating with clinical stage and outcome. Given the unique molecular structure of SQSTM-1 and its diverse activity, identifying means of limiting SQSTM-1-dependent autophagy to promote an effective immune response in PDAC could be a promising treatment strategy.


Assuntos
Autofagia , Descoberta de Drogas/métodos , Neoplasias Pancreáticas , Proteína Sequestossoma-1/metabolismo , Autofagia/efeitos dos fármacos , Autofagia/imunologia , Humanos , Terapia de Alvo Molecular/métodos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/metabolismo , Transdução de Sinais/efeitos dos fármacos
10.
J Clin Endocrinol Metab ; 107(1): e214-e223, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34410414

RESUMO

CONTEXT: A personalized antiplatelet therapy guided by a novel platelet function testing (PFT), PL-12, is considered an optimized treatment strategy in stable coronary artery disease (CAD) patients undergoing percutaneous coronary intervention (PCI). However, the safety and efficacy of any dual-antiplatelet therapy (DAPT) strategy may differ in relation to diabetes status. OBJECTIVE: The aim of this study was to compare the outcomes of PFT-guided personalized DAPT in stable CAD patients with and without diabetes mellitus. METHODS: The PATH-PCI trial randomly assigned 2285 stable CAD patients to either personalized antiplatelet therapy or standard antiplatelet treatment. We investigated the association and interaction of diabetes on clinical outcomes across 2 treatment groups. RESULTS: We did not find a significant difference between the personalized group and the standard group in net adverse clinical events in either diabetes patients (10.3% vs 13.4%, P = .224) or in the nondiabetic group (3.1% vs 5.0%, P = .064). In diabetes patients (n = 646, 28.3%), the overall ischemic event rates were significantly low (6.8% vs 11.3%, HR = 0.586, 95% CI, 0.344-0.999, P = .049) and the bleeding event rates did not differ between the 2 groups (3.5% vs 3.3%, HR = 1.066, 95% CI, 0.462-2.458, P = .882). Similarly, in nondiabetic patients, the overall ischemic event rates were significantly low (1.8% vs 4.2%, HR = 0.428, 95% CI, 0.233-0.758, P = .006) and the bleeding event rates did not differ between the 2 groups (1.6% vs 0.9%, HR = 1.802, 95% CI: 0.719-4.516, P = .209). CONCLUSION: The present study suggests that personalized antiplatelet therapy according to PFT can reduce ischemic events but not increase bleedings in stable CAD patients with or without diabetes who have undergone PCI.


Assuntos
Doença da Artéria Coronariana/terapia , Diabetes Mellitus Tipo 2/fisiopatologia , Terapia Antiplaquetária Dupla/métodos , Intervenção Coronária Percutânea/mortalidade , Inibidores da Agregação Plaquetária/uso terapêutico , Medicina de Precisão , Doença da Artéria Coronariana/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico
11.
Front Cardiovasc Med ; 9: 709868, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35369313

RESUMO

Background: The influence of the albumin/derived neutrophil and lymphocyte ratio (ALB-dNLR) on the outcomes of patients with coronary artery disease (CAD) after percutaneous coronary intervention (PCI) is not known. Here, we aimed to determine the association between the ALB-dNLR score and post-PCI CAD patient outcomes. Methods: A total of 6,050 patients from the First Affiliated Hospital of Xinjiang Medical University were enrolled between January 2008 and December 2016. These patients were divided into three groups according to their ALB-dNLR scores (0 points, n = 1,121; 1 point, n = 3,119; 2 points, n = 1,810). Mortality after PCI [all-cause (ACM) and cardiac (CM)] was taken as the primary endpoint. The prognostic value of the ALB-dNLR score was determined with the Cox proportional hazard model after adjustment for covariates. Results: The ACM and CM rates differed among participants in the three groups (P = 0.007 and P = 0.034, respectively). Multivariate Cox analysis showed that the ALB-dNLR score independently predicted both ACM [1 point vs. 0 points, HR = 1.249 (95% CI: 0.79-1.774), P = 0.215; 2 points vs. 0 points, HR = 1.777 (95% CI: 1.239-2.549), P = 0.002] and CM [1 point vs. 0 points, HR = 1.294 (95% CI: 0.871-1.922), P = 0.202; 2 points vs. 0 points, HR = 1.782 (95% CI: 1.185-1.782), P = 0.027]. We also found that among male patients in the three groups, both ACM and CM rates differed (P = 0.006 and P = 0.017, respectively). Multivariate Cox analysis showed that the ALB-dNLR score independently predicted both ACM [1 point vs. 0 points, HR = 1.237 (95% CI: 0.806-0.330), P = 0.330; 2 points vs. 0 points, HR = 1.790 (95% CI: 1.159-2.764), P = 0.009] and CM [1 point vs. 0 points HR = 1.472 (95% CI: 0.892-2.430), P = 0.130; 2 points vs. 0 points, HR = 1.792 (95% CI: 1.182-3.289), P = 0.009]. Conclusion: The ALB-dNLR score is a credible predictor for mortality in patients with CAD who have undergone PCI.

12.
ACS Omega ; 6(48): 32508-32516, 2021 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-34901600

RESUMO

BACKGROUND: In this study, we developed a novel risk score named the blood routine test parameters (BRTP) score to predict the clinical outcomes in coronary artery disease (CAD) patients who had undergone percutaneous coronary intervention (PCI). METHODS: There were 6049 patients with CAD after PCI enrolled in CORFCHD-PCI from January 2008 to December 2016. We divided these patients into two groups according to diabetes (diabetic group, n = 3809, and nondiabetic group, n = 2240). During a follow-up time of 35.9 ± 22.6 months, we compared the incidences of all-cause mortality (ACM) and cardiac mortality (CM), which were assigned as the primary outcomes between patients with a high BRTP score (≥5 points) and those with a low BRTP score (<5 points). RESULTS: We found that the BRTP score independently predicted the risk for ACM and CM in both diabetic patients [ACM, hazard risk (HR) = 1.748 (95% confidence interval (CI): 1.186-2.575), P = 0.005; CM, HR = 1.728 (95% CI: 1.120-2.667), P = 0.014] and nondiabetic patients [ACM, HR = 1.682 (95% CI: 1.208-2.340), P = 0.002; CM, HR = 1.718 (95% CI: 1.188-2.484), P = 0.004]. However, the BRTP score was found to be an independent predictor for major adverse cardiovascular event (MACE) and major adverse cardiovascular and cerebrovascular event (MACCE) in diabetic patients [MACE, HR = 1.366 (95% CI: 1.076-1.734), P = 0.010; MACCE, HR = 1.330 (95% CI: 1.035-1.710), P = 0.026] but not in nondiabetic patients [MACE, HR = 1.241 (95% CI: 0.994-1.549), P = 0.056; MACCE, HR = 1.238 (95% CI: 0.981-1.562), P = 0.072]. CONCLUSIONS: This study suggests that the BRTP score is an independent and novel predictor of mortality in CAD patients who had undergone PCI, especially in patients with comorbidity of diabetes. TRIAL REGISTRATION: ChiCTR-ROC-16010153. Registered 14, December, 2016.

13.
Bioengineered ; 12(2): 12521-12534, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34927535

RESUMO

The aim of this study was to determine the diversity of intestinal microflora and its correlation with clinical parameters in diabetic patients and healthy subjects and to assess the importance of intestinal flora in patients with diabetes. Forty-four patients with diabetes were included. The control group included 47 healthy people. Their data, biochemical indicators and results from 16S rRNA sequencing of their fecal samples were collected. Compared with the healthy population, the intestinal flora of the diabetic patients was obviously abnormal. Within the diabetes group, the abundances of the genera Faecalibacterium, Prevotella, and Roseburia were higher, and the abundances of the genera Shigella and Bifidobacterium were lower. In the correlation analysis between bacteria and clinical indicators, it was found that the genera Veillonella and unclassified_Enterobacteriaceae were negatively related to blood glucose, while the genera Phascolarctobacterium, unidentified_Bacteroidales and Prevotella were significantly positively correlated with fasting blood glucose. Twelve microbial markers were detected in the random forest model, and the area under the curve (AUC) was 84.1%. This index was greater than the diagnostic effect of fasting blood glucose. This was also supported by the joint diagnostic model of microorganisms and clinical indicators. In addition, the intestinal flora significantly improved the diagnosis of diabetes. In conclusion, it can be concluded from these results that intestinal flora is essential for the occurrence and development of diabetes, which seems to be as important as blood glucose itself.Abbreviations: PCoA: principal coordinate analysis; NMDS: non econometric multidimensional scaling analysis; LEfSe: linear discriminant analysis effect size; LDA: linear discriminant analysis; POD: probability of disease; BMI: body mass index; DCA: decision curve analysis.


Assuntos
Diabetes Mellitus/diagnóstico , Diabetes Mellitus/microbiologia , Microbioma Gastrointestinal/fisiologia , Bactérias/genética , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/genética , Humanos , Masculino , Pessoa de Meia-Idade , RNA Ribossômico 16S/genética
14.
Sensors (Basel) ; 21(21)2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34770267

RESUMO

For high-resolution side scan sonar images, accurate and fast segmentation of sonar images is crucial for underwater target detection and recognition. However, due to the characteristics of low signal-to-noise ratio (SNR) and complex environmental noise of sonar, the existing methods with high accuracy and good robustness are mostly iterative methods with high complexity and poor real-time performance. For this purpose, a region growing based segmentation using the likelihood ratio testing method (RGLT) is proposed. This method obtains the seed points in the highlight and the shadow regions by likelihood ratio testing based on the statistical probability distribution and then grows them according to the similarity criterion. The growth avoids the processing of the seabed reverberation regions, which account for the largest proportion of sonar images, thus greatly reducing segmentation time and improving segmentation accuracy. In addition, a pre-processing filtering method called standard deviation filtering (STDF) is proposed to improve the SNR and remove the speckle noise. Experiments were conducted on three sonar databases, which showed that RGLT has significantly improved quantitative metrics such as accuracy, speed, and segmentation visual effects. The average accuracy and running times of the proposed segmentation method for 100 × 400 images are separately 95.90% and 0.44 s.


Assuntos
Algoritmos , Processamento de Imagem Assistida por Computador , Funções Verossimilhança , Razão Sinal-Ruído , Som
15.
Mil Med Res ; 8(1): 58, 2021 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-34753510

RESUMO

BACKGROUND: Administration of propofol, an intravenous anesthetic with antioxidant property, immediately at the onset of post-ischemic reperfusion (propofol postconditioning, P-PostC) has been shown to confer cardioprotection against ischemia-reperfusion injury, while the underlying mechanism remains incompletely understood. The FoxO transcription factors are reported to play critical roles in activating cardiomyocyte survival signaling throughout the process of cellular injuries induced by oxidative stress and are also involved in hypoxic postconditioning mediated neuroprotection, however, the role of FoxO in postconditioning mediated protection in the heart and in particular in high glucose condition is unknown. METHODS: Rat heart-derived H9c2 cells were exposed to high glucose (HG) for 48 h (h), then subjected to hypoxia/reoxygenation (H/R, composed of 8 h of hypoxia followed by 12 h of reoxygenation) in the absence or presence of postconditioning with various concentrations of propofol (P-PostC) at the onset of reoxygenation. After having identified the optical concentration of propofol, H9c2 cells were subjected to H/R and P-PostC in the absence or presence of FoxO1 or FoxO3a gene silencing to explore their roles in P-PostC mediated protection against apoptotic and autophagic cell deaths under hyperglycemia. RESULTS: The results showed that HG with or without H/R decreased cell viability, increased lactate dehydrogenase (LDH) leakage and the production of reactive oxygen species (ROS) in H9c2 cells, all of which were significantly reversed by propofol (P-PostC), especially at the concentration of 25 µmol/L (P25) (all P < 0.05, NC vs. HG; HG vs. HG + HR; HG + HR + P12.5 or HG + HR + P25 or HG + HR + P50 vs. HG + HR). Moreover, we found that propofol (P25) decreased H9c2 cells apoptosis and autophagy that were concomitant with increased FoxO1 and FoxO3a expression (all P < 0.05, HG + HR + P25 vs. HG + HR). The protective effects of propofol (P25) against H/R injury were reversed by silencing FoxO1 or FoxO3a (all P < 0.05, HG + HR + P25 vs. HG + HR + P25 + siRNA-1 or HG + HR + P25 + siRNA-5). CONCLUSION: It is concluded that propofol postconditioning attenuated H9c2 cardiac cells apoptosis and autophagy induced by H/R injury through upregulating FoxO1 and FoxO3a under hyperglycemia.


Assuntos
Hiperglicemia , Propofol , Animais , Apoptose , Autofagia , Fatores de Transcrição Forkhead/farmacologia , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Hipóxia , Pós-Condicionamento Isquêmico , Propofol/farmacologia , Propofol/uso terapêutico , Ratos
16.
Front Cardiovasc Med ; 8: 732193, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34765652

RESUMO

Objective: To summarize the clinical features, hematology and imaging features of Takotsubo syndrome. Methods: The hospitalization data of Takotsubo syndrome patients in the First Affiliated Hospital of Xinjiang Medical University from January 2015 to December 2020 were collected, and their clinical characteristics were summarized. Patient outcomes were clarified through follow-up visits, and relevant objective indicators were statistically analyzed before and after admission. The characteristics of TTS incidence in Chinese population were summarized by searching three (Wanfang, CNKI, China's VIP database) major databases in China (PRISMA). Results: A total of 9 patients were enrolled, including 6 females (66.7%). The mean age of onset was 46.4 years old, the median time from onset to treatment was 1 day. The main symptom of 8 cases (88.9%) was chest pain, 1 case had a main symptom of syncope, and 7 cases (77.8%) had mood fluctuations or mental stimulation as the main symptom of the disease. Paired T-tests were conducted on routine blood, biochemical, coagulation, myocardial markers, inflammatory indicators and objective indicators of ECG before and after admission. The study found that the counts of white blood cells and neutrophils were statistically significant (P < 0.05). Prolongation of the QT interval was observed in all 9 patients. After a mean follow-up of 24 ± 28 months, no adverse cardiovascular events or recurrence occurred. Conclusion: Takotsubo syndrome is a group of clinical syndromes with emotional or somatic stimulation and chest pain as the main symptoms, partly accompanied by an increase in white blood cells, neutrophilic granulocyte count, creatine kinase, and troponin and is characterized by a prolonged QT interval and no obvious coronary stenosis. The prognosis is generally good, with few serious complications.

17.
Natl Sci Rev ; 8(9): nwab115, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34691744

RESUMO

This perspectives article surveys the most promising privacy-preserving cryptographic technologies including secure multiparty computation, zero-knowledge proofs and fully homomorphic encryption, and their various real-world applications.

18.
Blood Adv ; 5(17): 3362-3372, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34477819

RESUMO

The use of umbilical cord blood transplant has been substantially limited by the finite number of hematopoietic stem and progenitor cells in a single umbilical cord blood unit. Small molecules that not only quantitatively but also qualitatively stimulate enhancement of hematopoietic stem cell (HSC) self-renewal ex vivo should facilitate the clinical use of HSC transplantation and gene therapy. Recent evidence has suggested that the cyclin-dependent kinase inhibitor, p18INK4C (p18), is a critical regulator of mice HSC self-renewal. The role of p18 in human HSCs and the effect of p18 inhibitor on human HSC expansion ex vivo need further studies. Here we report that knockdown of p18 allowed for an increase in long-term colony-forming cells in vitro. We then identified an optimized small molecule inhibitor of p18, 005A, to induce ex vivo expansion of HSCs that was capable of reconstituting human hematopoiesis for at least 4 months in immunocompromised mice, and hence, similarly reconstituted secondary recipients for at least 4 more months, indicating that cells exposed to 005A were still competent in secondary recipients. Mechanistic studies showed that 005A might delay cell division and activate both the Notch signaling pathway and expression of transcription factor HoxB4, leading to enhancement of the self-renewal of long-term engrafting HSCs and the pool of progenitor cells. Taken together, these observations support a role for p18 in human HSC maintenance and that the p18 inhibitor 005A can enhance the self-renewal of long-term HSCs.


Assuntos
Inibidor de Quinase Dependente de Ciclina p18 , Células-Tronco Hematopoéticas , Animais , Benzoatos , Ciclo Celular , Inibidor de Quinase Dependente de Ciclina p18/genética , Hematopoese , Humanos , Camundongos
19.
Lipids Health Dis ; 20(1): 118, 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34587955

RESUMO

BACKGROUND: The present study was aimed to establish a prediction model for in-stent restenosis (ISR) in subjects who had undergone percutaneous coronary intervention (PCI) with drug-eluting stents (DESs). MATERIALS AND METHODS: A retrospective cohort study was conducted. From September 2010 to September 2013, we included 968 subjects who had received coronary follow-up angiography after primary PCI. The logistic regression analysis, receiver operator characteristic (ROC) analysis, nomogram analysis, Hosmer-Lemeshow χ2 statistic, and calibration curve were applied to build and evaluate the prediction model. RESULTS: Fifty-six patients (5.79%) occurred ISR. The platelet distribution width (PDW), total cholesterol (TC), systolic blood pressure (SBP), low-density lipoprotein cholesterol (LDL-C), and lesion vessels had significant differences between ISR and non-ISR groups (all P < 0.05). And these variables were independently associated with ISR (all P < 0.05). Furthermore, they were identified as predictors (all AUC > 0.5 and P < 0.05) to establish a prediction model. The prediction model showed a good value of area under curve (AUC) (95%CI): 0.72 (0.64-0.80), and its optimized cut-off was 6.39 with 71% sensitivity and 65% specificity to predict ISR. CONCLUSION: The incidence of ISR is 5.79% in CAD patients with DES implantation in the Xinjiang population, China. The prediction model based on PDW, SBP, TC, LDL-C, and lesion vessels was an effective model to predict ISR in CAD patients with DESs implantation.


Assuntos
Plaquetas/metabolismo , Doença da Artéria Coronariana/sangue , Stents Farmacológicos/efeitos adversos , Lipídeos/sangue , Idoso , Angiografia/métodos , Calibragem , Doença da Artéria Coronariana/diagnóstico , Reestenose Coronária , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Análise Multivariada , Nomogramas , Curva ROC , Análise de Regressão , Estudos Retrospectivos , Risco
20.
Bioengineered ; 12(1): 7263-7275, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34590550

RESUMO

Asymptomatic hyperuricemia (AH) is an early stage of gout. Emerging evidence shows that the intestinal microbiota is related to gout. However, the relationship between AH and the intestinal microbiota is poorly understood. Therefore, the aim of the current study was to explore the possible correlation between AH and intestinal flora. We compared the intestinal microbial communities of AH (45 cases) and healthy subjects (45 cases) by 16S rRNA gene sequencing and clustering analysis on the incorporated population. Intestinal-type clustering can be divided into two groups, and significant differences in the proportion of AH are found among different bowel types. Alpha diversity indices were higher in the AH group than in the control group, and beta diversity indices also showed significant differences. A total of 19 genera were found different between the AH group and the control group. Compared with the control group, some probiotics are increased in the AH population. Two groups were ranked by importance of bacteria. We found the different bacteria partially coincided with the important bacteria, and the joint diagnosis level of the important bacteria was good. Conclusion: There were significant differences in the composition of intestinal biota between AH patients and healthy subjects. Some probiotics increased in AH.


Assuntos
Microbioma Gastrointestinal/genética , Hiperuricemia , Idoso , Doenças Assintomáticas , Bactérias/genética , Fezes/microbiologia , Feminino , Humanos , Hiperuricemia/epidemiologia , Hiperuricemia/microbiologia , Masculino , Pessoa de Meia-Idade , Probióticos
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