Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 136
Filtrar
2.
Front Endocrinol (Lausanne) ; 12: 719920, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34539572

RESUMO

Observational studies report some association between circulating bilirubin levels and osteoporosis, but it is unknown if this association is causal or confounded. In this two-sample Mendelian randomization (MR) study, we included a large genome-wide association study (GWAS) associated with total bilirubin levels among 317,639 people, a large meta-analysis to identify genetic variants associated with bone mineral density (BMD) estimated by heel quantitative ultrasound (eBMD) among 426,824 individuals and fracture among 1.2 million individuals. The results revealed that circulating bilirubin levels had no causal influence on eBMD (beta-estimate: 0.004, 95% confidence interval [CI]: -0.019 to 0.028, SE:0.012, P-value=0.705) or the risk of fracture (beta-estimate: -0.009, 95% CI: -0.035 to 0.017, SE:0.013, P-value=0.488), which were both confirmed by multiple sensitivity analyses. Our results confirm that circulating bilirubin levels have no causal role in eBMD or the incidence of fracture, indicating that circulating bilirubin levels is unlikely to be a causal risk factor for osteoporosis or fracture.

3.
Proc Natl Acad Sci U S A ; 118(30)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34282012

RESUMO

The Qinghai-Tibetan Plateau, with low precipitation, low oxygen partial pressure, and temperatures routinely dropping below -30 °C in winter, presents several physiological challenges to its fauna. Yet it is home to many endemic mammalian species, including the plateau pika (Ochotona curzoniae). How these small animals that are incapable of hibernation survive the winter is an enigma. Measurements of daily energy expenditure (DEE) using the doubly labeled water method show that pikas suppress their DEE during winter. At the same body weight, pikas in winter expend 29.7% less than in summer, despite ambient temperatures being approximately 25 °C lower. Combined with resting metabolic rates (RMRs), this gives them an exceptionally low metabolic scope in winter (DEE/RMRt = 1.60 ± 0.30; RMRt is resting metabolic rate at thermoneutrality). Using implanted body temperature loggers and filming in the wild, we show that this is achieved by reducing body temperature and physical activity. Thyroid hormone (T3 and T4) measurements indicate this metabolic suppression is probably mediated via the thyroid axis. Winter activity was lower at sites where domestic yak (Bos grunniens) densities were higher. Pikas supplement their food intake at these sites by eating yak feces, demonstrated by direct observation, identification of yak DNA in pika stomach contents, and greater convergence in the yak/pika microbiotas in winter. This interspecific coprophagy allows pikas to thrive where yak are abundant and partially explains why pika densities are higher where domestic yak, their supposed direct competitors for food, are more abundant.

4.
Environ Technol ; : 1-8, 2021 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-34223810

RESUMO

A new type of metal-free catalyst was successfully prepared by doping boron (B) in the carbon nanotube. The catalyst had 99.4% removal of phenol in 60 min at pH 7 by activating peroxymonosulfate (PMS). In order to explore the origin of the high catalytic activity, the samples were characterized by Raman and electron paramagnetic resonance (EPR), and the reactive oxygen species (ROS) in the process of catalytic degradation were investigated. The Raman results showed that the defect sites increased after doping, which indicated that the B doping increases the active sites on the surface of the carbon nanotubes. Identification experiments of ROS found that not only hydroxyl radicals (·OH) and sulfate radical (SO4-∙), but also singlet oxygen (1O2) exist in the system. The presence of multiple free radicals indicated the existence of free radical reaction pathway, and the presence of 1O2 confirmed the existence of non-radical reaction pathway. These results indicated that there were dual reaction pathways for the activation of persulfate by B-doped carbon nanotubes, which was the intrinsic nature for the high catalytic activity of the system.

5.
J Forensic Leg Med ; 82: 102209, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34229151

RESUMO

The occurrence of air embolism is highly related to medical operations, and air embolism can cause sudden death. Such situations require attention in forensic work. This article reports two cases of iatrogenic air embolism confirmed by autopsy. In case 1, air embolism occurred after hydrogen peroxide was used to irrigate and disinfect a wound on the patient's left forearm. Approximately 90 ml of 3% hydrogen peroxide solution was used in case 1, and this volume can produce approximately 890 ml of oxygen by complete decomposition, which is far more than the average lethal air embolism volume. Attention should be given to the risk of air embolism when using hydrogen peroxide for irrigation and disinfection. In case 2, air embolism occurred during left ureteroscopy and stent placement. Due to inappropriate processing, the normal saline pump infused air into the patient at a high pressure of 120 mmHg. Based on our autopsy findings, we discuss the pathways of arterial air embolism and cerebral air embolism. In addition to the air entrainment volume and accumulation rate, the location of air accumulation also significantly impacts the risk of air embolism. After an arterial air embolus develops into a coronary and/or cerebral air embolus, the lethal air volume drops to only a few milliliters.


Assuntos
Morte Súbita/etiologia , Embolia Aérea/etiologia , Peróxido de Hidrogênio/efeitos adversos , Irrigação Terapêutica/efeitos adversos , Ureteroscopia/efeitos adversos , Adolescente , Autopsia , Evolução Fatal , Feminino , Humanos , Doença Iatrogênica , Masculino , Pessoa de Meia-Idade
6.
J Forensic Leg Med ; 81: 102204, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34192655

RESUMO

Systemic vasculitis (SV) is a condition characterized by vascular inflammatory disease that often involves the medium and small arteries of various organs throughout the body. SV is difficult to diagnose due to the diversity of clinical symptoms and manifestations, and only tissue biopsy is of great significance. Even so, complications or secondary lesions of SV can also lead to death. In forensic medicine, we can often observe multiple vasculitis in histological observations, which is easily overlooked as a primary cause of death in the final diagnosis. Twenty SV cases were registered in our institution from a total of 1088 completed autopsies, which represents 1.83% of the total autopsies. The ages of these 20 SV patients ranged from 16 to 73 years, and the mean age was 41.1 ± 15.9 years. SV usually involves multiple organs, such as the heart, lung, liver, kidney, gastrointestinal system and brain, simultaneously. The intensity of the lesions in the heart and kidney seemed to be more severe than the lesion intensity in other organs in most cases. The causes of death were identified as acute myocarditis (8 cases), acute heart failure (3 cases), cerebral artery rupture (3 cases), cardiovascular artery rupture (2 cases), acute interstitial pneumonia (2 cases), aortic aneurysm rupture (1 case) and acute renal failure (1 case). The typical histopathological changes (smooth muscle degeneration, fibrinoid necrosis, inflammatory cell infiltration and microthrombosis) of arteries observed in this study were of great significance for diagnosing SV. In this article, we try to analyse and summarize the lesion characteristics in cases of death caused by SV in order to provide some help for forensic workers in identifying such cases.


Assuntos
Patologia Legal , Vasculite Sistêmica/diagnóstico , Vasculite Sistêmica/patologia , Adolescente , Adulto , Idoso , Autopsia , Causas de Morte , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mudanças Depois da Morte , Estudos Retrospectivos , Adulto Jovem
7.
Endocrinology ; 162(9)2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34089599

RESUMO

The obesity pandemic requires effective preventative and therapeutic intervention strategies. Successful and sustained obesity treatment is currently limited to bariatric surgery. Modulating the release of gut hormones is considered promising to mimic bariatric surgery with its beneficial effects on food intake, body weight, and blood glucose levels. The gut peptide secretin was the first molecule to be termed a hormone; nevertheless, only recently has it been established as a legitimate anorexigenic peptide. In contrast to gut hormones that crosstalk with the brain either directly or by afferent neuronal projections, secretin mediates meal-associated brown fat thermogenesis to induce meal termination, thereby qualifying this physiological mechanism as an attractive, peripheral target for the treatment of obesity. In this perspective, it is of pivotal interest to deepen our as yet superficial knowledge on the physiological roles of secretin as well as meal-associated thermogenesis in energy balance and body weight regulation. Of note, the emerging differences between meal-associated thermogenesis and cold-induced thermogenesis must be taken into account. In fact, there is no correlation between these 2 entities. In addition, the investigation of potential effects of secretin in hedonic-driven food intake, bariatric surgery and chronic treatment using suitable application strategies to overcome pharmacokinetic limitations will provide further insight into its potential to influence energy balance. The aim of this article is to review the facts on secretin's metabolic effects, address prevailing gaps in our knowledge, and provide an overview on the opportunities and challenges of the therapeutic potential of secretin in body weight control.

8.
Leg Med (Tokyo) ; 53: 101930, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34130173

RESUMO

The aim of this study was to detect the postmortem serum total IgE levels in frozen corpses and identify whether the death incident caused by an anaphylaxis in forensic medicine. Autopsy cases with pathological death (total, n = 106; 4-214 h postmortem) include cardiac disease (n = 15), pulmonary infection (n = 12), central nervous system disorder (n = 6), pulmonary emboliszn (n = 7), hapetic disease (n = 5), kidney disease (n = 6), enteric disease (n = 10), necrotizing pancreatitis (n = 7), diffuse peritonitis (n = 6), MODS (n = 6), toxicosis (n = 5:), anaphylactic shock (n = 7), bronchial asthma (n = 8) and other disease (n = 6) were examined. Results showed that there was no significant difference between serum IgE levels and ages, postmortem intervals (PMIs), gender as well as survival time. Serum IgE levels of deaths due to anaphylactic shock and bronchial asthma were higher than that of other groups. Forensic pathology examination results showed the main pathology changes of bronchial asthma were mucous congestion in bronchial lumen and eosinophils infiltration in bronchial mucosa. The main pathological features of anaphylactic shock were laryngeal edema and eosinophils infiltration in multiple organs (lung and spleen). This research proved that there was a great significance for IgE to infer whether the individual died due to an anaphylaxis even for a long PMI in frozen corpses. Furthermore, we can also preliminarily determine the type of allergic death combined with the examination of forensic pathology. These findings further verify the feasibility of postmortem serum IgE in the diagnosis of forensic causes of death and broaden the application scope of this marker.

9.
Nat Metab ; 3(6): 798-809, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34158656

RESUMO

Brown adipose tissue (BAT) thermogenesis is activated by feeding. Recently, we revealed a secretin-mediated gut-BAT-brain axis, which stimulates satiation in mice, but the purpose of meal-induced BAT activation in humans has been unclear. In this placebo-controlled, randomized crossover study, we investigated the effects of intravenous secretin on BAT metabolism (measured with [18F]FDG and [15O]H2O positron emission tomography) and appetite (measured with functional magnetic resonance imaging) in healthy, normal weight men (GUTBAT trial no. NCT03290846). Participants were blinded to the intervention. Secretin increased BAT glucose uptake (primary endpoint) compared to placebo by 57% (median (interquartile range, IQR), 0.82 (0.77) versus 0.59 (0.53) µmol per 100 g per min, 95% confidence interval (CI) (0.09, 0.89), P = 0.002, effect size r = 0.570), while BAT perfusion remained unchanged (mean (s.d.) 4.73 (1.82) versus 6.14 (3.05) ml per 100 g per min, 95%CI (-2.91, 0.07), P = 0.063, effect size d = -0.549) (n = 15). Whole body energy expenditure increased by 2% (P = 0.011) (n = 15). Secretin attenuated blood-oxygen level-dependent activity (primary endpoint) in brain reward circuits during food cue tasks (significance level false discovery rate corrected at P = 0.05) (n = 14). Caloric intake did not significantly change, but motivation to refeed after a meal was delayed by 39 min (P = 0.039) (n = 14). No adverse effects were detected. Here we show in humans that secretin activates BAT, reduces central responses to appetizing food and delays the motivation to refeed after a meal. This suggests that meal-induced, secretin-mediated BAT activation is relevant in the control of food intake in humans. As obesity is increasing worldwide, this appetite regulating axis offers new possibilities for clinical research in treating obesity.


Assuntos
Tecido Adiposo Marrom/metabolismo , Saciação , Secretina/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Animais , Encéfalo/fisiologia , Ingestão de Energia , Metabolismo Energético , Comportamento Alimentar , Trato Gastrointestinal/fisiologia , Glucose/metabolismo , Humanos , Camundongos , Termogênese
10.
EMBO Rep ; 22(7): e51289, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34056831

RESUMO

The recruitment of thermogenic brite adipocytes within white adipose tissue attenuates obesity and metabolic comorbidities, arousing interest in understanding the underlying regulatory mechanisms. The molecular network of brite adipogenesis, however, remains largely unresolved. In this light, long noncoding RNAs (lncRNAs) emerged as a versatile class of modulators that control many steps within the differentiation machinery. Leveraging the naturally varying propensities of different inbred mouse strains for white adipose tissue browning, we identify the nuclear lncRNA Ctcflos as a pivotal orchestrator of thermogenic gene expression during brite adipocyte differentiation. Mechanistically, Ctcflos acts as a pleiotropic regulator, being essential for the transcriptional recruitment of the early core thermogenic regulatory program and the modulation of alternative splicing to drive brite adipogenesis. This is showcased by Ctcflos-regulated gene transcription and splicing of the key browning factor Prdm16 toward the isoform that is specific for the thermogenic gene program. Conclusively, our findings emphasize the mechanistic versatility of lncRNAs acting at several independent levels of gene expression for effective regulation of key differentiation factors to direct cell fate and function.


Assuntos
Adipogenia , RNA Longo não Codificante , Adipogenia/genética , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Processamento Alternativo , Animais , Camundongos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Termogênese
11.
Cancer Med ; 10(10): 3346-3357, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33932127

RESUMO

BACKGROUND: Chronic alcohol consumption is more frequently associated with advanced, aggressive hepatocellular carcinoma (HCC) tumors. Alcohol adversely impacts ER/Golgi membrane trafficking and Golgi protein N-glycosylation in hepatocytes; these effects have been attributed (in part) to dysregulated adenosine diphosphate-ribosylation factor (ARF) GTPase signaling. Here, we investigated the role of the ARF GTPase guanine exchange factor PSD4 in HCC progression. METHODS: R-based bioinformatics analysis was performed on publicly available array data. Modulating gene expression was accomplished via lentiviral vectors. Gene expression was analyzed using quantitative real-time PCR and immunoblotting. PSD4 promoter methylation was assessed using quantitative methylation-specific PCR. Phospho-p65(S276)/DNMT1 binding to the PSD4 promoter was analyzed via chromatin immunoprecipitation. We constructed ethanol/DEN-induced and DEN only-induced transgenic murine models of HCC. RESULTS: We identified PSD4 as a hypermethylated, suppressed gene in alcohol-related HCC tumors; however, PSD4 was not dysregulated in all-cause HCC tumors. Certain HCC cell lines also displayed varying degrees of PSD4 downregulation. PSD4 overexpression or knockdown decreased and increased cell migration and invasiveness, respectively. Mechanistically, PSD4 transcription was repressed by TNF-α-induced phospho-p65(S276)'s recruitment of DNA methyltransferase 1 (DNMT1), resulting in PSD4 promoter methylation. PSD4 inhibited pro-EMT CDC42 activity, resulting in downregulation of E-cadherin and upregulation of N-cadherin and vimentin. Hepatocyte-specific PSD4 overexpression reduced ethanol/DEN-induced HCC tumor progression and EMT marker expression in vivo. CONCLUSIONS: PSD4 is a hypermethylated, suppressed gene in alcohol-related HCC tumors that negatively modulated pro-EMT CDC42 activity. Furthermore, we present a novel phospho-NF-κB p65(S276)/DNMT1-mediated promoter methylation mechanism by which TNF-α/NF-κB signaling represses PSD4 transcription in HCC cells.


Assuntos
Álcoois/efeitos adversos , Carcinoma Hepatocelular/genética , Epigênese Genética/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Neoplasias Hepáticas/genética , NF-kappa B/genética , Transcrição Genética/genética , Fator de Necrose Tumoral alfa/genética , Consumo de Bebidas Alcoólicas/genética , Animais , Caderinas/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , DNA (Citosina-5-)-Metiltransferase 1/genética , Metilação de DNA/genética , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Células Hep G2 , Hepatócitos/patologia , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Transgênicos , Gravidez , Regiões Promotoras Genéticas/genética , Transdução de Sinais/genética , Fator de Transcrição RelA/genética
12.
Chemosphere ; 275: 130058, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33652283

RESUMO

Preparation of carbonaceous catalysts by doping with boron (B) is one of the most promising strategies for substitution of toxic transition metal catalysts in advanced oxidation processes. This study was dedicated to reveal the intrinsic structure-performance relationship of peroxomonosulfate (PMS) activation by B-doped carbon nanotubes toward catalytic oxidation of pollutants. Performance tests showed the catalyst realized more than 95% phenol removal at pH 7 in 1 h and 69.4% total organic carbon removal. The catalysts were characterized using scanning electron microscopy (SEM), transmission electron microscope (TEM), Raman spectroscopy, X-ray photoelectron spectroscopy (XPS) and electron paramagnetic resonance (EPR). Characterization results indicated that the topography of carbon nanotube was not significantly changed after B doped, while the defect sites increased from 1.05 to 1.23. The newly formed active sites may be presented in the form of C3B, CBO2 and CBO3, and reactive oxygen species (ROS) including OH, SO4-•, O2-• and 1O2 might be generated after activation by the active sites. Furthermore, B-MWNT-PMS∗ was also be detected by In-situ Raman, confirming the non-radical pathway and electron transfer mechanism. Beside of phenol, the reaction system of B-MWNT/PMS also can remove methylene blue, bisphenol S and diuron at pH = 7, confirming the universality and promising of this advanced oxidation technology.


Assuntos
Nanotubos de Carbono , Boro , Catálise , Oxirredução , Peróxidos
13.
Angew Chem Int Ed Engl ; 60(16): 9032-9037, 2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33529488

RESUMO

Capture and storage of the long-lived 85 Kr is an efficient approach to mitigate the emission of volatile radionuclides from the spent nuclear fuel reprocessing facilities. However, it is challenging to separate krypton (Kr) from xenon (Xe) because of the chemical inertness and similar physical properties. Herein we prepared high-silica CHA zeolite membranes with ultra-high selectivity and irradiation stability for Kr/Xe separation. The suitable aperture size and rigid framework endures the membrane a strong size-exclusion effect. The ultrahigh selectivity of 51-152 together with the Kr permeance of 0.7-1.3×10-8  mol m-2 s-1 Pa-1 of high-silica CHA zeolite membranes far surpass the state-of-the-art polymeric membranes. The membrane is among the most stable polycrystalline membranes for separation of humid Kr/Xe mixtures. Together with the excellent irradiation stability, high-silica CHA zeolite membranes pave the way to separate radioactive Kr from Xe for a notable reduction of the volatile nuclear waste storage volume.

14.
Clin Microbiol Infect ; 27(7): 1000-1006, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33421578

RESUMO

OBJECTIVES: Delay in diagnosis of tuberculosis (TB) is an important but under-appreciated problem. Our study aimed to analyse the patient pathway and possible risk factors of long diagnostic delay (LDD). METHODS: We enrolled 400 new bacteriologically diagnosed patients with pulmonary TB from 20 hospitals across China. LDD was defined as an interval between the initial care visit and the confirmation of diagnosis exceeding 14 days. Its potential risk factors were investigated by multivariate logistic regression and multilevel logistic regression. Hospitals in China were classified by increasing size, from level 0 to level 3. TB laboratory equipment in hospitals was also evaluated. RESULTS: The median diagnostic delay was 20 days (IQR: 7-72 days), and 229 of 400 patients (57.3%, 95%CI 52.4-62.1) had LDD; 15% of participants were diagnosed at the initial care visit. Compared to level 0 facilities, choosing level 2 (OR 0.27, 95%CI 0.12-0.62, p 0.002) and level 3 facilities (OR 0.34, 95%CI 0.14-0.84, p 0.019) for the initial care visit was independently associated with shorter LDD. Equipping with smear, culture, and Xpert at initial care visit simultaneously also helped to avoid LDD (OR 0.28, 95%CI 0.09-0.82, p 0.020). The multilevel logistic regression yielded similar results. Availability of smear, culture, and Xpert was lower in level 0-1 facilities than in level 2-3 facilities (p < 0.001, respectively). CONCLUSIONS: Most patients failed to be diagnosed at the initial care visit. Patients who went to low-level facilities initially had a higher risk of LDD. Improvement of TB laboratory equipment, especially at low-level facilities, is urgently needed.

15.
Forensic Sci Int ; 318: 110594, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33276201

RESUMO

miRNA markers have been an area of forensic interest to identify body fluid sources in recent years. In this study, reverse transcription and quantitative real time polymerase chain reaction (RT-qPCR) were performed to detect the existence of blood-specific miRNA markers in bloodstained samples under different environmental conditions, Blood samples from 6 individuals were deposited onto glass plates and exposed to different temperature, humidity, ultraviolet light intensity, and natural condition. When samples were stored to a series of estimated test times, total RNA was extracted and the Ct values of the target RNAs were detected, targets included two miRNA markers (hsa-miR-16-5p, hsa-miR-451a) and one reference gene (U6 snRNA). Analysis results showed that miR-451a represented strong stability and could be detected at all detection points. Meanwhile, each RNAs exhibited unique degradation characteristics, compared to U6, miRNAs showed stronger stability. Additionally, rain had an adverse effect on RNAs stability and accelerates its degradation rate.


Assuntos
Manchas de Sangue , MicroRNAs/fisiologia , Estabilidade de RNA/fisiologia , Manejo de Espécimes , Escuridão , Feminino , Humanos , Umidade , Masculino , Chuva , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Temperatura , Raios Ultravioleta
16.
Artif Organs ; 45(7): 762-769, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33326621

RESUMO

Our aim was to investigate the effect of artificial liver blood purification treatment on the survival of severe/critical patients with coronavirus disease 2019 (COVID-19). A total of 101 severe and critical patients with coronavirus SARS-CoV-2 infection were enrolled in this open, case-control, multicenter, prospective study. According to the patients' and their families' willingness, they were divided into two groups. One was named the treatment group, in which the patients received artificial liver therapy plus comprehensive treatment (n = 50), while the other was named the control group, in which the patients received only comprehensive treatment (n = 51). Clinical data and laboratory examinations, as well as the 28-day mortality rate, were collected and analyzed. Baseline data comparisons on average age, sex, pre-treatment morbidity, initial symptoms, vital signs, pneumonia severity index score, blood routine examination and biochemistry indices etc. showed no difference between the two groups. Cytokine storm was detected, with a significant increase of serum interleukin-6 (IL-6) level. The serum IL-6 level decreased from 119.94 to 20.49 pg/mL in the treatment group and increased from 40.42 to 50.81 pg/mL in the control group (P < .05), indicating that artificial liver therapy significantly decreased serum IL-6. The median duration of viral nucleic acid persistence was 19 days in the treatment group (ranging from 6 to 67 days) and 17 days in the control group (ranging from 3 to 68 days), no significant difference was observed (P = .36). As of 28-day follow-up,17 patients in the treatment group experienced a median weaning time of 24 days, while 11 patients in the control group experienced a median weaning time of 35 days, with no significant difference between the two groups (P = .33). The 28-day mortality rates were 16% (8/50) in the treatment group and 50.98% (26/51) in the control group, with a significant difference (z = 3.70, P < .001). Cytokine storm is a key factor in the intensification of COVID-19 pneumonia. The artificial liver therapy blocks the cytokine storm by clearing inflammatory mediators, thus preventing severe cases from progressing to critically ill stages and markedly reducing short-term mortality.


Assuntos
COVID-19/terapia , Síndrome da Liberação de Citocina/prevenção & controle , Fígado Artificial , Troca Plasmática/instrumentação , Idoso , Biomarcadores/sangue , COVID-19/sangue , COVID-19/mortalidade , COVID-19/virologia , Estudos de Casos e Controles , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/mortalidade , Síndrome da Liberação de Citocina/virologia , Citocinas/sangue , Feminino , Mortalidade Hospitalar , Interações Hospedeiro-Patógeno , Humanos , Masculino , Pessoa de Meia-Idade , Troca Plasmática/efeitos adversos , Troca Plasmática/mortalidade , Estudos Prospectivos , SARS-CoV-2/patogenicidade , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Carga Viral
17.
Acta Pharmacol Sin ; 2020 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-33244163

RESUMO

Vicagrel, a novel irreversible P2Y12 receptor inhibitor, is undergoing phase III trials for the treatment of acute coronary syndromes in China. In this study, we evaluated the pharmacokinetics, mass balance, and metabolism of vicagrel in six healthy male Chinese subjects after a single oral dose of 20 mg [14C]vicagrel (120 µCi). Vicagrel absorption was fast (Tmax = 0.625 h), and the mean t1/2 of vicagrel-related components was ~38.0 h in both plasma and blood. The blood-to-plasma radioactivity AUCinf ratio was 0.55, suggesting preferential distribution of drug-related material in plasma. At 168 h after oral administration, the mean cumulative excreted radioactivity was 96.71% of the dose, including 68.03% in urine and 28.67% in feces. A total of 22 metabolites were identified, and the parent vicagrel was not detected in plasma, urine, or feces. The most important metabolic spot of vicagrel was on the thiophene ring. In plasma pretreated with the derivatization reagent, M9-2, which is a methylated metabolite after thiophene ring opening, was the predominant drug-related component, accounting for 39.43% of the radioactivity in pooled AUC0-8 h plasma. M4, a mono-oxidation metabolite upon ring-opening, was the most abundant metabolite in urine, accounting for 16.25% of the dose, followed by M3-1, accounting for 12.59% of the dose. By comparison, M21 was the major metabolite in feces, accounting for 6.81% of the dose. Overall, renal elimination plays a crucial role in vicagrel disposition, and the thiophene ring is the predominant metabolic site.

18.
Artigo em Inglês | MEDLINE | ID: mdl-33252252

RESUMO

We studied the metabolic phenotype of a novel Ucp1-LUC-iRFP713 knock-in reporter gene mouse model originally generated to monitor endogenous Ucp1 gene expression. Both reporter mice and reporter cells reliably reflected Ucp1 gene expression in vivo and in vitro. We here report an unexpected reduction in UCP1 content in homozygous knock-in (KI) reporter mice. As a result, the thermogenic capacity of KI mice stimulated by norepinephrine was largely blunted, making them more sensitive to an acute cold exposure. In return, these reporter mice with reduced UCP1 expression enabled us to investigate the physiological role of UCP1 in the prevention of weight gain. We observed no substantial differences in body mass across the three genotypes, irrespective of the type of diet or the ambient temperature, possibly due to the insufficient UCP1 activation. Indeed, activation of UCP1 by daily injection of the selective ß3-adrenergic receptor agonist CL316,243 resulted in significantly greater reduction of body weight in WT mice than in KI mice. Taken together, we conclude that the intact expression of UCP1 is essential for cold-induced thermogenesis but the presence of UCP1 per se does not protect mice from diet-induced obesity.

19.
Br J Clin Pharmacol ; 86(9): 1860-1874, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32267573

RESUMO

AIMS: We investigated the impacts of CYP2C19 polymorphisms on pharmacokinetics and pharmacodynamics of vicagrel in healthy Chinese subjects. METHODS: CYP2C19 extensive metabolizers (EMs), intermediate metabolizers (IMs) and poor metabolizers (PMs; 16 subjects/group) participated in a randomized, open-label, 2-period cross-over study. Each study period lasted 7 days, with a loading dose of 24 mg of vicagrel or 300 mg of clopidogrel on day 1, and maintenance doses of 6 mg of vicagrel or 75 mg of clopidogrel daily from day 2 to day 7. The pharmacokinetics and pharmacodynamics were assessed on day 1 and day 7. RESULTS: After a loading dose, the AUC0-t of the active metabolite H4 by vicagrel was slightly lower in IMs and PMs (decreased by 21 and 27%, respectively) compared to EMs. Similar results were found after maintenance doses. In EMs, the AUC0-t of H4 by vicagrel was somewhat higher than clopidogrel after the loading dose, and comparable with clopidogrel (90% confidence interval 0.94, 1.21) after the maintenance doses. However, it was much higher than clopidogrel in PMs, with a 1.28-fold (loading dose) and a 73% (maintenance doses) increases compared to clopidogrel (P < 0.001). Consequently, the inhibition of platelet aggregation by vicagrel was greater than clopidogrel after both loading dose (28.2 vs 12.4% at 4 hours, P < 0.01) and maintenance doses (42.8 vs 24.6% at 4 hours, P < 0.001) in PMs. CONCLUSIONS: CYP2C19 polymorphisms have less impact on vicagrel as compared to clopidogrel. Drug exposure and response to vicagrel in PMs were even higher than to clopidogrel in IMs.

20.
Mol Cell Probes ; 52: 101568, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32251686

RESUMO

Gene fusion is caused by the linkage of previously separate genes or sequences. Recently, an increasing number of novel fusion genes have been identified and associated with tumor progression, and several of them have been suggested as promising targets for tumor therapy. However, there are hardly any studies reporting the association of fusion genes with the progression of oral squamous cell carcinoma (OSCC). In this study, we identified a total of 11 fused genes in OSCC cells. We further analyzed the structure of one fused gene, TRIM52-RACK1, and detected its function in tumor progression in vitro. We found that TRIM52-RACK1 was caused by a deletion of 181,257,187-181,247,386 at 5q35.3 and it promoted OSCC cell proliferation, migration, and invasion. Therefore, TRIM52-RACK1 can be a promising target for tumor therapy in OSCC.


Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias Bucais/genética , Proteínas de Fusão Oncogênica/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Humanos , Invasividade Neoplásica , Proteínas de Fusão Oncogênica/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...