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1.
J Immunol Res ; 2021: 5123823, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34485535

RESUMO

Acute pancreatitis (AP) is one of the leading causes of hospital admission, 20% of which could progress to the severe type with extensive acinar cell necrosis. Clinical studies have reported that diabetes is an independent risk factor of the incidence of AP and is associated with higher severity than nondiabetic subjects. However, how diabetes participates in AP progression is not well defined. To investigate this question, wild-type (wt) and diabetic db/db mice at the age of 16 weeks were used in the study. AP was induced in wt recipients by 10 injections of 50 µg/kg caerulein with a 1 h interval. One hour after the last caerulein injection, bone marrow cells (BMC) isolated from wt and db/db mice were injected intraperitoneally into the recipients (1 × 107cells/recipient). The recipients with no BMC injection served as controls. Thirteen hours after BMC injection, serum lipase activity was 1.8- and 1.3-folds higher in mice that received db/db BMC, compared with those with no injection and wt BMC injection, respectively (p ≤ 0.02 for both). By H&E staining, the overall severity score was 14.7 for no cell injection and 16.6 for wt BMC injection and increased to 22.6 for db/db BMC injection (p ≤ 0.002 for both). In particular, mice with db/db BMC injection developed more acinar cell necrosis and vacuolization than the other groups (p ≤ 0.03 for both). When sections were stained with an antibody against myeloperoxidase (MPO), the density of MPO+ cells in pancreatitis was 1.9- and 1.6-folds higher than wt BMC and no BMC injection groups, separately (p ≤ 0.02 for both). Quantified by ELISA, db/db BMC produced more IL-6, GM-CSF, and IL-10 compared with wt BMC (p ≤ 0.04 for all). In conclusion, BMC of db/db mice produced more inflammatory cytokines. In response to acinar cell injury, diabetic BMC aggravated the inflammation cascade and acinar cell injury, leading to the progression of acute pancreatitis.

2.
Front Immunol ; 12: 723585, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34489974

RESUMO

Objectives: Our objective was to determine the antibody and cytokine profiles in different COVID-19 patients. Methods: COVID-19 patients with different clinical classifications were enrolled in this study. The level of IgG antibodies, IgA, IgM, IgE, and IgG subclasses targeting N and S proteins were tested using ELISA. Neutralizing antibody titers were determined by using a toxin neutralization assay (TNA) with live SARS-CoV-2. The concentrations of 8 cytokines, including IL-2, IL-4, IL-6, IL-10, CCL2, CXCL10, IFN-γ, and TNF-α, were measured using the Protein Sample Ella-Simple ELISA system. The differences in antibodies and cytokines between severe and moderate patients were compared by t-tests or Mann-Whitney tests. Results: A total of 79 COVID-19 patients, including 49 moderate patients and 30 severe patients, were enrolled. Compared with those in moderate patients, neutralizing antibody and IgG-S antibody titers in severe patients were significantly higher. The concentration of IgG-N antibody was significantly higher than that of IgG-S antibody in COVID-19 patients. There was a significant difference in the distribution of IgG subclass antibodies between moderate patients and severe patients. The positive ratio of anti-S protein IgG3 is significantly more than anti-N protein IgG3, while the anti-S protein IgG4 positive rate is significantly less than the anti-N protein IgG4 positive rate. IL-2 was lower in COVID-19 patients than in healthy individuals, while IL-4, IL-6, CCL2, IFN-γ, and TNF-α were higher in COVID-19 patients than in healthy individuals. IL-6 was significantly higher in severe patients than in moderate patients. The antibody level of anti-S protein was positively correlated with the titer of neutralizing antibody, but there was no relationship between cytokines and neutralizing antibody. Conclusions: Our findings show the severe COVID-19 patients' antibody levels were stronger than those of moderate patients, and a cytokine storm is associated with COVID-19 severity. There was a difference in immunoglobulin type between anti-S protein antibodies and anti-N protein antibodies in COVID-19 patients. And clarified the value of the profile in critical prevention.


Assuntos
Anticorpos Antivirais/sangue , COVID-19/imunologia , Citocinas/sangue , SARS-CoV-2/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Neutralizantes/sangue , COVID-19/classificação , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulina A/sangue , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Glicoproteína da Espícula de Coronavírus/imunologia
3.
Sci Rep ; 11(1): 14646, 2021 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-34282189

RESUMO

From 1990 until 2017, global air-pollution related mortality increased by 40%. Few studies addressed the renal responses to ultrafine particulate [≤ 2.5 µm (PM2.5)], including black carbon (BC), which penetrate into the blood stream. In a Flemish population study, glomerular filtration estimated from serum creatinine (eGFR) and the urinary albumin-to-creatinine ratio were measured in 2005-2009 in 820 participants (women, 50.7%; age, 51.1 years) with follow-up of 523 after 4.7 years (median). Serum creatinine, eGFR, chronic kidney disease (eGFR < 60 mL/min/1.73 m2) and microalbuminuria (> 3.5/> 2.5 mg per mmol creatinine in women/men) were correlated in individual participants via their residential address with PM2.5 [median 13.1 (range 0.3-2.9) µg/m3] and BC [1.1 (0.3-18) µg/m3], using mixed models accounting for address clusters. Cross-sectional and longitudinally, no renal outcome was associated with PM2.5 or BC in models adjusted for sex and baseline or time varying covariables, including age, blood pressure, heart rate, body mass index, plasma glucose, the total-to-HDL serum cholesterol ratio, alcohol intake, smoking, physical activity, socioeconomic class, and antihypertensive treatment. The subject-level geocorrelations of eGFR change with to BC and PM2.5 were 0.13 and 0.02, respectively (P ≥ 0.68). In conclusion, in a population with moderate exposure, renal function was unrelated to ultrafine particulate.

4.
Immunity ; 54(7): 1611-1621.e5, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34166623

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants continue to emerge during the global pandemic and may facilitate escape from current antibody therapies and vaccine protection. Here we showed that the South African variant B.1.351 was the most resistant to current monoclonal antibodies and convalescent plasma from coronavirus disease 2019 (COVID-19)-infected individuals, followed by the Brazilian variant P.1 and the United Kingdom variant B.1.1.7. This resistance hierarchy corresponded with Y144del and 242-244del mutations in the N-terminal domain and K417N/T, E484K, and N501Y mutations in the receptor-binding domain (RBD) of SARS-CoV-2. Crystal structure analysis of the B.1.351 triple mutant (417N-484K-501Y) RBD complexed with the monoclonal antibody P2C-1F11 revealed the molecular basis for antibody neutralization and escape. B.1.351 and P.1 also acquired the ability to use mouse and mink ACE2 receptors for entry. Our results demonstrate major antigenic shifts and potential broadening of the host range for B.1.351 and P.1 variants, which poses serious challenges to current antibody therapies and vaccine protection.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Anticorpos Neutralizantes/imunologia , Evasão da Resposta Imune , SARS-CoV-2/imunologia , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/química , Variação Antigênica/genética , COVID-19/imunologia , COVID-19/virologia , Especificidade de Hospedeiro , Humanos , Evasão da Resposta Imune/genética , Camundongos , Vison , Mutação , Ligação Proteica , SARS-CoV-2/genética , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Internalização do Vírus
5.
Dis Markers ; 2021: 5598824, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34158873

RESUMO

Assessing the length of hospital stay (LOS) in patients with coronavirus disease 2019 (COVID-19) pneumonia is helpful in optimizing the use efficiency of hospital beds and medical resources and relieving medical resource shortages. This retrospective cohort study of 97 patients was conducted at Beijing You'An Hospital between January 21, 2020, and March 21, 2020. A multivariate Cox proportional hazards regression based on the smallest Akaike information criterion value was used to select demographic and clinical variables to construct a nomogram. Discrimination, area under the receiver operating characteristic curve (AUC), calibration, and Kaplan-Meier curves with the log-rank test were used to assess the nomogram model. The median LOS was 13 days (interquartile range [IQR]: 10-18). Age, alanine aminotransferase, pneumonia, platelet count, and PF ratio (PaO2/FiO2) were included in the final model. The C-index of the nomogram was 0.76 (95%confidence interval [CI] = 0.69-0.83), and the AUC was 0.88 (95%CI = 0.82-0.95). The adjusted C-index was 0.75 (95%CI = 0.67-0.82) and adjusted AUC 0.86 (95%CI = 0.73-0.95), both after 1000 bootstrap cross internal validations. A Brier score of 0.11 (95%CI = 0.07-0.15) and adjusted Brier score of 0.130 (95%CI = 0.07-0.20) for the calibration curve showed good agreement. The AUC values for the nomogram at LOS of 10, 20, and 30 days were 0.79 (95%CI = 0.69-0.89), 0.89 (95%CI = 0.83-0.96), and 0.96 (95%CI = 0.92-1.00), respectively, and the high fit score of the nomogram model indicated a high probability of hospital stay. These results confirmed that the nomogram model accurately predicted the LOS of patients with COVID-19. We developed and validated a nomogram that incorporated five independent predictors of LOS. If validated in a future large cohort study, the model may help to optimize discharge strategies and, thus, shorten LOS in patients with COVID-19.


Assuntos
COVID-19/terapia , Tempo de Internação , Nomogramas , SARS-CoV-2 , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos
6.
Cell Res ; 31(7): 732-741, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34021265

RESUMO

SARS-CoV-2 variants could induce immune escape by mutations on the receptor-binding domain (RBD) and N-terminal domain (NTD). Here we report the humoral immune response to circulating SARS-CoV-2 variants, such as 501Y.V2 (B.1.351), of the plasma and neutralizing antibodies (NAbs) elicited by CoronaVac (inactivated vaccine), ZF2001 (RBD-subunit vaccine) and natural infection. Among 86 potent NAbs identified by high-throughput single-cell VDJ sequencing of peripheral blood mononuclear cells from vaccinees and convalescents, near half anti-RBD NAbs showed major neutralization reductions against the K417N/E484K/N501Y mutation combination, with E484K being the dominant cause. VH3-53/VH3-66 recurrent antibodies respond differently to RBD variants, and K417N compromises the majority of neutralizing activity through reduced polar contacts with complementarity determining regions. In contrast, the 242-244 deletion (242-244Δ) would abolish most neutralization activity of anti-NTD NAbs by interrupting the conformation of NTD antigenic supersite, indicating a much less diversity of anti-NTD NAbs than anti-RBD NAbs. Plasma of convalescents and CoronaVac vaccinees displayed comparable neutralization reductions against pseudo- and authentic 501Y.V2 variants, mainly caused by E484K/N501Y and 242-244Δ, with the effects being additive. Importantly, RBD-subunit vaccinees exhibit markedly higher tolerance to 501Y.V2 than convalescents, since the elicited anti-RBD NAbs display a high diversity and are unaffected by NTD mutations. Moreover, an extended gap between the third and second doses of ZF2001 leads to better neutralizing activity and tolerance to 501Y.V2 than the standard three-dose administration. Together, these results suggest that the deployment of RBD-vaccines, through a third-dose boost, may be ideal for combating SARS-CoV-2 variants when necessary, especially for those carrying mutations that disrupt the NTD supersite.


Assuntos
Anticorpos Neutralizantes/imunologia , Vacinas contra COVID-19/farmacologia , COVID-19/imunologia , COVID-19/prevenção & controle , Imunidade Humoral , SARS-CoV-2/imunologia , Vacinas de Produtos Inativados/farmacologia , Animais , Anticorpos Neutralizantes/sangue , COVID-19/sangue , Vacinas contra COVID-19/imunologia , Linhagem Celular , Células HEK293 , Humanos , Modelos Moleculares , Mutação , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinas de Produtos Inativados/imunologia , Vacinas de Subunidades/imunologia , Vacinas de Subunidades/farmacologia
7.
Front Immunol ; 12: 614436, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33790892

RESUMO

The novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic of the coronavirus disease 2019 (COVID-19), which elicits a wide variety of symptoms, ranging from mild to severe, with the potential to lead to death. Although used as the standard method to screen patients for SARS-CoV-2 infection, real-time PCR has challenges in dealing with asymptomatic patients and those with an undetectable viral load. Serological tests are therefore considered potent diagnostic tools to complement real-time PCR-based diagnosis and are used for surveillance of seroprevalence in populations. However, the dynamics of the antibody response against SARS-CoV-2 currently remain to be investigated. Here, through analysis of plasma samples from 84 patients with COVID-19, we observed that the response of virus-specific antibodies against three important antigens, RBD, N and S, dynamically changed over time and reached a peak 5-8 weeks after the onset of symptoms. The antibody responses were irrespective of sex. Severe cases were found to have higher levels of antibody response, larger numbers of inflammatory cells and C-reactive protein levels. Within the mild/moderate cases, pairwise comparison indicated moderate association between anti-RBD vs. anti-N, anti-RBD vs. anti-S1S2, and anti-N vs. anti-S1S2. Furthermore, the majority of cases could achieve IgM and IgG seroconversion at 2 weeks since the disease onset. Analysis of neutralizing antibodies indicated that these responses were able to last for more than 112 days but decline significantly after the peak. In summary, our findings demonstrate the longitudinally dynamic changes in antibody responses against SARS-CoV-2, which can contribute to the knowledge of humoral immune response after SARS-CoV-2 infection and are informative for future development of vaccine and antibody-based therapies.


Assuntos
Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , COVID-19/imunologia , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Adulto , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Pequim , COVID-19/patologia , China , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Masculino , Pessoa de Meia-Idade , Fosfoproteínas/imunologia , Domínios Proteicos/imunologia , Soroconversão , Índice de Gravidade de Doença , Centros de Atenção Terciária
8.
Cell ; 184(7): 1895-1913.e19, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33657410

RESUMO

A dysfunctional immune response in coronavirus disease 2019 (COVID-19) patients is a recurrent theme impacting symptoms and mortality, yet a detailed understanding of pertinent immune cells is not complete. We applied single-cell RNA sequencing to 284 samples from 196 COVID-19 patients and controls and created a comprehensive immune landscape with 1.46 million cells. The large dataset enabled us to identify that different peripheral immune subtype changes are associated with distinct clinical features, including age, sex, severity, and disease stages of COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was found in diverse epithelial and immune cell types, accompanied by dramatic transcriptomic changes within virus-positive cells. Systemic upregulation of S100A8/A9, mainly by megakaryocytes and monocytes in the peripheral blood, may contribute to the cytokine storms frequently observed in severe patients. Our data provide a rich resource for understanding the pathogenesis of and developing effective therapeutic strategies for COVID-19.


Assuntos
COVID-19/imunologia , Megacariócitos/imunologia , Monócitos/imunologia , RNA Viral , SARS-CoV-2/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , China , Estudos de Coortes , Citocinas/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , RNA Viral/isolamento & purificação , Análise de Célula Única , Transcriptoma/imunologia , Adulto Jovem
9.
Signal Transduct Target Ther ; 6(1): 134, 2021 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-33774649

RESUMO

To discover new drugs to combat COVID-19, an understanding of the molecular basis of SARS-CoV-2 infection is urgently needed. Here, for the first time, we report the crucial role of cathepsin L (CTSL) in patients with COVID-19. The circulating level of CTSL was elevated after SARS-CoV-2 infection and was positively correlated with disease course and severity. Correspondingly, SARS-CoV-2 pseudovirus infection increased CTSL expression in human cells in vitro and human ACE2 transgenic mice in vivo, while CTSL overexpression, in turn, enhanced pseudovirus infection in human cells. CTSL functionally cleaved the SARS-CoV-2 spike protein and enhanced virus entry, as evidenced by CTSL overexpression and knockdown in vitro and application of CTSL inhibitor drugs in vivo. Furthermore, amantadine, a licensed anti-influenza drug, significantly inhibited CTSL activity after SARS-CoV-2 pseudovirus infection and prevented infection both in vitro and in vivo. Therefore, CTSL is a promising target for new anti-COVID-19 drug development.


Assuntos
Antivirais/farmacologia , COVID-19/metabolismo , Catepsina L , Inibidores de Cisteína Proteinase/farmacologia , Desenvolvimento de Medicamentos , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Internalização do Vírus/efeitos dos fármacos , Adolescente , Adulto , Idoso , Animais , COVID-19/tratamento farmacológico , COVID-19/genética , Catepsina L/antagonistas & inibidores , Catepsina L/genética , Catepsina L/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética
10.
Respiration ; 100(2): 116-126, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33486496

RESUMO

BACKGROUND: There is still no clinical evidence available to support or to oppose corticosteroid treatment for coronavirus disease 2019 (COVID-19) pneumonia. OBJECTIVE: To investigate the efficacy and safety of corticosteroid given to the hospitalized patients with COVID-19 pneumonia. METHODS: This was a prospective, multicenter, single-blind, randomized control trial. Adult patients with COVID-19 pneumonia who were admitted to the general ward were randomly assigned to either receive methylprednisolone or not for 7 days. The primary end point was the incidence of clinical deterioration 14 days after randomization. RESULTS: We terminated this trial early because the number of patients with COVID-19 pneumonia in all the centers decreased in late March. Finally, a total of 86 COVID-19 patients underwent randomization. There was no difference of the incidence of clinical deterioration between the methylprednisolone group and control group (4.8 vs. 4.8%, p = 1.000). The duration of throat viral RNA detectability in the methylprednisolone group was 11 days (interquartile range, 6-16 days), which was significantly longer than that in the control group (8 days [2-12 days], p = 0.030). There were no significant differences between the 2 groups in other secondary outcomes. Mass cytometry discovered CD3+ T cells, CD8+ T cells, and NK cells in the methylprednisolone group which were significantly lower than those in the control group after randomization (p < 0.05). CONCLUSIONS: From this prematurely closed trial, we found that the short-term early use of corticosteroid could suppress the immune cells, which may prolong severe acute respiratory syndrome coronavirus 2 shedding in patients with COVID-19 pneumonia. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04273321.


Assuntos
COVID-19/tratamento farmacológico , Glucocorticoides/uso terapêutico , Hospitalização , Metilprednisolona/uso terapêutico , Faringe/química , RNA Viral/isolamento & purificação , Eliminação de Partículas Virais , Adulto , Idoso , Antibacterianos/uso terapêutico , Antivirais/uso terapêutico , Complexo CD3 , Linfócitos T CD8-Positivos , COVID-19/sangue , COVID-19/terapia , COVID-19/transmissão , Teste de Ácido Nucleico para COVID-19 , Progressão da Doença , Intervenção Médica Precoce , Oxigenação por Membrana Extracorpórea , Feminino , Humanos , Células Matadoras Naturais , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Oxigenoterapia , Quartos de Pacientes , Faringe/virologia , Modelos de Riscos Proporcionais , Respiração Artificial , SARS-CoV-2 , Método Simples-Cego , Subpopulações de Linfócitos T , Linfócitos T , Fatores de Tempo , Resultado do Tratamento
11.
Adv Drug Deliv Rev ; 172: 234-248, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33417981

RESUMO

Cardiomyopathy and fibrosis are the main causes of heart failure in diabetes patients. For therapeutic purposes, a delivery system is required to enhance antidiabetic drug efficacy and specifically target profibrotic pathways in cardiomyocytes. Nanoparticles (NPs) have distinct advantages, including biocompatibility, bioavailability, targeting efficiency, and minimal toxicity, which make them ideal for antidiabetic treatment. In this review, we overview the latest information on the pathogenesis of cardiomyopathy and fibrosis in diabetes patients. We summarize how NP applications improve insulin and liraglutide efficacy and their sustained release upon oral administration. We provide a comprehensive review of the results of NP clinical trials in diabetes patients and of animal studies investigating the effects of NP-mediated anti-fibrotic treatments. Collectively, the application of advanced NP delivery systems in the treatment of cardiomyopathy and fibrosis in diabetes patients is a promising and innovative therapeutic strategy.

13.
Front Immunol ; 11: 585647, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33133104

RESUMO

Cytokine storm resulting from SARS-CoV-2 infection is one of the leading causes of acute respiratory distress syndrome (ARDS) and lung fibrosis. We investigated the effect of inflammatory molecules to identify any marker that is related to lung fibrosis in coronavirus disease 2019 (COVID-19). Seventy-six COVID-19 patients who were admitted to Youan Hospital between January 21 and March 20, 2020 and recovered were recruited for this study. Pulmonary fibrosis, represented as fibrotic volume on chest CT images, was computed by an artificial intelligence (AI)-assisted program. Plasma samples were collected from the participants shortly after admission, to measure the basal inflammatory molecules levels. At discharge, fibrosis was present in 46 (60.5%) patients whose plasma interferon-γ (IFN-γ) levels were twofold lower than those without fibrosis (p > 0.05). The multivariate-adjusted logistic regression analysis demonstrated the inverse association risk of having lung fibrosis and basal circulating IFN-γ levels with an estimate of 0.43 (p = 0.02). Per the 1-SD increase of basal IFN-γ level in circulation, the fibrosis volume decreased by 0.070% (p = 0.04) at the discharge of participants. The basal circulating IFN-γ levels were comparable with c-reactive protein in the discrimination of the occurrence of lung fibrosis among COVID-19 patients at discharge, unlike circulating IL-6 levels. In conclusion, these data indicate that decreased circulating IFN-γ is a risk factor of lung fibrosis in COVID-19.


Assuntos
Infecções por Coronavirus/complicações , Interferon gama/sangue , Pneumonia Viral/complicações , Fibrose Pulmonar/etiologia , Idoso , Inteligência Artificial , Biomarcadores/sangue , COVID-19 , Estudos de Coortes , Infecções por Coronavirus/sangue , Infecções por Coronavirus/diagnóstico por imagem , Infecções por Coronavirus/imunologia , Estudos Transversais , Feminino , Humanos , Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/diagnóstico por imagem , Pneumonia Viral/imunologia , Fibrose Pulmonar/sangue , Fibrose Pulmonar/diagnóstico por imagem , Fatores de Risco , Tomografia Computadorizada por Raios X
14.
Nat Commun ; 11(1): 5859, 2020 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-33203833

RESUMO

The outbreak of COVID-19 has become a worldwide pandemic. The pathogenesis of this infectious disease and how it differs from other drivers of pneumonia is unclear. Here we analyze urine samples from COVID-19 infection cases, healthy donors and non-COVID-19 pneumonia cases using quantitative proteomics. The molecular changes suggest that immunosuppression and tight junction impairment occur in the early stage of COVID-19 infection. Further subgrouping of COVID-19 patients into moderate and severe types shows that an activated immune response emerges in severely affected patients. We propose a two-stage mechanism of pathogenesis for this unusual viral infection. Our data advance our understanding of the clinical features of COVID-19 infections and provide a resource for future mechanistic and therapeutics studies.


Assuntos
Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Betacoronavirus/patogenicidade , Biomarcadores/urina , COVID-19 , Infecções por Coronavirus/urina , Progressão da Doença , Humanos , Tolerância Imunológica , Pandemias , Pneumonia/imunologia , Pneumonia/patologia , Pneumonia/urina , Pneumonia Viral/urina , Proteoma/análise , SARS-CoV-2 , Junções Íntimas/patologia
15.
Signal Transduct Target Ther ; 5(1): 240, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33060566

RESUMO

The COVID-19 pandemic has emerged as a global health emergency due to its association with severe pneumonia and relative high mortality. However, the molecular characteristics and pathological features underlying COVID-19 pneumonia remain largely unknown. To characterize molecular mechanisms underlying COVID-19 pathogenesis in the lung tissue using a proteomic approach, fresh lung tissues were obtained from newly deceased patients with COVID-19 pneumonia. After virus inactivation, a quantitative proteomic approach combined with bioinformatics analysis was used to detect proteomic changes in the SARS-CoV-2-infected lung tissues. We identified significant differentially expressed proteins involved in a variety of fundamental biological processes including cellular metabolism, blood coagulation, immune response, angiogenesis, and cell microenvironment regulation. Several inflammatory factors were upregulated, which was possibly caused by the activation of NF-κB signaling. Extensive dysregulation of the lung proteome in response to SARS-CoV-2 infection was discovered. Our results systematically outlined the molecular pathological features in terms of the lung response to SARS-CoV-2 infection, and provided the scientific basis for the therapeutic target that is urgently needed to control the COVID-19 pandemic.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/genética , Lesão Pulmonar/genética , Pneumonia Viral/genética , Proteoma/genética , Proteômica/métodos , Síndrome Respiratória Aguda Grave/genética , Idoso , Autopsia , COVID-19 , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Citocinas/genética , Citocinas/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ontologia Genética , Humanos , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Lesão Pulmonar/virologia , Masculino , Redes e Vias Metabólicas , Anotação de Sequência Molecular , NF-kappa B/genética , NF-kappa B/metabolismo , Pandemias , Pneumonia Viral/metabolismo , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Proteoma/metabolismo , SARS-CoV-2 , Síndrome Respiratória Aguda Grave/metabolismo , Síndrome Respiratória Aguda Grave/patologia , Síndrome Respiratória Aguda Grave/virologia , Índice de Gravidade de Doença , Transdução de Sinais
16.
Front Med (Lausanne) ; 7: 501, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32903864

RESUMO

Background: Abnormal liver function is a common indication of coronavirus disease 2019 (COVID-19) patients. Two proposed mechanisms are liver injury mediated by angiotensin-converting enzyme 2 (ACE2) and the involvement of the systemic immune response. We investigated the role played by these to determine the cause of liver abnormality in the early stages of COVID-19. Methods: A cross-sectional study was conducted among confirmed cases of COVID-19 at Beijing Youan Hospital from January 21, 2020, to February 24, 2020. We compared clinical characteristics, viremia status, and cytokine profile on admission between patients with and without liver disorder. Results: Of the 44 COVID-19 patients analyzed, there were no differences in the clinical symptoms and signs, disease severity, or computed tomography (CT) image features between the two groups. Lymphopenia was more common in the liver disorder group. Further, C-reactive protein levels were much higher in the hepatic disorder group, with significantly higher concentrations of IL-6, IL-10, and M-CSF. Viremia was detected in only 7% of patients. Conclusions: Due to the infrequency of viremia, ACE2-mediated viral hepatitis does not seem to account for the commonly observed liver disorders in COVID-19 patients. By contrast, a dysregulated immune response may be a crucial pathogenic factor for liver disorder in the early stages of COVID-19.

17.
Clin Chim Acta ; 510: 613-616, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32858058

RESUMO

BACKGROUND: Qualitative and quantitative detection of nucleic acids of SARS-CoV-2, the pathogen that causes coronavirus disease 2019 (COVID-19), plays a significant role in COVID-19 diagnosis, surveillance, prevention, and control. METHODS: A total of 117 samples from 30 patients with confirmed COVID-19 and 61 patients without COVID-19 were collected. Reverse transcriptase quantitative PCR (RT-qPCR) and droplet digital PCR (ddPCR) were used for qualitative and quantitative analyses of these samples to evaluate the diagnostic performance and applicability of the two methods. RESULTS: The positive detection rates of RT-qPCR and ddPCR were 93.3% and 100%, respectively. Among the 117 samples, 6 samples were tested single-gene positive by RT-qPCR but positive by ddPCR, and 3 samples were tested negative by RT-qPCR but positive by ddPCR. The viral load of samples with inconsistent results were relatively low (3.1-20.5 copies/test). There were 17 samples (37%) with a viral load below 20 copies/test among the 46 positive samples, and only 9 of them were successfully detected by RT-qPCR. A severe patient was dynamically monitored. All 6 samples from this patient were tested negative by RT-qPCR, but 4 samples were tested positive by ddPCR with a low viral load. CONCLUSION: Qualitative analysis of COVID-19 samples can meet the needs of clinical screening and diagnosis, while quantitative analysis provides more information to the research community. Although both ddPCR and RT-qPCR can provide qualitative and quantitative results, ddPCR showed higher sensitivity and lower limit of detection than RT-qPCR, and it does not rely on the standard curve to quantify viral load. Therefore, ddPCR offers greater advantages than RT-qPCR.


Assuntos
Infecções por Coronavirus/diagnóstico , Pneumonia Viral/diagnóstico , Adulto , Idoso , COVID-19 , Estudos de Casos e Controles , Infecções por Coronavirus/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sensibilidade e Especificidade , Carga Viral
18.
Hypertension ; 76(2): 420-431, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32639887

RESUMO

To identify potential application of GLP1-RAs (glucagon-like peptide-1 receptor agonists) and SGLT2-Is (sodium-dependent glucose cotrasnsporter-2 inhibitors) in cardiovascular medicine, we performed PubMed search until March 31, 2020 and selected placebo-controlled randomized trials (RCTs) in patients with type 2 diabetes mellitus. Twenty-four hour ambulatory and office blood pressure (BP), major adverse cardiovascular events (MACE), progression of chronic kidney disease (CKD), and changes in glycated hemoglobin and body weight were aggregated across RCTs using random-effect models. In 2238 patients (7 RCTs), SGLT2-Is lowered 24-hour systolic/diastolic BP by 4.4/1.9 mm Hg (95% CI, 3.4-5.5/1.2-2.6 mm Hg), whereas 2 GLP1-RAs RCTs produced contradictory BP results. Over 1.3 to 5.4 years of follow-up of 56 004 patients (7 RCTs), aggregate hazard ratios associated with GLP1-RA treatment were 0.88 (0.84-0.93) for MACE, 0.84 (0.74-0.89) for CKD, and ranged from 0.84 to 0.90 for individual MACE end points (P≤0.01). Across 5 SGLT2-Is RCTs, including 43 467 patients with 1.5 to 4.2 years follow-up, hazard ratios were 0.87 (0.82-0.93) for MACE, 0.68 (0.62-0.75) for HF, 0.82 (0.72-0.93) for cardiovascular death, 0.87 (0.79-0.96) for myocardial infarction, and 0.61 (0.56-0.67) for worsening CKD. The risk of HF and CKD, but not MACE, decreased with more BP lowering. Stricter glycemic control was associated with higher HF risk, but unrelated to MACE or CKD. The aggregate effect sizes on systolic BP, body weight, and glycated hemoglobin were -1.61 mm Hg, -2.40 kg, and -0.69% for GLP1-RAs, and -2.53 mm Hg, -1.15 kg and -0.24%, for SGLT2-Is (P<0.001). In conclusion, GLP1-RAs and SGLT2-Is reduced cardiovascular risk with differential benefit profiles.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Pressão Sanguínea/fisiologia , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/fisiopatologia , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Humanos , Hipoglicemiantes/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem
19.
Cell Death Dis ; 11(6): 429, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-32513989

RESUMO

Although most patients with COVID-19 pneumonia have a good prognosis, some patients develop to severe or critical illness, and the mortality of critical cases is up to 61.5%. However, specific molecular information about immune response in critical patients with COVID-19 is poorly understood. A total of 54 patients were enrolled and divided into three groups, among which 34 were common, 14 were severe, and 6 were critical. The constitution of peripheral blood mononuclear cells (PBMC) in patients was analyzed by CyTOF. The profile of cytokines was examined in plasma of patients using luminex. The IL-2 signaling pathway was investigated in the PBMC of patients by qRT-PCR. The count and percentage of lymphocytes were significantly decreased in critical patients compared to common and severe patients with COVID-19 pneumonia. The count of T cells, B cells, and NK cells was remarkably decreased in critical patients compared to normal controls. The percentage of CD8+ T cells was significantly lower in critical patients than that in common and severe patients with COVID-19 pneumonia. The expression of IL-2R, JAK1, and STAT5 decreased in PBMC of common, severe, and critical patients, but IL-2 level was elevated in severe patients and decreased in critical patients with COVID-19 pneumonia. The decrease of CD8+ T cells in critical patients with COVID-19 pneumonia may be related to the IL-2 signaling pathway. The inhibition of IL-2/IL-2R gives rise to CD8+ T cell and lymphocyte decrease through JAK1-STAT5 in critical patients with COVID-19 pneumonia.


Assuntos
Betacoronavirus , Linfócitos T CD8-Positivos/imunologia , Infecções por Coronavirus/sangue , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Interleucina-2/sangue , Janus Quinase 1/metabolismo , Pneumonia Viral/sangue , Fator de Transcrição STAT5/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19 , Infecções por Coronavirus/virologia , Estado Terminal , Feminino , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/virologia , SARS-CoV-2
20.
Clin Infect Dis ; 71(10): 2688-2694, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-32497196

RESUMO

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a pandemic with no specific antiviral treatments or vaccines. There is an urgent need for exploring the neutralizing antibodies from patients with different clinical characteristics. METHODS: A total of 117 blood samples were collected from 70 COVID-19 inpatients and convalescent patients. Antibodies were determined with a modified cytopathogenic neutralization assay (NA) based on live severe acute respiratory syndrome coronavirus 2 and enzyme-linked immunosorbent assay (ELISA). The dynamics of neutralizing antibody levels at different time points with different clinical characteristics were analyzed. RESULTS: The seropositivity rate reached up to 100.0% within 20 days since onset, and remained 100.0% till days 41-53. The total geometric mean titer was 1:163.7 (95% confidence interval [CI], 128.5-208.6) by NA and 1:12 441.7 (95% CI, 9754.5-15 869.2) by ELISA. The antibody level by NA and ELISA peaked on days 31-40 since onset, and then decreased slightly. In multivariate generalized estimating equation analysis, patients aged 31-45, 46-60, and 61-84 years had a higher neutralizing antibody level than those aged 16-30 years (ß = 1.0470, P = .0125; ß = 1.0613, P = .0307; ß = 1.3713, P = .0020). Patients with a worse clinical classification had a higher neutralizing antibody titer (ß = 0.4639, P = .0227). CONCLUSIONS: The neutralizing antibodies were detected even at the early stage of disease, and a significant response was shown in convalescent patients.


Assuntos
Anticorpos Neutralizantes , COVID-19 , Adolescente , Adulto , Anticorpos Antivirais , Humanos , Pacientes Internados , Pessoa de Meia-Idade , SARS-CoV-2 , Adulto Jovem
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