Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 442
Filtrar
1.
Neurol India ; 69(5): 1359-1362, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34747813

RESUMO

Cerebral small vessel disease (CSVD) is a well-known cause of vascular dementia. Though a majority of these cases are sporadic, familial monogenic causes are being frequently identified as well. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a rare autosomal recessive CSVD, caused by mutation in HTRA 1 gene on chromosome 10q (10q25.3-q26.2) in homozygous or compound heterozygous form. Indian literature has been quite scant with very few case reports of CARASIL, and only three familial cases were confirmed with mutational analysis. Testing facilities of HTRA 1 genetic mutation are now more widely available in India than before, and should be encouraged for appropriate patients. This would help in diagnosing, prognosticating and avoiding unnecessary further investigations and medications for these patients. We herein review the Indian scenario and our previously reported experiences of this disorder, while adding a case from north India with a befitting clinical history, family history, neuroimaging and documented HTRA1 genetic mutation.


Assuntos
Leucoencefalopatias , Alopecia , Infarto Cerebral , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Humanos , Leucoencefalopatias/genética , Mutação/genética , Doenças da Coluna Vertebral
2.
Int J Mol Sci ; 22(19)2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34639128

RESUMO

The mammalian high temperature requirement A (HtrA) proteins are a family of evolutionarily conserved serine proteases, consisting of four homologs (HtrA1-4) that are involved in many cellular processes such as growth, unfolded protein stress response and programmed cell death. In humans, while HtrA1, 2 and 3 are widely expressed in multiple tissues with variable levels, HtrA4 expression is largely restricted to the placenta with the protein released into maternal circulation during pregnancy. This limited expression sets HtrA4 apart from the rest of the family. All four HtrAs are active proteases, and their specific cellular and physiological roles depend on tissue type. The dysregulation of HtrAs has been implicated in many human diseases such as cancer, arthritis, neurogenerative ailments and reproductive disorders. This review first discusses HtrAs broadly and then focuses on the current knowledge of key molecular characteristics of individual human HtrAs, their similarities and differences and their reported physiological functions. HtrAs in other species are also briefly mentioned in the context of understanding the human HtrAs. It then reviews the distinctive involvement of each HtrA in various human diseases, especially cancer and pregnancy complications. It is noteworthy that HtrA4 expression has not yet been reported in any primary tumour samples, suggesting an unlikely involvement of this HtrA in cancer. Collectively, we accentuate that a better understanding of tissue-specific regulation and distinctive physiological and pathological roles of each HtrA will improve our knowledge of many processes that are critical for human health.


Assuntos
Serina Peptidase 1 de Requerimento de Alta Temperatura A/metabolismo , Neoplasias/patologia , Complicações na Gravidez/patologia , Animais , Feminino , Humanos , Neoplasias/enzimologia , Gravidez , Complicações na Gravidez/enzimologia , Transdução de Sinais
3.
Pract Neurol ; 21(5): 448-451, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34433685

RESUMO

A 44-year-old Caucasian man presented with seizures and cognitive impairment. He had marked retinal drusen, and MR brain scan showed features of cerebral small vessel disease; he was diagnosed with a leukoencephalopathy of uncertain cause. He died at the age of 46 years and postmortem brain examination showed widespread small vessel changes described as a vasculopathy of unknown cause. Seven years postmortem, whole-genome sequencing identified a homozygous nonsense HTRA1 mutation (p.Arg302Ter), giving a retrospective diagnosis of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy.


Assuntos
CADASIL , Leucoencefalopatias , Adulto , Alopecia , CADASIL/complicações , CADASIL/diagnóstico por imagem , CADASIL/genética , Infarto Cerebral , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Humanos , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Estudos Retrospectivos , Doenças da Coluna Vertebral
4.
J Stroke Cerebrovasc Dis ; 30(9): 105997, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34303089

RESUMO

OBJECTIVES: To identify the underlying genetic defect for a consanguineous family with an unusually high number of members affected by cerebral small vessel disease. MATERIALS AND METHODS: A total of 6 individuals, of whom 3 are severely affected, from the family were clinically and radiologically evaluated. SNP genotyping was performed in multiple members to demonstrate genome-wide runs-of-homozygosity. Coding variants in the most likely candidate gene, HTRA1 were explored by Sanger sequencing. Published HTRA1-related phenotypes were extensively reviewed to explore the effect of number of affected alleles on phenotypic expression. RESULTS: Genome-wide homozygosity mapping identified a 3.2 Mbp stretch on chromosome 10q26.3 where HTRA1 gene is located. HTRA1 sequencing revealed an evolutionarily conserved novel homozygous c.824C>T (p.Pro275Leu) mutation, affecting the serine protease domain of HtrA1. Early-onset of cognitive and motor deterioration in homozygotes are in consensus with CARASIL. However, there was a clear phenotypic variability between homozygotes which includes alopecia, a suggested hallmark of CARASIL. All heterozygotes, presenting as CADASIL type 2, had spinal disk degeneration and several neuroimaging findings, including leukoencephalopathy and microhemorrhage despite a lack of severe clinical presentation. CONCLUSION: Here, we clearly demonstrate that CARASIL and CADASIL type 2 are two clinical consequences of the same disorder with different severities thorough the evaluation of the largest collection of homozygotes and heterozygotes segregating in a family. Considering the semi-dominant inheritance of HTRA1-related phenotypes, genetic testing and clinical follow-up must be offered for all members of a family with HTRA1 mutations regardless of symptoms.


Assuntos
Alopecia/genética , CADASIL/genética , Infarto Cerebral/genética , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Leucoencefalopatias/genética , Mutação , Doenças da Coluna Vertebral/genética , Adulto , Idade de Início , Alopecia/diagnóstico , Alopecia/fisiopatologia , CADASIL/diagnóstico , CADASIL/fisiopatologia , Infarto Cerebral/diagnóstico , Infarto Cerebral/fisiopatologia , Consanguinidade , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Hereditariedade , Heterozigoto , Homozigoto , Humanos , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Índice de Gravidade de Doença , Doenças da Coluna Vertebral/diagnóstico , Doenças da Coluna Vertebral/fisiopatologia
5.
Adv Clin Exp Med ; 30(8): 859-864, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34310874

RESUMO

BACKGROUND: Age-related macular degeneration (AMD) mainly affects the central region of retina and has many late-stage manifestations. OBJECTIVES: Age-related macular degeneration is a leading cause of irreversible blindness in older people. The main feature of AMD is retinal pigment epithelium (RPE) degeneration. In this study, we aimed to explore the influence of HTRA1 expression on the proliferation and migration of RPE cells. MATERIAL AND METHODS: Human ARPE-19 cells were transfected with an HTRA1 overexpression lentivirus or HTRA1 siRNA to silence HtrA1 expression. Quantitave reverse-transcription polymerase chain reaction (qRT-PCR) and western blotting were used to verify the relative level of HTRA1 mRNA and expression of HTRA1 protein of transfected human ARPE-19 cells. The MTT clone formation and transwell assays were used to confirm the effect of HTRA1 expression on the proliferation, colony forming ability and migration of ARPE-19 cells. RESULTS: The proliferation capacity (shown as optical density value) of ARPE-19 cells in the HTRA1-overexpressing group at culture times of 24 h and 48 h were 0.595 ±0.032 and 0.867 ±0.037 respectively, which were much higher than in the mock group. However, the proliferative capacity of cells in the HTRA1-silenced group decreased with increasing time of culture, compared with the mock group. The number of cloned and migrating cells in the HTRA1-overexpressing group were much higher than in the mock group, whereas the numbers in the HTRA1-silenced group were significantly lower. CONCLUSIONS: Overexpression of HTRA1 promotes proliferation and migration of RPE cells, which can help maintain the function of sensory neurons in the retina. Therefore, HTRA1 may be a suitable target for AMD treatments.


Assuntos
Degeneração Macular , Epitélio Pigmentado da Retina , Idoso , Proliferação de Células , Células Cultivadas , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Humanos
6.
Int J Mol Sci ; 22(7)2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33916165

RESUMO

Alpha-1 antitrypsin (A1AT) is a glycoprotein that has been shown to protect tissues from proteolytic damage under various inflammatory conditions. Several studies show that A1AT may be associated with pre-eclampsia. However, the role of A1AT expression in placental physiology is not fully understood. In the present study, we aim to characterize the expression and function of placental A1AT. A1AT knockdown is found to reduce the expression of the serine protease HTRA1 in a trophoblast cell line. In addition, A1AT overexpression (A1AT-OE) increases the expression of HTRA1, IL6, CXCL8, and several markers of endoplasmic reticulum (ER) stress. Treatment with tunicamycin or thapsigargin, which induces ER stress, increases HTRA1 expression. Furthermore, immunohistochemistry reveals that HTRA1 is expressed in trophoblasts and the endometrial decidual cells of human placentas. An invasion assay shows that A1AT and HTRA1 stimulate cell invasion, but treatment with the ER stress inhibitors reduces the expression of HTRA1 and ER stress markers and prevents cell invasion in A1AT-OE trophoblasts. These results suggest that endogenous A1AT regulates inflammatory cytokine expression and HTRA1-induced trophoblast invasion via the induction of ER stress. It is concluded that an imbalance in the functional link between A1AT and ER stress at the maternal-fetal interface might cause abnormal placental development.


Assuntos
Estresse do Retículo Endoplasmático , Inflamação/metabolismo , Trofoblastos/metabolismo , Resposta a Proteínas não Dobradas , alfa 1-Antitripsina/metabolismo , Biomarcadores/metabolismo , Linhagem Celular , Feminino , Serina Peptidase 1 de Requerimento de Alta Temperatura A/metabolismo , Humanos , Pré-Eclâmpsia/etiologia , Gravidez
7.
Exp Eye Res ; 210: 108605, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33930395

RESUMO

Age-related macular degeneration (AMD) is the most common cause of central vision loss among elderly populations in industrialized countries. Genome-wide association studies have consistently associated two genomic loci with progression to late-stage AMD: the complement factor H (CFH) locus on chromosome 1q31 and the age-related maculopathy susceptibility 2-HtrA serine peptidase 1 (ARMS2-HTRA1) locus on chromosome 10q26. While the CFH risk variant has been shown to alter complement activity, the ARMS2-HTRA1 risk haplotype remains enigmatic due to high linkage disequilibrium and inconsistent functional findings spanning two genes that are plausibly causative for AMD risk. In this review, we detail the genetic and functional evidence used to support either ARMS2 or HTRA1 as the causal gene for AMD risk, emphasizing both the historical development and the current understanding of the ARMS2-HTRA1 locus in AMD pathogenesis. We conclude by summarizing the evidence in favor of HTRA1 and present our hypothesis whereby HTRA1-derived ECM fragments mediate AMD pathogenesis.


Assuntos
Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Degeneração Macular/genética , Proteínas/genética , Cromossomos Humanos Par 10/genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Desequilíbrio de Ligação
8.
J Neurol ; 268(9): 3316-3324, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33661357

RESUMO

BACKGROUND: High Temperature Requirement Serine Protease A1 (HTRA1) degrades extracellular matrix molecules (ECMs) and growth factors. It interacts with several proteins implicated in multiple sclerosis (MS), but has not previously been linked to the disease. OBJECTIVE: Investigate the levels of HTRA1 in cerebrospinal fluid (CSF) in different subtypes of MS and brain tissue. METHODS: Using ELISA, HTRA1 levels were compared in CSF from untreated patients with relapsing-remitting MS (RRMS, n = 23), secondary progressive MS (SPMS, n = 26) and healthy controls (HCs, n = 26). The effect of disease modifying therapies (DMTs) were examined in both patient groups. Cellular distribution in human brain was studied using immunochemistry and the oligointernode database, based on a single-nuclei RNA expression map. RESULTS: HTRA1 increased in RRMS and SPMS compared to HCs. DMT decreased HTRA1 levels in both types of MS. Using ROC analysis, HTRA1 cut-offs could discriminate HCs from RRMS patients with 100% specificity and 82.6% sensitivity. In the brain, HTRA1 was expressed in glia and neurons. CONCLUSION: HTRA1 is a promising CSF biomarker for MS correlating with disease- and disability progression. Most cell species of the normal and diseased CNS express HTRA1 and the expression pattern could reflect pathological processes involved in MS pathogenesis.


Assuntos
Serina Peptidase 1 de Requerimento de Alta Temperatura A/líquido cefalorraquidiano , Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla Recidivante-Remitente , Biomarcadores/química , Estudos de Casos e Controles , Progressão da Doença , Humanos , Esclerose Múltipla Crônica Progressiva/líquido cefalorraquidiano , Esclerose Múltipla Recidivante-Remitente/líquido cefalorraquidiano
9.
BMC Geriatr ; 21(1): 192, 2021 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-33743591

RESUMO

BACKGROUND: Sarcopenia is a multifactorial pathophysiologic condition of skeletal muscle mass and muscle strength associated with aging. However, biomarkers for predicting the occurrence of sarcopenia are rarely discussed in recent studies. The aim of the study was to elucidate the relationship between sarcopenia and several pertinent biomarkers. METHODS: Using the Gene Expression Omnibus (GEO) profiles of the National Center for Biotechnology Information, the associations between mRNA expression of biomarkers and sarcopenia were explored, including high temperature requirement serine protease A1 (HtrA1), procollagen type III N-terminal peptide (P3NP), apelin, and heat shock proteins 70 (Hsp72). We enrolled 408 community-dwelling adults aged 65 years and older with sarcopenia and nonsarcopenia based on the algorithm proposed by the Asian Working Group for Sarcopenia (AWGS). Muscle strength is identified by hand grip strength using an analogue isometric dynamometer. Muscle mass is estimated by skeletal mass index (SMI) using a bioelectrical impedance analysis. Physical performance is measured by gait speed using 6 m walking distance. The associations between these biomarkers and sarcopenia were determined using receiver operating characteristic (ROC) curve analysis and multivariate regression models. RESULTS: From the GEO profiles, the sarcopenia gene set variation analysis score was correlated significantly with the mRNA expression of APLNR (p < 0.001) and HSPA2 (p < 0.001). In our study, apelin was significantly associated with decreased hand grip strength with ß values of - 0.137 (95%CI: - 0.229, - 0.046) in men. P3NP and HtrA1 were significantly associated with increased SMI with ß values of 0.081 (95%CI: 0.010, 0.153) and 0.005 (95%CI: 0.001, 0.009) in men, respectively. Apelin and HtrA1 were inversely associated with the presence of sarcopenia with an OR of 0.543 (95%CI: 0.397-0.743) and 0.003 (95%CI: 0.001-0.890) after full adjustment. The cutoff point of HtrA1 was associated with the presence of sarcopenia with an OR of 0.254 (95%CI: 0.083-0.778) in men. The cutoff point of apelin was negatively associated with the presence of sarcopenia with an OR of 0.254 (95%CI: 0.083-0.778). CONCLUSION: Our study highlights that P3NP, HtrA, and apelin are useful for diagnosis of sarcopenia in the clinical setting.


Assuntos
Apelina/metabolismo , Serina Peptidase 1 de Requerimento de Alta Temperatura A/metabolismo , Fragmentos de Peptídeos/metabolismo , Pró-Colágeno/metabolismo , Sarcopenia , Idoso , Apelina/genética , Estudos Transversais , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Força da Mão , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Humanos , Masculino , Força Muscular , Músculo Esquelético , Fragmentos de Peptídeos/genética , Pró-Colágeno/genética , Sarcopenia/diagnóstico , Sarcopenia/epidemiologia , Sarcopenia/genética
10.
Int J Med Sci ; 18(8): 1840-1847, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33746601

RESUMO

High temperature requirement protein A1 (HtrA1) was identified as the causative gene of autosomal recessive arteriopathy and associated with lacunar ischemic stroke (IS) in European. This study aimed at evaluating the association of HTRA1 with IS and four tagging single-nucleotide polymorphisms (SNPs) were genotyped in a cohort of 4,098 Chinese. The mRNA level of HTRA1 in 72 IS cases and 72 hypertension controls were measured and compared. In whole population, SNP rs2268350 (C>T) was significantly associated with IS incidence (P=0.034). Stratification analysis observed significant association of rs2268350 in male, smoking and drinking populations, rs2672587 (C>G) in smoking and nonsmoking populations and rs3793917 (C>G) in smoking, nonsmoking and nondrinking populations with stroke respectively (P<0.05). The additive interaction and multiplicative interaction between rs2268350 and smoking were both of significant (P<0.05) after adjustment for the covariates. There was a cumulated risk of IS among genotypes of rs3793917 (P=0.009) and rs2672587 (P=0.047) in smoking population. The mRNA level of HTRA1 in non-smokers with rs2268350 CC was significantly higher than smokers with rs2268350 CT/TT (P=0.046) in IS cases. Our findings support that HTRA1 confers the genetic susceptibility to IS and smoking might modify the genetic effect of HTRA1 on IS by suppressing HTRA1 mRNA expression.


Assuntos
Predisposição Genética para Doença , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , AVC Isquêmico/genética , Fumar/epidemiologia , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Feminino , Seguimentos , Interação Gene-Ambiente , Humanos , Incidência , AVC Isquêmico/epidemiologia , Masculino , Pessoa de Meia-Idade , não Fumantes/estatística & dados numéricos , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Fumantes/estatística & dados numéricos , Fumar/efeitos adversos
11.
BMC Ophthalmol ; 21(1): 97, 2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-33618707

RESUMO

BACKGROUND: The prevalence of age-related macular degeneration (AMD) varies from 6.8 to 18.3% for all forms of AMD and from 0.6 to 2.6% for late AMD according to race, suggesting the existence of genetic differences among races. The purpose of this study was to determine the genetic causes of differences in the prevalence of AMD among individuals of different races. METHODS: We collected 138 AMD-associated single nucleotide polymorphisms (SNPs) from a genome-wide association studies catalog. Their population-level allele frequencies were derived based on the 1000 Genomes Project and Korean Reference Genome Database. We used Fisher's exact tests to assess whether the effect allele at a given SNP was significantly enriched or depleted in the database. RESULTS: European, American, and South Asian populations showed similar heatmap patterns, whereas East Asian, and Korean populations had distinct patterns. Korean populations exhibited patterns that were different from those of the other groups; rs5754227 (SYN3), rs1626340 (TGFBR1/COL15A1), rs3750846(ARMS2/HTRA1), and rs9564692 (B3GALTL) were enriched, whereas rs2230199 (C3) and rs73036519 (EXOC3L2/MARK4) were depleted in Koreans; these SNPs are associated with late AMD. The genetic risk score calculated from allele frequencies was not less in East Asians than in Europeans. CONCLUSION: The prevalence of AMD is lower in Asians than in Europeans. However, our study showed that genetic risk scores in East Asians were similar to those in Europeans, which may explain why the global projected number of people with AMD by 2040 is in largest for East Asians, including Koreans.


Assuntos
Degeneração Macular , Polimorfismo de Nucleotídeo Único , Grupos Étnicos , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Humanos , Degeneração Macular/genética
12.
J Biol Chem ; 296: 100456, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33636181

RESUMO

The disease-initiating molecular events for age-related macular degeneration (AMD), a multifactorial retinal disease affecting many millions of elderly individuals worldwide, are still unknown. Of the over 30 risk and protective loci so far associated with AMD through whole genome-wide association studies (GWAS), the Age-Related Maculopathy Susceptibility 2 (ARMS2) gene locus represents one of the most highly associated risk regions for AMD. A unique insertion/deletion (in/del) sequence located immediately upstream of the High Temperature Requirement A1 (HTRA1) gene in this region confers high risk for AMD. Using electrophoretic mobility shift assay (EMSA), we identified that two Gtf2i-ß/δ transcription factor isoforms bind to the cis-element 5'- ATTAATAACC-3' contained in this in/del sequence. The binding of these transcription factors leads to enhanced upregulation of transcription of the secretory serine protease HTRA1 in transfected cells and AMD patient-derived induced pluripotent stem cells (iPSCs). Overexpression of Htra1 in mice using a CAG-promoter demonstrated increased blood concentration of Htra1 protein, caused upregulation of vascular endothelial growth factor (VEGF), and produced a choroidal neovascularization (CNV)-like phenotype. Finally, a comparison of 478 AMD patients to 481 healthy, age-matched controls from Japan, India, Australia, and the USA showed a statistically increased level of secreted HTRA1 blood concentration in AMD patients compared with age-matched controls. Taken together, these results suggest a common mechanism across ethnicities whereby increased systemic blood circulation of secreted serine protease HTRA1 leads to subsequent degradation of Bruch's membrane and eventual CNV in AMD.


Assuntos
Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Proteínas/genética , Fatores de Transcrição TFII/genética , Idoso , Idoso de 80 Anos ou mais , Animais , Feminino , Serina Peptidase 1 de Requerimento de Alta Temperatura A/metabolismo , Humanos , Mutação INDEL/genética , Degeneração Macular/genética , Degeneração Macular/fisiopatologia , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Isoformas de Proteínas/genética , Proteínas/metabolismo , Fatores de Transcrição TFII/metabolismo , Fatores de Transcrição TFIII/genética , Fatores de Transcrição TFIII/metabolismo
13.
Aging (Albany NY) ; 13(4): 5120-5135, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33535173

RESUMO

Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition associated with high morbidity and mortality. This study aimed to use weighted gene co-expression network analysis (WGCNA) to explore the molecular pathogenesis of the emphysema phenotype of COPD. After obtaining lung mRNA expression profiles from ten patients with the emphysema phenotype of COPD and eight controls, emphysema-associated gene modules were identified with WGCNA. Among 13 distinct modules, the green-yellow and brown modules showed the strongest correlations with emphysema severity and lung function and were thus selected as hub modules. On gene ontology analysis, these two modules were mainly enriched in immune response, B cell receptor (BCR) signaling pathway, extracellular matrix (ECM) organization, and collagen fibril organization. Pathway analysis primarily showed enrichment in BCR signaling pathways, ECM receptor interaction, and NF-κB and TGF-ß signaling pathways for the two hub modules. Several genes, including FCRLA, MS4A1, CD19, FKBP10, C1S and HTRA1, among others, were identified as hub genes. Our results shed light on the potential genetic mechanisms underlying the pathogenesis of the emphysema phenotype of COPD. However, further research will be needed to confirm the involvement of the identified genes and to determine their therapeutic relevance.


Assuntos
Redes Reguladoras de Genes , Doença Pulmonar Obstrutiva Crônica/genética , Enfisema Pulmonar/genética , Idoso , Antígenos CD19/genética , Estudos de Casos e Controles , Complemento C1s/genética , Matriz Extracelular/genética , Feminino , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Humanos , Masculino , Pessoa de Meia-Idade , NF-kappa B/genética , Doença Pulmonar Obstrutiva Crônica/metabolismo , Enfisema Pulmonar/metabolismo , RNA Mensageiro , Receptores de Antígenos de Linfócitos B/genética , Receptores Fc/genética , Proteínas de Ligação a Tacrolimo/genética , Transcriptoma , Fator de Crescimento Transformador beta/genética
14.
Int Immunopharmacol ; 92: 107369, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33493738

RESUMO

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease. It is urgent to identify biomarkers to precisely predict mortality. METHODS: Gene expression data of bronchoalveolar lavage (BAL) cells and clinical information were downloaded from the Gene Expression Omnibus database. We identified key modules associated with prognosis using weighted gene co-expression network analysis (WGCNA). Then we screened genes with the least absolute shrinkage and selection operator Cox regression. Finally, we constructed a prognostic gene signature using multivariate Cox regression. The risk model was evaluated using the time-dependent receiver operating characteristic (ROC) curve and the concordance index. Additionally, the risk model was validated using an external independent dataset. RESULTS: Two key modules, strongly associated with inflammation and immune response, were identified by WGCNA. Four genes, including TLR2, CCR2, HTRA1, and SFN, were screened to construct the prognostic model. The patients with a high-risk score had a significantly worse prognosis than patients with a low-risk score. Time-dependent ROC analysis showed that the risk model had a moderate predictive performance for overall survival in the training and external validation datasets. CONCLUSIONS: Our study provides new insights into the prognostic value of BAL cells in IPF and it may be helpful to assist clinicians in making treatment decisions for the personalized management of IPF.


Assuntos
Proteínas 14-3-3/genética , Biomarcadores/metabolismo , Lavagem Broncoalveolar/métodos , Exorribonucleases/genética , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Fibrose Pulmonar Idiopática/patologia , Receptor 2 Toll-Like/genética , Transcriptoma , Idoso , Biologia Computacional/métodos , Bases de Dados Genéticas , Feminino , Humanos , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/metabolismo , Masculino , Prognóstico , Curva ROC , Receptores CCR2/genética
15.
Int Ophthalmol ; 41(3): 995-1002, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33387109

RESUMO

BACKGROUND: Age-related macular degeneration (AMD) is one of the major causes of blindness, and the incidence of this disease has been increasing in recent years. OBJECTIVE: To investigate the association between the single nucleotide polymorphisms (SNPs) of the high temperature requirement factor A-1 (HTRA1) and complement factor H (CFH) genes and susceptibility to AMD in Ningbo, China. METHODS: Ninety-eight patients with AMD and seventy-three controls were recruited at the Sixth Hospital of Ningbo from August 2017 to April 2019 in China. Genomic DNA was extracted from the venous blood provided by the hospital, and the genotypes of the AMD susceptibility genes CFH and HTAR1 were detected by polymerase chain reaction and sequenced directly. The SNPs rs11200638 on the HTRA1 gene and rs3753394 on the CFH gene were selected for genotype and association analysis. The correlations between the different genotypes of HTRA1 and CFH and AMD were analysed by the Chi-squared test. RESULTS: All the genotypes adhered to the Hardy-Weinberg equilibrium. There were three genotypes (AA, AG and GG) in HTRA1 (rs11200638). The differences in genotypes and allele frequency between the AMD group and the control group were statistically significant (P < 0.05). The A allele was a risk allele (OR: 4.19, 95% Cl: 2.28 ~ 7.70, P < 0.05), with a frequency of 61.7% in patients versus 43.8% in controls. However, the rs3753394 SNP in CFH was not associated with AMD in our study (P > 0.05). CONCLUSIONS: The rs11200638 SNP of the HTRA1 gene is associated with AMD, and the AA genotype is a risk factor for AMD in the Ningbo population. There is no significant correlation between the rs3753394 SNP of the CFH gene and AMD.


Assuntos
Fator H do Complemento , Degeneração Macular , China/epidemiologia , Fator H do Complemento/genética , Frequência do Gene , Genótipo , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Humanos , Lactente , Degeneração Macular/genética , Polimorfismo de Nucleotídeo Único , Serina Endopeptidases/genética , Vitamina B 12/análogos & derivados
16.
Breast Cancer ; 28(2): 307-320, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32951185

RESUMO

BACKGROUND: Non-metastatic locally advanced breast carcinoma (LABC) treatment involves neoadjuvant chemotherapy (NCT). We evaluated the association of clinical-pathological data and immunoexpression of hormone receptors, HER2 and Ki67, and new biomarkers, RPL37A, MTSS1 and HTRA1, with pathological complete response (PCR) or tumour resistance (stable disease or disease progression), disease-free survival (DFS) and cancer-specific survival (CSS). METHODS: This is a retrospective study of 333 patients with LABC who underwent NCT. Expression of MTSS1, RPL37A and HTRA1/PRSS11 was evaluated by immunohistochemistry in TMA slides. Cutoff values were established for low and high tumour expression. ROC plotter evaluated response to NCT. Chi-square test for factors related to PCR, and Kaplan-Meier test and Cox model for factors related to DFS and CSS were prformed. RESULTS: The mean follow-up was 70.0 months and PCR rate was 15.6%. At 120 months, DFS rate was 32.5% and CSS rate was 67.1%. In multivariate analysis, there was an association between: (1) necrosis presence, intense inflammatory infiltrate, ER absence, HER2 molecular subtype and high RPL3A expression with increased odds of PCR; (2) lymph node involvement (LNI), high Ki67, low RPL37A and high HTRA1 expression with increased risk for NCT non-response; (3) LNI, high proliferation, necrosis absence, low RPL37A and high HTRA1 expression with increased recurrence risk; (4) advanced LNI, ER negative tumours, high HTRA1, low RPL37A expression and desmoplasia presence with higher risk of cancer death. CONCLUSION: RPL37A is a potential biomarker for response to NCT and for prognosis. Additional studies evaluating HTRA1 and MTSS1 prognostic value are needed.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Serina Peptidase 1 de Requerimento de Alta Temperatura A/metabolismo , Proteínas dos Microfilamentos/metabolismo , Terapia Neoadjuvante/métodos , Proteínas de Neoplasias/metabolismo , Proteínas Ribossômicas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/mortalidade , Progressão da Doença , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Imuno-Histoquímica/métodos , Antígeno Ki-67/metabolismo , Pessoa de Meia-Idade , Prognóstico , Receptor ErbB-2/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida
17.
J Recept Signal Transduct Res ; 41(2): 188-195, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32777973

RESUMO

Multiple studies have assessed the contribution of rs10490924 on chromosome 10q26 surrounding HTRA1/ARMS2 gene to age-related macular degeneration (AMD) risk. However, the causal allele at this locus is still inconclusive. In this meta-analysis, we systematically characterized the potential association between rs10490924 polymorphism and AMD risk. Data available from 12 case-control studies, including a total of 5244 cases and 2755 controls in three different ethnic populations, were used to evaluate the correlation between rs10490924 G/T polymorphism (Ala69Ser) and AMD risk. In overall populations, the results indicated the Ala69Ser polymorphism was significantly associated with AMD under allelic (OR = 0.35, 95% CI = 0.30-0.40), homozygous (OR = 0.12, 95%CI = 0.09-0.17), dominant (OR = 0.18, 95%CI = 0.14-0.24), recessive (OR = 0.33, 95%CI = 0.28-0.39), and heterozygous genetic models (OR = 0.26, 95% CI = 0.21-0.33). Similar results were observed in subgroup analysis. This meta-analysis suggests that rs10490924 (Ala69Ser) polymorphism was significantly associated with the susceptibility of AMD in all ethnicities, Ala69 carriers are resistant to AMD risk.


Assuntos
Predisposição Genética para Doença , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Degeneração Macular/genética , Proteínas/genética , Alelos , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Degeneração Macular/patologia , Masculino , Polimorfismo de Nucleotídeo Único/genética
18.
Eur J Ophthalmol ; 31(3): 1281-1290, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-32578437

RESUMO

INTRODUCTION: This post-hoc case-control study compares single nucleotide polymorphism (SNP) profile of eyes with vascularized pigment epithelial detachment (vPED) due to age-related macular degeneration (ARMD) with: (1) Control-1 eyes (no ARMD and AREDS Severity Scale 0); and (2) Control-2 eyes (drusen or AREDS Severity Scale 2). SNP profile of High Responders (HR) was also compared with Low Responders (LR) to ranibizumab. METHODS: Blood samples from 40 patients with vPED treated with ranibizumab were sent for SNP-specific genotype analysis for comparison of variant allele frequencies of 23 SNPs associated with ARMD (VAF) to VAF in 184 Control-1 eyes, and VAF in 85 Control-2 eyes. VAF of HR-50 (⩾50% decrease in PED height) and VAF of HR-75 (⩾75% decrease in PED height) were also compared with VAF of LR. RESULTS: These SNPs were more frequent in vPED than Control-1 eyes: APOE rs4420638 (A/G), HTRA1 rs104904924 (G/T), VEGF rs943080 (T/C), CFH rs1061170 (T/C), CFH rs2274700 (C/T), CFH rs10737680 (A/C), CFH rs10801555 (G/A). These SNPs were more frequent in vPED than Control-2 eyes: APOE rs4420638 (A/G), CFI rs4698775 (G/T), COL15A1/TGFBR1 rs334353 (T/G). FRK rs3812111 (T/A) was more frequent in HR-50 and HR-75 eyes compared with LR. CONCLUSION: Seven SNPs were more frequent in vPED eyes than non-ARMD eyes, and three SNPs were more frequent in vPED eyes than drusen eyes. Adjusting for multiplicity, only CFH rs2274700 (C/T) was significant for first comparison, and only COL15A1/TGFBR1 rs334353 (T/G) was significant for second comparison. APOE rs4420638 (A/G) was the single SNP more frequently linked to vPED eyes for both comparisons. FRK rs3812111 (T/A) was consistently associated with high responders.


Assuntos
Degeneração Macular , Descolamento Retiniano , Inibidores da Angiogênese/uso terapêutico , Estudos de Casos e Controles , Angiofluoresceinografia , Serina Peptidase 1 de Requerimento de Alta Temperatura A , Humanos , Injeções Intravítreas , Degeneração Macular/tratamento farmacológico , Degeneração Macular/genética , Polimorfismo de Nucleotídeo Único , Descolamento Retiniano/tratamento farmacológico , Descolamento Retiniano/genética , Epitélio Pigmentado da Retina , Fator A de Crescimento do Endotélio Vascular/genética , Acuidade Visual
19.
Circ Res ; 128(3): 386-400, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33292062

RESUMO

RATIONALE: Current thrombolytic agents activate plasminogen to plasmin which triggers fibrinolysis to dissolve thrombi. Since plasmin is a nonspecific proteolytic enzyme, all of the current plasmin-dependent thrombolytics lead to serious hemorrhagic complications, demanding a new class of fibrinolytic enzymes independent from plasmin activation and undesirable side effects. We speculated that the mammalian version of bacterial heat-shock proteins could selectively degrade intravascular thrombi, a typical example of a highly aggregated protein mixture. OBJECTIVE: The objective of this study is to identify enzymes that can dissolve intravascular thrombi specifically without affecting fibrinogen and fibronectin so that the wound healing processes remain uninterrupted and tissues are not damaged. In this study, HtrA (high-temperature requirement A) proteins were tested for its specific proteolytic activity on intravascular thrombi independently from plasmin activation. METHODS AND RESULTS: HtrA1 and HtrA2/Omi proteins, collectively called as HtrAs, lysed ex vivo blood thrombi by degrading fibrin polymers. The thrombolysis by HtrAs was plasmin-independent and specific to vascular thrombi without causing the systemic activation of plasminogen and preventing nonspecific proteolysis of other proteins including fibrinogen and fibronectin. As expected, HtrAs did not disturb clotting and wound healing of excised wounds from mouse skin. It was further confirmed in a tail bleeding and a rebleeding assay that HtrAs allowed normal clotting and maintenance of clot stability in wounds, unlike other thrombolytics. Most importantly, HtrAs completely dissolved blood thrombi in tail thrombosis mice, and the intravenous injection of HtrAs to mice with pulmonary embolism completely dissolved intravascular thrombi and thus rescued thromboembolism. CONCLUSIONS: Here, we identified HtrA1 and HtrA2/Omi as plasmin-independent and highly specific thrombolytics that can dissolve intravascular thrombi specifically without bleeding risk. This work is the first report of a plasmin-independent thrombolytic pathway, providing HtrA1 and HtrA2/Omi as ideal therapeutic candidates for various thrombotic diseases without hemorrhagic complications.


Assuntos
Fibrina/metabolismo , Fibrinólise/efeitos dos fármacos , Fibrinolíticos/farmacologia , Serina Peptidase 1 de Requerimento de Alta Temperatura A/farmacologia , Serina Peptidase 2 de Requerimento de Alta Temperatura A/farmacologia , Embolia Pulmonar/tratamento farmacológico , Trombose/tratamento farmacológico , Animais , Modelos Animais de Doenças , Feminino , Fibrinolíticos/toxicidade , Hemorragia/induzido quimicamente , Serina Peptidase 1 de Requerimento de Alta Temperatura A/toxicidade , Serina Peptidase 2 de Requerimento de Alta Temperatura A/toxicidade , Humanos , Cinética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Embolia Pulmonar/sangue , Embolia Pulmonar/enzimologia , Proteínas Recombinantes/farmacologia , Trombose/sangue , Trombose/enzimologia , Cicatrização/efeitos dos fármacos
20.
Toxicol Pathol ; 49(3): 610-620, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33297886

RESUMO

FHTR2163 is an antigen-binding fragment of a humanized immunoglobulin G1 monoclonal antibody directed against high-temperature requirement A serine peptidase 1 (HTRA1) that is being developed as a potential intravitreal (ITV) treatment for patients with geographic atrophy (GA), an advanced form of dry age-related macular degeneration. The nonclinical toxicology program was designed to assess the safety and tolerability of HTRA1 inhibition following ITV administration of FHTR2163 to support ITV administration in patients with GA. FHTR2163 was well tolerated in a single-dose ITV-administered 8-day toxicity study in cynomolgus monkeys following a 50 µL high (>700 mOsm/kg) osmolality formulation up to 12.5 mg/eye; however, 100 µL (2× 50 µL injections) of a high-osmolality formulation resulted in transient retinal detachment. Repeat-dose ITV administration every 2 weeks of FHTR2163 was well tolerated in 8- and 26-week studies with ITV injection of 100 µL (2× 50 µL) of iso-osmolar formulation up to 15 mg/eye, or 50 µL of the high-osmolality formulation up to 12.5 mg/eye. Observed transient and reversible ocular effects included inflammation and perivascular infiltrates, consistent with an immune response attributed to the administration of heterologous (humanized) protein. Overall, FHTR2163 was well tolerated, and the nonclinical package supported the continued clinical development of FHTR2163 in patients with GA.


Assuntos
Atrofia Geográfica , Animais , Anticorpos Monoclonais Humanizados , Atrofia Geográfica/tratamento farmacológico , Serina Peptidase 1 de Requerimento de Alta Temperatura A , Humanos , Fragmentos Fab das Imunoglobulinas , Injeções Intravítreas , Macaca fascicularis
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...