RESUMO
Sepsis is a systemic inflammatory response syndrome caused by an infection progressing to sepsis-associated organ failure (such as lung injury). Our previous review revealed that Astragaloside IV (ASI-IV), one of the primary bioactive ingredients in Astragalus membranaceus (Fisch) Bge (Huang-Qi), had been shown to exert anti-inflammatory and immunomodulatory effects. Nevertheless, it is still unclear whether ASI-IV could attenuate septic lung injury via activating regulatory T-cells (Tregs). This study was designed to evaluate the therapeutic potential of ASI-IV on sepsis-induced lung injury and to further explore its underlying mechanism. In the murine models of cecal ligation and puncture (CLP) and lipopolysaccharide (LPS) induced sepsis, ASI-IV can markedly improve the survival rate and reduce inflammatory lung injury, protect mice against exacerbated inflammatory responses by decreasing myeloid cell infiltration and down-regulating IL-6 and TNF-α in lung tissue. Meanwhile, Treg cell-related gene expression, including Foxp3 and IL-10, significantly increased after ASI-IV treatment. Furthermore, ASI-IV notably promoted the differentiation of naïve CD4+ T cells into T regulatory cells without obviously affecting Th1 and Th17 differentiation. Our results indicated that ASI-IV could attenuate septic lung injury by promoting Treg cell expansion and inhibiting inflammatory responses. It represents a promising agent for the treatment of sepsis.
Assuntos
Lesão Pulmonar , Saponinas , Sepse , Camundongos , Animais , Linfócitos T Reguladores , Sepse/tratamento farmacológico , Saponinas/farmacologia , Saponinas/uso terapêutico , Saponinas/metabolismo , Modelos Animais de DoençasRESUMO
CXC chemokine receptor6 (CXCR6)-based immunotherapy plays a significant role in autoimmune diseases, however, little is known about possible small compounds that inhibit pathogenic CXCR6+ T cells for treating multiple sclerosis (MS). Baicalein, a flavonoid isolated from Scutellarin baicalensis (Huang Qin), was shown to exert therapeutic effects on MS, but the underlying mechanisms are largely unknown. In the current study, we found that baicalein inhibited Th1 and Th17 differentiation in vitro. Oral administration of baicalein (25 mg/kg) significantly reduced the disease severity and the infiltration process, decreased the extent of demyelination in EAE, and selectively blocked IL-17A production and specific antibodies (IgG and IgG3) in MOG35-55-induced specific immune responses. In addition, the expression of CD4 cell effectors (CD44hiCD62Llow) and pathogenic Th17 cells was decreased by baicalein treatment. Furthermore, baicalein treatment largely decreased CXCR6+ CD4 and CD8 cells and prominently inhibited CXCR6+ Th17 cells in EAE. Taken together, the findings of this study suggest for the first time that baicalein may ameliorate EAE by suppressing pathogenetic CXCR6+ CD4 cells.
Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Animais , Camundongos , Quimiocinas CXC/metabolismo , Células Th1 , Diferenciação Celular , Imunoglobulina G/uso terapêutico , Células Th17 , Camundongos Endogâmicos C57BL , Receptores CXCR6/metabolismoRESUMO
Introduction: This study sought to explore the immunogenicity of a booster dose of an inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in people living with human immunodeficiency virus (HIV) and identify the factors affecting the magnitude of anti-SARS-CoV-2 antibody levels. Materials and methods: A total of 34 people living with HIV (PLWH) and 34 healthy donors (HD) were administered a booster dose of the same SARS-CoV-2 vaccine. Anti-SARS-CoV-2 antibody and immunoglobulin G (IgG) levels were measured using the SARS-CoV-2 S protein neutralizing antibody Enzyme-Linked Immunosorbent Assay (ELISA) and 2019-nCov IgG Chemiluminescent Immunoassay Microparticles, respectively. Spearman correlation analysis was used to measure the correlation between laboratory markers and neutralizing antibody and IgG levels. Peripheral blood mononuclear cells (PBMCs) were extracted from each subject using density gradient centrifugation and the numbers of memory T and T follicular helper (Tfh) cells were determined using flow cytometry. Results: PLWH had a marked reduction in CD4 and B cell levels that was accompanied by a lower CD4/CD8 T cell ratio. However, those who received a supplementary dose of inactivated SARS-CoV-2 vaccines exhibited antibody positivity rates that were analogous to levels previously observed. The booster vaccine led to a reduction in IgG and neutralizing antibody levels and the amplitude of this decline was substantially higher in the PLWH than HD group. Correlation analyses revealed a strong correlation between neutralizing antibody levels and the count and proportion of CD4 cells. Anti-SARS-CoV-2 IgG antibody levels followed a similar trend. The expression of memory T and Tfh cells was considerably lower in the PLWH than in the HD group. Discussion: PLWH had an attenuated immune response to a third (booster) administration of an inactivated SARS-CoV-2 vaccine, as shown by lower neutralizing antibody and IgG levels. This could be attributed to the reduced responsiveness of CD4 cells, particularly memory T and cTfh subsets. CD4 and cTfh cells may serve as pivotal markers of enduring and protective antibody levels. Vaccination dose recalibration may be critical for HIV-positive individuals, particularly those with a lower proportion of CD4 and Tfh cells.
Assuntos
COVID-19 , Soropositividade para HIV , Humanos , Vacinas contra COVID-19 , HIV , Células T Auxiliares Foliculares , Leucócitos Mononucleares , COVID-19/prevenção & controle , SARS-CoV-2 , Anticorpos Neutralizantes , Anticorpos Antivirais , Imunoglobulina GRESUMO
Previous studies have indicated that MW9, a chalcones derivative bearing heterocyclic moieties, has considerable antiinflammatory activity in vitro. Whether MW9 may be used to treat inflammationbased diseases, such as multiple sclerosis, remains unknown. The present study was designed to determine the effect and underlying mechanism of MW9 in experimental autoimmune encephalomyelitis (EAE). Female C57BL/6 mice immunized with MOG3555 were treated with or without MW9, then the clinical scores and other relevant parameters were investigated. Production of cytokines and specific antibodies were monitored by ELISA assays. Surface marker, Treg cell, and intracellular cytokines (IL17A and IFNγ) were detected by flow cytometry, and mRNA expression in the helperT (TH)17 cellrelated signaling pathway was examined by reverse transcriptionquantitative (RTq) PCR analysis. TH17 cell differentiation assay was performed. Herein, the present results demonstrated that oral administration of MW9 reduced the severity of disease in EAE mice through slowing down infiltration process, inhibiting the demyelination, blocking antiMOG3555 IgG antibody production (IgG, IgG2a and IgG3), and decreasing accumulation of CD11b+Gr1+ neutrophils from EAE mice. MW9 treatments also led to significantly decreased IL17A production and IL17 expression in CD4+ Tcells, but had no detectable influence on development of TH1 and Tregulatory cells ex vivo. RTqPCR analysis showed that within the spinal cords of the mice, MW9 blocked transcriptional expression of TH17associated genes, including Il17a, Il17f, Il6 and Ccr6. In TH17 cell differentiation assay, MW9 inhibited differentiation of 'naïve' CD4+ Tcells into TH17 cells and reduced the IL17A production. The data demonstrated that MW9 could attenuate EAE in part through suppressing the formation and activities of pathogenic TH17 cells.
Assuntos
Chalconas , Encefalomielite Autoimune Experimental , Animais , Diferenciação Celular , Chalconas/farmacologia , Citocinas/metabolismo , Feminino , Imunoglobulina G/farmacologia , Interleucina-17/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Células Th1 , Células Th17RESUMO
BACKGROUNDS: To date, the effects of SARS-CoV-2 vaccines on people living with HIV (PLWH) were mainly focused on messenger RNA (mRNA) and adenovirus vector-based vaccines, and little is known about the effects of inactivated virus-based vaccine. This study was designed to determine the effects of inactivated SARS-CoV-2 vaccines on PLWH. METHODS: Twenty-four HIV-positive individuals and 24 healthy donors (HD) were respectively recruited from Malipo Country People's Hospital and community in Kunming city. Enumeration of lymphocyte and CD4+CD45RO+ memory T cells were evaluated by flow cytometry. Competitive ELISA was used to measure the level of Anti-SARS-CoV-2 neutralization antibody. Spearman or Pearson correlation analysis was used to analyze the relationship between laboratory indicators and neutralization antibodies in PLWH. T-cell responses (Th1, Th2, Th17, Treg) and intracellular expression of cytokines (IL-2 and TNF-α) in CD4 or CD8 were induced by spike protein in SARS-CoV-2 (SARS-2-S) and further measured by intracellular staining. RESULTS: CD4, B cells, CD4+CD45RO+ memory T cells in peripheral blood of PLWH are dramatically decreased in comparison with HD. Importantly, PLWH display comparable neutralizing antibody positive rate to HD after inoculation with inactivated SARS-CoV-2 vaccine. However, PLWH showed weaker responses to vaccines exhibited by lower levels of neutralizing antibodies. Correlation analysis shows that this is possibly caused by low number of CD4 and B cells. Furthermore, SARS-2-S-induced Th2 and Th17 responses are also decreased in PLWH, while no influences on Treg and other cytokines (IL-2, TNF-α and IFN-γ) observed. CONCLUSIONS: PLWH and HD have comparable neutralizing antibodies positive rates, but PLWH display weaker responses to inactivated SARS-CoV-2 vaccines in magnitude, which suggests that a booster dose or dose adjustment are required for HIV-infected individuals, especially for those with lower counts of CD4 T and B cells.
Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Infecções por HIV/imunologia , Vacinas de Produtos Inativados/imunologia , Adulto , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , COVID-19/imunologia , COVID-19/virologia , Vacinas contra COVID-19/administração & dosagem , Feminino , Infecções por HIV/sangue , Infecções por HIV/complicações , Voluntários Saudáveis , Humanos , Imunogenicidade da Vacina , Masculino , Células T de Memória/imunologia , Pessoa de Meia-Idade , SARS-CoV-2/imunologia , Células Th17/imunologia , Células Th2/imunologia , Vacinas de Produtos Inativados/administração & dosagemRESUMO
AIM: Jian Pi Shen Shi Formula (JPSSF) is a beneficial treatment for hyperuricemia and related tissue damage in the clinical setting. This study was designed to investigate its therapeutic potential and underlying mechanisms in uricase-deficient rats (Uox-/- rats). METHODS: Uox-/- rats were used to assess the therapeutic potential of JPSSF on hyperuricemia. Protein extracts from renal tissues of a Uox-/- group and a JPSSF group were analyzed using tandem mass tag labeling quantitative proteomic workflow. Collagen deposition in Uox-/- rat kidneys was analyzed by Masson trichromatic staining. The gene expression associated with collagen-binding-related signaling pathways in the kidneys was further explored using quantitative polymerase chain reaction assay. The protein expressions of collagen 1a1 (col1a1), col6a1, and α-smooth muscle actin were measured by Western blotting and immunohistochemistry. RESULTS: JPSSF significantly decreased renal function indices and alleviated renal injuries. The action of JPSSF was manifested by down-regulation of col6a1 and interleukin-1 receptor-associated kinase-like 2, which blocked the binding sites on collagen and further prevented kidney injury. The anti-renal fibrosis effect of JPSSF was confirmed by reducing the collagen deposition and hydroxyproline concentrations. JPSSF treatment also intensely down-regulated the mRNA and protein expressions of col6a1, col1a1, and α-smooth muscle actin, which inhibited the function of the collagen-binding-related signaling pathway. CONCLUSION: Our results indicated that JPSSF notably ameliorated hyperuricemia and related renal fibrosis in Uox-/- rats through lowering uric acid and down-regulating the function of the collagen-binding pathway. This suggested that JPSSF is a potential empirical formula for treating hyperuricemia and accompanying renal fibrosis.