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  1 / 18656 MEDLINE  
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[PMID]:29331278
[Au] Autor:Sobhy MMK; Mahmoud SS; El-Sayed SH; Rizk EMA; Raafat A; Negm MSI
[Ad] Endereço:Medical Parasitology Department, Kasr Al-Ainy School of Medicine, Cairo University, Egypt.
[Ti] Título:Impact of treatment with a Protein Tyrosine Kinase Inhibitor (Genistein) on acute and chronic experimental Schistosoma mansoni infection.
[So] Source:Exp Parasitol;185:115-123, 2018 Feb.
[Is] ISSN:1090-2449
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Schistosomiasis mansoni is considered one of the most common fibrotic diseases resulting from inflammation and deposition of fibrous tissue around parasitic eggs trapped in the liver, causing morbidity and mortality. Chemotherapy against schistosomiasis is largely dependent on Praziquantel (PZQ). Yet, the huge administration of it in endemic areas and its incompetence towards the immature stages have raised serious alarms against the development of drug resistance. Few drugs are directed to reverse schistosomal liver fibrosis, particularly at the chronic and advanced stages of the disease. Recently, protein tyrosine kinase (PTK) inhibitors have been identified as potent anti-schistosomal and anti-fibrotic drugs against schistosomes, that may suppress and reverse Schistosoma mansoni (S. mansoni) induced liver fibrosis. The present study was designed to assess the anti-schistosomal and antifibrotic activity of Genistein, a PTK inhibitor, in comparison to PZQ, on both acute and chronic S. mansoni-infected mice using different parasitological, histopathological and immunohistochemical studies. Genistein showed a significant reduction (P < .05) in total worm burden, tissue egg load, mean hepatic granulomas diameter and numbers, percentage of collagen and expression of transforming growth factor-beta 1 (TGF-ß 1) in the examined hepatocytes with elevation in percentage of degenerated ova, in comparison to the control groups, in both acute and chronic stages of infection. The best results were obtained when Genistein was combined with PZQ. Therefore, it was concluded that Genistein showed a promising anti-schistosomal and anti-fibrotic properties which could make it one of the new potential targets in chemotherapy against schistosomiasis.
[Mh] Termos MeSH primário: Genisteína/uso terapêutico
Inibidores de Proteínas Quinases/uso terapêutico
Proteínas Tirosina Quinases/antagonistas & inibidores
Esquistossomose mansoni/tratamento farmacológico
[Mh] Termos MeSH secundário: Doença Aguda
Animais
Anti-Helmínticos/farmacologia
Anti-Helmínticos/uso terapêutico
Biomphalaria
Doença Crônica
Colágeno/análise
Feminino
Genisteína/farmacologia
Granuloma/tratamento farmacológico
Granuloma/patologia
Processamento de Imagem Assistida por Computador
Imuno-Histoquímica/veterinária
Fígado/química
Fígado/parasitologia
Fígado/patologia
Cirrose Hepática/tratamento farmacológico
Cirrose Hepática/parasitologia
Cirrose Hepática/patologia
Masculino
Camundongos
Praziquantel/farmacologia
Praziquantel/uso terapêutico
Inibidores de Proteínas Quinases/farmacologia
Schistosoma mansoni/efeitos dos fármacos
Schistosoma mansoni/patogenicidade
Esquistossomose mansoni/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anthelmintics); 0 (Protein Kinase Inhibitors); 6490C9U457 (Praziquantel); 9007-34-5 (Collagen); DH2M523P0H (Genistein); EC 2.7.10.1 (Protein-Tyrosine Kinases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180214
[Lr] Data última revisão:
180214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180115
[St] Status:MEDLINE


  2 / 18656 MEDLINE  
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[PMID]:29369209
[Au] Autor:Wang Y; Tang XY; Yuan J; Wu SQ; Chen G; Zhang MM; Wang MG; Zhang WY; He JQ
[Ad] Endereço:Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
[Ti] Título:Bone marrow granulomas in a high tuberculosis prevalence setting: A clinicopathological study of 110 cases.
[So] Source:Medicine (Baltimore);97(4):e9726, 2018 Jan.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Granulomas were reported in 0.3% to 3% of bone marrow biopsies. The aim of the study was to evaluate the incidence and etiology of bone marrow granulomas (BMGs) in the West China Hospital, which located at a high tuberculosis (TB) prevalence area in China.A retrospective case review was performed on 11,339 bone marrow biopsies at the West China Hospital of Sichuan University between January 2011 and December 2015. Cases with BMGs were retrieved and their clinical data and histopathological features were collected, examined, and analyzed.Out of 11,339, 110 cases showed granulomatous lesions in the bone marrow biopsies (0.97%). Etiologies were indentified in 80 cases (72.8%), with infections being the most common (64.5%), following by malignancies (4.5%) and autoimmune diseases (3.6%). Among infectious cases, 87.32% (62/71) cases were diagnosed as TB, a positive acid-fast stain or/and polymerase chain reaction (PCR) result for mycobacterium TB DNA fragment amplification was obtained for 35 cases. In 30 cases (27.27%), a definite diagnosis could not be established.In a TB high prevalence region in China, with a combined histological, clinical, serological, and molecular approach, we were able to clarify the cause in 72.73% of the bone marrow granulomatous cases. TB is the most common underlying etiologies. Therefore, acid-fast stain and quantitative PCR for mycobacterium TB DNA amplification are recommended as a routine for bone marrow biopsies in TB high prevalence regions.
[Mh] Termos MeSH primário: Doenças da Medula Óssea/etiologia
Granuloma/etiologia
Tuberculose Pulmonar/epidemiologia
[Mh] Termos MeSH secundário: Adulto
Doenças da Medula Óssea/diagnóstico
Doenças da Medula Óssea/epidemiologia
Brucelose/diagnóstico
China/epidemiologia
Diagnóstico Diferencial
Feminino
Granuloma/diagnóstico
Granuloma/epidemiologia
Seres Humanos
Masculino
Meia-Idade
Micoses/diagnóstico
Prevalência
Estudos Retrospectivos
Tuberculose Pulmonar/complicações
[Pt] Tipo de publicação:EVALUATION STUDIES; JOURNAL ARTICLE
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180208
[Lr] Data última revisão:
180208
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180126
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000009726


  3 / 18656 MEDLINE  
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[PMID]:29245330
[Au] Autor:Ahn JH; Kim JS; Choi JH; Chung JH
[Ad] Endereço:aDepartment of Internal Medicine, Regional Center for Respiratory Disease, Yeungnam University Medical CenterbDepartment of Pathology, College of Medicine, Yeungnam University, Daegu, Republic of Korea.
[Ti] Título:A first case report of pulmonary hyalinizing granuloma associated with immunoglobulin A nephropathy.
[So] Source:Medicine (Baltimore);96(49):e9088, 2017 Dec.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:RATIONALE: Pulmonary hyalinizing granuloma (PHG) is a rare benign disease that has been shown to be associated with the deposition of immune complexes in the lung parenchyma caused by infection or autoimmune diseases. There have been no reports of PHG in association with immunoglobulin A nephropathy (IgAN). PATIENT CONCERNS: A 30-year-old woman visited with a 12-month history of dyspnea on exertion and cough that had worsened 1 month before her visit. DIAGNOSIS: PHG associated with IgAN. INTERVENTIONS: Steroid pulse therapy was performed. OUTCOMES: The patient was discharged uneventfully. LESSONS: We present a case of PHG presenting as multiple pulmonary nodules mimicking metastatic lung cancer, which was diagnosed using wedge resection of the right middle lobe through video-assisted thoracoscopic surgery.
[Mh] Termos MeSH primário: Glomerulonefrite por IGA/complicações
Granuloma/patologia
Pneumopatias/patologia
[Mh] Termos MeSH secundário: Adulto
Broncoscopia
Terapia Combinada
Meios de Contraste
Diagnóstico Diferencial
Feminino
Granuloma/diagnóstico por imagem
Granuloma/tratamento farmacológico
Granuloma/cirurgia
Seres Humanos
Biópsia Guiada por Imagem
Pneumopatias/diagnóstico por imagem
Pneumopatias/tratamento farmacológico
Pneumopatias/cirurgia
Tomografia Computadorizada com Tomografia por Emissão de Pósitrons
Testes de Função Respiratória
Esteroides/uso terapêutico
Cirurgia Torácica Vídeoassistida
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Contrast Media); 0 (Steroids)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180108
[Lr] Data última revisão:
180108
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171217
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000009088


  4 / 18656 MEDLINE  
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[PMID]:27772637
[Au] Autor:Fogo AB; Lusco MA; Najafian B; Alpers CE
[Ad] Endereço:Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN. Electronic address: agnes.fogo@vanderbilt.edu.
[Ti] Título:AJKD Atlas of Renal Pathology: Pauci-immune Necrotizing Crescentic Glomerulonephritis.
[So] Source:Am J Kidney Dis;68(5):e31-e32, 2016 Nov.
[Is] ISSN:1523-6838
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/patologia
Glomerulonefrite/patologia
Rim/patologia
[Mh] Termos MeSH secundário: Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/metabolismo
Membrana Basal Glomerular/metabolismo
Membrana Basal Glomerular/patologia
Membrana Basal Glomerular/ultraestrutura
Glomerulonefrite/metabolismo
Granuloma/patologia
Seres Humanos
Rim/metabolismo
Rim/ultraestrutura
Túbulos Renais/metabolismo
Túbulos Renais/patologia
Túbulos Renais/ultraestrutura
Microscopia
Microscopia Eletrônica
Microscopia de Fluorescência
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171205
[Lr] Data última revisão:
171205
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE


  5 / 18656 MEDLINE  
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Texto completo SciELO Brasil
[PMID]:28954117
[Au] Autor:Fraga RC; Kakizaki P; Valente NYS; Portocarrero LKL; Teixeira MFS; Senise PF
[Ad] Endereço:Private clinic - Vitória (ES), Brazil.
[Ti] Título:Do you know this syndrome? Heerfordt-Waldenström syndrome.
[So] Source:An Bras Dermatol;92(4):571-572, 2017 Jul-Aug.
[Is] ISSN:1806-4841
[Cp] País de publicação:Brazil
[La] Idioma:eng
[Ab] Resumo:Heerfordt-Waldenström syndrome is a rare subacute variant of sarcoidosis, characterized by enlargement of the parotid or salivary glands, facial nerve paralysis and anterior uveitis. Granulomas with a peripheral lymphocyte deficit are found in the anatomic pathology of affected organs. It is normally self-limiting, with cure achieved between 12 and 36 months, but some prolonged cases have been reported. Diagnosis of the syndrome is clinical, and treatment depends on the degree of systemic impairment. Oral corticosteroids represent the first line treatment option. The mortality rate ranges between 1 and 5% of cases.
[Mh] Termos MeSH primário: Paralisia Facial/complicações
Doenças Parotídeas/diagnóstico
Febre Uveoparotídea/diagnóstico
[Mh] Termos MeSH secundário: Adulto
Feminino
Granuloma/patologia
Seres Humanos
Doenças Parotídeas/complicações
Síndrome
Febre Uveoparotídea/complicações
[Pt] Tipo de publicação:CASE REPORTS
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170928
[St] Status:MEDLINE


  6 / 18656 MEDLINE  
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[PMID]:28934421
[Au] Autor:Madigan CA; Cameron J; Ramakrishnan L
[Ad] Endereço:Department of Microbiology.
[Ti] Título:A Zebrafish Model of Mycobacterium leprae Granulomatous Infection.
[So] Source:J Infect Dis;216(6):776-779, 2017 Sep 15.
[Is] ISSN:1537-6613
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Understanding the pathogenesis of leprosy granulomas has been hindered by a paucity of tractable experimental animal models. Mycobacterium leprae, which causes leprosy, grows optimally at approximately 30°C, so we sought to model granulomatous disease in the ectothermic zebrafish. We found that noncaseating granulomas develop rapidly and eventually eradicate infection. rag1 mutant zebrafish, which lack lymphocytes, also form noncaseating granulomas with similar kinetics, but these control infection more slowly. Our findings establish the zebrafish as a facile, genetically tractable model for leprosy and reveal the interplay between innate and adaptive immune determinants mediating leprosy granuloma formation and function.
[Mh] Termos MeSH primário: Modelos Animais de Doenças
Granuloma/microbiologia
Hanseníase/microbiologia
Mycobacterium leprae
[Mh] Termos MeSH secundário: Animais
Masculino
Peixe-Zebra
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170922
[St] Status:MEDLINE
[do] DOI:10.1093/infdis/jix329


  7 / 18656 MEDLINE  
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[PMID]:28902908
[Au] Autor:Amaral KB; Silva TP; Dias FF; Malta KK; Rosa FM; Costa-Neto SF; Gentile R; Melo RCN
[Ad] Endereço:Laboratory of Cellular Biology, Department of Biology, Federal University of Juiz de Fora (UFJF), Juiz de Fora, MG, Brazil.
[Ti] Título:Histological assessment of granulomas in natural and experimental Schistosoma mansoni infections using whole slide imaging.
[So] Source:PLoS One;12(9):e0184696, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The pathology of schistosomiasis mansoni, a neglected tropical disease of great clinical and socioeconomic importance, results from the parasite eggs that become trapped in host tissues, particularly in the liver and intestines. Continuous antigenic stimulation from these eggs leads to recruitment of inflammatory cells to the sites of infection with formation of periovular granulomas. These complex structures have variable size and composition and are the most striking histopathological feature of schistosomiasis mansoni. However, evaluation of granulomas by conventional microscopy methods is time-consuming and limited, especially in large-scale studies. Here, we used high resolution Whole Slide Imaging (WSI), which allows fast scanning of entire histological slides, and multiple morphometric evaluations, to assess the granulomatous response elicited in target organs (liver, small and large intestines) of two models of schistosomiasis mansoni. One of the advantages of WSI, also termed virtual microscopy, is that it generates images that simultaneously offer high resolution and a wide field of observation. By using a model of natural (Nectomys squamipes, a wild reservoir captured from endemic areas in Brazil) and experimental (Swiss mouse) infection with Schistosoma mansoni, we provided the first detailed WSI characterization of granulomas and other pathological aspects. WSI and quantitative analyses enabled a fast and reliable assessment of the number, evolutional types, frequency and areas of granulomas and inflammatory infiltrates and revealed that target organs are differentially impacted by inflammatory responses in the natural and experimental infections. Remarkably, high-resolution analysis of individual eosinophils, key cells elicited by this helminthic infection, showed a great difference in eosinophil numbers between the two infections. Moreover, features such as the intestinal egg path and confluent granulomas were uncovered. Thus, WSI may be a suitable tool for detailed and precise histological analysis of granulomas and other pathological aspects for clinical and research studies of schistosomiasis.
[Mh] Termos MeSH primário: Arvicolinae/parasitologia
Granuloma/patologia
Doenças Negligenciadas/patologia
Esquistossomose mansoni/patologia
[Mh] Termos MeSH secundário: Animais
Granuloma/parasitologia
Processamento de Imagem Assistida por Computador/métodos
Intestino Delgado/parasitologia
Intestino Delgado/patologia
Fígado/parasitologia
Fígado/patologia
Camundongos
Microscopia/métodos
Doenças Negligenciadas/parasitologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170914
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184696


  8 / 18656 MEDLINE  
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[PMID]:28885868
[Au] Autor:Adenuga D; Goyak K; Lewis RJ
[Ad] Endereço:a ExxonMobil Biomedical Sciences, Inc. , Annandale , NJ , USA.
[Ti] Título:Evaluating the MoA/human relevance framework for F-344 rat liver epithelioid granulomas with mineral oil hydrocarbons.
[So] Source:Crit Rev Toxicol;47(9):750-766, 2017 Oct.
[Is] ISSN:1547-6898
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Toxicology feeding studies of mineral oil hydrocarbons (MOHs), within the carbon number range C -C , results in species-specific epithelioid granulomas in the liver of F-344 rats but not in other rat strains, or species. While MOH has been detected, and some pathological effects have been shown to occur in other organs/tissues of F-344 rats and other rat strains/species, it is generally accepted that the effect of toxicological concern is species-specific inflammatory liver granuloma. As oil retention and other MOH-related nontoxic pathological changes in the liver are observed in humans, some have hypothesized that the potential for oil accumulation over a lifetime, through dietary sources, may predispose humans to similar liver effects as observed in F-344 rats. To address this concern, a mode of action/human relevance framework (MoA/HRF) analysis for MOH-induced epithelioid granuloma in the F-344 rat model was developed. The key events for the development of liver epithelioid granulomas were identified as increased MOH intestinal absorption, preferential tissue retention and ultimately formation of necrotic granulomas encased by infiltrating inflammatory lymphocytes. The hypothesized MoA was evaluated using the modified Bradford Hill considerations for causality and was considered to be established in the F-344 rodent model. However, key strain/species differences in the rate of intestinal absorption, tissue retention of MOH and inflammatory response to MOH in the liver were identified. Overall, the F-344 rat MoA was not considered to be relevant to humans, consistent with data showing no evidence for the formation of epithelioid granulomas with humans even in cases of massive ingestion of MOHs.
[Mh] Termos MeSH primário: Granuloma/induzido quimicamente
Hidrocarbonetos/metabolismo
Neoplasias Hepáticas/induzido quimicamente
Óleo Mineral/toxicidade
[Mh] Termos MeSH secundário: Animais
Seres Humanos
Hidrocarbonetos/toxicidade
Fígado/efeitos dos fármacos
Fígado/metabolismo
Óleo Mineral/química
Ratos
Especificidade da Espécie
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Hydrocarbons); 8020-83-5 (Mineral Oil)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170909
[St] Status:MEDLINE
[do] DOI:10.1080/10408444.2017.1319336


  9 / 18656 MEDLINE  
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[PMID]:28880895
[Au] Autor:Phillips BL; Gautam US; Bucsan AN; Foreman TW; Golden NA; Niu T; Kaushal D; Mehra S
[Ad] Endereço:Tulane National Primate Research Center, Covington, Louisiana, United States of America.
[Ti] Título:LAG-3 potentiates the survival of Mycobacterium tuberculosis in host phagocytes by modulating mitochondrial signaling in an in-vitro granuloma model.
[So] Source:PLoS One;12(9):e0180413, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:CD4+ T-cell mediated Th1 immune responses are critical for immunity to TB. The immunomodulatory protein, lymphocyte activation gene-3 (LAG-3) decreases Th1-type immune responses in T-cells. LAG-3 expression is significantly induced in the lungs of macaques with active TB and correlates with increased bacterial burden. Overproduction of LAG-3 can greatly diminish responses and could lead to uncontrolled Mtb replication. To assess the effect of LAG-3 on the progression of Mtb infection, we developed a co-culture system wherein blood-derived macrophages are infected with Mtb and supplemented with macaque blood or lung derived CD4+ T-cells. Silencing LAG-3 signaling in macaque lung CD4+ T-cells enhanced killing of Mtb in co-cultures, accompanied by reduced mitochondrial electron transport and increased IFN-γ expression. Thus, LAG-3 may modulate adaptive immunity to Mtb infection by interfering with the mitochondrial apoptosis pathway. Better understanding this pathway could allow us to circumvent immune features that promote disease.
[Mh] Termos MeSH primário: Antígenos CD/metabolismo
Granuloma/metabolismo
Mycobacterium tuberculosis/imunologia
Mycobacterium tuberculosis/patogenicidade
Fagócitos/metabolismo
Fagócitos/microbiologia
[Mh] Termos MeSH secundário: Imunidade Adaptativa/genética
Imunidade Adaptativa/fisiologia
Animais
Antígenos CD/genética
Linfócitos T CD4-Positivos/metabolismo
Diferenciação Celular/fisiologia
Células Cultivadas
Técnicas de Cocultura
Citometria de Fluxo
Granuloma/imunologia
Granuloma/microbiologia
Macaca mulatta
Microscopia Confocal
Mitocôndrias/imunologia
Mitocôndrias/metabolismo
Mitocôndrias/microbiologia
Fagócitos/imunologia
RNA Interferente Pequeno/genética
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Transdução de Sinais/fisiologia
Transcriptoma/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, CD); 0 (CD223 antigen); 0 (RNA, Small Interfering)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170908
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0180413


  10 / 18656 MEDLINE  
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[PMID]:28821621
[Au] Autor:Khan MZ; Bhaskar A; Upadhyay S; Kumari P; Rajmani RS; Jain P; Singh A; Kumar D; Bhavesh NS; Nandicoori VK
[Ad] Endereço:From the National Institute of Immunology and.
[Ti] Título:Protein kinase G confers survival advantage to during latency-like conditions.
[So] Source:J Biol Chem;292(39):16093-16108, 2017 Sep 29.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Protein kinase G (PknG), a thioredoxin-fold-containing eukaryotic-like serine/threonine protein kinase, is a virulence factor in , required for inhibition of phagolysosomal fusion. Here, we unraveled novel functional facets of PknG during latency-like conditions. We found that PknG mediates persistence under stressful conditions like hypoxia and abets drug tolerance. PknG mutant displayed minimal growth in nutrient-limited conditions, suggesting its role in modulating cellular metabolism. Intracellular metabolic profiling revealed that PknG is necessary for efficient metabolic adaptation during hypoxia. Notably, the PknG mutant exhibited a reductive shift in mycothiol redox potential and compromised stress response. Exposure to antibiotics and hypoxic environment resulted in higher oxidative shift in mycothiol redox potential of PknG mutant compared with the wild type. Persistence during latency-like conditions required kinase activity and thioredoxin motifs of PknG and is mediated through phosphorylation of a central metabolic regulator GarA. Finally, using a guinea pig model of infection, we assessed the role of PknG in manifestation of disease pathology and established a role for PknG in the formation of stable granuloma, hallmark structures of latent tuberculosis. Taken together, PknG-mediated GarA phosphorylation is important for maintenance of both mycobacterial physiology and redox poise, an axis that is dispensable for survival under normoxic conditions but is critical for non-replicating persistence of mycobacteria. In conclusion, we propose that PknG probably acts as a modulator of latency-associated signals.
[Mh] Termos MeSH primário: Antígenos de Bactérias/metabolismo
Proteínas de Bactérias/metabolismo
Granuloma/etiologia
Tuberculose Latente/microbiologia
Mycobacterium tuberculosis/metabolismo
Processamento de Proteína Pós-Traducional
Proteínas Serina-Treonina Quinases/metabolismo
[Mh] Termos MeSH secundário: Motivos de Aminoácidos
Substituição de Aminoácidos
Animais
Antibióticos Antituberculose/farmacologia
Antígenos de Bactérias/genética
Proteínas de Bactérias/química
Proteínas de Bactérias/genética
Feminino
Deleção de Genes
Granuloma/metabolismo
Granuloma/microbiologia
Cobaias
Isoniazida/farmacologia
Cinética
Tuberculose Latente/metabolismo
Tuberculose Latente/fisiopatologia
Metabolômica/métodos
Viabilidade Microbiana/efeitos dos fármacos
Mycobacterium tuberculosis/efeitos dos fármacos
Mycobacterium tuberculosis/crescimento & desenvolvimento
Mycobacterium tuberculosis/fisiologia
Fosforilação/efeitos dos fármacos
Mutação Puntual
Processamento de Proteína Pós-Traducional/efeitos dos fármacos
Proteínas Serina-Treonina Quinases/química
Proteínas Serina-Treonina Quinases/genética
Estresse Fisiológico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibiotics, Antitubercular); 0 (Antigens, Bacterial); 0 (Bacterial Proteins); 0 (CFP17 protein, Mycobacterium tuberculosis); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.1 (protein kinase G, Mycobacterium tuberculosis); V83O1VOZ8L (Isoniazid)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170820
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.797563



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