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1.
Transl Oncol ; 48: 102058, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39079408

RESUMO

BACKGROUND: The efficacy of immunotherapy plus neoadjuvant chemotherapy and concurrent chemoradiotherapy (CCRT) for locally advanced nasopharyngeal carcinoma (LA-NPC) has not been reported. This study retrospectively compared the efficacy of tislelizumab plus neoadjuvant chemotherapy and CCRT with neoadjuvant chemotherapy followed by CCRT. METHODS: Ninety patients with stages III-IVa NPC were identified between January 2020 and March 2021 at the Affiliate Hospital of Guangdong Medical University. Forty-three patients in the observation group (OG) received tislelizumab plus nano albumin-paclitaxel and cisplatin (nab-TP) regimen, followed by CCRT, while forty-seven patients in the control group (CG) received nab-TP regimen followed by CCRT. RESULTS: The complete response rate after neoadjuvant therapy was significantly higher in the OG compared to the CG (37.2% vs. 12.8 %). The objective response rates were 88.4 % in the OG and 70.2 % in the CG. The 3-year progression-free survival (PFS) rates for OG and CG patients were 93.0 % and 78.7 %, respectively (P = 0.04, HR = 0.31). The overall survival (OS) rates for the OG and the CG were 95.3 % and 87.2 %, respectively (P = 0.15, HR = 0.36). Locoregional relapse-free survival (LRFS) rates were 90.7 % for the OG and 72.3 % for the CG (P = 0.04, HR = 0.38), and distant metastasis-free survival (DMFS) rates were 95.3 % for the OG, and 80.9 % for the CG (P = 0.04, HR = 0.30). For PD-L1 high-expression and low-expression rates, the 3-year PFS rates were 89.2 % and 85.7 % (P = 0.77, HR = 1.21), and the OS rates were 90.2 % and 89.2 % (P = 0.65, HR = 1.36), respectively. CONCLUSION: Tislelizumab combined with neoadjuvant chemotherapy and CCRT showed encouraging therapeutic effects and good tolerability in patients with LA-NPC compared to the standard treatment.

2.
Front Immunol ; 15: 1389993, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38665917

RESUMO

Kikuchi-Fujimoto disease (KFD) is a benign, self-limiting illness that can progress to systemic lupus erythematosus (SLE) in approximately 30% of cases. Neurological injuries can occur in both diseases, albeit with distinct presentations. Venous sinus thrombosis is a serious cerebrovascular complication in patients with neuropsychiatric SLE but is rarely observed in patients with KFD. The involvement of various antibodies, particularly antiphospholipid antibodies, can cause vascular endothelial cell injury, resulting in focal cerebral ischemia and intracranial vascular embolism in SLE. However, there are cases in which thrombotic pathology occurs without antiphospholipid antibody positivity, attributed to vascular lesions. In this report, we present a case of KFD and lupus encephalopathy featuring cerebral venous sinus thrombosis, despite the patient being negative for antiphospholipid antibody. We also conducted a comparative analysis of C3 and C4 levels in cerebrospinal fluid (CSF) and peripheral blood, along with the protein ratio in CSF and serum, to elucidate the pathological changes and characteristics of lupus encephalopathy.


Assuntos
Linfadenite Histiocítica Necrosante , Lúpus Eritematoso Sistêmico , Trombose dos Seios Intracranianos , Humanos , Linfadenite Histiocítica Necrosante/diagnóstico , Linfadenite Histiocítica Necrosante/complicações , Linfadenite Histiocítica Necrosante/patologia , Trombose dos Seios Intracranianos/etiologia , Trombose dos Seios Intracranianos/diagnóstico , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/diagnóstico , Feminino , Adulto
3.
Cell Chem Biol ; 31(3): 487-501.e7, 2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38232732

RESUMO

Structural dynamics of human immunodeficiency virus 1 (HIV-1) envelope (Env) glycoprotein mediate cell entry and facilitate immune evasion. Single-molecule FRET using peptides for Env labeling revealed structural dynamics of Env, but peptide use risks potential effects on structural integrity/dynamics. While incorporating noncanonical amino acids (ncAAs) into Env by amber stop-codon suppression, followed by click chemistry, offers a minimally invasive approach, this has proved to be technically challenging for HIV-1. Here, we develope an intact amber-free HIV-1 system that overcomes hurdles of preexisting viral amber codons. We achieved dual-ncAA incorporation into Env on amber-free virions, enabling single-molecule Förster resonance energy transfer (smFRET) studies of click-labeled Env that validated the previous peptide-based labeling approaches by confirming the intrinsic propensity of Env to dynamically sample multiple conformational states. Amber-free click-labeled Env also enabled real-time tracking of single virion internalization and trafficking in cells. Our system thus permits in-virus bioorthogonal labeling of proteins, compatible with studies of virus entry, trafficking, and egress from cells.


Assuntos
HIV-1 , Provírus , Humanos , Imagem Individual de Molécula , Proteínas/metabolismo , Peptídeos/metabolismo
4.
Am J Respir Cell Mol Biol ; 70(1): 50-62, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37607215

RESUMO

Progressive lung scarring because of persistent pleural organization often results in pleural fibrosis (PF). This process affects patients with complicated parapneumonic pleural effusions, empyema, and other pleural diseases prone to loculation. In PF, pleural mesothelial cells undergo mesomesenchymal transition (MesoMT) to become profibrotic, characterized by increased expression of α-smooth muscle actin and matrix proteins, including collagen-1. In our previous study, we showed that blocking PI3K/Akt signaling inhibits MesoMT induction in human pleural mesothelial cells (HPMCs) (1). However, the downstream signaling pathways leading to MesoMT induction remain obscure. Here, we investigated the role of mTOR complexes (mTORC1/2) in MesoMT induction. Our studies show that activation of the downstream mediator mTORC1/2 complex is, likewise, a critical component of MesoMT. Specific targeting of mTORC1/2 complex using pharmacological inhibitors such as INK128 and AZD8055 significantly inhibited transforming growth factor ß (TGF-ß)-induced MesoMT markers in HPMCs. We further identified the mTORC2/Rictor complex as the principal contributor to MesoMT progression induced by TGF-ß. Knockdown of Rictor, but not Raptor, attenuated TGF-ß-induced MesoMT in these cells. In these studies, we further show that concomitant activation of the SGK1/NDRG1 signaling cascade is essential for inducing MesoMT. Targeting SGK1 and NDRG1 with siRNA and small molecular inhibitors attenuated TGF-ß-induced MesoMT in HPMCs. Additionally, preclinical studies in our Streptococcus pneumoniae-mediated mouse model of PF showed that inhibition of mTORC1/2 with INK128 significantly attenuated the progression of PF in subacute and chronic injury. In conclusion, our studies demonstrate that mTORC2/Rictor-mediated activation of SGK1/NDRG1 is critical for MesoMT induction and that targeting this pathway could inhibit or even reverse the progression of MesoMT and PF.


Assuntos
Doenças Pleurais , Pleurisia , Animais , Camundongos , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina , Fatores de Transcrição , Fator de Crescimento Transformador beta/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina , Fibrose
5.
bioRxiv ; 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36909529

RESUMO

The HIV-1 envelope (Env) glycoprotein is conformationally dynamic and mediates membrane fusion required for cell entry. Single-molecule fluorescence resonance energy transfer (smFRET) of Env using peptide tags has provided mechanistic insights into the dynamics of Env conformations. Nevertheless, using peptide tags risks potential effects on structural integrity. Here, we aim to establish minimally invasive smFRET systems of Env on the virus by combining genetic code expansion and bioorthogonal click chemistry. Amber stop-codon suppression allows site-specifically incorporating noncanonical/unnatural amino acids (ncAAs) at introduced amber sites into proteins. However, ncAA incorporation into Env (or other HIV-1 proteins) in the virus context has been challenging due to low copies of Env on virions and incomplete amber suppression in mammalian cells. Here, we developed an intact amber-free virus system that overcomes impediments from preexisting ambers in HIV-1. Using this system, we successfully incorporated dual ncAAs at amber-introduced sites into Env on intact virions. Dual-ncAA incorporated Env retained similar neutralization sensitivities to neutralizing antibodies as wildtype. smFRET of click-labeled Env on intact amber-free virions recapitulated conformational profiles of Env. The amber-free HIV-1 infectious system also permits in-virus protein bioorthogonal labeling, compatible with various advanced microscopic studies of virus entry, trafficking, and egress in living cells. Amber-free HIV-1 infectious systems actualized minimal invasive Env tagging for smFRET, versatile for in-virus bioorthogonal click labeling in advanced microscopic studies of virus-host interactions.

6.
Int Immunopharmacol ; 107: 108644, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35259711

RESUMO

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by synovial hyperplasia, cartilage damage, and ultimate bone destruction. The signaling lymphocytic activation molecule family member 8 (SLAMF8) is a cell surface receptor expressed on various immune cells. This study aimed to investigate the role of SLAMF8 in the pathogenesis of RA. The SLAMF8 gene was identified as a differentially expressed gene in RA by analyzing the Gene Expression Omnibus database and synovial tissue samples collected from RA patients. Upregulation of SLAMF8 was associated with increased disease activity and inflammation in RA. Mice with collagen type II-induced arthritis (CIA) showed highly expressed SLAMF8, severe paw swelling, elevated inflammatory cytokine production, and excessive accumulation of immune cells. However, knockout of SLAMF8 alleviated collagen type II immunization-induced synovial hyperplasia and joint arthritis in mice. The in-vitro and in-vivo study showed that genetic deletion of SLAMF8 significantly inhibited upregulation of Toll-like receptor 4 (TLR4) and activation of the nuclear factor kappa B (NF-κB) pathway in fibroblast-like synoviocytes and bone marrow-derived macrophages derived from WT and SLAMF8 knockout mice under lipopolysaccharide stimulation. In conclusion, SLAMF8 was aberrantly expressed in RA patient and played an indispensable role in initiating inflammation and maintaining the pro-inflammatory environment in the inflamed joint. Targeted inhibition of SLAMF8 attenuated the severity of RA via blocking the TLR4/NF-κB signaling pathway. These data suggested that SLAMF8 may be a potential target for the treatment of RA.


Assuntos
Artrite Experimental , Artrite Reumatoide , Animais , Artrite Experimental/patologia , Artrite Reumatoide/metabolismo , Colágeno Tipo II , Humanos , Hiperplasia , Inflamação/metabolismo , Proteínas de Membrana , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo , Transdução de Sinais , Família de Moléculas de Sinalização da Ativação Linfocitária , Receptor 4 Toll-Like/genética
7.
J Ethnopharmacol ; 283: 114707, 2022 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-34619319

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Guizhi-Shaoyao-Zhimu decoction (GSZD), a classical traditional Chinese medicine (TCM) prescription, is used empirically to treat various types of arthritis in TCM clinical practice. However, the underlying mechanisms of GSZD on gouty inflammation are not totally elucidated. AIM OF STUDY: The purpose of this study is to investigate the effects of GSZD on peritoneal recruitment of neutrophils, production of proinflammatory mediators, activations of nuclear factor (NF)-κB and nucleotide oligomerization domain-like receptor protein-3 (NLRP3) inflammasome in mice with monosodium urate crystal (MSU)-induced peritonitis (MIP). MATERIALS AND METHODS: Mice were intragastrically administered with GSZD for 7 days. After the last administration, mice were intraperitoneally injected with MSU. Peritoneal exudates of mice were harvested, and total peritoneal cells were calculated. Levels of interleukin (IL)-1ß, IL-6 and monocyte chemotactic protein (MCP)-1 in peritoneal exudates were tested by enzyme-linked immunosorbent assay. Expressions of IL-1ß, NLRP3, cysteinyl aspartate specific proteinase (caspase)-1, apoptosis-associated speck-like protein containing the caspase activation and recruitment domain (ASC), phosphorylated (p)-p65, inhibitor of NF-κB (IκB)α, p-IκB kinase (IKK)ß, nuclear p65, p-mitogen-activated protein kinases (MAPKs) in peritoneal cells were analyzed by Western blot. Binding activity of NF-κB to DNA was measured by a Trans AM™ kit for p65. Interaction between ASC and pro-caspase-1 was assessed by co-immunoprecipitation assay. RESULTS: Total peritoneal cells, levels of IL-1ß, IL-6 and MCP-1 were significantly reduced by GSZD treatment in peritoneal exudates of MIP mice. As for the activation of NF-κB, GSZD treatment significantly reduced the levels of p-p65, p-IKKß, nuclear p65 and p-MAPKs, enhanced the level of IκBα and abated the binding ability of NF-κB to DNA in peritoneal cells of MIP mice. As for the activation of NLRP3 inflammasome, GSZD treatment significantly reduced the levels of IL-1ß, NLRP3 and caspase-1, and alleviated the interaction between ASC and pro-caspase-1 in peritoneal cells of MIP mice. Nevertheless, GSZD didn't remarkably change the level of ASC. CONCLUSIONS: These results suggest that GSZD attenuates the MSU-induced inflammation through inhibiting the activations of NF-κB and NLRP3 inflammasome.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Gota/tratamento farmacológico , Inflamação/tratamento farmacológico , Ácido Úrico/metabolismo , Animais , Caspase 1/metabolismo , Modelos Animais de Doenças , Inflamassomos/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Peritonite/tratamento farmacológico , Peritonite/patologia
8.
Ying Yong Sheng Tai Xue Bao ; 32(12): 4327-4338, 2021 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-34951274

RESUMO

To study the feasibility of simulating the spatial distribution of hydrogen and oxygen stable isotopes composition (δ2H and δ18O) in the surface soil based on the machine learning method and to investigate large-scale distribution of δ2H and δ18O in the upper reaches of Minjiang River, 183 soil samples were collected from the 0-10 cm soil layer. After variable selection, back propagation (BP) neural network, random forests (RF) and support vector machine (SVM) were used to model the δ2H and δ18O of the study area, with the accuracies being evaluated. The structural equation model (SEM) was used to reveal the mechanism between the auxiliary variables and the δ2H and δ18O of soil water. The results showed that the RF model had the highest prediction accuracy, and could explain 75.0% and 64.0% of the variations of δ2H and δ18O in the surface soil, respectively. In this model, soil water content was the most important auxiliary variable, contributing 48.9% and 37.4% to δ2H and δ18O. Vegetation factors had stronger influence on δ2H and δ18O in the surface soil than climate factors, and the influence of climate factors on δ2H and δ18O was media-ted by vegetation factors. Among all the auxiliary variables, hydrogen/oxygen isotope of precipitation had the lowest effect on δ2H and δ18O due to the fractionation. The δ2H and δ18O in the surface soil of the upper reaches of the Minjiang River changed significantly across different months during the growing season. The increases of δ2H and δ18O in the early growing season and the decreases in the late growing season were mainly affected by vegetation, while climate change led to a small fluctuation in the middle growing season.


Assuntos
Hidrogênio , Rios , Hidrogênio/análise , Isótopos de Oxigênio/análise , Solo
9.
Sci Rep ; 11(1): 21210, 2021 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-34707211

RESUMO

Pleural fibrosis (PF) is a chronic and progressive lung disease which affects approximately 30,000 people per year in the United States. Injury and sustained inflammation of the pleural space can result in PF, restricting lung expansion and impairing oxygen exchange. During the progression of pleural injury, normal pleural mesothelial cells (PMCs) undergo a transition, termed mesothelial mesenchymal transition (MesoMT). While multiple components of the fibrinolytic pathway have been investigated in pleural remodeling and PF, the role of the urokinase type plasminogen activator receptor (uPAR) is unknown. We found that uPAR is robustly expressed by pleural mesothelial cells in PF. Downregulation of uPAR by siRNA blocked TGF-ß mediated MesoMT. TGF-ß was also found to significantly induce uPA expression in PMCs undergoing MesoMT. Like uPAR, uPA downregulation blocked TGF-ß mediated MesoMT. Further, uPAR is critical for uPA mediated MesoMT. LRP1 downregulation likewise blunted TGF-ß mediated MesoMT. These findings are consistent with in vivo analyses, which showed that uPAR knockout mice were protected from S. pneumoniae-mediated decrements in lung function and restriction. Histological assessments of pleural fibrosis including pleural thickening and α-SMA expression were likewise reduced in uPAR knockout mice compared to WT mice. These studies strongly support the concept that uPAR targeting strategies could be beneficial for the treatment of PF.


Assuntos
Transição Epitelial-Mesenquimal , Pneumonia Bacteriana/metabolismo , Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Infecções Estreptocócicas/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Actinas/metabolismo , Animais , Células Cultivadas , Epitélio/metabolismo , Epitélio/patologia , Fibrose , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Pleura/metabolismo , Pleura/patologia , Pneumonia Bacteriana/patologia , Infecções Estreptocócicas/patologia , Ativador de Plasminogênio Tipo Uroquinase/genética
10.
J Ethnopharmacol ; 275: 114123, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33894285

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Simiao Wan (SMW) is a classical traditional Chinese medicine (TCM) prescription to empirically treat gouty arthritis (GA) in TCM clinical practice. However, the potential mechanisms of SMW on GA are not fully evaluated. AIM OF STUDY: The aim of this study is to investigate the role of macrophage polarization in the anti-GA activity of SMW. MATERIALS AND METHODS: Rats were intragastricly treated with SMW for consecutive 7 days. On day 6, monosodium urate (MSU) crystal-induced arthritis (MIA) in the ankle joint was prepared. Paw volume, gait score and histological score were measured. Levels of interleukin (IL)-1ß and IL-10 in serum were detected by enzyme-linked immunosorbent assay. Expressions of inducible nitric oxide synthase (iNOS), arginase (Arg)-1, phosphorylated (p)-p65, inhibitor of nuclear factor (NF)-κB (IκB)α, p-signal transducer and transcription activator (STAT)3 and p-Janus kinase (JAK)2 in synovial tissues were determined by Western blot. RESULTS: The elevated paw volume, gait score and histological score in MIA rats were significantly decreased by SMW treatment. Meanwhile, SMW significantly decreased the IL-1ß level and increased the IL-10 level in serum of MIA rats. Furthermore, SMW reduced the expressions of iNOS, p-p65 and enhanced the expressions of Arg-1, IκBα, p-STAT3 and p-JAK2 in synovial tissues of MIA rats. CONCLUSIONS: The results suggest that SMW attenuates the inflammation in MIA rats through promoting macrophage M2 polarization.


Assuntos
Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , Artrite Experimental/prevenção & controle , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Macrófagos/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Antirreumáticos/química , Arginase/metabolismo , Artrite Experimental/patologia , Medicamentos de Ervas Chinesas/química , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/patologia , Extremidades/patologia , Marcha/efeitos dos fármacos , Proteínas I-kappa B/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/patologia , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Janus Quinase 2/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Proteínas de Neoplasias/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Proteínas de Transporte Nucleocitoplasmático/metabolismo , Ratos Sprague-Dawley , Fator de Transcrição STAT3/metabolismo , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/metabolismo , Ácido Úrico/toxicidade
11.
Genomics Proteomics Bioinformatics ; 19(4): 534-548, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33713851

RESUMO

Transcriptional regulators (TRs) participate in essential processes in cancer pathogenesis and are critical therapeutic targets. Identification of drug response-related TRs from cell line-based compound screening data is often challenging due to low mRNA abundance of TRs, protein modifications, and other confounders (CFs). In this study, we developed a regression-based pharmacogenomic and ChIP-seq data integration method (RePhine) to infer the impact of TRs on drug response through integrative analyses of pharmacogenomic and ChIP-seq data. RePhine was evaluated in simulation and pharmacogenomic data and was applied to pan-cancer datasets with the goal of biological discovery. In simulation data with added noises or CFs and in pharmacogenomic data, RePhine demonstrated an improved performance in comparison with three commonly used methods (including Pearson correlation analysis, logistic regression model, and gene set enrichment analysis). Utilizing RePhine and Cancer Cell Line Encyclopedia data, we observed that RePhine-derived TR signatures could effectively cluster drugs with different mechanisms of action. RePhine predicted that loss-of-function of EZH2/PRC2 reduces cancer cell sensitivity toward the BRAF inhibitor PLX4720. Experimental validation confirmed that pharmacological EZH2 inhibition increases the resistance of cancer cells to PLX4720 treatment. Our results support that RePhine is a useful tool for inferring drug response-related TRs and for potential therapeutic applications. The source code for RePhine is freely available at https://github.com/coexps/RePhine.


Assuntos
Neoplasias , Fatores de Transcrição , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Farmacogenética , Processamento de Proteína Pós-Traducional , Software , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
12.
Am J Respir Cell Mol Biol ; 64(4): 492-503, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33513310

RESUMO

Pleural organization may occur after empyema or complicated parapneumonic effusion and can result in restrictive lung disease with pleural fibrosis (PF). Pleural mesothelial cells (PMCs) may contribute to PF through acquisition of a profibrotic phenotype, mesothelial-mesenchymal transition (MesoMT), which is characterized by increased expression of α-SMA (α-smooth muscle actin) and other myofibroblast markers. Although MesoMT has been implicated in the pathogenesis of PF, the role of the reactive oxygen species and the NOX (nicotinamide adenine dinucleotide phosphate oxidase) family in pleural remodeling remains unclear. Here, we show that NOX1 expression is enhanced in nonspecific human pleuritis and is induced in PMCs by THB (thrombin). 4-Hydroxy-2-nonenal, an indicator of reactive oxygen species damage, was likewise increased in our mouse model of pleural injury. NOX1 downregulation blocked THB- and Xa (factor Xa)-mediated MesoMT, as did pharmacologic inhibition of NOX1 with ML-171. NOX1 inhibition also reduced phosphorylation of Akt, p65, and tyrosine 216-GSK-3ß, signaling molecules previously shown to be implicated in MesoMT. Conversely, ML-171 did not reverse established MesoMT. NOX4 downregulation attenuated TGF-ß- and THB-mediated MesoMT. However, NOX1 downregulation did not affect NOX4 expression. NOX1- and NOX4-deficient mice were also protected in our mouse model of Streptococcus pneumoniae-mediated PF. These data show that NOX1 and NOX4 are critical determinants of MesoMT.


Assuntos
Transição Epitelial-Mesenquimal , NADPH Oxidase 1/metabolismo , Pleura/enzimologia , Pleurisia/enzimologia , Pneumonia Pneumocócica/enzimologia , Espécies Reativas de Oxigênio/metabolismo , Streptococcus pneumoniae/patogenicidade , Animais , Células Cultivadas , Modelos Animais de Doenças , Fator Xa/metabolismo , Fibrose , Interações Hospedeiro-Patógeno , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidase 1/deficiência , NADPH Oxidase 1/genética , NADPH Oxidase 4/genética , NADPH Oxidase 4/metabolismo , Pleura/microbiologia , Pleura/patologia , Pleurisia/microbiologia , Pleurisia/patologia , Pleurisia/fisiopatologia , Pneumonia Pneumocócica/microbiologia , Pneumonia Pneumocócica/patologia , Transdução de Sinais , Trombina/metabolismo
13.
Forensic Sci Int Genet ; 47: 102275, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32305739

RESUMO

Microhaplotypes (MH) are comprised of multiple single nucleotide polymorphisms (SNPs) that are located within 300 bases of genomic sequence. Improved tools are needed to facilitate broader application of microhaplotypes in a diverse range of populations and forensic settings. We designed an assay for multiplex sequencing of 90 microhaplotypes (mMHseq) that include 46 MH loci with high Effective Number of Alleles (Ae) from previous studies [1], and 44 high Ae MH loci containing between four to fourteen SNPs that were identified from the 1000 Genomes (1KG) Project. The unique design of mMHseq integrates a novel method for multiplex amplification from small DNA amounts, and multiplex sequencing of 48 samples in a single MiSeq run to detect all relevant MH variation. Assay performance was evaluated in a cohort of 156 individuals from seven different world populations from Africa, Asia, and Europe. Three of those populations from East Africa (Chagga, Sandawe, and Zaramo) and one from Eastern Europe (Adygei) had sufficient individuals sequenced by the assay to be included in statistical analyses with the 26 1KG populations. For those 30 populations the mean global average Ae was 5.08 (range: 2.7-11.54) and mean informativeness for biogeographic variation (In) was 0.30 (range: 0.08-0.70). Eighty-five novel SNPs were detected in 58 of the 90 microhaplotypes. Open-source, web-based software was developed to visualize haplotype phase data for each microhaplotype and individual. Our approach for multiplex microhaplotype sequencing can be customized and expanded as novel loci are being discovered.


Assuntos
Marcadores Genéticos , Haplótipos , Sequenciamento de Nucleotídeos em Larga Escala , Etnicidade/genética , Genética Forense/métodos , Genética Populacional , Humanos , Software
14.
Semin Arthritis Rheum ; 50(6): 1500-1506, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32115236

RESUMO

OBJECTIVE: Systemic autoinflammatory diseases (SAIDs) are a group of disorders characterized by a dysregulation of innate immune system leading to multi-systemic inflammation. We aim to assess the neurological manifestations of Chinese adult patients with SAIDs. METHODS: Eighty adult patients (≥16 years) were diagnosed as SAIDs from April 2015 to June 2019, at the center of adult autoinflammatory diseases, Department of Rheumatology, Peking Union Medical College Hospital. Clinical and genetic features of these patients were collected. All patients underwent neurologic, ophthalmologic and otolaryngologic evaluation. RESULTS: Totally 31 out of 80 (38.8%) patients had neurological manifestations, including 14 familial Mediterranean fever (45.2%), 6 NLRP3-associated autoinflammatory disease (19.4%), 5 tumor necrosis factor receptor-associated periodic fever syndrome (16.1%), 5 NLRP12-associated autoinflammatory disease (16.1%), and 1 Yao syndrome (3.2%). Twenty patients (64.5%) were adult-onset. The median time of diagnosis delay was 11.7 years (0.5-50 years). The common neurological damage included headache (28 patients, 90.3%), sensorineural hearing loss (6, 19.4%), dizziness (4, 12.9%), cerebral infarction/hemorrhage (4, 12.9%), chronic aseptic meningitis (3, 9.7%), intracranial hypertension (3, 9.7%), papilledema (3, 9.7%), optic neuritis (2, 6.5%), and hydrocephalus (1, 3.2%). Severe neurological damage was observed in 8 patients (25.8%), including brain atrophy, hydrocephalus, complete hearing loss, chronic aseptic meningitis and optic neuritis. CONCLUSION: Neurological damage was diverse in SAIDs patients. Neurological symptoms should be fully realized by physicians, in not only pediatric but also adult patients with SAIDs. CSF analysis and brain images should be performed promptly. Early diagnosis and appropriate treatment are essential to avoid irreversible neurological complications.


Assuntos
Febre Familiar do Mediterrâneo , Doenças do Sistema Nervoso , Adulto , Povo Asiático , Criança , China/epidemiologia , Febre , Humanos , Doenças do Sistema Nervoso/etiologia
15.
Biochem Biophys Res Commun ; 522(1): 21-25, 2020 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-31735335

RESUMO

PTPN2 is one of the members of the protein Tyrosine Phosphatases (PTPs) family. To explore the promotive effect of upregulated PTPN2 induced by inflammatory response or oxidative stress on the progression of thyroid cancer. PTPN2 level in thyroid cancer tissues and cell lines was detected. Kaplan-Meier method was applied for evaluating the prognostic value of PTPN2 in thyroid cancer patients. After stimulation of inflammatory response (treatment of IFN-γ and TNF-α), or oxidative stress (treatment of H2O2), protein level of PTPN2 in K1 cells was measured by Western blot. Regulatory effects of PTPN2 on EdU-positive staining and Ki-67 positive cell ratio in K1 cells either with H2O2 stimulation or not were determined. PTPN2 was upregulated in thyroid cancer tissues and cell lines. Its level was higher in metastatic thyroid cancer patients than those of non-metastatic ones. High level of PTPN2 predicted worse prognosis of thyroid cancer. Treatment of either IFN-γ or TNF-α upregulated protein level of PTPN2 in K1 cells. Meanwhile, H2O2 stimulation upregulated PTPN2, which was reversed by NAC administration. With the stimulation of increased doses of H2O2, EdU-positive staining and Ki-67 positive cell ratio were dose-dependently elevated. Silence of PTPN2 attenuated proliferative ability and Ki-67 expression in K1 cells either with H2O2 stimulation or not. Inflammatory response or oxidative stress induces upregulation of PTPN2, thus promoting the progression of thyroid cancer.


Assuntos
Regulação Neoplásica da Expressão Gênica , Inflamação/metabolismo , Estresse Oxidativo , Proteína Tirosina Fosfatase não Receptora Tipo 2/metabolismo , Neoplasias da Glândula Tireoide/enzimologia , Antioxidantes/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Inativação Gênica , Humanos , Peróxido de Hidrogênio/farmacologia , Estimativa de Kaplan-Meier , Antígeno Ki-67/metabolismo , Metástase Neoplásica , Proteína Tirosina Fosfatase não Receptora Tipo 2/genética , Neoplasias da Glândula Tireoide/patologia
16.
Sci Rep ; 9(1): 18925, 2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31831767

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with a median survival of 3 years after diagnosis. Although the etiology of IPF is unknown, it is characterized by extensive alveolar epithelial cell apoptosis and proliferation of myofibroblasts in the lungs. While the origins of these myofibroblast appear to be diverse, fibroblast differentiation contributes to expansion of myofibroblasts and to disease progression. We found that agents that contribute to neomatrix formation and remodeling in pulmonary fibrosis (PF); TGF-ß, Factor Xa, thrombin, plasmin and uPA all induced fibroblast/myofibroblast differentiation. These same mediators enhanced GSK-3ß activation via phosphorylation of tyrosine-216 (p-Y216). Inhibition of GSK-3ß signaling with the novel inhibitor 9-ING-41 blocked the induction of myofibroblast markers; α-SMA and Col-1 and reduced morphological changes of myofibroblast differentiation. In in vivo studies, the progression of TGF-ß and bleomycin mediated PF was significantly attenuated by 9-ING-41 administered at 7 and 14 days respectively after the establishment of injury. Specifically, 9-ING-41 treatment significantly improved lung function (compliance and lung volumes; p < 0.05) of TGF-ß adenovirus treated mice compared to controls. Similar results were found in mice with bleomycin-induced PF. These studies clearly show that activation of the GSK-3ß signaling pathway is critical for the induction of myofibroblast differentiation in lung fibroblasts ex vivo and pulmonary fibrosis in vivo. The results offer a strong premise supporting the continued investigation of the GSK-3ß signaling pathway in the control of fibroblast-myofibroblast differentiation and fibrosing lung injury. These data provide a strong rationale for extension of clinical trials of 9-ING-41 to patients with IPF.


Assuntos
Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Indóis/farmacologia , Pulmão/enzimologia , Maleimidas/farmacologia , Fibrose Pulmonar/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Pulmão/patologia , Pulmão/fisiopatologia , Camundongos , Fibrose Pulmonar/enzimologia , Fibrose Pulmonar/patologia , Fibrose Pulmonar/fisiopatologia
17.
Arch Med Sci ; 15(6): 1490-1497, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31749878

RESUMO

INTRODUCTION: Arteriosclerosis obliterans (ASO) is a disease that affects the lower extremities. The mechanism of ASO is associated with the proliferation and migration of vascular smooth muscle cells (VSMCs). miR-21 plays a key role in various biological processes of the cardiovascular system, associated with the proliferation, migration and apoptosis of VSMCs. It is unclear, however, if miR-21 is involved in the regulation of ASO. MATERIAL AND METHODS: Human aortic smooth muscle cells (HASMCs) were transfected with miR-21 mimics and co-treated with protein kinase B (AKT) or a mitogen-activated protein kinase (ERK) inhibitor. Expression levels of p-AKT or p-ERK were measured by western blot. Cell apoptosis was assessed using the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and visualized under a fluorescence microscope. Cell proliferation was monitored by bromodeoxyuridine (BrdU) labeling; cell migration and invasion were determined by the Transwell assay. RESULTS: miR-21 was upregulated in arteries of ASO, the pathogenesis of which involved the activation of p-AKT and p-ERK1/2. Inhibition of the AKT or ERK activity was consistent with the attenuation of the miR-21-induced HASMC migration and proliferation. HASMCs co-treated with miR-21 mimics and AKT or ERK inhibitor showed attenuation of the miR-21-induced high elongation ratio. CONCLUSIONS: We demonstrated that the expression of miR-21 in HASMCs could find potential application in cardiac therapy. Inhibition of the activity of AKT or ERK could attenuate miR-21-induced cell proliferation and migration as well as altering morphology of HASMCs. The present study aimed to indicate the potential roles of miR-21 in ASO processes, and the results provided a novel therapeutic approach for treating ASO and new targets for preventing ASO in earlier stages.

18.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(5): 598-602, 2019 May 30.
Artigo em Chinês | MEDLINE | ID: mdl-31140426

RESUMO

OBJECTIVE: To investigate the protective effect of quercetin against lipopolysaccharide (LPS)- induced acute kidney injury (AKI) in mice and explore its mechanism. METHODS: Forty male BALB/c mice were randomly divided into control group (with saline treatment), 15 mg/kg LPS group, and quercetin-treated groups with intragastric quercetin treatment (once daily for 3 consecutive days) at low (25 mg/kg) and high (50 mg/kg) dose prior to 15 mg/kg LPS injection. LPS was administered by intraperitoneally injection 1 after the last gavage of quercetin. The mice were sacrificed 24 h after LPS injection for analysis of kidney pathologies, blood urea nitrogen (BUN) and creatinine levels; serum levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and IL-6 were detected by ELISA, and the expressions of Toll-like receptor-4 (TLR4), MyD88, TRAF-6 and NF-κBp65 in the kidney were detected by Western blotting. RESULTS: Quercetin significantly lessened renal pathologies, lowered BUN and creatinine levels (P < 0.05) and inhibited TNF-α, IL-1ß, and IL-6 production in mice with LPS-induced AKI (P < 0.05). Pretreatment with quercetin also significantly inhibited TLR4, MyD88, and TRAF-6 expressions and NF-κBp65 activation in the kidneys of the rats with LPS challenge (P < 0.05). CONCLUSIONS: Quercetin pretreatment can protect mice against LPSinduced AKI by inhibiting TLR4/NF-κB signaling pathway.


Assuntos
Injúria Renal Aguda , Antioxidantes , Quercetina , Receptor 4 Toll-Like , Fator de Necrose Tumoral alfa , Animais , Antioxidantes/farmacologia , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B , Quercetina/farmacologia , Ratos , Receptor 4 Toll-Like/efeitos dos fármacos , Fator de Necrose Tumoral alfa/efeitos dos fármacos
19.
Front Genet ; 10: 293, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31031796

RESUMO

Motivation: Gene set enrichment analysis is a widely accepted expression analysis tool which aims at detecting coordinated expression change within a pre-defined gene sets rather than individual genes. The benefit of gene set analysis over individual differentially expressed (DE) gene analysis includes more reproducible and interpretable results and detecting small but consistent change among gene set which could not be detected by DE gene analysis. There have been many successful gene set analysis applications in human diseases. However, when the sample size of a disease study is small and no other public data sets of the same disease are available, it will lead to lack of power to detect pathways of importance to the disease. Results: We have developed a novel joint gene set analysis statistical framework which aims at improving the power of identifying enriched gene sets through integrating multiple similar disease data sets. Through comprehensive simulation studies, we demonstrated that our proposed frameworks obtained much better AUC scores than single data set analysis and another meta-analysis method in identification of enriched pathways. When applied to two real data sets, the proposed framework could retain the enriched gene sets identified by single data set analysis and exclusively obtained up to 200% more disease-related gene sets demonstrating the improved identification power through information shared between similar diseases. We expect that the proposed framework would enable researchers to better explore public data sets when the sample size of their study is limited.

20.
Cancer Gene Ther ; 26(7-8): 234-247, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30546117

RESUMO

Recently, long non-coding RNAs (lncRNAs) are considered as critical regulators in pathogenesis progression of cerebral ischemia. In present study, lncRNA-small nucleolar RNA host gene 14 (SNHG14) was found upregulated in middle cerebral artery occlusion/reperfusion (MCAO/R) treated brain tissues and oxygen-glucose deprivation and reoxygenation (OGD/R) treated PC-12 cells. Interference of SNHG14 by shRNA vector enhanced neuron survival and suppressed inflammation in response to OGD/R insult. SNHG14 positively regulated the expression of Rho-associated coiled-coil-containing protein kinase 1 (ROCK1) via acting as a sponge of microRNA (miR)-136-5p. SNHG14 promoted neurological impairment and inflammatory response through elevating the expression of ROCK1 while decreasing miR-136-5p level in OGD/R induced damage. Collectively, we illustrated that SNHG14 could be a novel strategy for treatment ischemia stoke.


Assuntos
Isquemia Encefálica/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Traumatismo por Reperfusão/genética , Quinases Associadas a rho/genética , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Masculino , Ratos , Ratos Sprague-Dawley , Transfecção
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