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1.
Int J Mol Sci ; 22(18)2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34575968

RESUMO

Purple-colored leaves in plants attain much interest for their important biological functions and could be a potential source of phenotypic marker in selecting individuals in breeding. The transcriptional profiling helps to precisely identify mechanisms of leaf pigmentation in crop plants. In this study, two genetically unlike rice genotypes, the mutant purple leaf (pl) and wild (WT) were selected for RNA-sequencing and identifying the differentially expressed genes (DEGs) that are regulating purple leaf color. In total, 609 DEGs were identified, of which 513 and 96 genes were up- and down-regulated, respectively. The identified DEGs are categorized into metabolic process, carboxylic acid biosynthesis, phenylpropanoids, and phenylpropanoid biosynthesis process enrichment by GO analysis. Kyoto Encyclopedia of Genes and Genomes (KEGG) confirmed their association with phenylpropanoid synthesis, flavonoid synthesis, and phenylalanine metabolism. To explore molecular mechanism of purple leaf color, a set of anthocyanin biosynthetic and regulatory gene expression patterns were checked by qPCR. We found that OsPAL (Os02g0626100, Os02g0626400, Os04g0518400, Os05g0427400 and Os02g0627100), OsF3H (Os03g0122300), OsC4HL (Os05g0320700), and Os4CL5 (Os08g0448000) are associated with anthocyanin biosynthesis, and they were up-regulated in pl leaves. Two members of regulatory MYB genes (OsMYB55; Os05g0553400 and Os08g0428200), two bHLH genes (Os01g0196300 and Os04g0300600), and two WD40 genes (Os11g0132700 and Os11g0610700) also showed up-regulation in pl mutant. These genes might have significant and vital roles in pl leaf coloration and could provide reference materials for further experimentation to confirm the molecular mechanisms of anthocyanin biosynthesis in rice.

2.
Front Immunol ; 12: 670616, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34489929

RESUMO

Neutrophils are characterized by their heterogeneity. They fight against pathogens and are involved in tissue injury repair and immune system regulation. Neutrophils have an extremely short life span in the peripheral blood and undergo aging after being released from the bone marrow. The over-aggregation of aged neutrophils is associated with phenotypical and functional changes. Here, we aimed to investigate the dynamics of neutrophil aging and its relationship with T cell exhaustion in HIV-1 infection, as they are not well understood. In this study, we enrolled 23 treatment naïve (TN) patients, 23 individuals that had received antiretroviral therapy (ART), and 21 healthy controls (HC). In these cohorts, we measured the degree of neutrophil aging, and its possible correlation with T cell dysfunction. In TN patients, peripheral neutrophils showed a more distinct aging phenotype and were over-activated compared to those in ART-treated patients. The degree of neutrophil aging was positively correlated with HIV-1 RNA viral load and negatively correlated with CD4+ T cell count. Moreover, aged neutrophils had impaired reactive oxygen species (ROS) production after lipopolysaccharide (LPS) stimulation, and were characterized by increased PD-L1 and arginase-1 expression in a time-dependent manner. Aged neutrophils demonstrated an increased inhibition of IFN-γ and TNF-α secretion by CD8+ T cell compared to non-aged neutrophils. The inhibition effect could be partially reversed by blocking PD-L1 and arginase-1 in vitro, and LPS was identified as an important activator of neutrophil aging. These results provide evidence that dampening neutrophil aging may provide a novel approach to recover T cell dysfunction in patients with HIV-1 infection.

3.
J BUON ; 26(4): 1346-1354, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34564991

RESUMO

PURPOSE: To explore the predictive value of and the relationship between the gamma-glutamyl transpeptidase (GGT) to lymphocyte ratio (GLR) and computed tomography (CT) features in hepatocellular carcinoma (HCC) patients with postoperative adjuvant transarterial chemoembolization (PA-TACE). METHODS: Between January 2012 and June 2015, 150 HCC patients who underwent adjuvant TACE after hepatectomy in the Affiliated Hospital of Nantong University were selected. Baseline parameters, laboratory values, clinical variables, and CT features (including CT values, irregular rim-like arterial phase enhancement (IRE), and CT enhanced values) were evaluated in all of the patients. The Mann-Whitney U test was performed to assess the GLR values between the patients with microvascular invasion (MVI) and those without MVI. Spearman correlation analysis was performed to evaluate the relationship between IRE and GLR. A nomogram based on the multivariate analysis was constructed. RESULTS: Using multivariate analysis, GLR, MVI, α-fetoprotein levels, and IRE were found to be independent prognostic factors for overall survival (OS). In the MVI group, the GLR of patients was higher than that in the non-MVI group (z=-6.652, p<0.001). We observed a clear correlation between GLR and IRE (r=0.522, p<0.001). The nomogram was constructed and the calibration curve showed excellent predictive performance. CONCLUSIONS: We observed a correlation between GLR and CT features in HCC patients. The nomogram based on clinical data, pathological data, and CT features was suggested to predict the 5-year survival of HCC patients with PA-TACE, which offers an accurate, comprehensive, and reliable evaluation for individualized treatment.

4.
Signal Transduct Target Ther ; 6(1): 339, 2021 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-34497264

RESUMO

The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has placed a global public burden on health authorities. Although the virological characteristics and pathogenesis of COVID-19 has been largely clarified, there is currently no specific therapeutic measure. In severe cases, acute SARS-CoV-2 infection leads to immune disorders and damage to both the adaptive and innate immune responses. Having roles in immune regulation and regeneration, mesenchymal stem cells (MSCs) serving as a therapeutic option may regulate the over-activated inflammatory response and promote recovery of lung damage. Since the outbreak of the COVID-19 pandemic, a series of MSC-therapy clinical trials has been conducted. The findings indicate that MSC treatment not only significantly reduces lung damage, but also improves patient recovery with safety and good immune tolerance. Herein, we summarize the recent progress in MSC therapy for COVID-19 and highlight the challenges in the field.


Assuntos
COVID-19/terapia , Lesão Pulmonar/terapia , Pulmão/imunologia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/imunologia , SARS-CoV-2/imunologia , Animais , COVID-19/imunologia , COVID-19/patologia , Humanos , Pulmão/patologia , Pulmão/virologia , Lesão Pulmonar/imunologia , Lesão Pulmonar/virologia , Células-Tronco Mesenquimais/patologia
6.
Clin Immunol ; 229: 108773, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34102315

RESUMO

BACKGROUND: The dynamics of viral reservoir decay and naïve CD4 T-cell recovery between immunological non-responders (INR) and complete responders (CR) during long-term antiretroviral treatment (ART) are not fully known. METHODS: Twenty-eight chronic HIV-infected individuals on 5-year ART were divided into two groups: INR (CD4 counts ≤350 cells/µL, n = 13) and CR (CD4 counts ≥500 cells/µL, n = 15). The levels of HIV DNA and cell-associated HIV RNA (CA-RNA), CD4 counts, naïve CD4 counts and their correlations were analyzed at baseline, years 1, 3 and 5 of ART between the two groups. Expression of PD-1 on CD4 T-cells was quantified by flow cytometry. Linear mixed effect models were used to estimate the change procession in repeated measurements over 5 years. Slopes of the above-mentioned indicators were estimated using participant-specific linear regressions, respectively. RESULTS: INR maintained higher levels of HIV DNA and CA-RNA with higher percentages of PD-1+CD4 T-cells compared with CR during 5-year ART, concurrent with lower naïve CD4 T-cells. However, the rates of HIV DNA and CA-RNA decay in INR were not different from that in CR over time, and INR had higher rates of naïve CD4 T-cell percentage recovery. The baseline levels of HIV DNA were positively associated with the 5-year levels of HIV DNA, but negatively associated with the 5-year naïve CD4 counts. CONCLUSIONS: INR maintained significantly higher viral reservoir and lower naïve CD4 T-cells compared with CR during 5-year ART, however, the rates of reservoir decay and naïve CD4 T-cell percentage growth within INR were not lower than that in CR over time.


Assuntos
Terapia Antirretroviral de Alta Atividade , Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Adulto , Contagem de Linfócito CD4 , China , DNA Viral/sangue , DNA Viral/genética , Progressão da Doença , HIV/efeitos dos fármacos , HIV/genética , Infecções por HIV/tratamento farmacológico , Sobreviventes de Longo Prazo ao HIV , Humanos , Modelos Lineares , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , RNA Viral/genética , Fatores de Tempo , Carga Viral/efeitos dos fármacos
7.
Spectrochim Acta A Mol Biomol Spectrosc ; 262: 120079, 2021 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-34175762

RESUMO

Hyaluronidase (HAase) is an important enzyme involved in a promoting inflammation pathway. Flavonoids are a group of major polyphenols including flavonols (such as myricetin and rutin), dihydroflavones (such as naringin and hesperidin), and isoflavones (such as genistein and puerarin), which have been proved to possess anti-inflammatory effects. In this study, the binding of the six flavonoids to HAase was investigated by steady state and time-resolved fluorescence, circular dichroism (CD) spectroscopy and molecular docking methods. Fluorescence data reveal that the fluorescence quenching mechanism of HAase by flavonoids is all static quenching procedure regardless of their core structure. The binding affinity is strongest for rutin and ranks in the order rutin > hesperidin > myricetin > puerarin > genistein > naringin. The thermodynamic analysis implies that hydrophobic interaction, electrostatic force and hydrogen bonding are the main interaction forces. Synchronous fluorescence spectroscopy and CD spectroscopy indicate that flavonoids have the same core structure and have similar effects on the microenvironment around Trp and Tyr residues and the secondary structure of HAase. The results of molecular docking show that the binding of flavonoids with the catalytic amino acid residues of HAase may lead to the decrease of enzyme activity.


Assuntos
Flavonoides , Hialuronoglucosaminidase , Sítios de Ligação , Dicroísmo Circular , Simulação de Acoplamento Molecular , Ligação Proteica , Espectrometria de Fluorescência , Termodinâmica
8.
Front Immunol ; 12: 687296, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34177939

RESUMO

Background: Targeting immune checkpoints for HIV treatment potentially provides a double benefit resulting from the ability to restore viral-specific CD8+ T-cell functions and enhance HIV production from reservoir cells. Despite promising pre-clinical data, PD-1 blockade alone in HIV-1-infected patients with advanced cancer has shown limited benefits in controlling HIV, suggesting the need for additional targets beyond PD-1. CD39 and PD-1 are highly co-expressed on CD8+ T cells in HIV-1 infection. However, the characteristics of CD39 and PD-1 dual-positive CD8+ T-cell subsets in chronic HIV-1 infection remain poorly understood. Methods: This study enrolled 72 HIV-1-infected patients, including 40 treatment naïve and 32 ART patients. A total of 11 healthy individuals were included as controls. Different subsets of CD8+ T cells defined by CD39 and/or PD-1 expression were studied by flow cytometry. The relationships between the frequencies of the different subsets and parameters indicating HIV-1 disease progression were analyzed. Functional (i.e., cytokine secretion, viral inhibition) assays were performed to evaluate the impact of the blockade of adenosine and/or PD-1 signaling on CD8+ T cells. Results: The proportions of PD-1+, CD39+, and PD-1+CD39+ CD8+ T cells were significantly increased in treatment naïve patients but were partially lowered in patients on antiretroviral therapy. In treatment naïve patients, the proportions of PD-1+CD39+ CD8+ T cells were negatively correlated with CD4+ T-cell counts and the CD4/CD8 ratio, and were positively correlated with viral load. CD39+CD8+ T cells expressed high levels of the A2A adenosine receptor and were more sensitive to 2-chloroadenosine-mediated functional inhibition than their CD39- counterparts. In vitro, a combination of blocking CD39/adenosine and PD-1 signaling showed a synergic effect in restoring CD8+ T-cell function, as evidenced by enhanced abilities to secrete functional cytokines and to kill autologous reservoir cells. Conclusion: In patients with chronic HIV-1 infection there are increased frequencies of PD-1+, CD39+, and PD-1+CD39+ CD8+ T cells. In treatment naïve patients, the frequencies of PD-1+CD39+ CD8+ T cells are negatively correlated with CD4+ T-cell counts and the CD4/CD8 ratio and positively correlated with viral load. Combined blockade of CD39/adenosine and PD-1 signaling in vitro may exert a synergistic effect in restoring CD8+ T-cell function in HIV-1-infected patients.

9.
Signal Transduct Target Ther ; 6(1): 217, 2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34103473

RESUMO

We examined the safety and efficacy of human umbilical cord mesenchymal stem cell (hUC-MSC) infusion for immune non-responder (INR) patients with chronic HIV-1 infection, who represent an unmet medical need even in the era of efficient antiretroviral therapy (ART). Seventy-two INR patients with HIV were enrolled in this phase II randomized, double-blinded, multicenter, placebo-controlled, dose-determination trial (NCT01213186) from May 2013 to March 2016. They were assigned to receive high-dose (1.5 × 106/kg body weight) or low-dose (0.5 × 106/kg body weight) hUC-MSC, or placebo. Their clinical and immunological parameters were monitored during the 96-week follow-up study. We found that hUC-MSC treatment was safe and well-tolerated. Compared with baseline, there was a statistical increase in CD4+ T counts in the high-dose (P < 0.001) and low-dose (P < 0.001) groups after 48-week treatment, but no change was observed in the control group. Kaplan-Meier analysis revealed a higher cumulative probability of achieving an immunological response in the low-dose group compared with the control group (95.8% vs. 70.8%, P = 0.004). However, no significant changes in CD4/CD8+ T counts and CD4/CD8 ratios were observed among the three groups. In summary, hUC-MSC treatment is safe. However, the therapeutic efficacy of hUC-MSC treatment to improve the immune reconstitution in INR patients still needs to be further investigated in a large cohort study.

10.
Eur J Immunol ; 51(8): 2027-2039, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33974710

RESUMO

Immune deficiency is one of the hallmarks of HIV infection and a major cause of adverse outcomes in people living with HIV (PLWH). Long-lived memory CD8+ T cells (LLMCs) are essential executors of long-term protective immunity; however, the generation and maintenance of LLMCs during chronic HIV infection are not well understood. In the present study, we analyzed circulating LLMCs in healthy controls (HCs) and PLWH with different disease statuses, including treatment naïve patients (TNs), complete responders (CRs), and immunological nonresponders (INRs). We found that both TNs and INRs showed severely compromised LLMCs compared with HCs and CRs, respectively. The decrease of LLMCs in TNs correlated positively with the reduction of their precursors, namely memory precursor effector T cells (MPECs), which might be associated with elevated pro-inflammatory cytokines. Strikingly, INRs showed an accumulation of MPECs, which exhibited diminished responsiveness to interleukin 7 (IL-7), thereby indicating abrogated differentiation into LLMCs. Moreover, in vitro studies showed that treatment with dexamethasone could improve the IL7-phosphorylated (p)-signal transducer and activator of transcription (STAT5) response by upregulating the expression of the interleukin 7 receptor (IL-7Rα) on MPECs in INRs. These findings provide insights that will encourage the development of novel therapeutics to improve immune function in PLWH.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , Memória Imunológica/imunologia , Interleucina-7/imunologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
11.
Spectrochim Acta A Mol Biomol Spectrosc ; 258: 119859, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-33957444

RESUMO

Naringenin and naringin are two natural compounds with important health benefits, whether as food or drug. It is necessary to study the interactions between naringenin/naringin and digestive proteases, such as trypsin and pepsin. In this study, the bindings of naringenin and naringin to trypsin and pepsin were investigated using multi-spectroscopy analysis and computational modeling approaches. Fluorescence experiments indicate that both naringenin and naringin can quench the intrinsic fluorescence of trypsin/pepsin via static quenching mechanism. Naringin binds trypsin/pepsin in a more firmly way than naringenin. Thermodynamic analysis reveals that the interactions of naringenin/naringin and trypsin/pepsin are synergistically driven by enthalpy and entropy, and the major driving forces are hydrophobic, electrostatic interactions and hydrogen bonding. Synchronous fluorescence spectroscopy, circular dichroism spectroscopy and FT-IR show that naringenin/naringin may induce microenvironmental and conformational changes of trypsin and pepsin. Molecular docking reveals that naringenin binds in the close vicinity of the active site (Ser-195) of trypsin and Asp-32 (the catalytic activity of pepsin) appears in naringin-pepsin system. The direct interactions between naringenin or naringin and catalytic amino acid residues will inhibit the catalytic activity of trypsin and pepsin, respectively. The results of molecular dynamic simulation validate the reliability of the docking results.


Assuntos
Pepsina A , Dicroísmo Circular , Flavanonas , Simulação de Acoplamento Molecular , Pepsina A/metabolismo , Ligação Proteica , Reprodutibilidade dos Testes , Espectrometria de Fluorescência , Espectroscopia de Infravermelho com Transformada de Fourier , Tripsina/metabolismo
12.
Signal Transduct Target Ther ; 6(1): 174, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33958574

RESUMO

Severely immunosuppressed AIDS patients with recurrent opportunistic infections (OIs) represent an unmet medical need even in the era of antiretroviral therapy (ART). Here we report the development of a human leukocyte antigen (HLA)-mismatched allogeneic adaptive immune therapy (AAIT) for severely immunosuppressed AIDS patients. Twelve severely immunosuppressed AIDS patients with severe OIs were enrolled in this single-arm study. Qualified donors received subcutaneous recombinant granulocyte-colony-stimulating factor twice daily for 4-5 days to stimulate hematopoiesis. Peripheral blood mononuclear cells were collected from these donors via leukapheresis and transfused into the coupled patients. Clinical, immunological, and virological parameters were monitored during a 12-month follow-up period. We found AAIT combined with ART was safe and well-tolerated at the examined doses and transfusion regimen in all 12 patients. Improvements in clinical symptoms were evident throughout the study period. All patients exhibited a steady increase of peripheral CD4+ T cells from a median 10.5 to 207.5 cells/µl. Rapid increase in peripheral CD8+ T-cell count from a median 416.5 to 1206.5 cells/µl was found in the first 90 days since initiation of AAIT. In addition, their inflammatory cytokine levels and HIV RNA viral load decreased. A short-term microchimerism with donor cells was found. There were no adverse events associated with graft-versus-host disease throughout the study period. Overall, AAIT treatment was safe, and might help severely immunosuppressed AIDS patients to achieve a better immune restoration. A further clinical trial with control is necessary to confirm the efficacy of AAIT medication.

13.
J Clin Invest ; 131(6)2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33720048

RESUMO

Chronic HIV-1 infection is generally characterized by progressive CD4+ T cell depletion due to direct and bystander death that is closely associated with persistent HIV-1 replication and an inflammatory environment in vivo. The mechanisms underlying the loss of CD4+ T cells in patients with chronic HIV-1 infection are incompletely understood. In this study, we simultaneously monitored caspase-1 and caspase-3 activation in circulating CD4+ T cells, which revealed that pyroptotic and apoptotic CD4+ T cells are distinct cell populations with different phenotypic characteristics. Levels of pyroptosis and apoptosis in CD4+ T cells were significantly elevated during chronic HIV-1 infection, and decreased following effective antiretroviral therapy. Notably, the occurrence of pyroptosis was further confirmed by elevated gasdermin D activation in lymph nodes of HIV-1-infected individuals. Mechanistically, caspase-1 activation closely correlated with the inflammatory marker expression and was shown to occur through NLRP3 inflammasome activation driven by virus-dependent and/or -independent ROS production, while caspase-3 activation in CD4+ T cells was more closely related to T cell activation status. Hence, our findings show that NLRP3-dependent pyroptosis plays an essential role in CD4+ T cell loss in HIV-1-infected patients and implicate pyroptosis signaling as a target for anti-HIV-1 treatment.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1 , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Adolescente , Adulto , Apoptose/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Estudos de Casos e Controles , Caspase 1/metabolismo , Caspase 3/metabolismo , Feminino , Infecções por HIV/metabolismo , Infecções por HIV/patologia , Humanos , Inflamassomos/metabolismo , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Modelos Imunológicos , Piroptose/imunologia , Espécies Reativas de Oxigênio/metabolismo , Carga Viral , Adulto Jovem
14.
Signal Transduct Target Ther ; 6(1): 58, 2021 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-33568628

RESUMO

Treatment of severe Coronavirus Disease 2019 (COVID-19) is challenging. We performed a phase 2 trial to assess the efficacy and safety of human umbilical cord-mesenchymal stem cells (UC-MSCs) to treat severe COVID-19 patients with lung damage, based on our phase 1 data. In this randomized, double-blind, and placebo-controlled trial, we recruited 101 severe COVID-19 patients with lung damage. They were randomly assigned at a 2:1 ratio to receive either UC-MSCs (4 × 107 cells per infusion) or placebo on day 0, 3, and 6. The primary endpoint was an altered proportion of whole lung lesion volumes from baseline to day 28. Other imaging outcomes, 6-minute walk test (6-MWT), maximum vital capacity, diffusing capacity, and adverse events were recorded and analyzed. In all, 100 COVID-19 patients were finally received either UC-MSCs (n = 65) or placebo (n = 35). UC-MSCs administration exerted numerical improvement in whole lung lesion volume from baseline to day 28 compared with the placebo (the median difference was -13.31%, 95% CI -29.14%, 2.13%, P = 0.080). UC-MSCs significantly reduced the proportions of solid component lesion volume compared with the placebo (median difference: -15.45%; 95% CI -30.82%, -0.39%; P = 0.043). The 6-MWT showed an increased distance in patients treated with UC-MSCs (difference: 27.00 m; 95% CI 0.00, 57.00; P = 0.057). The incidence of adverse events was similar in the two groups. These results suggest that UC-MSCs treatment is a safe and potentially effective therapeutic approach for COVID-19 patients with lung damage. A phase 3 trial is required to evaluate effects on reducing mortality and preventing long-term pulmonary disability. (Funded by The National Key R&D Program of China and others. ClinicalTrials.gov number, NCT04288102.


Assuntos
COVID-19/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , SARS-CoV-2 , Cordão Umbilical , Idoso , Aloenxertos , COVID-19/mortalidade , COVID-19/fisiopatologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
15.
Eur J Immunol ; 51(1): 103-114, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32652569

RESUMO

Deficiency of Itch, an E3 ubiquitin ligase, usually induced severe systemic and progressive autoimmune disease. The Itch function is well studied in T cells but not in B cells. We hypothesize that B-cell-specific Itch deficiency promoted antigen-induced B-cell activation and antibody-expressing plasma cell (PC) production. We found that unlike Itch KO, Itch cKO (CD19cre Itchf/f ) mice did not demonstrated a significant increase in the sizes of spleens and LNs, antibody level, and base mutation of antibody gene. However, in line with the fact that Itch expression decreased in GC B cells, PCs, and plasmablast (PB)-like SP 2/0 cells, Itch deficiency promoted B-cell activation and antibody production induced by antigens including lipopolysaccharide (LPS) and sheep red blood cells (SRBCs). Mechanistically, we found that Itch deficiency promotes antigen-induced cytokine production because Itch controls the proteins (e.g., eIF3a, eIF3c, eIF3h) with translation initiation factor activity. Altogether, our data suggest that Itch deficiency promotes antigen-driven B-cell response. This may provide hints for Itch-targeted treatment of patients with autoimmune disease.


Assuntos
Linfócitos B/enzimologia , Linfócitos B/imunologia , Ubiquitina-Proteína Ligases/deficiência , Animais , Formação de Anticorpos , Antígenos/imunologia , Citocinas/biossíntese , Eritrócitos/imunologia , Fatores de Iniciação em Eucariotos/metabolismo , Humanos , Lipopolissacarídeos/imunologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Imunológicos , Ovinos , Ubiquitina-Proteína Ligases/genética
16.
Cell Mol Immunol ; 18(1): 38-44, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33159158

RESUMO

Previously, it was assumed that peripheral neutrophils are a homogeneous population that displays antimicrobial functions. However, recent data have revealed that neutrophils are heterogeneous and are additionally involved in tissue damage and immune regulation. The phenotypic and functional plasticity of neutrophils has been identified in patients with cancer, inflammatory disorders, infections, and other diseases. Currently, neutrophils, with their autocrine, paracrine, and immune modulation functions, have been shown to be involved in liver diseases, including viral hepatitis, nonalcoholic steatohepatitis, alcoholic liver disease, liver fibrosis, cirrhosis, liver failure, and liver cancer. Accordingly, this review summarizes the role of neutrophils in liver diseases.

17.
Emerg Microbes Infect ; 9(1): 2550-2561, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33131455

RESUMO

Using normalization of CD4 counts as the main evaluation parameter of complete immune restoration for HIV-1 patients under antiretroviral therapy (ART) might be not enough. A comprehensive evaluation system more accurately reflecting immune restoration are urgently needed. Totally, 91,805 HIV-1 patients from 17 tertiary hospitals in China during 2005-2018 were included in this study. Immune restoration and mortality were assessed. Patients initiated ART 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. The median CD8 count was relatively high (median range 732-845 cells/µL), regardless of the baseline CD4 counts. Furthermore, the probabilities of death in patients achieving CD4 counts ≥500 cells/µL and CD4/CD8 ratio ≥0.8 simultaneously 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-year of ART. In this study, a new binary-indicator would accurately assess immune restoration in the era of "treat all."

18.
Front Immunol ; 11: 585726, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33193409

RESUMO

Only a few signaling pathways have been reported in germinal center (GC) B-cell proliferation and death. In this study, we showed that a novel uncharacterized Gm614 protein is highly expressed in GC B cells from lupus-prone mice. Critically, ablation of this GC B-cell-specific Gm614 promoted GC B-cell death and mitigation of autoimmune symptoms, whereas overexpression protected GC B cells from death and exacerbated autoimmune symptoms. We demonstrated that mechanistically, nuclear-localized Gm614 reduced caspase-1 expression in GC B cells by binding with caspase-1 promoter to suppress its activation. Our results suggest that Gm614 protects GC B cells from death by suppressing caspase-1 transcription in autoimmune diseases. This may provide some hints for targeting the cell proliferation involved in autoimmune diseases.


Assuntos
Linfócitos B/metabolismo , Caspase 1/metabolismo , Centro Germinativo/imunologia , Lúpus Eritematoso Sistêmico , Animais , Linfócitos B/imunologia , Linfócitos B/patologia , Morte Celular/fisiologia , Centro Germinativo/metabolismo , Camundongos , Camundongos Endogâmicos MRL lpr , Transdução de Sinais/fisiologia , Transcrição Genética
19.
Shanghai Kou Qiang Yi Xue ; 29(3): 298-303, 2020 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-33043348

RESUMO

PURPOSE: To explore the percentage of residual support height (Ph) and the percentage of residual root surface area (Ps) in evaluating periodontal support ability by simulating different stages of periodontitis based on the curved surface modeling. METHODS: Fifteen cone-beam CT (CBCT) images including 420 teeth in total were collected. The data were reconstructed into 3-dimensional teeth models by Mimics software.The 3D surface model of the tooth was then optimized by Geomagic software and then imported into Solidworks software to simulate different periodontal support height. Ph and Ps were measured and calculated to evaluate the consistency of Ph and Ps results in all tooth types. The data were analyzed with SPSS 22.0 software package. RESULTS: RSA in incisors, canines and premolars: coronal 1/3>middle 1/3>apical 1/3. RSA in molars: middle 1/3>coronal 1/3>apical 1/3. Maxillary first molar had the largest RSA, accounting for 11.60% of the dentition, which was about 3.18 times than mandibular central incisor. The difference between Ph and Ps in all types of teeth was statistically significant (P<0.01). The 95% confidence interval(CI) of the difference between Ph and Ps in the maxillary incisor, mandibular incisor, mandibular canine was between the clinical consistency limit (-15%, 15%). In the remaining tooth types, 95%CI of the difference between Ph and Ps was beyond the clinical consistency limit (-15%, 15%). CONCLUSIONS: For single-root tooth, except maxillary canine, the remaining periodontal support height could replace periodontal support area. For multi-rooted tooth, judging the ability of periodontal support ability only by alveolar bone absorption ratio in 2D index has significant limitations. Full consideration is needed to focus on root morphological discrepancy when determining the extent of periodontal disease.


Assuntos
Periodonto , Raiz Dentária , Dente Pré-Molar , Tomografia Computadorizada de Feixe Cônico , Incisivo , Periodonto/diagnóstico por imagem
20.
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.


Assuntos
Contagem de Linfócito CD4 , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV/imunologia , Carga Viral , Adulto , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Biomarcadores Tumorais , Relação CD4-CD8 , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , RNA Viral
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