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1.
Clin Immunol ; 248: 109271, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36806705

RESUMEN

BACKGROUND: Little is known about the characteristics of lymphocyte subsets and the association with patient outcomes in COVID-19 with and without impaired kidney function. METHODS: Lymphocyte subsets were compared in COVID-19 patients with or without kidney dysfunction. The primary outcome was a composite of all-cause mortality or intensive care unit admission. Secondary outcomes included duration of viral shedding, length of hospital stay, and acute kidney injury. RESULTS: Lymphocyte subset cell counts demonstrated the lowest in patients with severe/critical COVID-19 and kidney dysfunction. Among all lymphocyte subset parameters, Th cell count was the most significant indicator for outcomes. ROC of the combined model of Th cell count and eGFR presented better predictive value than that of the other parameters. Th cell count <394.5 cells/µl and eGFR <87.5 ml/min/1·73m2 were independently associated with poor outcomes. The propensity score matching analysis revealed consistent results. CONCLUSIONS: Reduced Th cell count and eGFR may be applied as promising predictive indicators for identifying COVID-19 patients with high risk and poor outcomes.


Asunto(s)
COVID-19 , Humanos , SARS-CoV-2 , Subgrupos Linfocitarios , Recuento de Linfocitos , Riñón , Estudios Retrospectivos
2.
PLoS Pathog ; 16(7): e1008669, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32702076

RESUMEN

Hepatitis B virus (HBV) replicates its genomic DNA via viral DNA polymerase self-primed reverse transcription of a RNA pre-genome in the nucleocapsid assembled by 120 core protein (Cp) dimers. The arginine-rich carboxyl-terminal domain (CTD) of Cp plays an important role in the selective packaging of viral DNA polymerase-pregenomic (pg) RNA complex into nucleocapsid. Previous studies suggested that the CTD is initially phosphorylated at multiple sites to facilitate viral RNA packaging and subsequently dephosphorylated in association with viral DNA synthesis and secretion of DNA-containing virions. However, our recent studies suggested that Cp is hyper-phosphorylated as free dimers and its dephosphorylation is associated with pgRNA encapsidation. Herein, we provide further genetic and biochemical evidence supporting that extensive Cp dephosphorylation does take place during the assembly of pgRNA-containing nucleocapsids, but not empty capsids. Moreover, we found that cellular protein phosphatase 1 (PP1) is required for Cp dephosphorylation and pgRNA packaging. Interestingly, the PP1 catalytic subunits α and ß were packaged into pgRNA-containing nucleocapsids, but not empty capsids, and treatment of HBV replicating cells with core protein allosteric modulators (CpAMs) promoted empty capsid assembly and abrogated the encapsidation of PP1 α and ß. Our study thus identified PP1 as a host cellular factor that is co-packaged into HBV nucleocapsids, and plays an essential role in selective packaging of the viral DNA-polymerase-pgRNA complex through catalyzing Cp dephosphorylation.


Asunto(s)
Virus de la Hepatitis B/fisiología , Nucleocápside/metabolismo , Proteína Fosfatasa 1/metabolismo , ARN Viral/metabolismo , Ensamble de Virus/fisiología , Línea Celular , Hepatitis B/virología , Humanos , Fragmentos de Péptidos/metabolismo , Fosforilación , Proteínas del Núcleo Viral/metabolismo
3.
Bioorg Med Chem Lett ; 58: 128518, 2022 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-34979256

RESUMEN

Hepatitis B virus (HBV) core protein, the building block of the HBV capsid, plays multiple roles in viral replication, and is an attractive target for development of antiviral agents with a new mechanism of action. In addition to the heteroaryldihydropyrimidines (HAPs), sulfamoylbenzamides (SBAs), dibenzothiazepine derivatives (DBTs), and sulfamoylpyrrolamides (SPAs) that inhibit HBV replication by modulation of viral capsid assembly and are currently under clinical trials for the treatment of chronic hepatitis B (CHB), other chemical structures with activity to modulate HBV capsid assembly have also been explored. Here we describe our continued optimization of a benzamide originating from our high throughput screening. A new bicyclic carboxamide lead featuring an electron deficient non-planar core structure was discovered. Evaluations of its ADMET (absorption, distribution, metabolism, excretion and toxicity) and pharmacokinetic (PK) profiles demonstrate improved metabolic stability and good bioavailability.


Asunto(s)
Antivirales/farmacología , Virus de la Hepatitis B/efectos de los fármacos , Quinolinas/farmacología , Animales , Antivirales/síntesis química , Antivirales/química , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Estructura Molecular , Quinolinas/síntesis química , Quinolinas/química , Relación Estructura-Actividad , Proteínas del Núcleo Viral , Replicación Viral/efectos de los fármacos
4.
Med Chem Res ; 30(2): 459-472, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33456291

RESUMEN

We report herein the synthesis and evaluation of phenyl ureas derived from 4-oxotetrahydropyrimidine as novel capsid assembly modulators of hepatitis B virus (HBV). Among the derivatives, compound 27 (58031) and several analogs showed an activity of submicromolar EC50 against HBV and low cytotoxicities (>50 µM). Structure-activity relationship studies revealed a tolerance for an additional group at position 5 of 4-oxotetrahydropyrimidine. The mechanism study indicates that compound 27 (58031) is a type II core protein allosteric modulator (CpAMs), which induces core protein dimers to assemble empty capsids with fast electrophoresis mobility in native agarose gel. These compounds may thus serve as leads for future developments of novel antivirals against HBV.

5.
Antiviral Res ; 216: 105659, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37369283

RESUMEN

BACKGROUND: COVID-19 causes significant mortality during the recent pandemic. Data regarding the effectiveness of Paxlovid on COVID-19 patients with chronic kidney disease (CKD, eGFR <90 ml/min) are limited. METHODS: A retrospective cohort study was performed on the clinical data of the hospitalized adult patients with confirmed COVID-19 infection collected at Renji Hospital from April 7, 2022 to June 21, 2022. The association of Paxlovid treatment with early (within 5 days post diagnosis) or late (5 days or later post diagnosis) initiation time with clinical outcomes was assessed by Cox proportional hazards regression model with time-dependent covariates. RESULT: 1279 of 2387 enrollees were included in the study. Patients with early initiation of Paxlovid had a lower all-cause death rate compared to those with late initiation or without Paxlovid treatment (P = 0.046). For the CKD patients with Charlson comorbidity index (CCI) > 7, the early initiation of Paxlovid was associated with a lower all-cause death rate compared to the later initiation or the lack of Paxlovid treatment (P = 0.041). Cox regression analyses revealed that eGFR (HR 4.21 [95%, CI 1.62-10.99]), Paxlovid treatment (0.32 [0.13-0.77]), CCI (4.32 [1.64-11.40]), ICU admission (2.65 [1.09-6.49]), hsCRP (3.88 [1.46-7.80]), chronic liver disease (4.02 [1.09-14.85]) were the independent risk factors for all-cause death for CKD patients after adjusting for demographics and biochemical indexes. CONCLUSIONS: All-cause death, invasive ventilation, and ICU admission were all significantly lowered by an early initiation of Paxlovid treatment in COVID-19 patients with severe CKD.


Asunto(s)
COVID-19 , Insuficiencia Renal Crónica , Adulto , Humanos , COVID-19/complicaciones , Estudios Retrospectivos , Insuficiencia Renal Crónica/complicaciones , Factores de Riesgo
6.
Eur J Med Chem ; 259: 115634, 2023 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-37499290

RESUMEN

A key step of hepatitis B virus (HBV) replication is the selective packaging of pregenomic RNA (pgRNA) by core protein (Cp) dimers, forming a nucleocapsid where the reverse transcriptional viral DNA replication takes place. One approach in the development of new anti-HBV drugs is to disrupt the assembly of HBV nucleocapsids by misdirecting Cp dimers to assemble morphologically normal capsids devoid of pgRNA. In this study, we built upon our previous discovery of benzamide-derived HBV capsid assembly modulators by exploring fused bicyclic scaffolds with an exocyclic amide that is ß, γ to the fused ring, and identified 1,2,3,4-tetrahydroquinoxaline derived phenyl ureas as a novel scaffold. Structure-activity relationship studies showed that a favorable hydrophobic substitution can be tolerated at the 2-position of the 1,2,3,4-tetrahydroquinoxaline core, and the resulting compound 88 demonstrated comparable or improved antiviral potencies in mouse and human hepatocyte-derived HBV-replicating cell lines compared to our previously reported benzamide compound, 38017 (8). In addition, a novel bis-urea series based on 1,2,3,4-tetrahydroquinoxaline was also found to inhibit HBV DNA replication with sub-micromolar EC50 values. The mode of action of these compounds is consistent with specific inhibition of pgRNA encapsidation into nucleocapsids in hepatocytes.


Asunto(s)
Virus de la Hepatitis B , Hepatitis B , Humanos , Animales , Ratones , Virus de la Hepatitis B/metabolismo , Replicación Viral , Ensamble de Virus , Replicación del ADN , ARN Viral/genética , ADN Viral , Nucleocápside/metabolismo , Antivirales/química , Benzamidas/farmacología , Hepatitis B/tratamiento farmacológico
8.
China CDC Wkly ; 3(29): 624-626, 2021 Jul 16.
Artículo en Inglés | MEDLINE | ID: mdl-34594949

RESUMEN

WHAT IS ALREADY KNOWN ON THIS TOPIC?: Hydrogen peroxide sterilizeation is widely used for luminal devices. However, the low penetrability of the sterilant is of major concern. WHAT IS ADDED BY THIS REPORT?: This report investigated the effective sterilization of low-temperature hydrogen peroxide gas plasma sterilizers and compared the applicability of different biological monitoring methods based on medical luminal devices. WHAT ARE THE IMPLICATIONS FOR PUBLIC HEALTH PRACTICE?: It is recommended to use a biological process challenge device for monitoring the sterilization of luminal devices with low-temperature hydrogen peroxide gas plasma sterilizers.

9.
Antiviral Res ; 191: 105080, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33933516

RESUMEN

Assembly of hepatitis B virus (HBV) capsids is driven by the hydrophobic interaction of core protein (Cp) at dimer-dimer interface. Binding of core protein allosteric modulators (CpAMs) to a hydrophobic "HAP" pocket formed between the inter-dimer interface strengths the dimer-dimer interaction and misdirects the assembly of Cp dimers into non-capsid Cp polymers or morphologically normal capsids devoid of viral pregenomic (pg) RNA and DNA polymerase. In this study, we performed a systematic mutagenesis analysis to identify Cp amino acid residues at Cp dimer-dimer interface that are critical for capsid assembly, pgRNA encapsidation and resistance to CpAMs. By analyzing 70 mutant Cp with a single amino acid substitution of 25 amino acid residues around the HAP pocket, our study revealed that residue W102 and Y132 are critical for capsid assembly. However, substitution of many other residues did not significantly alter the amount of capsids, but reduced the amount of encapsidated pgRNA, suggesting their critical roles in pgRNA packaging. Interestingly, several mutant Cp with a single amino acid substitution of residue P25, T33 or I105 supported high levels of DNA replication, but conferred strong resistance to multiple chemotypes of CpAMs. In addition, we also found that WT Cp, but not the assembly incompetent Cp, such as Y132A Cp, interacted with HBV DNA polymerase (Pol). This later finding implies that encapsidation of viral DNA polymerase may depend on the interaction of Pol with a capsid assembly intermediate, but not free Cp dimers. Taking together, our findings reported herein shed new light on the mechanism of HBV nucleocapsid assembly and mode of CpAM action.


Asunto(s)
Antivirales/farmacología , Cápside/metabolismo , Virus de la Hepatitis B/efectos de los fármacos , Virus de la Hepatitis B/fisiología , Nucleocápside/metabolismo , ARN/metabolismo , Proteínas del Núcleo Viral/genética , Ensamble de Virus/fisiología , ADN Viral , Células Hep G2 , Virus de la Hepatitis B/química , Virus de la Hepatitis B/genética , Humanos , ARN/genética , ARN Viral/genética , Proteínas del Núcleo Viral/química , Proteínas del Núcleo Viral/metabolismo , Ensamble de Virus/genética
10.
Wei Sheng Yan Jiu ; 39(5): 577-9, 2010 Sep.
Artículo en Zh | MEDLINE | ID: mdl-21033434

RESUMEN

OBJECTIVE: To establish 3 drinking water emergent disinfection processing models, separated medicate dispensing, specific duty medicate dispensing, and centralized filtering, in flood/waterlog areas, and compare the effects of these 3 models on the drinking water disinfection processing. METHODS: From October to December, 2008, 18 villages were selected as the trial field in Yanglinwei town, Xiantao city, Hubei province, which were divided into three groups, separated medicate dispensing, specific duty medicate dispensing, and centralized filtering. Every 2 weeks, drinking water source water, yielding water of emergency central filtrate water equipment (ECFWE) and container water in the kitchen were sampled and microbe indices of the water sample, standard plate-count bacteria, total coliforms, thermotolerant coliform bacteria, Escherichia coli were measured. RESULTS: The microbe pollution of the water of these 3 water source groups are heavy, all failed. The eliminating rate of the standard plate-count bacteria of the drinking water emergent centralized processing equipment is 99.95%; those of the separate medicate dispensing, specific duty medicate dispensing and centralized filtering are 81.93%, 99.67%, and 98.28%, respectively. The passing rates of the microbe indice of the resident contained water are 13.33%, 70.00%, and 43.33%, respectively. The difference has statistical significance. CONCLUSIONS: The drinking water disinfection effects of the centralized filtering model and of the specific duty medicate dispensing model are better than that of the separated medicate dispensing model in the flood/waterlog areas.


Asunto(s)
Desastres , Desinfección/métodos , Inundaciones , Contaminación del Agua/prevención & control , Abastecimiento de Agua , China , Modelos Teóricos
11.
Antiviral Res ; 182: 104917, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32818519

RESUMEN

The core (capsid) protein of hepatitis B virus (HBV) is the building block of nucleocapsids where viral DNA reverse transcriptional replication takes place and mediates virus-host cell interaction important for the persistence of HBV infection. The pleiotropic role of core protein (Cp) in HBV replication makes it an attractive target for antiviral therapies of chronic hepatitis B, a disease that affects more than 257 million people worldwide without a cure. Recent clinical studies indicate that core protein allosteric modulators (CpAMs) have a great promise as a key component of hepatitis B curative therapies. Particularly, it has been demonstrated that modulation of Cp dimer-dimer interactions by several chemical series of CpAMs not only inhibit nucleocapsid assembly and viral DNA replication, but also induce the disassembly of double-stranded DNA-containing nucleocapsids to prevent the synthesis of cccDNA. Moreover, the different chemotypes of CpAMs modulate Cp assembly by interaction with distinct amino acid residues at the HAP pocket between Cp dimer-dimer interfaces, which results in the assembly of Cp dimers into either non-capsid Cp polymers (type I CpAMs) or empty capsids with distinct physical property (type II CpAMs). The different CpAMs also differentially modulate Cp metabolism and subcellular distribution, which may impact cccDNA metabolism and host antiviral immune responses, the critical factors for the cure of chronic HBV infection. This review article highlights the recent research progress on the structure and function of core protein in HBV replication cycle, the mode of action of CpAMs, as well as the current status and perspectives on the discovery and development of core protein-targeting antivirals. This article forms part of a symposium in Antiviral Research on "Wide-ranging immune and direct-acting antiviral approaches to curing HBV and HDV infections."


Asunto(s)
Antígenos del Núcleo de la Hepatitis B , Virus de la Hepatitis B/efectos de los fármacos , Hepatitis B Crónica/tratamiento farmacológico , Proteínas del Núcleo Viral/antagonistas & inhibidores , Animales , Antivirales/uso terapéutico , Replicación del ADN/efectos de los fármacos , ADN Viral , Células Hep G2 , Humanos , Ratones , Nucleocápside/efectos de los fármacos , Replicación Viral/efectos de los fármacos
12.
Wei Sheng Yan Jiu ; 36(5): 532-4, 2007 Sep.
Artículo en Zh | MEDLINE | ID: mdl-18095558

RESUMEN

OBJECTIVE: To investigate the contaminative, condition of planktonic algae, cyanobacteria, toxigenic microcystis and microcystin in Huayuankou Conservation Pool of Yellow River. METHODS: From March 2005 to January 2006, water samples were taken 15 times by 2. 5L plastic sampler from Huayuankou Conservation Pool. The density of algae were counted by using blood cell counter. Phycocyanin intergenic spacer region (PC-IGS) and microcystin synthetase gene B (mcyB) of toxigenic microcystis was identified by the whole cell PCR. The concentration of microcystin was determined by ELISA kit. The positive results of PCR and ELISA were compared. RESULTS: Bacillariophyta, chlorophyta, cyanophyta (cyanobacteria) and euglenophyta were main algaes in Huayuankou conservation pool, and the dominant algae and cell density changed seasonally. Algae cell density and cyanobacteria cell density were higher in summer and autumn than in spring and winter. From July to November, 2005, PC-IGS and mcyB were detected positively by whole cell PCR. Microcystin was positively detected from July, the concentration of microcystin changed from 0 to 0.25microg/L, it was more higher in summer than other seasons. CONCLUSION: Toxigenic microcystis and microcystin could be detected in Huayuankou Conservation Pool of Yellow River. Whole cell PCR could be used to identify toxigenic microcystis.


Asunto(s)
Microcistinas/análisis , Microcystis/crecimiento & desarrollo , Reacción en Cadena de la Polimerasa/métodos , Contaminación del Agua/análisis , Abastecimiento de Agua/análisis , China , Chlorophyta/crecimiento & desarrollo , Chlorophyta/metabolismo , Diatomeas/crecimiento & desarrollo , Diatomeas/metabolismo , Monitoreo del Ambiente , Microcystis/metabolismo
13.
Wei Sheng Yan Jiu ; 36(4): 424-6, 2007 Jul.
Artículo en Zh | MEDLINE | ID: mdl-17953206

RESUMEN

OBJECTIVE: To establish methods of isolation and purification of microcystis, and to identify it's biological property. METHODS: By the means of 96 well microplates and utmost dilution, microcystis was isolated and purified from Xiliu Lake of Zhengzhou. Absorbency of isolated microcystis was determined by visble light spectrophotometric method, and it's growth curve was ploted, calculated growth rate constant and double time. Toxigenicity of isolated microcystis was identified by means of the Whole cell PCR and ELISA, and the concentration of microcystin in crude extractive solution from freeze-dried microcystis cells was determined by ELISA. RESULTS: Two strains of microcystis, Microcystis XLH6 and Microcystis XLH10 were isolated successfully from Xiliu Lake. Their growth curves were "S" style, their growth rate constants rapidly ascended firstly, and then slowly descended. Average growth rate constants of the two strains were 0.294 and 0.345, average double times of the two strains were 82h and 70h, respectively. The results of the Whole cell PCR and ELISA of the two strains were positive, and both of them were toxigenic. Every milligram of freeze-dried Microcystis XLH6 and Microcystis XLH10 produced 1.4microg and 2.4microg microcystin. CONCLUSION: Xiliu Lake was polluted by toxigenic microcystis. 96 well microplates can be used to isolate microcystis.


Asunto(s)
Microcistinas/biosíntesis , Microcystis/aislamiento & purificación , Microcystis/metabolismo , Contaminantes del Agua/análisis , Abastecimiento de Agua/análisis , China , Técnicas de Cultivo , Microcistinas/análisis , Microcistinas/toxicidad , Microcystis/genética
14.
Wei Sheng Yan Jiu ; 35(2): 165-7, 2006 Mar.
Artículo en Zh | MEDLINE | ID: mdl-16758961

RESUMEN

OBJECTIVE: To investigate the contaminative condition of the floating algae (especially toxic cyanobacteria) in Xiliu Lake, and establish a whole-cell PCR method for identifying the toxic cyanobacteria. METHODS: The surface water of Xiliu Lake was sampled by plastic sampler from March, 2004, and the number of algae was counted by using blood cell counter. The phycocyanin intergenic spacer region (PC-IGS) and microcystin synthetase gene B (mcyB) were identified by whole-cell PCR in water samples, and the amplified product of mcyB was inserted into T vector and sequenced. RESULTS: Cyanobacteria, Chlorophyta, Bacillariophyta and Euglenophyta were main algae, and cyanobacteria was the dominant algae in summer and autumn. From July 7 to September 27,2 004, PC-IGS was detected positively in 11 samples, and from July 29 to September 27, mcyB was-detieted positively in 9 samples. Compared with the reported mcyB of Microcystis aeruginosa in Genbank, the homology of gene sequence was more than 97 t he homology of amino acid sequence was more than 94%. CONCLUSION: In summer and autumn toxic cyanobacteria could be detected in Xiliu Lake. Toxic cyanobacteria could be identified successfully by whole-cell PCR.


Asunto(s)
Cianobacterias/aislamiento & purificación , Agua Dulce/microbiología , Reacción en Cadena de la Polimerasa/métodos , Microbiología del Agua , Contaminación del Agua/análisis , China , Cianobacterias/genética , Eucariontes , Microcistinas/genética
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