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1.
Emerg Microbes Infect ; : 1-41, 2020 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-33131455

RESUMO

In the era of "treat all", using normalization of CD4 counts as the main evaluation parameter of complete immune restoration for HIV-1 patients under antiretroviral therapy (ART) might not enough. A comprehensive evaluation system more accurately reflecting immune restoration are urgently needed. We established a retrospective cohort of 91,805 HIV-1 patients from 17 tertiary hospitals based on China's National Free Antiretroviral Treatment Program database from 2005 to 2018. Immune restoration and mortality were assessed. ART was started in HIV-1 patients with baseline CD4 counts <50, 50-199, 200-349, 350-499, and ≥500 cells/µL, and results showed an increase in the median CD4 counts to 445 (12-year), 467 (12-year), 581 (11-year), 644 (7-year), and 768 cells/µL (5-year), as well as the CD4/CD8 ratio to 0.59 (12-year), 0.65 (12-year), 0.79 (11-year), 0.82 (7-year), 0.9 (5-year), respectively. Meanwhile, the median CD8 count was relatively high (median range 732-845 cells/µL), regardless of the baseline CD4 counts, even after the longest follow-up period. Furthermore, the probabilities of death in patients achieving a combination of CD4 counts ≥500 cells/µL and CD4/CD8 ratio ≥0.8 were significantly lower than those in patients achieving either CD4 counts ≥500 cells/µL (2.77% vs 3.50%, p = 0.02) or CD4/CD8 ≥0.8 (2.77% vs 4.28%, p < 0.001) after 12 years of ART. In this study, a new binary-indicator would accurately assess the immune system and predict the probability of death after long-term ART in the era of "treat all".

2.
Front Immunol ; 11: 1541, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32793212

RESUMO

Background: Whether varying CD8 counts influence the human immunodeficiency virus (HIV) reservoir and CD4 restoration in patients with CD4 counts ≥ 500 cells/µL after long-term antiretroviral therapy (ART) remains unknown. In this study, we analyzed relationships between CD8 levels and viral reservoir decay or CD4 recovery in immune restored patients on long-term ART. Methods: Chronic HIV-infected patients who received 5 years of ART with CD4 counts ≥ 500 cells/µL were grouped according to CD8 counts: CD8 <500 (Group 1), 500-1,000 (Group 2), and ≥1,000 cells/µL (Group 3). CD4 recovery, viral decay, CD8 T-cell function, and their correlations were analyzed during ART among the three groups. Results: Dynamics of viral decay and CD4 recovery were different among the three groups. Both viral decay and CD4 recovery were higher in Group 3 than the other two groups after 5 years of ART, mainly during years 3-5 of ART. Higher expression levels of Ki67 while PD-1 levels were lower on CD8 T-cells in Group 3 compared with the other groups, and Group 3 showed stronger CD8 T-cells functional capacity after 3 years of ART. Reduced HIV DNA levels and increased CD4 counts between years 3 and 5 of ART were positively correlated with CD8 counts and function. Conclusions: High CD8 counts are beneficial for persistent viral decay and CD4 recovery in immune restored patients during long-term ART.

3.
Signal Transduct Target Ther ; 5(1): 172, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32855385

RESUMO

No effective drug treatments are available for coronavirus disease 2019 (COVID-19). Host-directed therapies targeting the underlying aberrant immune responses leading to pulmonary tissue damage, death, or long-term functional disability in survivors require clinical evaluation. We performed a parallel assigned controlled, non-randomized, phase 1 clinical trial to evaluate the safety of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) infusions in the treatment of patients with moderate and severe COVID-19 pulmonary disease. The study enrolled 18 hospitalized patients with COVID-19 (n = 9 for each group). The treatment group received three cycles of intravenous infusion of UC-MSCs (3 × 107 cells per infusion) on days 0, 3, and 6. Both groups received standard COVID-treatment regimens. Adverse events, duration of clinical symptoms, laboratory parameters, length of hospitalization, serial chest computed tomography (CT) images, the PaO2/FiO2 ratio, dynamics of cytokines, and IgG and IgM anti-SARS-CoV-2 antibodies were analyzed. No serious UC-MSCs infusion-associated adverse events were observed. Two patients receiving UC-MSCs developed transient facial flushing and fever, and one patient developed transient hypoxia at 12 h post UC-MSCs transfusion. Mechanical ventilation was required in one patient in the treatment group compared with four in the control group. All patients recovered and were discharged. Our data show that intravenous UC-MSCs infusion in patients with moderate and severe COVID-19 is safe and well tolerated. Phase 2/3 randomized, controlled, double-blinded trials with long-term follow-up are needed to evaluate the therapeutic use of UC-MSCs to reduce deaths and improve long-term treatment outcomes in patients with serious COVID-19.


Assuntos
Anticorpos Antivirais/sangue , Betacoronavirus/imunologia , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Infecções por Coronavirus/terapia , Células-Tronco Hematopoéticas/virologia , Transplante de Células-Tronco Mesenquimais/métodos , Pneumonia Viral/terapia , Adulto , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Combinação de Medicamentos , Feminino , Glucocorticoides/uso terapêutico , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/imunologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Lopinavir , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Respiração Artificial , Ritonavir , Índice de Gravidade de Doença , Resultado do Tratamento
4.
Nat Immunol ; 21(9): 1107-1118, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32788748

RESUMO

In coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the relationship between disease severity and the host immune response is not fully understood. Here we performed single-cell RNA sequencing in peripheral blood samples of 5 healthy donors and 13 patients with COVID-19, including moderate, severe and convalescent cases. Through determining the transcriptional profiles of immune cells, coupled with assembled T cell receptor and B cell receptor sequences, we analyzed the functional properties of immune cells. Most cell types in patients with COVID-19 showed a strong interferon-α response and an overall acute inflammatory response. Moreover, intensive expansion of highly cytotoxic effector T cell subsets, such as CD4+ effector-GNLY (granulysin), CD8+ effector-GNLY and NKT CD160, was associated with convalescence in moderate patients. In severe patients, the immune landscape featured a deranged interferon response, profound immune exhaustion with skewed T cell receptor repertoire and broad T cell expansion. These findings illustrate the dynamic nature of immune responses during disease progression.


Assuntos
Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Interferon Tipo I/metabolismo , Pneumonia Viral/imunologia , Receptores Imunológicos/metabolismo , Adolescente , Adulto , Idoso , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/genética , Antígenos de Diferenciação de Linfócitos T/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Estudos de Coortes , Infecções por Coronavirus/sangue , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Proteínas Ligadas por GPI/metabolismo , Humanos , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , RNA-Seq , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Índice de Gravidade de Doença , Análise de Célula Única
5.
Nat Commun ; 11(1): 3410, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32641700

RESUMO

COVID-19 is associated with 5.1% mortality. Although the virological, epidemiological, clinical, and management outcome features of COVID-19 patients have been defined rapidly, the inflammatory and immune profiles require definition as they influence pathogenesis and clinical expression of COVID-19. Here we show lymphopenia, selective loss of CD4+ T cells, CD8+ T cells and NK cells, excessive T-cell activation and high expression of T-cell inhibitory molecules are more prominent in severe cases than in those with mild disease. CD8+ T cells in patients with severe disease express high levels of cytotoxic molecules. Histochemical studies of lung tissue from one fatality show sub-anatomical distributions of SARS-CoV-2 RNA and massive infiltration of T cells and macrophages. Thus, aberrant activation and dysregulation of CD8+ T cells occur in patients with severe COVID-19 disease, an effect that might be for pathogenesis of SARS-CoV-2 infection and indicate that immune-based targets for therapeutic interventions constitute a promising treatment for severe COVID-19 patients.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus/imunologia , Biomarcadores/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Quimiotaxia de Leucócito , China/epidemiologia , Infecções por Coronavirus/sangue , Infecções por Coronavirus/virologia , Citocinas/sangue , Feminino , Humanos , Inflamação , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Contagem de Leucócitos , Pulmão/imunologia , Pulmão/virologia , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/virologia
6.
Cell Metab ; 32(2): 188-202.e5, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32610096

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic presents an unprecedented threat to global public health. Herein, we utilized a combination of targeted and untargeted tandem mass spectrometry to analyze the plasma lipidome and metabolome in mild, moderate, and severe COVID-19 patients and healthy controls. A panel of 10 plasma metabolites effectively distinguished COVID-19 patients from healthy controls (AUC = 0.975). Plasma lipidome of COVID-19 resembled that of monosialodihexosyl ganglioside (GM3)-enriched exosomes, with enhanced levels of sphingomyelins (SMs) and GM3s, and reduced diacylglycerols (DAGs). Systems evaluation of metabolic dysregulation in COVID-19 was performed using multiscale embedded differential correlation network analyses. Using exosomes isolated from the same cohort, we demonstrated that exosomes of COVID-19 patients with elevating disease severity were increasingly enriched in GM3s. Our work suggests that GM3-enriched exosomes may partake in pathological processes related to COVID-19 pathogenesis and presents the largest repository on the plasma lipidome and metabolome distinct to COVID-19.


Assuntos
Infecções por Coronavirus/sangue , Infecções por Coronavirus/patologia , Exossomos/metabolismo , Gangliosídeo G(M3)/sangue , Gangliosídeos/sangue , Pneumonia Viral/sangue , Pneumonia Viral/patologia , Adulto , Idoso , Betacoronavirus , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Diglicerídeos/sangue , Feminino , Humanos , Masculino , Metaboloma/fisiologia , Metabolômica/métodos , Pessoa de Meia-Idade , Pandemias , Esfingomielinas/sangue , Espectrometria de Massas em Tandem , Adulto Jovem
7.
Cell Death Differ ; 2020 Jun 08.
Artigo em Inglês | MEDLINE | ID: covidwho-591591

RESUMO

SARS-CoV-2 is associated with a 3.4% mortality rate in patients with severe disease. The pathogenesis of severe cases remains unknown. We performed an in-depth prospective analysis of immune and inflammation markers in two patients with severe COVID-19 disease from presentation to convalescence. Peripheral blood from 18 SARS-CoV-2-infected patients, 9 with severe and 9 with mild COVID-19 disease, was obtained at admission and analyzed for T-cell activation profile, myeloid-derived suppressor cells (MDSCs) and cytokine profiles. MDSC functionality was tested in vitro. In four severe and in four mild patients, a longitudinal analysis was performed daily from the day of admission to the early convalescent phase. Early after admission severe patients showed neutrophilia, lymphopenia, increase in effector T cells, a persisting higher expression of CD95 on T cells, higher serum concentration of IL-6 and TGF-ß, and a cytotoxic profile of NK and T cells compared with mild patients, suggesting a highly engaged immune response. Massive expansion of MDSCs was observed, up to 90% of total circulating mononuclear cells in patients with severe disease, and up to 25% in the patients with mild disease; the frequency decreasing with recovery. MDSCs suppressed T-cell functions, dampening excessive immune response. MDSCs decline at convalescent phase was associated to a reduction in TGF-ß and to an increase of inflammatory cytokines in plasma samples. Substantial expansion of suppressor cells is seen in patients with severe COVID-19. Further studies are required to define their roles in reducing the excessive activation/inflammation, protection, influencing disease progression, potential to serve as biomarkers of disease severity, and new targets for immune and host-directed therapeutic approaches.

8.
Cell Death Differ ; 27(11): 3196-3207, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32514047

RESUMO

SARS-CoV-2 is associated with a 3.4% mortality rate in patients with severe disease. The pathogenesis of severe cases remains unknown. We performed an in-depth prospective analysis of immune and inflammation markers in two patients with severe COVID-19 disease from presentation to convalescence. Peripheral blood from 18 SARS-CoV-2-infected patients, 9 with severe and 9 with mild COVID-19 disease, was obtained at admission and analyzed for T-cell activation profile, myeloid-derived suppressor cells (MDSCs) and cytokine profiles. MDSC functionality was tested in vitro. In four severe and in four mild patients, a longitudinal analysis was performed daily from the day of admission to the early convalescent phase. Early after admission severe patients showed neutrophilia, lymphopenia, increase in effector T cells, a persisting higher expression of CD95 on T cells, higher serum concentration of IL-6 and TGF-ß, and a cytotoxic profile of NK and T cells compared with mild patients, suggesting a highly engaged immune response. Massive expansion of MDSCs was observed, up to 90% of total circulating mononuclear cells in patients with severe disease, and up to 25% in the patients with mild disease; the frequency decreasing with recovery. MDSCs suppressed T-cell functions, dampening excessive immune response. MDSCs decline at convalescent phase was associated to a reduction in TGF-ß and to an increase of inflammatory cytokines in plasma samples. Substantial expansion of suppressor cells is seen in patients with severe COVID-19. Further studies are required to define their roles in reducing the excessive activation/inflammation, protection, influencing disease progression, potential to serve as biomarkers of disease severity, and new targets for immune and host-directed therapeutic approaches.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/virologia , Ativação Linfocitária/imunologia , Células Supressoras Mieloides/citologia , Pneumonia Viral/virologia , Adulto , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Infecções por Coronavirus/imunologia , Citocinas/metabolismo , Progressão da Doença , Feminino , Humanos , Inflamação/imunologia , Células Supressoras Mieloides/imunologia , Pandemias , Pneumonia Viral/imunologia
10.
Cell Mol Immunol ; 2020 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-32210395

RESUMO

The viral reservoir is the major hurdle in developing and establishing an HIV cure. Understanding factors affecting the size and decay of this reservoir is crucial for the development of therapeutic strategies. Recent work highlighted that CD8+ T cells are involved in the control of viral replication in ART-treated HIV-1-infected individuals, but how CD8+ T cells sense and restrict the HIV reservoir are not fully understood. Here, we demonstrate that a population of unconventional CD45RA+, PanKIR+, and/or NKG2A+ virtual memory CD8+ T cells (TVM cells), which confer rapid and robust protective immunity against pathogens, plays an important role in restraining the HIV DNA reservoir in HIV-1-infected patients with effective ART. In patients undergoing ART, TVM cells negatively correlate with HIV DNA and positively correlate with circulating IFN-α2 and IL-15. Moreover, TVM cells constitutively express high levels of cytotoxic granule components, including granzyme B, perforin and granulysin, and demonstrate the capability to control HIV replication through both cytolytic and noncytolytic mechanisms. Furthermore, by using an ex vivo system, we showed that HIV reactivation is effectively suppressed by TVM cells through KIR-mediated recognition. This study suggests that TVM cells are a promising target to predict posttreatment virological control and to design immune-based interventions to reduce the reservoir size in ART-treated HIV-1-infected individuals.

11.
Microbiol Immunol ; 64(6): 458-468, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32221997

RESUMO

HIV replication can be inhibited by CXCR5+ CD8 T cells (follicular cytotoxic T cell [TFC]) which transfer into B-cell follicles where latent HIV infection persists. However, how cytokines affect TFC remain unclear. Understanding which cytokines show the ability to affect TFC could be a key strategy toward curing HIV. Similar mechanisms could be used for the growth and transfer of TFCs and follicular helper T (TFH) cells; as a result, we hypothesized that cytokines IL-6, IL-21, and transforming growth factor-ß (TGF-ß), which are necessary for the differentiation of TFH cells, could also dictate the development of TFCs. In this work, lymph node mononuclear cells and peripheral blood mononuclear cells from HIV-infected individuals were cocultured with IL-6, IL-21, and TGF-ß. We then carried out T-cell receptor (TCR) repertoire analysis to compare the differences between CXCR5- and CXCR5+ CD8 T cells. Our results showed that the percentage and function of TFC can be enhanced by stimulation with TGF-ß. Besides, TGF-ß stimulation enhanced the diversity of TCR and complementarity-determining region 3 sequences. HIV DNA showed a negative correlation with TFC. The use of TGF-ß to promote the expression of CXCR5+ CD8 T cells could become a new treatment approach for curing HIV.


Assuntos
Infecções por HIV/imunologia , Linfonodos/imunologia , Subpopulações de Linfócitos/imunologia , Receptores CXCR5/imunologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Fator de Crescimento Transformador beta/fisiologia , Adolescente , Adulto , Diferenciação Celular , Células Cultivadas , Técnicas de Cocultura , HIV-1 , Humanos , Interleucina-6/imunologia , Interleucinas/imunologia , Linfonodos/patologia , Subpopulações de Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Linfócitos T Citotóxicos/patologia , Linfócitos T Auxiliares-Indutores/patologia , Adulto Jovem
12.
AIDS ; 34(2): 189-195, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31634199

RESUMO

OBJECTIVE: CD4CD19 conjugates play an important role in regulating antibody responses and follicular helper T cells development in animal models. However, little is known regarding the characteristic of CD4CD19 conjugates in humans with chronic HIV-1 infection. METHODS: The numbers of CD4CD19 conjugates were counted in 86 HIV-1-infected patients, including 66 typical progressors and 20 complete responders. CD4CD19 conjugates were sorted by flow cytometry and dissociated into CD4 T singlets and CD19 B singlets. The phenotypes of these cells were analyzed in both typical progressors and complete responders, and the levels of HIV-1 DNA in CD4CD19 conjugates were measured in 10 complete responders. RESULTS: We identified CD4CD19 cells as one type of T-B conjugate in peripheral blood, and the numbers and percentages of CD4CD19 conjugates decreased with HIV-1 disease progression. Phenotypic analysis showed CD4CD19 conjugates expressed higher levels of surface CD32. mRNA analysis found that the mRNA levels for CD32b were significantly higher compared with CD32a in CD4CD19 conjugates. Further analysis found that CD4CD19 conjugates expressed higher levels of CCR7 and CXCR5 than CD4 T and CD19 B singlets. A virus infectivity assay showed that CD4CD19 conjugates expressed higher levels of HIV-1-p24 than CD4CD19 cells. CD4CD19 conjugates in lymph node from typical progressors expressed higher levels of HIV-1-p24 than CD4CD19 conjugates in respective peripheral blood. Importantly, CD4CD19 conjugates from complete responders contained higher levels of HIV-1 DNA than total CD4 T cells. CONCLUSION: Our study indicates that CD4CD19 conjugates actively participate in HIV-1 infection and latency, and may serve as a new cellular target to eliminate latency.

13.
Front Immunol ; 10: 2465, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31681335

RESUMO

Background: Treg cells represent important viral reservoirs during chronic HIV infection. CD39 is closely involved in Treg-mediated immunosuppressive effects. However, CD39 expression on nTregs and mTregs and a relationship with HIV DNA levels during HIV infection is still unclear. In this study, we analyzed the distribution of HIV DNA in Treg subsets and the association between HIV DNA and CD39 expression on Treg subsets. Methods: Sixty-two HIV-infected patients with different HIV stages and 14 uninfected individuals were enrolled. nTregs (CD4+CD25+CD127lowCD45RO-) and mTregs (CD4+CD25+CD127lowCD45RO+) were isolated by magnetic selection and flow cytometric sorting. HIV DNA was quantified by real-time polymerase chain reaction (PCR). CD39 expression on nTregs and mTregs was analyzed by flow cytometry. Results: Higher levels of HIV DNA were detected in mTregs than those in nTregs during chronic HIV infection. The frequency of CD39+ nTregs and HIV DNA levels in nTregs were increased in patients with advanced HIV infection. Furthermore, HIV DNA levels in nTregs correlated positively with CD39+ nTreg frequency. CD39+ nTreg frequency was also increased in immune non-responders. Conclusions: mTregs and nTregs are both important reservoirs of virus during chronic HIV infection and HIV DNA levels increase in nTregs in patients with advanced HIV infection. We observed increased frequency of CD39+ nTregs and HIV DNA levels in nTregs in patients with advanced HIV infection. HIV DNA levels in nTregs correlated positively with CD39+ nTreg frequency.

14.
Clin Immunol ; 202: 40-48, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30914281

RESUMO

γδ T cells are a unique population of lymphocytes that have regulatory roles in patients with chronic hepatitis B (CHB); however, their role in acute hepatitis B (AHB) infection remains unclear. Phenotype and function of γδ T cells were analyzed in 29 AHB patients, 28 CHB patients, and 30 healthy controls (HCs) using immunofunctional assays. Compared with HCs and CHB patients, decreased peripheral and increased hepatic γδ T cells were found in AHB patients. Increased hepatic γδ T cells in AHB patients were attributed to elevated hepatic chemokine levels. Peripheral γδ T cells exhibited highly activated and terminally differentiated memory phenotype in AHB patients. Consistently, peripheral γδ T cells in AHB patients showed increased cytotoxic capacity and enhanced antiviral activity which was further proved in longitudinal study. Activated γδ T cells in AHB patients exhibited increased cytotoxicity and capacity for viral clearance associated with liver injury and the control of infection.


Assuntos
Hepatite B/imunologia , Linfócitos Intraepiteliais/imunologia , Doença Aguda , Adolescente , Adulto , Quimiocinas/imunologia , Doença Crônica , DNA Viral/análise , Feminino , Hepatite B/virologia , Vírus da Hepatite B/genética , Humanos , Fígado/imunologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
15.
J Cell Mol Med ; 23(3): 2032-2041, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30585398

RESUMO

Alcoholic liver disease (ALD) is a progressive liver disease that can cause a series of complications, including cirrhosis, liver failure and hepatocellular carcinoma. Granulocytic myeloid-derived suppressor cell (gMDSC) populations have been observed to expand in various liver diseases and to inhibit innate and adaptive immunity in patients with liver disease. However, the characteristics of gMDSCs in patients with ALD have not been studied. We studied 24 healthy controls (HCs) and 107 patients with ALD and found an accumulation of gMDSCs in the peripheral blood of patients with alcoholic liver cirrhosis (ALC). Furthermore, ALC patients with a poor prognosis displayed a significant increase in peripheral gMDSCs and showed an increased capacity for arginase I production compared to HCs. In contrast, plasma arginase I levels in ALC patients were negatively correlated with total bilirubin and international normalized ratio, two key parameters of liver damage. Importantly, gMDSCs accumulated in the livers of ALC patients, and the frequency of liver gMDSCs significantly correlated with that of peripheral gMDSCs. In addition, gMDSC enrichment in vitro significantly inhibited the function of natural killer (NK) cells, perhaps preventing the NK-induced apoptosis of hepatic stellate cells. In summary, increased peripheral and intrahepatic gMDSC populations are present in patients with ALC and may contribute to enhancing the severity of liver cirrhosis.

16.
J Cell Mol Med ; 23(2): 887-897, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30478965

RESUMO

Alcoholic liver disease (ALD) is a complication that is a burden on global health and economy. Interleukin-33 (IL-33) is a newly identified member of the IL-1 cytokine family and is released as an "alarmin" during inflammation. Soluble suppression of tumourigenicity 2 (sST2), an IL-33 decoy receptor, has been reported as a new biomarker for the severity of systemic and highly inflammatory diseases. Here, we found the levels of plasma sST2, increased with the disease severity from mild to severe ALD. Importantly, the plasma sST2 levels in ALD patients not only correlated with scores for prognostic models (Maddrey's discriminant function, model for end-stage liver disease and Child-Pugh scores) and indexes for liver function (total bilirubin, international normalized ratio, albumin, and cholinesterase) but also correlated with neutrophil-associated factors as well as some proinflammatory cytokines. In vitro, lipopolysaccharide-activated monocytes down-regulated transmembrane ST2 receptor but up-regulated sST2 mRNA and protein expression and produced higher levels of tumour necrosis factor-α (TNF-α). By contrast, monocytes pretreated with recombinant sST2 showed decreased TNF-α production. In addition, although plasma IL-33 levels were comparable between healthy controls and ALD patients, we found the IL-33 expression in liver tissues from ALD patients was down-regulated at both RNA and protein levels. Immunohistochemical staining further showed that the decreased of IL-33-positive cells were mainly located in liver lobule area. These results suggested that sST2, but not IL-33, is closely related to the severity of ALD. Consequently, sST2 could be used as a potential biomarker for predicting the prognosis of ALD.

18.
Zhongguo Zhong Yao Za Zhi ; 43(1): 134-138, 2018 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-29552823

RESUMO

A quantitative nuclear magnetic resonance method(qNMR) was established for determination of the absolute content of febrifugine. Proton nuclear magnetic resonance spectroscopy of febrifugine was obtained in DMSO-d6 with hydroquinone as the internal standard substance on a Bruker Ascend 600 MHz superconducting nuclear resonance spectrometer at 298 K. The specific parameters were as follows: the observing frequency was 600 MHz,spectra width was 7 211 Hz, pulse width was 9.70 µs, pulse sequence was zg30,scan times was 32 and relaxation time was 2 s. The proton signal peaked at δ 7.71 for febrifugine and δ 6.55 for hydroquinone were selected as the quantification peaks. Linear regression of quantitative peak area ratio of febrifugine-hydroquinone versus their mass ratio yielded a correlation coefficient of 0.999 6 and a regression equation of Y=0.083 3X+0.008 6.The linear range of febrifugine was 2.17-17.07 g·L⁻¹,the precision RSD was 0.78%(n=6),the repeatability RSD was 1.2%(n=6),and the contents of three batches of febrifugine sample were 94.91%,95.09% and 95.52%,respectively. The content of febrifugine was 96.44% determined by high performance liquid chromatography(HPLC). The relative error of the content of febrigugine determinted by qNMR and HPLC methods was 1.27%. The results showed that the internal standard method of proton nuclear magnetic resonance spectroscopy could be used to determine the absolute content of febrifugine.


Assuntos
Espectroscopia de Ressonância Magnética , Piperidinas/análise , Quinazolinas/análise , Prótons
19.
Cell Metab ; 27(2): 339-350.e3, 2018 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-29414684

RESUMO

Sterile inflammation after tissue damage is a ubiquitous response, yet it has the highest amplitude in the liver. This has major clinical consequences, for alcoholic and non-alcoholic steatohepatitis (ASH and NASH) account for the majority of liver disease in industrialized countries and both lack therapy. Requirements for sustained sterile inflammation include increased oxidative stress and activation of the HIF-1α signaling pathway. We demonstrate the ability of digoxin, a cardiac glycoside, to protect from liver inflammation and damage in ASH and NASH. Digoxin was effective in maintaining cellular redox homeostasis and suppressing HIF-1α pathway activation. A proteomic screen revealed that digoxin binds pyruvate kinase M2 (PKM2), and independently of PKM2 kinase activity results in chromatin remodeling and downregulation of HIF-1α transactivation. These data identify PKM2 as a mediator and therapeutic target for regulating liver sterile inflammation, and demonstrate a novel role for digoxin that can effectively protect the liver from ASH and NASH.


Assuntos
Digoxina/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Hepatopatia Gordurosa não Alcoólica/genética , Piruvato Quinase/metabolismo , Ativação Transcricional/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Cromatina/metabolismo , Modelos Animais de Doenças , Endotoxinas , Histonas/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inflamação/genética , Inflamação/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Oxirredução , Ligação Proteica/efeitos dos fármacos , Piruvato Quinase/química , Células THP-1 , Transcrição Genética/efeitos dos fármacos
20.
Zhongguo Zhong Yao Za Zhi ; 42(16): 3178-3184, 2017 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-29171238

RESUMO

To investigate the stability and degradation kinetics of febrifugine. The results showed that within 24 hours, febrifugine content was decreased by only 1% in mobile phase solvent, but its content was decreased to be 90% of the initial content in the water, methanol, 50% methanol and 10% acetonitrile solution. When the pH value of the solution was between 3 and 7, the retention rate of febrifugine in 24 hours was over 98%, but its content was decreased by about 12% in alkaline solution (pH 9.0). The higher the temperature, the worse the stability of febrifugine. At 40-80 ℃, the content of febrifugine was decreased to be 60% of its initial content in 10 hours, but the content was decreased by only 5% in 10 h at 20 ℃.However, no matter 40 ℃or 60 ℃, febrifugine was mainly transformed into isofebrifugine, and the total content of febrifugine and isofebrifugine was equal to their initial total content in 10 hours, while incase of 80 ℃, the total content was decreased to be 83.33% in 10 h, which suggested that the structure of febrifugine was absolutely changed, not just isomerized to be isofebrigugine at high temperature. Light had a significant impact on the stability of febrifugine. Under bright light, the content of febrifugine was reduced by about 23% in 108 h, but it only decreased by about 10% in the natural light or darkness. In artificial gastric fluid (pH 1.4) and artificial intestinal fluid (pH 6.8), the content of febrifugine was decreased by less than 5% in 10 h. After storage at high temperature(60 ℃), high humidity [(75±1)%] and strong light (3 000 lx) conditions for 10 d, the content of solid febrifugine was decreased by 0.27%, 7.6% and 5.39%, respectively. The degradation of febrifugine basically complied with the first-order reaction kinetic process in the following conditions: in water, methanol, 50%methanol and 10% acetonitrile solvents, alkaline solution (pH>7), different light intensity and different temperatures (20,40 ℃). Therefore, no matter the isolation and purification of febrifugine or the production of the related preparations, it should be done fast in the acidic solution, low temperature and dark conditions, while the febrifugine solid should be kept in dry and dark conditions.


Assuntos
Piperidinas/química , Quinazolinas/química , Estabilidade de Medicamentos , Concentração de Íons de Hidrogênio , Cinética , Temperatura
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