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1.
J Pharm Anal ; 13(6): 616-624, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37440907

RESUMO

Glioblastoma (GBM) is a lethal cancer with limited therapeutic options. Dendritic cell (DC)-based cancer vaccines provide a promising approach for GBM treatment. Clinical studies suggest that other immunotherapeutic agents may be combined with DC vaccines to further enhance antitumor activity. Here, we report a GBM case with combination immunotherapy consisting of DC vaccines, anti-programmed death-1 (anti-PD-1) and poly I:C as well as the chemotherapeutic agent cyclophosphamide that was integrated with standard chemoradiation therapy, and the patient remained disease-free for 69 months. The patient received DC vaccines loaded with multiple forms of tumor antigens, including mRNA-tumor associated antigens (TAA), mRNA-neoantigens, and hypochlorous acid (HOCl)-oxidized tumor lysates. Furthermore, mRNA-TAAs were modified with a novel TriVac technology that fuses TAAs with a destabilization domain and inserts TAAs into full-length lysosomal associated membrane protein-1 to enhance major histocompatibility complex (MHC) class I and II antigen presentation. The treatment consisted of 42 DC cancer vaccine infusions, 26 anti-PD-1 antibody nivolumab administrations and 126 poly I:C injections for DC infusions. The patient also received 28 doses of cyclophosphamide for depletion of regulatory T cells. No immunotherapy-related adverse events were observed during the treatment. Robust antitumor CD4+ and CD8+ T-cell responses were detected. The patient remains free of disease progression. This is the first case report on the combination of the above three agents to treat glioblastoma patients. Our results suggest that integrated combination immunotherapy is safe and feasible for long-term treatment in this patient. A large-scale trial to validate these findings is warranted.

2.
Science ; 379(6637): eabg2482, 2023 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-36927018

RESUMO

Autoimmune diseases such as ankylosing spondylitis (AS) can be driven by emerging neoantigens that disrupt immune tolerance. Here, we developed a workflow to profile posttranslational modifications involved in neoantigen formation. Using mass spectrometry, we identified a panel of cysteine residues differentially modified by carboxyethylation that required 3-hydroxypropionic acid to generate neoantigens in patients with AS. The lysosomal degradation of integrin αIIb [ITGA2B (CD41)] carboxyethylated at Cys96 (ITGA2B-ceC96) generated carboxyethylated peptides that were presented by HLA-DRB1*04 to stimulate CD4+ T cell responses and induce autoantibody production. Immunization of HLA-DR4 transgenic mice with the ITGA2B-ceC96 peptide promoted colitis and vertebral bone erosion. Thus, metabolite-induced cysteine carboxyethylation can give rise to pathogenic neoantigens that lead to autoreactive CD4+ T cell responses and autoantibody production in autoimmune diseases.


Assuntos
Autoanticorpos , Doenças Autoimunes , Cisteína , Cadeias HLA-DRB1 , Integrina alfa2 , Processamento de Proteína Pós-Traducional , Espondilite Anquilosante , Animais , Camundongos , Autoanticorpos/metabolismo , Doenças Autoimunes/genética , Doenças Autoimunes/metabolismo , Autoimunidade/genética , Autoimunidade/imunologia , Cisteína/metabolismo , Cadeias HLA-DRB1/genética , Cadeias HLA-DRB1/metabolismo , Camundongos Transgênicos , Integrina alfa2/metabolismo , Microbioma Gastrointestinal , Humanos , Espondilite Anquilosante/genética , Espondilite Anquilosante/metabolismo
3.
Signal Transduct Target Ther ; 8(1): 46, 2023 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-36717539

RESUMO

Meplazumab, a humanized CD147 antibody, has shown favourable safety and efficacy in our previous clinical studies. In DEFLECT (NCT04586153), 167 patients with severe COVID-19 were enroled and randomized to receive three dosages of meplazumab and a placebo. Meplazumab at 0.12 mg/kg, compared to the placebo group, showed clinical benefits in significantly reducing mortality by 83.6% (2.4% vs. 14.6%, p = 0.0150), increasing the proportion of patients alive and discharged without supplemental oxygen (82.9% vs. 70.7%, p = 0.0337) and increasing the proportion of patients who achieved sustained clinical improvement (41.5% vs. 31.7%). The response rate in the 0.2 mg/kg group was relatively increased by 16.0% compared with the placebo group (53.7% vs. 46.3%). Meplazumab also reduced the viral loads and multiple cytokine levels. Compare with the placebo group, the 0.3 mg/kg significantly increased the virus negative rate by 40.6% (p = 0.0363) and reduced IL-8 level (p = 0.0460); the 0.2 mg/kg increased the negative conversion rate by 36.9%, and reduced IL-4 (p = 0.0365) and IL-8 levels (p = 0.0484). In this study, the adverse events occurred at a comparable rate across the four groups, with no unexpected safety findings observed. In conclusion, meplazumab promoted COVID-19 convalescence and reduced mortality, viral load, and cytokine levels in severe COVID-19 population with good safety profile.


Assuntos
COVID-19 , Humanos , Adulto , SARS-CoV-2 , Interleucina-8 , Citocinas
4.
Nat Commun ; 13(1): 676, 2022 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-35115492

RESUMO

Ferroptosis is a nonapoptotic cell death process that requires cellular iron and the accumulation of lipid peroxides. In progressive rheumatoid arthritis (RA), synovial fibroblasts proliferate abnormally in the presence of reactive oxygen species (ROS) and elevated lipid oxidation. Here we show, using a collagen-induced arthritis (CIA) mouse model, that imidazole ketone erastin (IKE), a ferroptosis inducer, decreases fibroblast numbers in the synovium. Data from single-cell RNA sequencing further identify two groups of fibroblasts that have distinct susceptibility to IKE-induced ferroptosis, with the ferroptosis-resistant fibroblasts associated with an increased TNF-related transcriptome. Mechanistically, TNF signaling promotes cystine uptake and biosynthesis of glutathione (GSH) to protect fibroblasts from ferroptosis. Lastly, low dose IKE together with etanercept, a TNF antagonist, induce ferroptosis in fibroblasts and attenuate arthritis progression in the CIA model. Our results thus imply that the combination of TNF inhibitors and ferroptosis inducers may serve as a potential candidate for RA therapy.


Assuntos
Artrite Experimental/prevenção & controle , Artrite Reumatoide/prevenção & controle , Ferroptose/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Imidazóis/farmacologia , Cetonas/farmacologia , Piperazinas/farmacologia , Inibidores do Fator de Necrose Tumoral/farmacologia , Animais , Artrite Experimental/genética , Artrite Experimental/metabolismo , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Quimioterapia Combinada , Etanercepte/farmacologia , Etanercepte/uso terapêutico , Fibroblastos/citologia , Fibroblastos/metabolismo , Glutationa/metabolismo , Humanos , Imidazóis/uso terapêutico , Cetonas/uso terapêutico , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos , Piperazinas/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Membrana Sinovial/citologia , Inibidores do Fator de Necrose Tumoral/uso terapêutico
5.
Signal Transduct Target Ther ; 6(1): 194, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001849

RESUMO

Recent evidence suggests that CD147 serves as a novel receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Blocking CD147 via anti-CD147 antibody could suppress the in vitro SARS-CoV-2 replication. Meplazumab is a humanized anti-CD147 IgG2 monoclonal antibody, which may effectively prevent SARS-CoV-2 infection in coronavirus disease 2019 (COVID-19) patients. Here, we conducted a randomized, double-blinded, placebo-controlled phase 1 trial to evaluate the safety, tolerability, and pharmacokinetics of meplazumab in healthy subjects, and an open-labeled, concurrent controlled add-on exploratory phase 2 study to determine the efficacy in COVID-19 patients. In phase 1 study, 59 subjects were enrolled and assigned to eight cohorts, and no serious treatment-emergent adverse event (TEAE) or TEAE grade ≥3 was observed. The serum and peripheral blood Cmax and area under the curve showed non-linear pharmacokinetic characteristics. No obvious relation between the incidence or titer of positive anti-drug antibody and dosage was observed in each cohort. The biodistribution study indicated that meplazumab reached lung tissue and maintained >14 days stable with the lung tissue/cardiac blood-pool ratio ranging from 0.41 to 0.32. In the exploratory phase 2 study, 17 COVID-19 patients were enrolled, and 11 hospitalized patients were involved as concurrent control. The meplazumab treatment significantly improved the discharged (P = 0.005) and case severity (P = 0.021), and reduced the time to virus negative (P = 0.045) in comparison to the control group. These results show a sound safety and tolerance of meplazumab in healthy volunteers and suggest that meplazumab could accelerate the recovery of patients from COVID-19 pneumonia with a favorable safety profile.


Assuntos
Anticorpos Monoclonais Humanizados , Tratamento Farmacológico da COVID-19 , COVID-19/metabolismo , Pulmão/metabolismo , SARS-CoV-2/metabolismo , Adolescente , Adulto , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , COVID-19/patologia , Método Duplo-Cego , Feminino , Humanos , Pulmão/patologia , Pulmão/virologia , Masculino , Pessoa de Meia-Idade
6.
Signal Transduct Target Ther ; 5(1): 283, 2020 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-33277466

RESUMO

In face of the everlasting battle toward COVID-19 and the rapid evolution of SARS-CoV-2, no specific and effective drugs for treating this disease have been reported until today. Angiotensin-converting enzyme 2 (ACE2), a receptor of SARS-CoV-2, mediates the virus infection by binding to spike protein. Although ACE2 is expressed in the lung, kidney, and intestine, its expressing levels are rather low, especially in the lung. Considering the great infectivity of COVID-19, we speculate that SARS-CoV-2 may depend on other routes to facilitate its infection. Here, we first discover an interaction between host cell receptor CD147 and SARS-CoV-2 spike protein. The loss of CD147 or blocking CD147 in Vero E6 and BEAS-2B cell lines by anti-CD147 antibody, Meplazumab, inhibits SARS-CoV-2 amplification. Expression of human CD147 allows virus entry into non-susceptible BHK-21 cells, which can be neutralized by CD147 extracellular fragment. Viral loads are detectable in the lungs of human CD147 (hCD147) mice infected with SARS-CoV-2, but not in those of virus-infected wild type mice. Interestingly, virions are observed in lymphocytes of lung tissue from a COVID-19 patient. Human T cells with a property of ACE2 natural deficiency can be infected with SARS-CoV-2 pseudovirus in a dose-dependent manner, which is specifically inhibited by Meplazumab. Furthermore, CD147 mediates virus entering host cells by endocytosis. Together, our study reveals a novel virus entry route, CD147-spike protein, which provides an important target for developing specific and effective drug against COVID-19.


Assuntos
Basigina/genética , COVID-19/genética , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Animais , Basigina/imunologia , COVID-19/imunologia , COVID-19/patologia , COVID-19/virologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Camundongos , Pandemias , Ligação Proteica/imunologia , Domínios Proteicos/genética , Domínios Proteicos/imunologia , SARS-CoV-2/patogenicidade , Glicoproteína da Espícula de Coronavírus/genética , Internalização do Vírus
7.
Arthritis Rheumatol ; 72(6): 943-956, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32362074

RESUMO

OBJECTIVE: This study was undertaken to uncover the pathophysiologic role of discoidin domain receptor 2 (DDR-2), a putative fibrillar collagen receptor, in inflammation promotion and joint destruction in rheumatoid arthritis (RA). METHODS: In synovial tissue from patients with RA and from mice with collagen antibody-induced arthritis (CAIA) (using Ddr2-/- and DBA/1 mice), gene and protein expression levels of DDR-2, interleukin-15 (IL-15), and Dkk-1 were measured by quantitative reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemistry. Gene knockdown of DDR2 in human RA fibroblast-like synoviocytes (FLS) was conducted via small interfering RNA. Interaction between the long noncoding RNA H19 and microRNA 103a (miR-103a) was assessed in RA FLS using RNA pulldown assays. Cellular localization of H19 was examined using fluorescence in situ hybridization assays. Chromatin immunoprecipitation and dual luciferase reporter assays were applied to verify H19 transcriptional and posttranscriptional regulation by miR-103a. RESULTS: DDR2 messenger RNA (mRNA) expression was significantly associated with the levels of IL-15 and Dkk-1 mRNA in the synovial tissue of RA patients (r2 = 0.2022-0.3293, all P < 0.05; n = 33) and with the serum levels of IL-15 and Dkk-1 in mice with CAIA (P < 0.05). In human RA FLS, activated DDR-2 induced the expression of H19 through c-Myc. Moreover, H19 directly interacted with and promoted the degradation of miR-103a. CONCLUSION: These results indicate a novel role for activated DDR-2 in RA FLS, showing that DDR-2 is responsible for regulating the expression of IL-15 and Dkk-1 in RA FLS and is involved in the promotion of inflammation and joint destruction during pathophysiologic development of RA. Moreover, DDR-2 inhibition, acting through the H19-miR-103a axis, leads to reductions in the inflammatory reaction and severity of joint destruction in mice with CAIA, suggesting that inhibition of DDR-2 may be a potential therapeutic strategy for RA.


Assuntos
Artrite Experimental/metabolismo , Artrite Reumatoide/genética , Receptor com Domínio Discoidina 2/metabolismo , Interleucina-15/metabolismo , Transdução de Sinais/genética , Animais , Regulação da Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Inflamação , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Camundongos , Camundongos Endogâmicos DBA , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Membrana Sinovial/metabolismo , Sinoviócitos/metabolismo
8.
Mar Drugs ; 16(6)2018 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-29794973

RESUMO

Chitosan oligosaccharide (COS), a natural polysaccharide with good antioxidant and anti-inflammatory properties, is the depolymerized product of chitosan possessing various biological activities. The present study was designed to investigate the possible anti-aging effect of COS on the aging model mouse induced by d-galactose (d-gal) and explore the underlying mechanism. In the experiment, 48 male Kunming mice (KM mice) were randomly divided into the normal group, model group, positive group, and low-medium-high dose polysaccharide groups (300, 600, 1200 mg/kg/day). The results showed that COS, by intragastric gavage after subcutaneous injection of d-gal (250 mg/kg/day) into the neck of mice consecutively for eight weeks, gradually recovered the body weight, the activity of daily living, and organ indices of mice, as well as effectively ameliorated the histological deterioration of the liver and kidney in mice triggered by d-gal. To be specific, COS obviously improved the activities of antioxidant enzymes in liver and kidney of KM mice, including catalase (CAT), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD), as well as decreased malondialdehyde (MDA) levels when compared with those in model group mice. Furthermore, COS not only elevated the diminished levels of serum immunoglobulin G (IgG) and IgM induced by d-gal, but also significantly inhibited the d-gal-caused upregulation of serum alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), uric acid (UA) and creatinine (CREA) levels as compared with those of mice in the model group. These results demonstrate that COS has an obvious anti-aging activity in d-gal-induced subacute aging mice, the mechanism of which, to some extent, is associated with enhancing the antioxidant defenses, reducing oxidative stress, and improving the immune function of aging model mice.


Assuntos
Envelhecimento/efeitos dos fármacos , Antioxidantes/farmacologia , Quitosana/farmacologia , Oligossacarídeos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Envelhecimento/imunologia , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Peso Corporal/efeitos dos fármacos , Catalase/metabolismo , Galactose/imunologia , Glutationa Peroxidase/metabolismo , Sistema Imunitário/efeitos dos fármacos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Rim/efeitos dos fármacos , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Masculino , Malondialdeído/sangue , Camundongos , Modelos Animais , Superóxido Dismutase/metabolismo
9.
J Clin Rheumatol ; 2018 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-29389685

RESUMO

BACKGROUND: Intra-articular (IA) injections are an integral part of the management of rheumatoid arthritis (RA). However, there are few reports regarding the association between drug effectiveness and cost. OBJECTIVES: The aim of this study was to assess the cost-effectiveness of various combinations of IA injections of betamethasone, hyaluronic acid (HA) or etanercept for oligoarthritis in RA. METHODS: Seventy RA patients were assigned to 4 groups according to the IA injection drug(s): betamethasone alone, betamethasone + etanercept, betamethasone + HA, or etanercept alone. Data for the following were collected before and after IA injection: erythrocyte sedimentation rate, C-reactive protein (CRP), disease activity score in 28 joints calculated with CRP, and patient global visual analog scale. In addition, power Doppler ultrasonography and gray-scale ultrasonography scores were obtained for synovitis, and passive range of motion of joints was measured. RESULTS: Sixty-eight RA patients completed the trial. Compared with patients given etanercept alone, the visual analog scale, power Doppler ultrasonography, and gray-scale ultrasonography scores of each of the other groups were significantly better at each time point. At 1 month, the passive range of motion of joints in patients given betamethasone + HA was significantly better than that of each of the other groups. Synovial hyperplasia improved significantly in all groups, but less so in those given etanercept alone. All other clinical parameters of the 4 groups were similar. The costs per joint for the betamethasone-alone, betamethasone + etanercept, betamethasone + HA, and etanercept-alone groups were, respectively, $7.55, $181.77, $42.68, and $174.22. CONCLUSIONS: Intra-articular injection of betamethasone alone was the most cost-effective treatment for oligoarthritis of RA. Betamethasone combined with HA injection resulted in the best improvement in joint function.

10.
Am J Clin Exp Immunol ; 6(4): 43-51, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28695056

RESUMO

We aimed to investigate whether vitamin D levels affect the expression of autophagy related genes (Atgs) and the counts of T-cell subsets in active systemic lupus erythematosus (SLE), as well as to assess the association between Atgs and T-cell subsets. Serum levels of 25(OH)D3, Atgs and T-cell subsets were measured in 50 patients with active SLE. Serum 25(OH)D3 levels <10 ng/ml and 10-30 ng/ml were defined as severe vitamin D deficiency and vitamin D insufficiency, respectively. Comparisons were made between values of severe vitamin D deficiency and vitamin D insufficiency patients, and the correlations between Atgs in PBMCs and T-cell subsets were carried out. mTOR mRNA levels were higher (P=0.036) and LC3 mRNA levels were lower (P<0.001) in severe vitamin D deficiency group compared to vitamin D insufficiency group. The counts of CD4+ T cells and the CD4/CD8 ratio were significantly higher in severe vitamin D deficiency group compared to vitamin D insufficiency group (P=0.001, P<0.001,respectively). LC3 mRNA levels correlated negatively with CD4+ T cells counts (r=-0.302, P=0.033), while correlated positively with CD8+ T cells counts (r=0.299, P=0.035). Serum 25(OH)D3 levels correlated negatively with the counts of CD4+ T cells (r=-0.423, P=0.002) and correlated positively with the counts of CD8+ T cells (r=0.318, P=0.024). Our results suggested that severe vitamin D deficiency affected the expression of Atgs in PBMCs and T-cell subsets in active SLE, indicating that vitamin D may affect T-cell subsets via regulating autophagy.

11.
Med Sci Monit ; 23: 2985-2992, 2017 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-28626213

RESUMO

BACKGROUND To observe and demonstrate therapeutic effects and side effects of two selective COX-2 inhibitors, imrecoxib and celecoxib, on patients with axial spondyloarthritis (axSpA) and observe the correlation between imaging scores and serum DKK-1 levels. MATERIAL AND METHODS Sixty patients with axSpA were randomly assigned to receive 200 mg imrecoxib or 200 mg celecoxib twice daily. Fifty-one patients who completed follow-up were included in the study. At baseline, week 4, and week 12, the clinical parameters, inflammatory markers (ESR, CRP), and adverse reactions were recorded. Serum DKK-1 levels were investigated by enzyme-linked immunosorbent assay. Radiographic scores were calculated by sacroiliac joint SPARCC (Spondyloarthritis Research Consortium of Canada) score method at baseline serum DKK-1 levels and week 12. RESULTS Patients in the imrecoxib group (n=25) and patients in the celecoxib group (n=26) were improved at week 4. At week 12, all clinical parameters and inflammatory markers were improved in the two groups and the differences was not statistically significant. Serum DKK-1 levels were decreased and the differences were not statistically significant. Serum DKK-1 levels in patients in the imrecoxib group at baseline were negatively correlated with all study parameters, while those in the celecoxib group had correlations with BASFI (r=-0.048, p=0.027) and Schober test (r=0.437, p=0.048), without any correlation with other clinical parameters or inflammatory markers. CONCLUSIONS Patients experienced significant improvement in disease activity, functional parameters, and inflammatory markers when treated with selective COX-2 inhibitors for 12 weeks, and the efficacy of imrecoxib was not inferior to celecoxib. Selective COX-2 inhibitors imrecoxib and celecoxib had no obvious effects on serum DKK-1 levels.


Assuntos
Celecoxib/uso terapêutico , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Pirróis/uso terapêutico , Espondilartrite/sangue , Espondilartrite/tratamento farmacológico , Sulfetos/uso terapêutico , Biomarcadores/metabolismo , Celecoxib/efeitos adversos , Celecoxib/farmacologia , Demografia , Seguimentos , Humanos , Inflamação/patologia , Pirróis/efeitos adversos , Pirróis/farmacologia , Espondilartrite/diagnóstico por imagem , Sulfetos/efeitos adversos , Sulfetos/farmacologia , Resultado do Tratamento
12.
PLoS One ; 12(4): e0175828, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28414748

RESUMO

Chronic kidney disease (CKD) stage 3 was divided into stage G3a and stage G3b in the 2013 Kidney Disease Improving Global Outcomes guidelines. Whether it is appropriate to regard 45 mL/min/per 1.73 m2 as the threshold value of G3a/G3b staging and whether dividing CKD stage 3 into G3a/G3b plays a useful role in assessing the prognosis of patients with IgA nephropathy (IgAN) remain unknown. Three hundred and ninety patients from the First Affiliated Hospital of Zhengzhou University and Peking University First Hospital diagnosed with IgAN in CKD stage 3 were enrolled and successfully followed up. Cox proportional hazards model was used to analyze hazard ratios of reaching the composite endpoints (doubling of serum creatinine, end-stage renal disease: estimated glomerular filtration rate (eGFR) <15 ml/min/per 1.73 m2 or renal replacement therapy, or death) for patients with different eGFR and risk factors affecting composite endpoints. The Kaplan-Meier method was used to calculate the cumulative renal survival rate of patients. When eGFR was lower than 45 ml/min/per 1.73 m2, the hazard ratio increased sharply for patients in CKD stage 3 who reached the composite endpoints. Renal injury and prognosis were significantly different between patients in the G3a and G3b groups. Stage G3b was a major risk factor affecting prognosis. A threshold value of 45 ml/min/per 1.73 m2 appears appropriate to assess the prognosis of IgAN patients with CKD stage 3. Dividing IgAN patients with CKD stage 3 into G3a and G3b is very useful to help understand disease conditions and for predicting the risk for disease progression.


Assuntos
Glomerulonefrite por IGA/diagnóstico , Glomerulonefrite por IGA/patologia , Imunoglobulina A/imunologia , Insuficiência Renal Crônica/diagnóstico por imagem , Insuficiência Renal Crônica/patologia , Adulto , Progressão da Doença , Feminino , Taxa de Filtração Glomerular/fisiologia , Glomerulonefrite por IGA/imunologia , Humanos , Rim/imunologia , Rim/patologia , Testes de Função Renal/métodos , Masculino , Prognóstico , Estudos Prospectivos , Insuficiência Renal Crônica/imunologia , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Taxa de Sobrevida
13.
Am J Clin Exp Immunol ; 6(1): 1-8, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28123902

RESUMO

To determine the expression of mTOR, Becline-1, LC3 and p62 in the peripheral blood mononuclear cells (PBMCs) of systemic lupus erythematosus (SLE) and assess their relationship with disease activity and immunologic features. The expression of mTOR, Becline-1, LC3 and p62 was detected by RT-PCR in 81 SLE subjects and 86 age- and sex-matched healthy controls. Data regarding demographics and clinical parameters were collected. Disease activity of SLE was evaluated according to the SLE Disease Activity Index (SLEDAI) score. Independent sample t-test was used to analyze the expression of mTOR, Becline-1, LC3, and p62 in the two groups. Pearson's or Spearman's correlation was performed to analyze their relationship with disease activity and immunologic features. The mean levels of Becline-1, LC3 and p62 mRNA were significantly higher in SLE patients than the controls (9.96×10-4 vs 7.38×10-4 for Becline-1 with P<0.001; 4.04×10-5 vs 2.62×10-5 for LC3 with P<0.001; 9.51×10-4 vs 7.59×10-4 for p62 with P=0.008). However, the levels of mTOR mRNA in SLE patients were not significantly different from that in controls. Correlation analysis showed that Becline-1, LC3 and p62 mRNA levels correlated positively with SLEDAI, IgG and ds-DNA, negatively with C3. Our results suggested that autophagosomes formation were activated and their degradation were blocked in SLE. Moreover, the maintenance of autophagy balance can improve disease activity and immune disorders in SLE patients.

14.
Am J Clin Exp Immunol ; 5(3): 48-54, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27335701

RESUMO

We aimed to determine the prevalence of hypovitaminosis D in patients with autoimmune rheumatic diseases (ARDs) in China and its association with demographic characteristics of the patients. We recruited 384 patients in this cross-sectional study including 121 cases of systemic lupus erythematosus (SLE), 131 rheumatoid arthritis (RA), 102 spondyloarthritis (SpA) and 30 other ARDs. For each patient, demographic information was collected and serum concentration of 25OHD3 was measured by electrochemiluminescence immunoassay (ECLIA). The multivariate logistic regression model was used to investigate the association between vitamin D deficiency and patient characteristics. The mean serum vitamin D level of the 384 patients was 18.91 (8.12) ng/mL, and the median age was 37.33 (12.01) yrs. Among these patients, 222 (57.81%) and 127 (33.07%) were found to be vitamin D deficiency and insufficiency, respectively. From the disease perspective, the percentages of insufficiency and deficiency were as follow: 97.52% and 84.30% in SLE, 87.02% and 48.85% in RA, 88.24% and 40.20% in SpA, 90.89% and 57.81% in other ARDs patients. The causative factors for vitamin D deficiency included SLE per se (OR 12.54, P < 0.001) and high body mass index (BMI) (OR 1.88, P < 0.001). However, the seniors were less likely to have vitamin D deficiency (OR 0.95, P = 0.005). No correlation was disclosed between vitamin D deficiency and gender or disease duration. Hypovitaminosis D is highly prevalent among autoimmune rheumatic diseases population in China. The SLE per se and the obesity are the risk factors for vitamin D deficiency. Clinicians are advised to supplement vitamin D in these patients.

15.
Biochem Biophys Res Commun ; 473(2): 442-8, 2016 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-26970310

RESUMO

Abnormal perpetual inflammatory response and sequential cytokine-induced prostaglandin E2 (PGE2) play important roles in the pathogenesis of rheumatoid arthritis (RA). The underlying regulatory mechanism, however, remain largely unknown. Here, we discovered that expression level of Metastasis associated protein 1 (MTA1), an important chromatin modifier that plays a critical role in transcriptional regulation by modifying DNA accessibility for cofactors, was upregulated in human rheumatoid synovial tissues. Furthermore, a knockdown of MTA1 by siRNA in the human fibroblast-like synovial cell line MH7A was found to impair the 4-hydroxynonenal (4-HNE)-induced transcriptional expression levels of certain proinflammatory cytokines including IL-1ß, TNF-α and IL-6. Moreover, endogenous MTA1 was required for the cytokines-induced PGE2 synthesis by rheumatoid synoviocytes. Collectively, the coordinated existence of MTA1 inside distinct cascade loops points to its indispensable role in the modulation of the integrated cytokine network along the pathogenesis of RA. Further exploration of the functional details of this master transcriptional regulator should be an attractive strategy to identify novel therapeutic target for RA and warrants execution.


Assuntos
Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Dinoprostona/imunologia , Histona Desacetilases/imunologia , Proteínas Repressoras/imunologia , Transdução de Sinais , Membrana Sinovial/imunologia , Membrana Sinovial/patologia , Aldeídos/imunologia , Artrite Reumatoide/genética , Linhagem Celular , Citocinas/genética , Citocinas/imunologia , Regulação da Expressão Gênica , Histona Desacetilases/análise , Histona Desacetilases/genética , Humanos , Proteínas Repressoras/análise , Proteínas Repressoras/genética , Membrana Sinovial/metabolismo , Transativadores
16.
Artigo em Chinês | MEDLINE | ID: mdl-26094408

RESUMO

OBJECTIVE: To investigate the effect and current situation of the standardized construction of laboratories of schis- tosomiasis control institutions in Hubei Province, so as to provide the evidence for establishing and improving the quality control system of diagnosis of schistosomiasis after the transmission of schistosomiasis was under control. METHODS: According to the procedures of self-examination, field operation, and laboratory on-site, five laboratories were assessed, and all the results were analyzed comparatively. RESULTS: The average number of staffs were (7.00±1.58) persons, and the staffs of the laboratories of the schistosomiasis control institutions with senior professional titles in the city level were more than that in the county level (t = 5.563, P < 0.05). The average space was (3.20±1.64) rooms, and the average area was (117.00±88.29) m2. The average score of field operation was (96.40±4.49) points. The average score of laboratory on-site assessment was (106.6±6.15) points. The highest and lowest of the laboratory on-site assessment scores were environment and facilities (19.60 ± 0.55) points and management system of laboratory quality control (15.70±2.39) points (F = 2.869, P < 0.05), respectively. CONCLUSION: The cultivation of laboratory staff should be strengthened, and the diagnostic capacity should be maintained and improved. The laboratory quality control system should be paid more attention to, and the construction and management of schistosomiasis laboratories should be standardized.


Assuntos
Controle de Doenças Transmissíveis/normas , Laboratórios/normas , Esquistossomose/prevenção & controle , Adolescente , Adulto , Idoso , Animais , Bovinos , Criança , China/epidemiologia , Cidades , Controle de Doenças Transmissíveis/instrumentação , Controle de Doenças Transmissíveis/métodos , Reservatórios de Doenças/parasitologia , Meio Ambiente , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Schistosoma/fisiologia , Esquistossomose/epidemiologia , Esquistossomose/parasitologia , Caramujos/crescimento & desenvolvimento , Caramujos/parasitologia , Recursos Humanos , Adulto Jovem
17.
Int J Immunogenet ; 42(1): 4-10, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25545293

RESUMO

Human leucocyte antigen (HLA)-B27 expression is correlated with spondyloarthritis (SpA), but its role in disease pathogenesis remains unclear. The aim of the study was to determine whether HLA-B27 free heavy chain (FHC) contributes to SpA pathogenesis. Flow cytometry was used to analyse the FHC expression on CD3+ and CD14+ cells in the peripheral blood (PB) and synovial fluid (SF) from SpA patients, healthy controls, and rheumatoid arthritis (RA) patients. Human monocytic U937 cell lines stably expressing enhanced green fluorescence protein (EGFP)/HLA-B27, EGFP/HLA-A2 or EGFP alone were created to further investigate the relation between HLA-B27 and FHC expression. The relative FHC level on CD14+ PB cells was significantly higher in SpA patients than in controls, but lower than on the SF cells of SpA patients. No significant correlation was found for relative FHC expression with HLA-B27 or ß2-microglobulin expression. HLA-B27-transfected U937 cells expressed higher FHC levels than either EGFP/HLA-A2- or EGFP-transfected cells. HLA class I FHC expression was significantly increased on monocytes of SpA patients and HLA-B27-transfected cells, implying that FHC, perhaps mostly derived from HLA-B27, plays an important role in SpA pathogenesis.


Assuntos
Antígeno HLA-B27/imunologia , Antígenos de Histocompatibilidade Classe I/biossíntese , Cadeias Pesadas de Imunoglobulinas/biossíntese , Monócitos/imunologia , Espondiloartropatias/imunologia , Adolescente , Adulto , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Complexo CD3/metabolismo , Linhagem Celular Tumoral , Feminino , Proteínas de Fluorescência Verde/biossíntese , Proteínas de Fluorescência Verde/genética , Antígeno HLA-B27/genética , Humanos , Receptores de Lipopolissacarídeos/metabolismo , Masculino , Pessoa de Meia-Idade , Espondiloartropatias/patologia , Líquido Sinovial/citologia , Transfecção , Células U937 , Adulto Jovem , Microglobulina beta-2/biossíntese
18.
Arthritis Res Ther ; 16(6): 478, 2014 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-25404518

RESUMO

INTRODUCTION: Activated platelets exert a proinflammatory action that can be largely ascribed to their ability to interact with monocytes. However, the mechanisms that promote dynamic changes in monocyte subsets in rheumatoid arthritis (RA) have not been clearly identified. The aim of this study was to determine whether platelet activation and the consequent formation of monocyte-platelet aggregates (MPA) might induce a proinflammatory phenotype in circulating monocytes in RA. METHODS: The surface phenotype of platelets and the frequencies of monocyte subpopulations in the peripheral blood of RA patients were determined using flow cytometry. Platelets were sorted and co-cultured with monocytes. In addition, monocyte activation was assessed by measuring the nuclear factor κB (NF-κB) pathway. The disease activity was evaluated using the 28-joint disease activity score. RESULTS: Platelet activation, circulating intermediate monocytes (Mon2) and MPA formation were significantly elevated in RA, especially in those with active disease status. Furthermore, Mon2 monocytes showed higher CD147 expression and responded to direct cell contact with activated platelets with higher cytokine production and matrix metallopeptidase 9 (MMP-9) secretion, which increased the expression of CD147. After the addition of specific antibodies for CD147, those effects were abolished. Furthermore, the NF-κB-driven inflammatory pathway may be involved in this process. CONCLUSION: These findings indicate an important role of platelet activation and the consequent formation of MPA in the generation of the proinflammatory cytokine milieu and for the promotion and maintenance of the pathogenically relevant Mon2 monocyte compartment in RA, which is likely to play an important role in the pathogenesis of autoimmunity.


Assuntos
Artrite Reumatoide/metabolismo , Basigina/metabolismo , Plaquetas/metabolismo , Mediadores da Inflamação/metabolismo , Monócitos/metabolismo , Fenótipo , Adulto , Idoso , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Basigina/genética , Basigina/imunologia , Plaquetas/imunologia , Técnicas de Cocultura , Feminino , Humanos , Mediadores da Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Transdução de Sinais/fisiologia , Adulto Jovem
19.
Curr Pharm Des ; 19(27): 4893-9, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23343120

RESUMO

This study was designed to evaluate the distribution of Tregs/Th17/Th1 cells in type 2 diabetic patients with foot disease before and after human umbilical cord blood mesenchymal stem cell (hUCB-MSCs) transplantation. Fifteen diabetic patients with foot disease under insulin therapy received hUCB-MSC transplantation. The hUCB-MSCs were directly injected into the quadriceps thigh muscles in patients with foot disease (cell quantity at 2 x 106 per point). Physical attributes, blood cytokines, blood glucose and insulin dosage were evaluated before treatment and 1, 2, 4, 8, and 12 weeks thereafter. The ratios of Treg/Th17, Treg/Th1, and Th17/Th1 cells were measured using flow cytometry and their correlation with various cytokines (FoxP3, IL-17, INF-γ, C-RP, TNF-α, and VEGF) was scrutinized. Levels of blood glucose and insulin dosage were significantly reduced in all 15 patients following hUCB-MSC transplantation. The ratios of CD4⁺CD25(hi)FoxP3⁺ Treg/Th17 and CD4⁺CD25(hi)FoxP3⁺ Treg/Th1 cells were significantly increased 4 weeks after transplantation (p < 0.01), while the ratio of Th17/Th1 cells remained unchanged. Serum levels of VEGF peaked at 4 weeks following transplantation. Levels of C-RP and TNF-α were significantly reduced 4 weeks after transplantation. Intriguingly, the ratios of Treg/Th17 were positively correlated with VEGF levels, and were inversely correlated with plasma IL-6 levels. Our data indicated that immune disorders are associated with the development of type 2 diabetes and its complications. Levels of blood glucose and required insulin dosage were reduced after hUCB-MSC transplantation accompanied with improved clinical profiles in diabetic patients. These data favor a role for Treg cells in the onset and progression of T2D.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Diabetes Mellitus Tipo 2/complicações , Pé Diabético/terapia , Transplante de Células-Tronco Mesenquimais , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologia , Adulto , Idoso , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Citocinas/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Pé Diabético/sangue , Pé Diabético/imunologia , Monitoramento de Medicamentos , Feminino , Humanos , Hipoglicemia/prevenção & controle , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêutico , Injeções Intramusculares , Insulina/administração & dosagem , Insulina/uso terapêutico , Masculino , Transplante de Células-Tronco Mesenquimais/métodos , Pessoa de Meia-Idade , Coxa da Perna
20.
Zhonghua Nei Ke Za Zhi ; 51(6): 441-4, 2012 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-22943753

RESUMO

OBJECTIVE: To investigate the incidence and correlative factors of metabolic syndrome (MS) in patients with systemic lupus erythematosus (SLE). METHODS: A total of 116 SLE patients and 115 controls were enrolled into the study. The incidence of MS, SLE disease activity index (SLEDAI) of patients with SLE combined with MS (MS-SLE) and patients without MS (n-MS-SLE), lupus characteristics, cumulative glucocorticoids, administration dose of glucocorticoids and hydroxychloroquine were compared between SLE group and the control group. RESULTS: The incidence of MS of SLE group was obviously higher than that of the control (34.48% vs 14.78%, P < 0.05). The ratios of patients with lower HDL-C, higher TG and higher blood pressure in SLE group (50.86%, 56.03%, 46.55%) were higher than those in the controls (34.78%, 16.52%, 20.00%, all P < 0.05). MS-SLE group had significantly higher mean waist circumference, BMI, systolic blood pressure and diastolic blood pressure and lower HDL-C than n-MS-SLE group (all P < 0.05). No significant difference was found regarding duration of disease, renal involvement, ESR, C-reactive protein,high-sensitivity C-reactive protein, SLEDAI, cumulative and current glucocorticoids use in MS-SLE group and n-MS-SLE group. The ratio of patients taking hydroxychloroquine in n-MS-SLE group was higher than that of MS-SLE group (46.05% vs 15.00%, P < 0.05). CONCLUSIONS: Patients with SLE has a higher incidence rate of MS. Hydroxychloroquine may reduce their MS incidence.


Assuntos
Glucocorticoides/uso terapêutico , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Síndrome Metabólica/etiologia , Adolescente , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Hidroxicloroquina/uso terapêutico , Incidência , Masculino , Pessoa de Meia-Idade , Adulto Jovem
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