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1.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 46(7): 704-710, 2021 Jul 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-34382586

RESUMO

OBJECTIVES: To investigate the risk factors for serious infections among hospitalized systemic lupus erythematosus (SLE) patients, and to provide the advice for preventing serious infections in SLE patients. METHODS: Information of SLE patients hospitalized from March 2017 to February 2019 at the Department of Rheumatology and Immunology, Xiangya Hospital, Central South University was obtained. The patients were assigned into a serious infection group and a non-serious infection group. The risk factors for serious infections among SLE inpatients were identified by comparison between the 2 groups and multivariate logistic regression analysis. RESULTS: There were 463 SLE inpatients in total, and 144 were in the serious infection group and 319 in the non-serious infection group. Multivariate logistic regression analysis showed that age ≥54.50 years old (OR=4.958, P<0.001), cardiovascular involvement (OR=6.287, P<0.001), hematologic involvement (OR=2.643, P=0.003), serum albumin <20 g/L (OR=2.340, P=0.036), C-reaction protein (CRP)/erythrocyte sedimentation rate (ESR)≥0.12 (OR=2.430, P=0.002), glucocorticoid dose ≥8.75 mg/d prednisone-equivalent (OR=2.465, P=0.002), and the combined use of immunosuppressive agents (OR=2.847, P=0.037) were the risk factors for serious infections in SLE inpatients. CONCLUSIONS: SLE patients with older age, cardiovascular involvement, hematologic involvement, low serum albumin are prone to suffering serious infections. Increased CRP/ESR ratio indicates serious infections in SLE inpatients. High-dose glucocorticoid and the combined use of immunosuppressive agents can increase the risk of serious infections in SLE inpatients.


Assuntos
Pacientes Internados , Lúpus Eritematoso Sistêmico , Idoso , Glucocorticoides/efeitos adversos , Humanos , Lúpus Eritematoso Sistêmico/complicações , Pessoa de Meia-Idade , Prednisona , Fatores de Risco
2.
Chin Med J (Engl) ; 134(12): 1457-1464, 2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34039871

RESUMO

BACKGROUND: Clinical observational studies revealed that 99Tc-methylene diphosphonate (99Tc-MDP) could reduce joint pain and swollenness in rheumatoid arthritis (RA) patients. This multicenter, randomized, double-blind, double-dummy study aimed to evaluate the effects of 99Tc-MDP plus methotrexate (MTX) vs. MTX alone or 99Tc-MDP alone on disease activity and structural damage in MTX-naïve Chinese patients with moderate to severe RA. METHODS: Eligible patients with moderate to severely active RA were randomized to receive 99Tc-MDP plus MTX (n = 59) vs. MTX (n = 59) alone or 99Tc-MDP (n = 59) alone for 48 weeks from six study sites across four provinces in China. The primary outcomes were the American College of Rheumatology 20% improvement (ACR20) response rates at week 24 and changes in modified total Sharp score at week 48. RESULTS: At week 24, the proportion of participants achieving ACR20 was significantly higher in the MTX + 99Tc-MDP combination group (69.5%) than that in the MTX group (50.8%) or 99Tc-MDP group (47.5%) (P = 0.03 for MTX + 99Tc-MDP vs. MTX, and MTX + 99Tc-MDP vs.99Tc-MDP, respectively). The participants in the MTX + 99Tc-MDP group and the 99Tc-MDP group had significantly less important radiographic progression than the participants in the MTX group over the 48 weeks (MTX + 99Tc-MDP vs. MTX: P = 0.03, 99Tc-MDP vs. MTX: P = 0.03, respectively). There was no significant difference in terms of adverse events (AEs) among the groups. No serious AEs were observed. CONCLUSIONS: This study demonstrated that the combination of 99Tc-MDP with MTX inhibited structural damage and improved disease activity in RA patients compared with MTX and 99Tc-MDP monotherapies, without increasing the rate of AEs. Additional clinical studies of 99Tc-MDP therapy in patients with RA are warranted. TRIAL REGISTRATION: Chictr.org, ChiCTR-IPR-14005684; http://www.chictr.org.cn/showproj.aspx?proj=10088.


Assuntos
Antirreumáticos , Artrite Reumatoide , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , China , Difosfonatos , Método Duplo-Cego , Quimioterapia Combinada , Humanos , Metotrexato/uso terapêutico , Tecnécio/uso terapêutico , Resultado do Tratamento
3.
Stem Cell Res ; 53: 102326, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33845242

RESUMO

Skin fibroblasts derived from a 71-year-old healthy woman were reprogrammed into induced pluripotent stem cells (iPSCs) by the transduction of retroviruses expressing OCT4, SOX2, KLF4 and c-MYC, respectively. The generated iPSCs maintained a normal karyotype and expressed various pluripotency markers. Moreover, they could be induced to form embryoid bodies in vitro and teratomas in vivo, indicating the full capacity of differentiating into three germ layers. This iPSC line could be differentiated into multiple cell subtypes for cellular modeling and drug discovery.


Assuntos
Células-Tronco Pluripotentes Induzidas , Idoso , Diferenciação Celular , Corpos Embrioides , Feminino , Fibroblastos , Camadas Germinativas , Humanos
4.
Stem Cell Res ; 53: 102336, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33865102

RESUMO

We established an induced pluripotent stem cell (iPSC) reprogrammed from dermal fibroblasts of a 53-year-old healthy man. Retroviruses expressing Yamanaka factors (OCT4, SOX2, KLF4 and c-MYC) were employed to initiate the reprogramming and were silenced in iPSCs. The generated iPSCs were pluripotent as determined by immunostaining and expression of pluripotency markers. They were further induced as embryoid bodies in vitro and teratomas in vivo, reminiscent of their full capacity of differentiating into three germ layers. They are with a normal karyotype and genetically identical to donor fibroblasts. This iPSC line provides excellent cell sources for studying and modeling human-specific physiology.


Assuntos
Células-Tronco Pluripotentes Induzidas , Teratoma , Diferenciação Celular , Reprogramação Celular , Corpos Embrioides , Fibroblastos , Humanos , Masculino , Pessoa de Meia-Idade
5.
Int Urol Nephrol ; 53(9): 1875-1881, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33675470

RESUMO

PURPOSE: Anti-neutrophil cytoplasmic autoantibody-associated vasculitis (AAV) is predominantly a disease of the elderly, and the incidence increases with age. However, there are few data focusing on the clinical features in elderly onset AAV, especially in very elderly onset AAV in China. The aim of this study was to explore whether elderly onset AAV shows any specific clinical features and outcomes in Chinese patients. METHODS: We performed a retrospective study in Xiangya Hospital, a mixed tertiary medical center in south China. A total of 177 patients presenting with AAV were included between January 1, 2010 and December 31, 2017. Patients were divided into younger group (age < 65 years) and older group (age ≥ 65 years) which was sub-divided into elderly group (age 65-74 years) and very elderly group (age ≥ 75 years). And their medical records were analyzed by retrospective review. RESULTS: We found patients in the very elderly group had more chest and cardiovascular involvement (P = 0.033 and P = 0.017). Older AAV patients had less renal involvement and lower serum C4 level (P = 0.013 and P = 0.003). Very elderly AAV patients had lower platelet counts. Patients in the younger group had a higher level of BVAS among three groups (P < 0.05 younger group vs. very elderly group; P < 0.05 younger group vs. elderly group). There were no significant difference in the proportion of ESRD patients among the three groups (P = 0.473). Patients in the very elderly group had the poorest patient survival (P = 0.002). CONCLUSION: Older AAV patients had less renal involvement, lower serum C4 level and BVAS. The very elderly group got the most chest and cardiovascular involvement and had lower platelet counts. Older age is associated with higher mortality in AAV patients.

6.
Immunol Cell Biol ; 99(7): 697-710, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33655578

RESUMO

Defects causing concomitant loss of CD25 expression in regulatory T cells (Tregs) have been identified in systemic lupus erythematosus (SLE). However, the cause of this deficiency is not fully understood. Carcinoembryonic antigen related cell adhesion molecule 1 (CEACAM1), an immune co-receptor, contributes to general T-cell function and activation. Our previous study revealed that CEACAM1 expression was upregulated in peripheral blood mononuclear cells (PBMCs) from patients with SLE. However, its role remains unclear. Herein, we confirmed CEACAM1, especially CEACAM1-S, was upregulated in PBMCs from patients with SLE. CEACAM1-S over-expression inhibits CD4+ CD25+ Treg differentiation, whereas knockdown of CEACAM1 had the opposite effect in vitro. CEACAM1-S is the target of miR-31. MiR-31 mimic inhibits CEACAM1 expression and enhances CD4+ CD25+ Treg differentiation, which was reversed by CEACAM1-S over-expression. Moreover, the circulating TGF-ß level was upregulated in SLE patients and TGF-ß reduced miR-31 expression via enhancing NF-κB activity. Importantly, CEACAM1 and TGF-ß mRNA levels were downregulated, while the miR-31 level and the abundance of CD4+ CD25+ Tregs were increased in inactive patients compared with that in patients with active SLE. In addition, CEACAM1-S expression was positively correlated with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, while CD4+ CD25+ Treg abundance and miR-31 level were negatively correlated with the SLEDAI score. In conclusion, reduced activity of miR-31 by TGF-ß, via the inhibition of NF-ᴋB, acted to inhibit the differentiation of CD4+ CD25+ Tregs by directly targeting CEACAM1-S and to promote autoimmunity.


Assuntos
Lúpus Eritematoso Sistêmico , MicroRNAs , Antígenos CD , Molécula 1 de Adesão Celular , Moléculas de Adesão Celular , Diferenciação Celular , Citometria de Fluxo , Humanos , Leucócitos Mononucleares , MicroRNAs/genética , Linfócitos T Reguladores , Fator de Crescimento Transformador beta
7.
Artigo em Inglês | MEDLINE | ID: mdl-33693494

RESUMO

OBJECTIVES: To evaluate the efficacy and safety of SHR4640, a highly selective urate transporter 1 inhibitor in Chinese subjects with hyperuricemia. METHODS: This was a randomized double-blind dose-ranging phase II study. Subjects whose serum uric acid levels ≥480 µmol/l with gout, or sUA levels ≥480 µmol/l without gout but with comorbidities, or sUA levels ≥540 µmol/l were enrolled. Subjects were randomly assigned (1:1:1:1:1) to receive once daily 2.5 mg/5 mg/10 mg of SHR4640, 50 mg of benzbromarone, and placebo, respectively. The primary end point was the proportion of subjects achieved target sUA level of ≤ 360 µmol/l at week 5. RESULTS: About 99.5% of subjects (n = 197) were male and 95.9% of subjects had gout history. The proportions of subjects achieved target sUA at week 5 were 32.5%, 72.5% and 61.5% in 5 mg, 10 mg of SHR4640 and benzbromarone groups, respectively, significantly higher than placebo group (0%; p< 0.05 for 5 mg and 10 mg of SHR4640 group). The sUA was reduced by 32.7%, 46.8% and 41.8% at week 5 with 5 mg, 10 mg of SHR4640 and benzbromarone, respectively, vs placebo (5.9%; p< 0.001 for each comparison). The incidences of gout flares requiring intervention were similar among all groups. Occurrences of treatment-emergent adverse events (TEAEs) were comparable across all groups, and serious TEAEs were not reported. CONCLUSIONS: The present study indicated a superior sUA-lowering effect, and well tolerated safety profile after 5-week treatment with once-daily 5 mg/10 mg of SHR4640 as comparing with placebo in Chinese subjects with hyperuricemia. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT03185793.

8.
Food Chem ; 351: 129336, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-33662909

RESUMO

To investigate the effect of relative humidity (RH) on chilling injury (CI), zucchini fruit were stored in cold rooms (4 ± 0.4 ℃) with different RHs (near-saturated RH [NSH] with 96-100% and normal RH with 72-76% served as control). Storage in NSH delayed weight loss and CI, maintained firmness and skin color. Higher antioxidant enzyme activities and greater scavenging capacities of free radicals were found in NSH-fruit than in the control fruit. The decrease of the unsaturated fatty acids was delayed in NSH-fruit due to lower activities of related membrane lipid degrading enzymes as compared to the control fruit. NSH-fruit also maintained higher activities of energy metabolism-associated enzymes than control fruit, leading to high levels of adenosine triphosphate (ATP). Taken together, we attributed the alleviation of CI by NSH storage to its enhancement of antioxidant capacities and its effect on maintaining higher energy status in zucchini fruit.


Assuntos
Antioxidantes/metabolismo , Temperatura Baixa , Cucurbita/metabolismo , Metabolismo Energético , Frutas/metabolismo , Umidade , Trifosfato de Adenosina/metabolismo , Armazenamento de Alimentos
9.
Stem Cell Res ; 53: 102277, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33706202

RESUMO

Early onset isolated dystonia (DYT1) is a hereditary neurological movement disease caused by a single amino-acid deletion in torsin A (TOR1A), a gene encoding a membrane-embedded ATPase. In this study, we generated an induced pluripotent stem cell (iPSC) line from fibroblasts of a DYT1 patient by the retroviral transduction of Yamanaka factors. The iPSCs retained the heterozygous TOR1A mutation (p.Glu303del), showed a normal karyotype, expressed pluripotency markers and exhibited the potential to differentiate into three germ layers both in vitro and in vivo. This DYT1 patient-specific iPSC will be used for modeling the dystonia pathophysiology and probably drug screening.


Assuntos
Distonia , Células-Tronco Pluripotentes Induzidas , Fibroblastos , Heterozigoto , Humanos , Chaperonas Moleculares , Mutação
10.
Environ Res ; 195: 110875, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33592226

RESUMO

Air pollution may trigger systemic lupus erythematosus (SLE). However, few studies have investigated the associations between air pollution and complications of SLE, such as lupus nephritis (LN). In this study, multicenter longitudinal data from 13 hospitals in China, including 8552 SLE patients with 24,762 visits, were used. Based on the generalized estimating equation (GEE) model, we assessed the associations of LN occurrence with short-term exposures to different air pollutants including particulate matter with an aerodynamic diameter < 2.5 µm (PM2.5), sulfur dioxide (SO2), nitrogen dioxide (NO2), carbon monoxide (CO), and ozone (O3). We identified 2672 LN patients, and about half of them were from east China. Our results based on the entire data set showed that PM2.5 and NO2 were risk factors for LN within one month after exposure, with odds ratio of 1.16 (95% confidence interval (CI), 1.08-1.19) at lag 18 day and 1.19 (95% CI, 1.12-1.26) at lag 16 day relative to an interquartile range (IQR) increase in PM2.5 and NO2, respectively. This positive association between LN and NO2 was also observed for south, west, and east China. In addition, we found that the short term exposure to CO and O3 was not generally associated with LN. Finally, the negative associations of LN with SO2 were found for the entire region and east China. Our results implied that SLE patients may gain the health benefits of air quality improvement in China. Our work also provided evidence that short-term variations in air pollution may trigger LN, and further studies are needed to confirm these findings and the potential pathogenic mechanisms should be explored.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Ozônio , Poluentes Atmosféricos/análise , Poluentes Atmosféricos/toxicidade , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , China/epidemiologia , Exposição Ambiental/análise , Humanos , Lúpus Eritematoso Sistêmico/epidemiologia , Nefrite Lúpica/induzido quimicamente , Nefrite Lúpica/epidemiologia , Dióxido de Nitrogênio/análise , Dióxido de Nitrogênio/toxicidade , Ozônio/análise , Material Particulado/análise , Material Particulado/toxicidade , Dióxido de Enxofre/análise
11.
Am J Med Sci ; 361(1): 63-68, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32988597

RESUMO

BACKGROUND: Specific factors correlated with hypothyroidism in systemic lupus erythematosus (SLE) patients remain unclear. Therefore, we aim to evaluate the prevalence of thyroid dysfunction in Chinese patients with SLE and the relationship between clinical hypothyroidism and SLE. METHODS: We conducted a cross sectional study of the prevalence of thyroid dysfunction in 672 patients with SLE and 605 age- and sex-matched healthy controls. Demographic, clinical, and biochemical data were compared between 58 patients with SLE with hypothyroidism and 197 patients with SLE with euthyroidism. Multivariate analysis was performed using binomial logistic regression analysis. Spearman's rank correlation was used to identify an association between thyroid function and disease activity. RESULTS: The prevalence of thyroid dysfunction was significantly higher in patients with SLE than in controls (70.7% vs 19.7%). SLE was associated with higher rates of hypothyroidism (9.6%, P ≤ 0.001) and euthyroid sick syndrome (49.6%, P ≤ 0.001) compared with control subjects. Further analyses showed that hypothyroidism in patients with SLE was associated with high blood pressure, renal disorder, high serum creatinine, high uric acid, hyperlipidaemia, low C3 and C4, positive anti-dsDNA antibodies, and high SLE disease activity index (SLEDAI) score. In multiple logistic regression models, albumin, platelet count, serum creatinine, and anti-dsDNA antibodies were associated with hypothyroidism. Finally, free tri-iodothyronine was significantly negatively correlated with SLEDAI score. CONCLUSIONS: Hypothyroidism was more prevalent in patients with SLE. There was a relationship between hypothyroidism with renal disorder and lupus activity. Albumin, platelet count, serum creatinine, and anti-dsDNA antibodies were correlated with hypothyroidism.


Assuntos
Hipotireoidismo/epidemiologia , Lúpus Eritematoso Sistêmico/epidemiologia , Adulto , China/epidemiologia , Estudos Transversais , Feminino , Humanos , Hipotireoidismo/complicações , Lúpus Eritematoso Sistêmico/complicações , Masculino , Prevalência
12.
Rheumatology (Oxford) ; 60(5): 2177-2189, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33165604

RESUMO

OBJECTIVES: Muscle cell necrosis is the most common pathological manifestation of idiopathic inflammatory myopathies. Evidence suggests that glycolysis might participate in it. However, the mechanism is unclear. This study aimed to determine the role of glycolysis in the muscle damage that occurs in DM/PM. METHODS: Mass spectrometry was performed on muscle lesions from DM/PM and control subjects. The expression levels of pyruvate kinase isozyme M2 (PKM2), the nucleotide-binding and oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and pyroptosis-related genes in muscle tissues or plasma were determined by real-time PCR, western blot analysis, IF and ELISA. In addition, IFNγ was used to stimulate myotubes, and the relationships among PMK2 expression, NLRP3 inflammasome activation and pyroptosis were investigated. RESULTS: Mass spectrometry and bioinformatics analysis suggested that multiple glycolysis processes, the NLRP3 inflammasome and programmed cell death pathway-related proteins were dysregulated in the muscle tissues of DM/PM. PKM2 and the NLRP3 inflammasome were upregulated and positively correlated in the muscle fibres of DM/PM. Moreover, the pyroptosis-related proteins were increased in muscle tissues of DM/PM and were further increased in PM. The levels of PKM2 in muscle tissues and IL-1ß in plasma were high in patients with anti-signal recognition particle autoantibody expression. The pharmacological inhibition of PKM2 in IFNγ-stimulated myotubes attenuated NLRP3 inflammasome activation and subsequently inhibited pyroptosis. CONCLUSION: Our study revealed upregulated glycolysis in the lesioned muscle tissues of DM/PM, which activated the NLRP3 inflammasome and leaded to pyroptosis in muscle cells. The levels of PKM2 and IL-1ß were high in patients with anti-signal recognition particle autoantibody expression. These proteins might be used as new biomarkers for muscle damage.

13.
Arthritis Rheumatol ; 73(2): 232-243, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33124780

RESUMO

OBJECTIVE: Changes in gut microbiota have been linked to systemic lupus erythematosus (SLE), but knowledge is limited. Our study aimed to provide an in-depth understanding of the contribution of gut microbiota to the immunopathogenesis of SLE. METHODS: Fecal metagenomes from 117 patients with untreated SLE and 52 SLE patients posttreatment were aligned with 115 matched healthy controls and analyzed by whole-genome profiling. For comparison, we assessed the fecal metagenome of MRL/lpr mice. The oral microbiota origin of the gut species that existed in SLE patients was documented by single-nucleotide polymorphism-based strain-level analyses. Functional validation assays were performed to demonstrate the molecular mimicry of newly found microbial peptides. RESULTS: Gut microbiota from individuals with SLE displayed significant differences in microbial composition and function compared to healthy controls. Certain species, including the Clostridium species ATCC BAA-442 as well as Atopobium rimae, Shuttleworthia satelles, Actinomyces massiliensis, Bacteroides fragilis, and Clostridium leptum, were enriched in SLE gut microbiota and reduced after treatment. Enhanced lipopolysaccharide biosynthesis aligned with reduced branched chain amino acid biosynthesis was observed in the gut of SLE patients. The findings in mice were consistent with our findings in human subjects. Interestingly, some species with an oral microbiota origin were enriched in the gut of SLE patients. Functional validation assays demonstrated the proinflammatory capacities of some microbial peptides derived from SLE-enriched species. CONCLUSION: This study provides detailed information on the microbiota of untreated patients with SLE, including their functional signatures, similarities with murine counterparts, oral origin, and the definition of autoantigen-mimicking peptides. Our data demonstrate that microbiome-altering approaches may offer valuable adjuvant therapies in SLE.


Assuntos
Autoanticorpos/imunologia , Autoantígenos/imunologia , Microbioma Gastrointestinal/imunologia , Lúpus Eritematoso Sistêmico/microbiologia , Mimetismo Molecular/imunologia , Actinobacteria , Actinomyces , Adulto , Aminoácidos de Cadeia Ramificada/biossíntese , Animais , Antirreumáticos/uso terapêutico , Bacteroides fragilis , Estudos de Casos e Controles , Clostridiales , Clostridium , Modelos Animais de Doenças , Feminino , Microbioma Gastrointestinal/genética , Humanos , Lipopolissacarídeos/biossíntese , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/fisiopatologia , Masculino , Metagenômica , Camundongos , Camundongos Endogâmicos MRL lpr , Boca/microbiologia , Polimorfismo de Nucleotídeo Único , Adulto Jovem
14.
Mol Genet Genomic Med ; 9(1): e1568, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33280276

RESUMO

BACKGROUND: Glycogen storage disease (GSD) type Ib is an autosomal recessive disease caused by defects of glucose-6-phosphate transporter (G6PT), encoded by the SLC37A4 gene. To date, over 100 mutations have been revealed in the SLC37A4 gene. GSD-Ib patients manifest a metabolic phenotype of impaired blood glucose homeostasis and also carry the additional complications of neutropenia and myeloid dysfunction. METHODS: Here, we present two daughters with an initial diagnosis of gout in a Chinese consanguineous family. Whole-exome sequencing was performed to identify the mutations. The mechanism of leukocytopenia was investigated. RESULTS: Whole-exome sequencing analysis of the proband identified a novel homozygous p.P119L mutation in SLC37A4, leading to a diagnosis of GSD-Ib. We found that the potential pathogenic p.P119L mutation leads to an unusual phenotype characterized by gout at onset, and GSD-Ib arising from this variant also manifests multiple metabolic abnormalities, leukocytopenia, and anemia, but no hepatomegaly. The leukocytes from the proband showed increased mRNA levels of sXBP-1, BIP, and CHOP genes in the unfolded protein response pathway, and enhanced Bax mRNA and caspase-3 activity, which might contribute to leukocytopenia. CONCLUSION: Our findings broaden the variation spectrum of SLC37A4 and suggest no strict genotype-phenotype correlations in GSD-Ib patients.

15.
Adv Ther ; 38(1): 772-781, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33237533

RESUMO

INTRODUCTION: Baricitinib is an oral, selective inhibitor of Janus kinase which demonstrates clinical efficacy in patients with rheumatoid arthritis (RA). This report aims to analyze the onset time of baricitinib in Chinese patients with moderately to severely active RA who had an inadequate response to methotrexate. METHODS: This post hoc analysis evaluated clinical improvements of Chinese patients treated with baricitinib 4 mg once daily compared with placebo, based on data from a phase 3 study RA-BALANCE. Efficacy measures including American College of Rheumatology 20% (ACR20) response, ACR core set values, Disease Activity Score modified to include the 28 diarthrodial joint count (DAS28) using high-sensitivity C-reactive protein (hsCRP), DAS28-erythrocyte sedimentation rate, Simplified Disease Activity Index, Clinical Disease Activity Index, DAS28-hsCRP ≤ 3.2 response (low disease activity), and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) were evaluated at weeks 1, 2, 4, 8, 12, 14, 16, 20, and 24 (except for FACIT-F evaluated every 4 weeks). A logistic regression model and an analysis of covariance model were used to analyze treatment comparisons of categorical and continuous measures, respectively. RESULTS: Statistically significant (p ≤ 0.05) improvements were observed as early as week 1 or 2 for the baricitinib group compared to placebo in almost all main efficacy measures. For other outcomes including 66 swollen joint count, 68 tender joint count, FACIT-F, and DAS28-hsCRP ≤ 3.2 response rate, differences were evident (p ≤ 0.05) by week 4 in the baricitinib group compared with placebo. Significant improvements in all efficacy measures were sustained through 24 weeks. CONCLUSIONS: Baricitinib demonstrated a rapid onset of efficacy on ACR20 response, ACR core set values, disease activity, and patient-reported outcome improvements in Chinese patients from RA-BALANCE. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02265705.


Assuntos
Antirreumáticos , Artrite Reumatoide , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Azetidinas , China , Método Duplo-Cego , Quimioterapia Combinada , Humanos , Metotrexato/uso terapêutico , Purinas , Pirazóis , Índice de Gravidade de Doença , Sulfonamidas , Resultado do Tratamento
16.
J Invest Dermatol ; 141(5): 1254-1263.e6, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33069728

RESUMO

Genetic factors play a key role in the pathogenesis of autoimmune diseases, whereas the disease-causing variants remain largely unknown. Herein, we performed an exome-wide association study of systemic sclerosis in a Han Chinese population. In the discovery stage, 527 patients with systemic sclerosis and 5,024 controls were recruited and genotyped. In the validation study, an independent sample set of 479 patients and 1,096 controls were examined. In total, we found that four independent signals reached genome-wide significance. Among them, rs7574865 (Pcombined = 3.87 × 10-12) located within signal transducer and activator of transcription 4 gene was identified previously using samples of European ancestry. Additionally, another signal including three SNPs in linkage disequilibrium might be unreported susceptibility loci located in the epidermis differentiation complex region. Furthermore, two SNPs located within exon 3 of IGHM (rs45471499, Pcombined = 1.15 × 10-9) and upstream of LRP2BP (rs4317244, Pcombined = 4.17 × 10-8) were found. Moreover, rs4317244 was identified as an expression quantitative trait locus for LRP2BP that regulates tight junctions, cell cycle, and apoptosis in endothelial cell lines. Collectively, our results revealed three signals associated with systemic sclerosis in Han Chinese and suggested the importance of LRP2BP in systemic sclerosis pathogenesis. Given the limited sample size and discrepancies between previous results and our study, further studies in multiethnic populations are required for verification.

17.
Genome Biol ; 21(1): 281, 2020 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-33213505

RESUMO

BACKGROUND: Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease characterized by the development of anti-nuclear antibodies. Susceptibility to SLE is multifactorial, with a combination of genetic and environmental risk factors contributing to disease development. Like other polygenic diseases, a significant proportion of estimated SLE heritability is not accounted for by common disease alleles analyzed by SNP array-based GWASs. Death-associated protein 1 (DAP1) was implicated as a candidate gene in a previous familial linkage study of SLE and rheumatoid arthritis, but the association has not been explored further. RESULTS: We perform deep sequencing across the DAP1 genomic segment in 2032 SLE patients, and healthy controls, and discover a low-frequency functional haplotype strongly associated with SLE risk in multiple ethnicities. We find multiple cis-eQTLs embedded in a risk haplotype that progressively downregulates DAP1 transcription in immune cells. Decreased DAP1 transcription results in reduced DAP1 protein in peripheral blood mononuclear cells, monocytes, and lymphoblastoid cell lines, leading to enhanced autophagic flux in immune cells expressing the DAP1 risk haplotype. Patients with DAP1 risk allele exhibit significantly higher autoantibody titers and altered expression of the immune system, autophagy, and apoptosis pathway transcripts, indicating that the DAP1 risk allele mediates enhanced autophagy, leading to the survival of autoreactive lymphocytes and increased autoantibody. CONCLUSIONS: We demonstrate how targeted sequencing captures low-frequency functional risk alleles that are missed by SNP array-based studies. SLE patients with the DAP1 genotype have distinct autoantibody and transcription profiles, supporting the dissection of SLE heterogeneity by genetic analysis.

18.
Eur Respir J ; 56(5)2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32616590

RESUMO

OBJECTIVES: Primary Sjögren's syndrome (pSS) is an important cause of pulmonary arterial hypertension (PAH), which remains insufficiently studied and needs attention. This study aimed to investigate the clinical characteristics, risk factors, prognosis and risk assessment of pSS-PAH. METHODS: We established a multicentre cohort of pSS-PAH diagnosed by right heart catheterisation. The case-control study was conducted with pSS-non-PAH patients as a control group to identify the risk factors for PAH. In the cohort study, survival was calculated, and risk assessment was performed at both baseline and follow-up visits. RESULTS: In total, 103 patients with pSS-PAH were enrolled, with 526 pSS-non-PAH patients as controls. The presence of anti-SSB (p<0.001, OR 4.095) and anti-U1RNP antibodies (p<0.001, OR 29.518), the age of pSS onset (p<0.001, OR 0.651) and the positivity of corneal staining (p=0.003, OR 0.409) were identified as independent risk factors for PAH. The 1-, 3- and 5-year survival rates were 94.0%, 88.8% and 79.0%, respectively. Cardiac index (p=0.010, hazard ratio (HR) 0.161), pulmonary vascular resistance (p=0.016, HR 1.105) and Sjögren's syndrome disease damage index (p=0.006, HR 1.570) were identified as potential predictors of death in pSS-PAH. Long-term outcomes were improved in patients in the low-risk category at baseline (p=0.002) and follow-up (p<0.0001). CONCLUSION: The routine screening of PAH is suggested in pSS patients with early onset and positivity for anti-SSB or anti-U1RNP antibodies. Patient prognosis might be improved by improving reserved cardiopulmonary function, by achieving a damage-free state and especially by achieving low-risk category, which supports the treat-to-target strategy for pSS-PAH.


Assuntos
Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Síndrome de Sjogren , Estudos de Casos e Controles , China/epidemiologia , Estudos de Coortes , Humanos , Hipertensão Pulmonar/epidemiologia , Estudos Retrospectivos , Síndrome de Sjogren/complicações , Síndrome de Sjogren/epidemiologia
19.
Semin Arthritis Rheum ; 50(4): 627-635, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32502727

RESUMO

Idiopathic inflammatory myopathies (IIMs) are a group of heterogeneous autoimmune diseases characterized by muscle weakness, muscle inflammation and extramuscular manifestations. Despite extensive efforts, the mechanisms of IIMs remain largely unknown, and treatment is still a challenge for physicians. Metabolism changes have emerged as a crucial player in autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). However, little is known about metabolism changes in IIMs. In this review, we focus on the alteration of metabolism profile in IIMs, and the relationships with clinical information. We highlight the potential roles of metabolism in the pathogenesis of IIMs and discuss future perspectives for metabolic checkpoint-based therapeutic interventions.

20.
J Dermatol Sci ; 98(2): 88-97, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32147195

RESUMO

BACKGROUND: Diffuse cutaneous systemic sclerosis (dSSc) is a systemic autoimmune disease with skin fibrosis. Neutrophils display important roles in autoimmunity, inflammation, vasculopathy and fibrosis. Exosomes (EXOs) are cell-derived vesicles contained various noncoding RNAs, mRNA and proteins with biological roles. OBJECTIVE: To investigate the roles of miRNAs and lncRNAs from dSSc neutrophils EXOs. METHODS: EXOs were isolated from cultured neutrophils supernatants and identified by transmission electron microscopy. Global expression of miRNAs and lncRNAs in neutrophils EXOs were sequenced by Illumina HiSeq 3000 and bioinformatic analyses were performed by R/Bioconductor. Genes were validated by real-time quantitative PCR. RESULTS: In profiles of neutrophils EXOs, we identified 22 dysregulated miRNAs and 281 dysregulated lncRNAs. Predicted target genes of them were enriched in GO, KEGG and Reactome pathways, Wnt, AMPK, IL-23 and NOTCH signaling pathways were selected for further analysis. Widely interactions among them were also found. Human dermal microvascular endothelial cells and human primary skin fibroblasts were stimulated with dSSc neutrophils EXOs, these fibrosis related genes were detected and some changes were found, such as ENST00000533886.1-hsa-miR-1268a-CAMK2G in Wnt and IL-23 signaling pathways, ENST00000610091.1-hsa-miR-299-3p, 512-3p-CPT1A in IL-23 and AMPK signaling pathways, NR_001564.2, ENST00000520562.1, ENST00000596567.1-hsa-miR-299-3p, 512-3p -TFDP2 in IL-23, AMPK and NOTCH signaling pathways. CONCLUSIONS: The profiles of miRNAs and lncRNAs of neutrophils EXOs provided novel clues for dSSc pathogenesis. We identified several gene pairs in the Wnt, AMPK, IL-23 and NOTCH signaling pathways, which could be potential biomarkers and therapeutic targets in dSSc.


Assuntos
Redes Reguladoras de Genes , Neutrófilos/metabolismo , RNA Longo não Codificante/metabolismo , RNA Mensageiro/metabolismo , Esclerodermia Difusa/genética , Adulto , Estudos de Casos e Controles , Linhagem Celular , Biologia Computacional , Exossomos/metabolismo , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Neutrófilos/citologia , RNA-Seq , Reação em Cadeia da Polimerase em Tempo Real , Esclerodermia Difusa/sangue , Transdução de Sinais/genética
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