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1.
Life Sci ; 270: 119120, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33545204

RESUMO

BACKGROUND AND AIMS: C-X-C ligand 16 (CXCL16) is an exceptional chemokine that is expressed as transmembrane and soluble forms. Our aim is to shed lights on the role of CXCL16/ADAM10 (a disintegrin and metalloproteinase) in cisplatin (CP)-induced renal toxicity as well as possible protective effect of enoxaparin. MAIN METHODS: Male albino mice were injected with CP (30 mg/kg, i.p.) in the presence or absence of enoxaparin (ENOX) (5 mg/kg, i.p.). Renal toxicity markers, serum level of cystatin-c, complete blood count (CBC), prothrombin time (Pt) and tissue expression of CXCL16, ADAM10, cluster of differentiation 3 (CD3), fibrinogen, tissue factor (TF), nuclear factor-κB (NF-κB) and tumour necrosis factor α (TNF-α) were measured. Besides, serum CXCL16 and histopathology were also analyzed. KEY FINDINGS: CP increased renal toxicity markers, renal expression of CXCL16/ADAM10, fibrinogen, TF and CD3 tissue expression in a time-dependent manner, and elevated serum cystatin-c, CXCL16 and tissue TNF-α, NF-κB. Alternatively, ENOX restored the deteriorated parameters and reduced tissue level of NF-κB. SIGNIFICANCE: This report, for the first time, showed that soluble CXCL16 resulting from ADAM10 cleavage may recruit T-cells to the renal glomeruli and tubules in CP toxicity. Furthermore, TF and fibrin, have similar expression and location pattern like CXCL16 and ADAM10 suggesting their possible interrelation. ENOX successfully restored the deteriorated parameters suggesting it may be an effective nephroprotective adjuvant therapy.


Assuntos
Quimiocina CXCL16/metabolismo , Enoxaparina/farmacologia , Proteínas ADAM/metabolismo , Proteína ADAM10/efeitos dos fármacos , Proteína ADAM10/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Linhagem Celular Tumoral , Quimiocina CXCL16/efeitos dos fármacos , Quimiocinas CXC/metabolismo , Cisplatino/efeitos adversos , Cisplatino/farmacologia , Enoxaparina/metabolismo , Rim/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos , NF-kappa B/metabolismo , Linfócitos T/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
2.
J Biol Regul Homeost Agents ; 35(1): 151-160, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33543608

RESUMO

Osteosarcoma (OS) is the most frequent primary malignancy in bone, and commonly occurs in children and adolescents. The aim of this study was to assess the aberrant expression of miR-1274a in OS patients, and to evaluate the role of miR-1274a as a prognostic biomarker and tumor suppressor in OS progression. miR-1274a expression was estimated using quantitative real-time polymerase chain reaction. The Kaplan-Meier method and Cox regression analysis were used to evaluate the prognostic value of miR-1274a in OS. Gain- and loss-of-function in vitro experiments were used to explore the functional role of miR-1274a in OS progression. A target gene of miR-1274a was analyzed using a dual-luciferase reporter assay. miR-1274a expression was decreased in OS tissues and associated with distant metastasis and clinical stages in OS patients. Low miR-1274a could predict poor overall survival and disease-free survival in OS. The overexpression of miR-1274a could inhibit OS cell proliferation, migration and invasion. Additionally, ADAM9 was demonstrated to serve as a direct target of miR-1274a in OS cells. In conclusion, reduced miR-1274a predicts poor prognosis and serves as a potential tumor suppressor in OS. ADAM9 is a target of miR-1274a, which may mediate the functional role of miR-1274a in OS progression.


Assuntos
Neoplasias Ósseas , MicroRNAs/genética , Osteossarcoma , Proteínas ADAM , Biomarcadores , Neoplasias Ósseas/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas de Membrana , Invasividade Neoplásica/genética , Osteossarcoma/genética , Prognóstico
3.
Zhonghua Yi Xue Za Zhi ; 100(48): 3874-3878, 2020 Dec 29.
Artigo em Chinês | MEDLINE | ID: mdl-33371634

RESUMO

Objective: To find the possible targets for the study and treatment of triple-negative breast cancer (TNBC), and to analyze and predict the key genes affecting the prognosis of TNBC by bioinformatics. Methods: Raw data on transcriptome sequencing of clinical specimens from patients with TNBC were searched by searching GEO Datasets in the National Center for Biotechnology Information (NCBI) database. The differential gene was then submitted to the Enrichr website for pathway enrichment. Survival analysis was used to finally identify the most significant differences in the prognosis of patients with TNBC. Results: Only ADAM9 gene showed a significant correlation with the poor prognosis of patients with TNBC (P<0.05), and ADAM9 only showed specificity associated with prognosis in patients with TNBC, and was not with other breast cancer types. Conclusion: ADAM9 gene has been proved to be related to the poor prognosis in patients with TNBC. Therefore, ADAM9 gene can be regarded as a possible key gene leading to lymph node metastasis and poor prognosis in patients with TNBC.


Assuntos
Neoplasias de Mama Triplo Negativas , Proteínas ADAM , Biologia Computacional , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Proteínas de Membrana , Prognóstico , Neoplasias de Mama Triplo Negativas/genética
4.
Medicine (Baltimore) ; 99(45): e23051, 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33157959

RESUMO

BACKGROUND: During the last decade, a number of studies have evaluated the potential association between some genetic polymorphisms and childhood asthma risk, however, the results of published studies appear conflicts. The aim of the present study was to investigate association between genetic polymorphisms and pediatric asthma. METHODS: Relevant studies were searched in PubMed, Embase, Web of Science, CNKI (China National Knowledge Infrastructure), Wanfang, and Weipu database. Pooled odds ratios (OR) with 95% confidence interval (CI) were calculated to evaluate the strength of the associations. RESULTS: Fifty five case-control studies were finally included in this meta-analysis, including 17,971 pediatric asthma cases and 17,500 controls. Eighteen polymorphisms were identified, of which, 9 polymorphisms were found to be associated with asthma risk in overall populations: IL-13 +2044G/A, IL-4 -590C/T, ADAM33 F+1, ADAM33 T2, ADAM33 T1, ADAM33 ST+4,ORMDL3 rs7216389, VDR FokI, VDR TaqI. Furthermore, IL-13 +2044G/A, IL-4 -590C/T, ADAM33 T2, ADAM33 T1, VDR BsmI polymorphisms may cause an increased risk of asthma among Chinese children. CONCLUSIONS: This meta-analysis found that IL-13 +2044G/A, IL-4 -590C/T, ADAM33 F+1, ADAM33 T2, ADAM33 T1, ADAM33 ST+4,ORMDL3 rs7216389, VDR FokI, and VDR TaqI polymorphisms might be risk factors for childhood asthma. Further study with large population and more ethnicities is needed to estimate these associations.


Assuntos
Proteínas ADAM/genética , Asma/genética , Interleucina-13/genética , Adolescente , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Gerenciamento de Dados , Feminino , Humanos , Lactente , Masculino , Polimorfismo Genético/genética , Fatores de Risco
5.
Arterioscler Thromb Vasc Biol ; 40(8): 1918-1934, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32522006

RESUMO

OBJECTIVE: ADAM (a disintegrin and metalloproteinase) 15-a membrane-bound metalloprotease from the ADAM (disintegrin and metalloproteinase) family-has been linked to endothelial permeability, inflammation, and metastasis. However, its function in aortic aneurysm has not been explored. We aimed to determine the function of ADAM15 in the pathogenesis of aortic remodeling and aneurysm formation. Approach and Results: Male Adam15-deficient and WT (wild type) mice (10 weeks old), on standard laboratory diet, received Ang II (angiotensin II; 1.5 mg/kg per day) or saline (Alzet pump) for 2 or 4 weeks. Ang II increased ADAM15 in WT aorta, while Adam15-deficiency resulted in abdominal aortic aneurysm characterized by loss of medial smooth muscle cells (SMCs), elastin fragmentation, inflammation, but unaltered Ang II-mediated hypertension. In the abdominal aortic tissue and primary aortic SMCs culture, Adam15 deficiency decreased SMC proliferation, increased apoptosis, and reduced contractile properties along with F-actin depolymerization to G-actin. Ang II triggered a markedly greater increase in THBS (thrombospondin) 1 in Adam15-deficient aorta, primarily the medial layer in vivo, and in aortic SMC in vitro; increased SSH1 (slingshot homolog 1) phosphatase activity and cofilin dephosphorylation that promoted F-actin depolymerization and G-actin accumulation. rhTHBS1 (recombinant THBS1) alone was sufficient to activate the cofilin pathway, increase G-actin, and induce apoptosis of aortic SMCs, confirming the key role of THBS1 in this process. Further, in human abdominal aortic aneurysm specimens, decreased ADAM15 was associated with increased THBS1 levels and loss of medial SMCs. CONCLUSIONS: This study is the first to demonstrate a key role for ADAM15 in abdominal aortic aneurysm through regulating the SMC function, thereby placing ADAM15 in a critical position as a potential therapeutic target for abdominal aortic aneurysm.


Assuntos
Proteínas ADAM/fisiologia , Angiotensina II/farmacologia , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/etiologia , Proteínas de Membrana/fisiologia , Remodelação Vascular/efeitos dos fármacos , Proteínas ADAM/deficiência , Animais , Proliferação de Células , Células Cultivadas , Humanos , Inflamação/etiologia , Masculino , Proteínas de Membrana/deficiência , Camundongos , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/fisiologia , Trombospondina 1/análise , Vasoconstrição
6.
Science ; 368(6495): 1132-1135, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32499443

RESUMO

The lumicrine system is a postulated signaling system in which testis-derived (upstream) secreted factors enter the male reproductive tract to regulate epididymal (downstream) pathways required for sperm maturation. Until now, no lumicrine factors have been identified. We demonstrate that a testicular germ-cell-secreted epidermal growth factor-like protein, neural epidermal growth factor-like-like 2 (NELL2), specifically binds to an orphan receptor tyrosine kinase, c-ros oncogene 1 (ROS1), and mediates the differentiation of the initial segment (IS) of the caput epididymis. Male mice in which Nell2 had been knocked out were infertile. The IS-specific secreted proteases, ovochymase 2 (OVCH2) and A disintegrin and metallopeptidase 28 (ADAM28), were expressed upon IS maturation, and OVCH2 was required for processing of the sperm surface protein ADAM3, which is required for sperm fertilizing ability. This work identifies a lumicrine system essential for testis-epididymis-spermatozoa (NELL2-ROS1-OVCH2-ADAM3) signaling and male fertility.


Assuntos
Comunicação Celular/fisiologia , Endopeptidases/metabolismo , Epididimo/metabolismo , Fertilidade , Infertilidade Masculina/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Espermatozoides/metabolismo , Testículo/metabolismo , Proteínas ADAM/metabolismo , Animais , Comunicação Celular/genética , Endopeptidases/genética , Infertilidade Masculina/genética , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo
7.
Zhonghua Xue Ye Xue Za Zhi ; 41(3): 216-221, 2020 Mar 14.
Artigo em Chinês | MEDLINE | ID: mdl-32311891

RESUMO

Objective: To analyze the clinical characteristics, treatment and prognosis of patients with thrombotic thrombocytopenic purpura (TTP) . Methods: 83 patients with TTP from May 1998 to May 2019 were analyzed retrospectively. Results: Among the 83 patients, there were 27 males and 56 females, with a median age of 39 (10-68) years. 41 cases (49.4%) showed pentalogy syndrome and 79 cases (95.2%) showed triad syndrome. 78.0% (46/59) of the patients had a PLASMIC score of 6 or higher. TTP gene mutations was detected in 5 of 10 patients. The activity of von Willebrand factor-cleaving protease (ADAMTS13) , which was detected in 10 patients before plasma exchange (PEX) , was less than 10% in 9 patients. 83 patients were treated with PEX/plasma infusion and glucocorticoid, 35 of which were treated combined with rituximab and/or immunosuppressant. The median follow-up was 34 (1-167) months, the effective rate was 81.9%, the remission rate was 63.9%, the relapse rate was (35.7 ±7.1) %, and the 3-year overall survival (OS) rate was (78.6 ±4.6) %. The effective rate (72.9%vs 94.3%, P=0.019) and OS rate[ (63.8±7.5) %vs (94.3±3.9) %, χ(2)=8.450, P=0.004] in the group treated with PEX/PI and glucocorticoid alone were lower than those in the group treated combined with rituximab and/or immunosuppressant. COX multivariate analysis showed that age (HR=1.111, 95%CI 1.044-1.184, P=0.001) and alanine transaminase (ALT) /aspartate aminotransferase (AST) (HR=1.353, 95%CI 1.072-1.708, P=0.011) were independent risk factors for OS. Conclusion: Most patients with TTP have triad syndrome, accompanied by a decrease in ADAMTS13 activity. Plasma infusion and glucocorticoid combined with rituximab, immunosuppressive therapy could improve overall survival. The prognosis of patients with older age and high ALT/AST ratio is poor.


Assuntos
Púrpura Trombocitopênica Trombótica , Proteínas ADAM , Proteína ADAMTS13 , Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Troca Plasmática , Estudos Retrospectivos , Rituximab , Adulto Jovem
8.
Int J Mol Sci ; 21(8)2020 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-32290531

RESUMO

Zinc-dependent matrix metalloproteinases (MMPs) belong to metzincins that comprise not only 23 human MMPs but also other metalloproteinases, such as 21 human ADAMs (a disintegrin and metalloproteinase domain) and 19 secreted ADAMTSs (a disintegrin and metalloproteinase thrombospondin domain). The many setbacks from the clinical trials of broad-spectrum MMP inhibitors for cancer indications in the late 1990s emphasized the extreme complexity of the participation of these proteolytic enzymes in biology. This editorial mini-review summarizes the Special Issue, which includes four review articles and 10 original articles that highlight the versatile roles of MMPs, ADAMs, and ADAMTSs, in normal physiology as well as in neoplastic and destructive processes in tissue. In addition, we briefly discuss the unambiguous involvement of MMPs in wound healing.


Assuntos
Metaloproteinases da Matriz/metabolismo , Proteínas ADAM/metabolismo , Animais , Humanos , Inibidores de Metaloproteinases de Matriz/farmacologia , Inibidores de Metaloproteinases de Matriz/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Domínios Proteicos , Trombospondinas/metabolismo
9.
J Hum Genet ; 65(8): 657-665, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32277175

RESUMO

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness among the elderly population. To accelerate the understanding of the genetics of AMD, we conducted a meta-analysis of genome-wide association studies (GWAS) combining data from the International AMD Genomics Consortium AMD-2016 GWAS (16,144 advanced AMD cases and 17,832 controls), AMD-2013 GWAS (17,181 cases and 60,074 controls), and new data on 4017 AMD cases and 14,984 controls from Genetic Epidemiology Research on Aging study. We identified 12 novel AMD loci near or within C4BPA-CD55, ZNF385B, ZBTB38, NFKB1, LINC00461, ADAM19, CPN1, ACSL5, CSK, RLBP1, CLUL1, and LBP. We then replicated the associations of the novel loci in independent cohorts, UK Biobank (5860 cases and 126,726 controls) and FinnGen (1266 cases and 47,560 control). In general, the concordance in effect sizes was very high (correlation in effect size estimates 0.89), 11 of 12 novel loci were in the expected direction, 5 were associated with AMD at a nominal significance level, and rs3825991 (near gene RLBP1) after Bonferroni correction. We identified an additional 21 novel genes using a gene-based test. Most of the novel genes are expressed in retinal tissue and could be involved in the pathogenesis of AMD (i.e., complement, inflammation, and lipid pathways). These findings enhance our understanding of the genetic architecture of AMD and shed light on the biological process underlying AMD pathogenesis.


Assuntos
Degeneração Macular/genética , Proteínas ADAM/genética , Proteínas da Fase Aguda/genética , Antígenos CD55/genética , Proteínas de Transporte/genética , Coenzima A Ligases/genética , Proteína de Ligação ao Complemento C4b/genética , Bases de Dados Genéticas , Proteínas do Olho/genética , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Glicoproteínas de Membrana/genética , Subunidade p50 de NF-kappa B/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Proteínas Repressoras/genética , Retina/metabolismo , Retina/patologia
10.
Life Sci ; 253: 117659, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32283055

RESUMO

Abdominal aortic aneurysm (AAA) is a chronic vascular degenerative disease featured by progressive dilation and remodeling of the vascular wall, which may lead to aortic rupture and high mortality. The occurrence and development of AAA involve multiple mechanisms, including extracellular matrix degradation, chronic inflammation, oxidative stress, apoptosis of vascular smooth muscle cells and innate immunity. Extracellular matrix degradation is considered as the most important mechanism causing AAA. Matrix metalloproteinases (MMPs) are key factors in this process, contributing greatly to the occurrence and development of AAA. But whether the zinc-dependent endopeptidases (ADAM/ADAMTS) are involved in this process is very little known. This study is a review about the role of MMPs and ADAM/ADAMT as well as the existing MMP inhibitors in abdominal aortic aneurysm, with the purpose of providing reference for the clinical treatment of abdominal aortic aneurysm.


Assuntos
Proteínas ADAM/metabolismo , Aneurisma da Aorta Abdominal/tratamento farmacológico , Inibidores de Metaloproteinases de Matriz/farmacologia , Metaloproteinases da Matriz/metabolismo , Animais , Endopeptidases/metabolismo , Humanos , Miócitos de Músculo Liso/citologia , Proteólise , Transdução de Sinais
11.
Sci Rep ; 10(1): 4930, 2020 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-32188902

RESUMO

GPNMB is involved in multiple cellular functions including cell adhesion, stress protection and stem cell maintenance. In skin, melanocyte-GPNMB is suggested to mediate pigmentation through melanosome formation, but details of keratinocyte-GPNMB have yet to be well understood. We confirmed the expression of GPNMB in normal human epidermal keratinocytes (NHEKs) by reducing the expression using siRNA. A higher calcium concentration of over 1.25 mM decreased the GPNMB expression. Histological staining showed that GPNMB was expressed in the basal layer of normal skins but completely absent in vitiligo skins. The normal expression of GPNMB in nevus depigmentosus skin suggested that lack of GPNMB is characteristic of vitiligo lesional skins. IFN-γ and IL-17A, two cytokines with possible causal roles in vitiligo development, inhibited GPNMB expression in vitro. Approximately 4-8% of the total GPNMB expressed on NHEKs were released possibly by ADAM 10 as a soluble form, but the process of release was not affected by the cytokines. The suppressive effect of IFN-γ on GPNMB was partially via IFN-γ/JAK2/STAT1 signaling axis. Decreased GPNMB expression in keratinocytes may affect melanocyte maintenance or survival against oxidative stress although further studies are needed. These findings indicate a new target for vitiligo treatment, focusing on the novel role of IFN-γ and IL-17 in downregulating keratinocyte-GPNMB.


Assuntos
Regulação da Expressão Gênica , Queratinócitos/metabolismo , Glicoproteínas de Membrana/genética , Vitiligo/genética , Proteínas ADAM/antagonistas & inibidores , Proteínas ADAM/metabolismo , Cálcio/metabolismo , Adesão Celular , Citocinas/metabolismo , Epiderme/metabolismo , Epiderme/patologia , Humanos , Janus Quinase 2/metabolismo , Glicoproteínas de Membrana/metabolismo , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais , Vitiligo/metabolismo , Vitiligo/patologia
12.
PLoS One ; 15(3): e0229241, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32119686

RESUMO

While genome-wide association studies have identified genes involved in differential treatment responses to inhaled corticosteroids (ICS) in asthma, few studies have evaluated the potential effects of age in this context. A significant proportion of asthmatics experience exacerbations (hospitalizations and emergency department visits) during ICS treatment. We evaluated the interaction of genetic variation and age on ICS response (measured by the occurrence of exacerbations) through a genome-wide interaction study (GWIS) of 1,321 adult and child asthmatic patients of European ancestry. We identified 107 genome-wide suggestive (P<10-05) age-by-genotype interactions, two of which also met genome-wide significance (P<5x10-08) (rs34631960 [OR 2.3±1.6-3.3] in thrombospondin type 1 domain-containing protein 4 (THSD4) and rs2328386 [OR 0.5±0.3-0.7] in human immunodeficiency virus type I enhancer binding protein 2 (HIVEP2)) by joint analysis of GWIS results from discovery and replication populations. In addition to THSD4 and HIVEP2, age-by-genotype interactions also prioritized genes previously identified as asthma candidate genes, including DPP10, HDAC9, TBXAS1, FBXL7, and GSDMB/ORMDL3, as pharmacogenomic loci as well. This study is the first to link these genes to a pharmacogenetic trait for asthma.


Assuntos
Corticosteroides/administração & dosagem , Antiasmáticos/administração & dosagem , Asma/tratamento farmacológico , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Proteínas ADAM/genética , Administração por Inalação , Adolescente , Corticosteroides/uso terapêutico , Adulto , Fatores Etários , Idoso , Antiasmáticos/uso terapêutico , Asma/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Proteínas de Ligação a DNA/genética , Serviço Hospitalar de Emergência , Feminino , Estudo de Associação Genômica Ampla , Histona Desacetilases/genética , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Repressoras/genética , Fatores de Transcrição/genética , Resultado do Tratamento , Adulto Jovem
13.
Arterioscler Thromb Vasc Biol ; 40(5): 1195-1206, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32212853

RESUMO

OBJECTIVE: MicroRNA-126-3p (miR-126) is required for angiogenesis during organismal development or the repair of injured arterial vasculature. The role of miR-126 in lung microvascular endothelial cells, which are essential for gas exchange and for lung injury repair and regeneration, remains poorly understood. Considering the significant heterogeneity of endothelial cells from different vascular beds, we aimed to determine the role of miR-126 in regulating lung microvascular endothelial cell function and to elucidate its downstream signaling pathways. Approach and Results: Overexpression and knockdown of miR-126 in primary human lung microvascular endothelial cells (HLMVEC) were achieved via transfections of miR-126 mimics and antisense inhibitors. Increasing miR-126 levels in HLMVEC reduced cell proliferation, weakened tube formation, and increased cell apoptosis, whereas decreased miR-126 levels stimulated cell proliferation and tube formation. Whole-genome RNA sequencing revealed that miR-126 was associated with an antiangiogenic and proapoptotic transcriptomic profile. Using validation assays and knockdown approaches, we identified that the effect of miR-126 on HLMVEC angiogenesis was mediated by the LAT1 (L-type amino acid transporter 1), via regulation of mTOR (mammalian target of rapamycin) signaling. Furthermore, downregulation of miR-126 in HLMVEC inhibited cell apoptosis and improved endothelial tube formation during exposure to environmental insults such as cigarette smoke. CONCLUSIONS: miR-126 inhibits HLMVEC angiogenic function by targeting the LAT1-mTOR signaling axis, suggesting that miR-126 inhibition may be useful for conditions associated with microvascular loss, whereas miR-126 augmentation may help control unwanted microvascular angiogenesis.


Assuntos
Células Endoteliais/metabolismo , Transportador 1 de Aminoácidos Neutros Grandes/metabolismo , Pulmão/irrigação sanguínea , MicroRNAs/metabolismo , Microvasos/metabolismo , Neovascularização Fisiológica , Proteínas ADAM/genética , Proteínas ADAM/metabolismo , Apoptose , Movimento Celular , Proliferação de Células , Células Cultivadas , Regulação da Expressão Gênica , Humanos , Transportador 1 de Aminoácidos Neutros Grandes/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , MicroRNAs/genética , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
14.
Pharmacol Rep ; 72(2): 418-426, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32048249

RESUMO

BACKGROUND: Anesthesia is a major component of surgery and recently considered an important regulator of cell phenotypes. Here we aimed to investigate propofol, an anesthesia drug, in suppressing pancreatic cancer (PDAC), focusing on A disintegrin and metalloprotease 8, (ADAM8) as a molecular mediator. METHODS: Quantitative real-time PCR and western blot were used to assess the change of ADAM8 expression in Panc1 PDAC cells treated with 5 or 10 µg/mL propofol, using cells treated with BB-94 inhibitor as controls. ADAM8 activity was measured through quantifying fluorescence release induced by PEPDAB013 decomposition. MTT assay, scratch wound assay and Matrigel invasion assay were used to investigate the proliferation, migration and invasion of the cells. Western blot and immunohistochemical analysis were used to quantify integrin ß1, ERK1/2, MMP2 and MMP9 expression. RESULTS: Propofol and BB-94 reduced ADAM8 expression, cell proliferation and migration of Panc1 cells. Tumor growth was inhibited by propofol and BB-94, concomitant with downregulation of integrin ß1, ERK1/2, MMP2 and MMP9. ADAM8 is downregulated by propofol, leading to inhibition of pancreatic cancer proliferation and migration. CONCLUSION: Pancreatic tumor growth is also inhibited by propofol and BB-94, which is attributed to suppression of ERK/MMPs signaling.


Assuntos
Proteínas ADAM/metabolismo , Antineoplásicos/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Neoplasias Pancreáticas/patologia , Propofol/farmacologia , Proteínas ADAM/genética , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Proteínas de Membrana/genética , Camundongos SCID , Invasividade Neoplásica , Metástase Neoplásica , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Propofol/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
15.
PLoS One ; 15(1): e0227279, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31999703

RESUMO

Fibrous dysplasia (FD) of bone is a complex disease of the skeleton caused by dominant activating mutations of the GNAS locus encoding for the α subunit of the G protein-coupled receptor complex (Gsα). The mutation involves a substitution of arginine at position 201 by histidine or cysteine (GsαR201H or R201C), which leads to overproduction of cAMP. Several signaling pathways are implicated downstream of excess cAMP in the manifestation of disease. However, the pathogenesis of FD remains largely unknown. The overall FD phenotype can be attributed to alterations of skeletal stem/progenitor cells which normally develop into osteogenic or adipogenic cells (in cis), and are also known to provide support to angiogenesis, hematopoiesis, and osteoclastogenesis (in trans). In order to dissect the molecular pathways rooted in skeletal stem/progenitor cells by FD mutations, we engineered human skeletal stem/progenitor cells with the GsαR201C mutation and performed transcriptomic analysis. Our data suggest that this FD mutation profoundly alters the properties of skeletal stem/progenitor cells by pushing them towards formation of disorganized bone with a concomitant alteration of adipogenic differentiation. In addition, the mutation creates an altered in trans environment that induces neovascularization, cytokine/chemokine changes and osteoclastogenesis. In silico comparison of our data with the signature of FD craniofacial samples highlighted common traits, such as the upregulation of ADAM (A Disintegrin and Metalloprotease) proteins and other matrix-related factors, and of PDE7B (Phosphodiesterase 7B), which can be considered as a buffering process, activated to compensate for excess cAMP. We also observed high levels of CEBPs (CCAAT-Enhancer Binding Proteins) in both data sets, factors related to browning of white fat. This is the first analysis of the reaction of human skeletal stem/progenitor cells to the introduction of the FD mutation and we believe it provides a useful background for further studies on the molecular basis of the disease and for the identification of novel potential therapeutic targets.


Assuntos
Células da Medula Óssea/fisiologia , Diferenciação Celular/genética , Cromograninas/genética , Displasia Fibrosa Óssea/patologia , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Células-Tronco/fisiologia , Proteínas ADAM/metabolismo , Adipogenia/genética , Tecido Adiposo Branco/metabolismo , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Células Cultivadas , Cromograninas/metabolismo , Simulação por Computador , Nucleotídeo Cíclico Fosfodiesterase do Tipo 7/metabolismo , Conjuntos de Dados como Assunto , Displasia Fibrosa Óssea/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Mutação com Ganho de Função , Perfilação da Expressão Gênica , Voluntários Saudáveis , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Osteoblastos/metabolismo , Osteogênese/genética , Cultura Primária de Células , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Células Estromais/fisiologia , Regulação para Cima
16.
Med Sci Monit ; 26: e920211, 2020 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-31927559

RESUMO

BACKGROUND The aim of this study was to investigate the mechanisms underlying the potential effects of hydrogen-rich water (HW) on articular cartilage in a rat osteoarthritis (OA) model. MATERIAL AND METHODS A rat model of OA was established using the modified Hulth method, and rats were forced to exercise for 30 min every day 1 week after surgery for 7 weeks. Mankin's method was used to score the severity of OA. The animals were assigned into the OA group, OA+HW group, and sham operation group. After 8 weeks, the animals in the OA group had a Mankin score >8 points, and HW was administered into the knee joint. After 2 weeks of treatment, articular cartilage was obtained for pathological examination, consisting of hematoxylin and eosin, toluidine blue, and Hoechst staining, as well as quantitative real-time PCR and Western blot analyses. This combination of pharmacological and molecular biological analyses was performed to examine the mechanism underlying the protective effect of HW on articular cartilage. RESULTS The antioxidant effects of HW suppressed oxidative damage, which may have aided the inhibition of ECM-degrading enzymes (MMP3, MMP13, ADAMT4, and ADAMT5), the upregulation of Col II and aggrecan expression, and the downregulation of COX-2, iNOS, and NO expression. The results of HE staining indicated intra-articular treatment of HW attenuated cartilage degradation. However, Hoechst staining in the OA group indicated the nuclei of the fragmented chondrocytes were condensed compared to the sham operation group, and this effect was inhibited by HW. CONCLUSIONS HW showed a protective effect against the progression of OA in an animal model, which may have been mediated by its anti-oxidant and anti-apoptotic activities.


Assuntos
Apoptose/efeitos dos fármacos , Cartilagem Articular/patologia , Matriz Extracelular/metabolismo , Hidrogênio/uso terapêutico , Osteoartrite/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Água/farmacologia , Proteínas ADAM/metabolismo , Agrecanas/metabolismo , Animais , Cartilagem Articular/efeitos dos fármacos , Caspase 3/metabolismo , Colágeno Tipo II/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Metaloproteinases da Matriz/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Osteoartrite/patologia , Substâncias Protetoras/farmacologia , Ratos Sprague-Dawley , Proteína X Associada a bcl-2/metabolismo
17.
Ann Neurol ; 87(3): 405-418, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31900946

RESUMO

OBJECTIVE: Leucine-rich glioma-inactivated 1 (LGI1) encephalitis is the second most common antibody-mediated encephalopathy, but insight into the intrathecal B-cell autoimmune response, including clonal relationships, isotype distribution, frequency, and pathogenic effects of single LGI1 antibodies, has remained limited. METHODS: We cloned, expressed, and tested antibodies from 90 antibody-secreting cells (ASCs) and B cells from the cerebrospinal fluid (CSF) of several patients with LGI1 encephalitis. RESULTS: Eighty-four percent of the ASCs and 21% of the memory B cells encoded LGI1-reactive antibodies, whereas reactivities to other brain epitopes were rare. All LGI1 antibodies were of IgG1, IgG2, or IgG4 isotype and had undergone affinity maturation. Seven of the overall 26 LGI1 antibodies efficiently blocked the interaction of LGI1 with its receptor ADAM22 in vitro, and their mean LGI1 signal on mouse brain sections was weak compared to the remaining, non-ADAM22-competing antibodies. Nevertheless, both types of LGI1 antibodies increased the intrinsic cellular excitability and glutamatergic synaptic transmission of hippocampal CA3 neurons in slice cultures. INTERPRETATION: Our data show that the patients' intrathecal B-cell autoimmune response is dominated by LGI1 antibodies and that LGI1 antibodies alone are sufficient to promote neuronal excitability, a basis of seizure generation. Fundamental differences in target specificity and antibody hypermutations compared to the CSF autoantibody repertoire in N-methyl-D-aspartate receptor encephalitis underline the clinical concept that autoimmune encephalitides are very distinct entities. Ann Neurol 2020;87:405-418.


Assuntos
Anticorpos Monoclonais/farmacologia , Autoanticorpos/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Neurônios/fisiologia , Proteínas ADAM/efeitos dos fármacos , Idoso , Animais , Anticorpos Monoclonais/líquido cefalorraquidiano , Autoanticorpos/líquido cefalorraquidiano , Região CA3 Hipocampal/fisiologia , Células Cultivadas , Encefalite/líquido cefalorraquidiano , Encefalite/imunologia , Feminino , Doença de Hashimoto/líquido cefalorraquidiano , Doença de Hashimoto/imunologia , Humanos , Isotipos de Imunoglobulinas , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/efeitos dos fármacos , Ratos , Transmissão Sináptica/efeitos dos fármacos
18.
Digestion ; 101(1): 18-24, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31722362

RESUMO

BACKGROUND: Cancer tissues consist of cancer cells and stroma, the latter of which dictates cancer tissue microenvironment. We recently reported that the desmoplastic reaction (DR) pattern at the invasive front in colorectal cancer (CRC) is a promising prognostic indicator. However, the molecular mechanisms of DR formation and contribution to patients' prognosis remain unclear. SUMMARY: The tumor tissue microenvironment composed of extracellular matrix (ECM), soluble factors (growth factors/cytokine/cytokine), and stromal cells controls tumor growth and spread. Among stromal cells, cancer-associated fibroblasts (CAFs) play a key role in development of the cancer tissue microenvironment, and they are responsible for DR formation. CAFs express a disintegrin and metalloproteinases (ADAMs), which modulate cancer tissue microenvironmental factors. We isolated CAFs and normal fibroblasts from colon tissues of patients with CRC and characterized them. CAFs showed the increased expression of several ADAM species including ADAM9, ADAM10, ADAM12, and ADAM17, and the expression was further increased on the ECM-coated plates. Our in vitro and in vivo studies using CAFs and CRC cells suggest that ADAM expression is associated with the morphological DR category, and ADAMs may affect cancer malignancy through tumor proliferation in CRC. Key Message: This review summarizes the present knowledge on ADAMs in cancer and describes our recent findings regarding the molecular biological background of DR mainly by focusing on ADAMs.


Assuntos
Proteínas ADAM/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Neoplasias Colorretais/metabolismo , Fibroblastos/metabolismo , Proteínas ADAM/biossíntese , Animais , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Progressão da Doença , Matriz Extracelular/metabolismo , Fibrose/metabolismo , Humanos , Camundongos , Metástase Neoplásica , Prognóstico , Células Estromais/metabolismo , Células Tumorais Cultivadas , Microambiente Tumoral
19.
Biochem Biophys Res Commun ; 521(1): 64-71, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31627897

RESUMO

Rosacea is a chronic inflammatory cutaneous disease which mainly affects central face, leading to cosmetic disfigurement and compromised social psychology in billions of rosacea patients. Though the exact etiology of rosacea remains elusive, accumulating evidence has highlighted the dysfunction of innate immunity and inflammation in rosacea pathogenesis. Disintegrin Metalloprotease ADAM-like Decysin-1 (ADAMDEC1) is an orphan ADAM-like metalloprotease which is believed to be closely related to inflammation. Here for the first time, we reported that Adamdec1 expression was significantly increased in the skin lesions of rosacea patients and LL37-induced rosacea-like mouse models. Immunofluorescence analysis revealed co-localization of ADAMDEC1 and macrophages in patient and mouse biopsies. In cellular experiment, the expression of ADAMDEC1 was prominently elevated in M1 but not M2 macrophages. Knocking down of ADAMDEC1 significantly blunted M1 polarization in macrophages induced from human monocytes and THP-1 cell lines. Furthermore, silencing of Adamdec1 in LL-37-induced mouse model also suppressed the expression of M1 signature genes such as IL-6, iNOS and TNF-α, resulting in attenuated rosacea-like phenotype and inflammation. Taken together, our results demonstrate that ADAMDEC1 plays a pro-inflammatory role in rosacea via modulating the M1 polarization of macrophages.


Assuntos
Proteínas ADAM/metabolismo , Inflamação/metabolismo , Macrófagos/metabolismo , Rosácea/metabolismo , Pele/metabolismo , Adulto , Feminino , Humanos , Pessoa de Meia-Idade
20.
Cell Mol Life Sci ; 77(2): 267-274, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31432233

RESUMO

Epilepsy is one of the most common brain disorders, which can be caused by abnormal synaptic transmissions. Many epilepsy-related mutations have been identified in synaptic ion channels, which are main targets for current antiepileptic drugs. One of the novel potential targets for therapy of epilepsy is a class of non-ion channel-type epilepsy-related proteins. The leucine-rich repeat glioma-inactivated protein 1 (LGI1) is a neuronal secreted protein, and has been extensively studied as a product of a causative gene for autosomal dominant lateral temporal lobe epilepsy (ADLTE; also known as autosomal dominant partial epilepsy with auditory features [ADPEAF]). At least 43 mutations of LGI1 have been found in ADLTE families. Additionally, autoantibodies against LGI1 in limbic encephalitis are associated with amnesia, seizures, and cognitive dysfunction. Although the relationship of LGI1 with synaptic transmission and synaptic disorders has been studied genetically, biochemically, and clinically, the structural mechanism of LGI1 remained largely unknown until recently. In this review, we introduce insights into pathogenic mechanisms of LGI1 from recent structural studies on LGI1 and its receptor, ADAM22. We also discuss the mechanism for pathogenesis of autoantibodies against LGI1, and the potential of chemical correctors as novel drugs for epilepsy, with structural aspects of LGI1-ADAM22.


Assuntos
Proteínas ADAM/genética , Epilepsia/genética , Epilepsia/patologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Animais , Autoanticorpos/metabolismo , Humanos , Mutação/genética
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