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1.
BMC Public Health ; 21(1): 1835, 2021 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-34635086

RESUMO

BACKGROUND: According to the World Health Organization, the coronavirus disease 2019 (COVID-19) pandemic has created situations that have a negative effect on people and threaten their mental health. Paraguay announced the Estado de Emergencia Sanitaria (Presidential Decree No. 3456) on March 16, 2020, which was followed by the imposition of a 24-h restriction on movement order on March 21. Self-quarantine at home may have been the most effective method of preventing the spread of infectious diseases; however, with the global pandemic becoming more prolonged and the consequent lengthening of the 24-h self-quarantine period, it is highly probable that both physical and psychological problems will arise. METHODS: In this study, a web-based cross-sectional method was used to analyze the factors influencing COVID-19-induced depressive feelings in Paraguayan public officials. RESULTS: Public officials reported a high level of depressive symptoms with a high level of apprehension in early stage of COVID-19. In addition, this study identified that when the self-quarantine period increased, levels of depressive feelings also increased. Since self-quarantine is characterized by the requirement that individuals endure an undetermined period within a confined area, it may have caused stress and anxiety, as well as the consequent experience of depressive feelings. CONCLUSIONS: Paraguayan government should develop a program for the delivery of mental health care and services to public officials in COVID-19 Pandemic period. Moreover, a program is required for people facing deteriorating mental health due to social isolation and loneliness caused by social distancing during the prolonged period of self-quarantine. Finally, mental health care programs should be organized in a community-focused way by utilizing online systems to enhance the effectiveness of mental health recovery.

2.
J Public Health Res ; 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34340299

RESUMO

BACKGROUND: The World Health Organization (WHO) defines the double burden of malnutrition as the new face of malnutrition. This is a serious problem in Latin American countries, especially Paraguay, which has a high obesity rate. This study aimed to gather data to inform a national strategy for confronting the double-burden challenge in Paraguay by 1) identifying whether the body mass index (BMI) of study subjects differed significantly according to social determinants, and 2) assessing the factors affecting BMI and the extent of their impact according to BMI quantile levels. DESIGN AND METHODS: Data were collected using a questionnaire adapted from the WHO World Health Survey. We collected 2,200 responses from September 16 to October 7, 2018. After excluding the questionnaires with missing data, we analyzed 1,994 respondents aged 17 years and older living in Limpio, Paraguay. The analyses included t-test and chi-squared test to identify significant differences and 10th quantile regression to assess associations. RESULTS: Analyses showed significant differences in participants' BMI levels based on age and diagnoses of diabetes or hypertension. In quantile regression analyses, age was significantly associated with BMI quantiles at all but one level. Educational attainment was significantly associated with the 10%-40% and 60%-70% quantiles of BMI. CONCLUSIONS: Age, education level, diabetes, and hypertension were significant predictors of obesity. Obesity programs that focus on people aged more than 60 years are required. In addition, targeted nutritional education may be a useful intervention.

4.
Theranostics ; 11(16): 8092-8111, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335982

RESUMO

Active c-Src non-receptor tyrosine kinase localizes to the plasma membrane via N-terminal lipid modification. Membranous c-Src causes cancer initiation and progression. Even though transmembrane 4 L six family member 5 (TM4SF5), a tetraspan(in), can be involved in this mechanism, the molecular and structural influence of TM4SF5 on c-Src remains unknown. Methods: Here, we investigated molecular and structural details by which TM4SF5 regulated c-Src devoid of its N-terminus and how cell-penetrating peptides were able to interrupt c-Src activation via interference of c-Src-TM4SF5 interaction in hepatocellular carcinoma models. Results: The TM4SF5 C-terminus efficiently bound the c-Src SH1 kinase domain, efficiently to the inactively-closed form. The complex involved protein tyrosine phosphatase 1B able to dephosphorylate Tyr530. The c-Src SH1 domain alone, even in a closed form, bound TM4SF5 to cause c-Src Tyr419 and FAK Y861 phosphorylation. Homology modeling and molecular dynamics simulation studies predicted the directly interfacing residues, which were further validated by mutational studies. Cell penetration of TM4SF5 C-terminal peptides blocked the interaction of TM4SF5 with c-Src and prevented c-Src-dependent tumor initiation and progression in vivo. Conclusions: Collectively, these data demonstrate that binding of the TM4SF5 C-terminus to the kinase domain of inactive c-Src leads to its activation. Because this binding can be abolished by cell-penetrating peptides containing the TM4SF5 C-terminus, targeting this direct interaction may be an effective strategy for developing therapeutics that block the development and progression of hepatocellular carcinoma.


Assuntos
Proteína Tirosina Quinase CSK/metabolismo , Carcinoma Hepatocelular/metabolismo , Proteínas de Membrana/metabolismo , Proteína Tirosina Quinase CSK/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Genes src/genética , Genes src/fisiologia , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/fisiologia , Peptídeos/metabolismo , Fosforilação , Proteínas Tirosina Quinases/metabolismo , Transdução de Sinais , Tetraspaninas/genética , Tetraspaninas/metabolismo
5.
Sci Rep ; 11(1): 14745, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285309

RESUMO

The first aim of this study was to develop a prothrombin time international normalized ratio (PT INR) prediction model. The second aim was to develop a warfarin maintenance dose decision support system as a precise warfarin dosing platform. Data of 19,719 inpatients from three institutions was analyzed. The PT INR prediction algorithm included dense and recurrent neural networks, and was designed to predict the 5th-day PT INR from data of days 1-4. Data from patients in one hospital (n = 22,314) was used to train the algorithm which was tested with the datasets from the other two hospitals (n = 12,673). The performance of 5th-day PT INR prediction was compared with 2000 predictions made by 10 expert physicians. A generator of individualized warfarin dose-PT INR tables which simulated the repeated administration of varying doses of warfarin was developed based on the prediction model. The algorithm outperformed humans with accuracy terms of within ± 0.3 of the actual value (machine learning algorithm: 10,650/12,673 cases (84.0%), expert physicians: 1647/2000 cases (81.9%), P = 0.014). In the individualized warfarin dose-PT INR tables generated by the algorithm, the 8th-day PT INR predictions were within 0.3 of actual value in 450/842 cases (53.4%). An artificial intelligence-based warfarin dosing algorithm using a recurrent neural network outperformed expert physicians in predicting future PT INRs. An individualized warfarin dose-PT INR table generator which was constructed based on this algorithm was acceptable.

6.
FASEB J ; 35(3): e21369, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33554392

RESUMO

Transmembrane 4 L six family member 5 (TM4SF5) translocates intracellularly and promotes cell migration, but how subcellular TM4SF5 traffic is regulated to guide cellular migration is unknown. We investigated the influences of the extracellular environment and intracellular signaling on the TM4SF5 traffic with regard to migration directionality. Cell adhesion to fibronectin (FN) but not poly-l-lysine enhanced the traffic velocity and straightness of the TM4SF5WT (but not palmitoylation-deficient mutant TM4SF5 Pal - ) toward the leading edges, depending on tubulin acetylation. Acetylated-microtubules in SLAC2B-positive cells reached mostly the juxtanuclear regions, but reached-out toward the leading edges upon SLAC2B suppression. TM4SF5 expression caused SLAC2B not to be localized at the leading edges. TM4SF5 colocalization with HDAC6 depended on paxillin expression. The trimeric complex consisting of TM4SF5, HDAC6, and SLAC2B might, thus, be enriched at the perinuclear cytosols toward the leading edges. More TM4SF5WT translocation to the leading edges was possible when acetylated-microtubules reached the frontal edges following HDAC6 inhibition by paxillin presumably at new cell-FN adhesions, leading to persistent cell migration. Collectively, this study revealed that cell-FN adhesion and microtubule acetylation could control intracellular traffic of TM4SF5 vesicles to the leading edges via coordinated actions of paxillin, SLAC2B, and HDAC6, leading to TM4SF5-dependent cell migration.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Membrana Celular/metabolismo , Matriz Extracelular/fisiologia , Proteínas de Membrana/metabolismo , Microtúbulos/metabolismo , Acetilação , Adesão Celular , Movimento Celular , Fibronectinas/fisiologia , Células Hep G2 , Desacetilase 6 de Histona/fisiologia , Humanos , Paxilina/fisiologia , Transporte Proteico
7.
Global Health ; 17(1): 3, 2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33402174

RESUMO

BACKGROUND: The World Health Organization (WHO) declared coronavirus disease (COVID-19) a pandemic on March 11, 2020. Previous studies of infectious diseases showed that infectious diseases not only cause physical damage to infected individuals but also damage to the mental health of the public. Therefore this study aims to analyze the factors that affected depression in the public during the COVID-19 pandemic to provide evidence for COVID-19-related mental health policies and to emphasize the need to prepare for mental health issues related to potential infectious disease outbreaks in the future. RESULTS: This study performed the following statistical analyses to analyze the factors that influence depression in the public during the COVID-19 pandemic. First, to confirm the level of depression in the public in each country, the participants' depression was plotted on a Boxplot graph for analysis. Second, to confirm personal and national factors that influence depression in individuals, a multi-level analysis was conducted. As a result, the median Patient Health Questionnaire-9 (PHQ-9) score for all participants was 6. The median was higher than the overall median for the Philippines, Indonesia, and Paraguay, suggesting a higher level of depression. In personal variables, depression was higher in females than in males, and higher in participants who had experienced discrimination due to COVID-19 than those who had not. In contrast, depression was lower in older participants, those with good subjective health, and those who practiced personal hygiene for prevention. In national variables, depression was higher when the Government Response Stringency Index score was higher, when life expectancy was higher, and when social capital was higher. In contrast, depression was lower when literacy rates were higher. CONCLUSIONS: Our study reveals that depression was higher in participants living in countries with higher stringency index scores than in participants living in other countries. Maintaining a high level of vigilance for safety cannot be criticized. However, in the current situation, where coexisting with COVID-19 has become inevitable, inflexible and stringent policies not only increase depression in the public, but may also decrease resilience to COVID-19 and compromise preparations for coexistence with COVID-19. Accordingly, when establishing policies such as social distancing and quarantine, each country should consider the context of their own country.


Assuntos
COVID-19/epidemiologia , Depressão/epidemiologia , Adulto , Fatores Etários , Controle de Doenças Transmissíveis/métodos , Estudos Transversais , Feminino , Saúde Global , Nível de Saúde , Humanos , Expectativa de Vida , Masculino , Saúde Mental , Pandemias , Fatores de Risco , SARS-CoV-2 , Índice de Gravidade de Doença , Fatores Sexuais , Capital Social , Fatores Socioeconômicos
8.
J Pathol ; 253(1): 55-67, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32918742

RESUMO

Nonalcoholic fatty liver disease is a chronic condition involving steatosis, steatohepatitis and fibrosis, and its progression remains unclear. Although the tetraspanin transmembrane 4 L six family member 5 (TM4SF5) is involved in hepatic fibrosis and cancer, its role in nonalcoholic steatohepatitis (NASH) progression is unknown. We investigated the contribution of TM4SF5 to liver pathology using transgenic and KO mice, diet- or drug-treated mice, in vitro primary cells, and in human tissue. TM4SF5-overexpressing mice exhibited nonalcoholic steatosis and NASH in an age-dependent manner. Initially, TM4SF5-positive hepatocytes and liver tissue exhibited lipid accumulation, decreased Sirtuin 1 (SIRT1), increased sterol regulatory-element binding proteins (SREBPs) and inactive STAT3 via suppressor of cytokine signaling (SOCS)1/3 upregulation. In older mice, TM4SF5 promoted inflammatory factor induction, SIRT1 expression and STAT3 activity, but did not change SOCS or SREBP levels, leading to active STAT3-mediated ECM production for NASH progression. A TM4SF5-associated increase in chemokines promoted SIRT1 expression and progression to NASH with fibrosis. Suppression of the chemokine CCL20 reduced immune cell infiltration and ECM production. Liver tissue from high-fat diet- or CCl4 -treated mice and human patients exhibited TM4SF5-dependent steatotic or steatohepatitic livers with links between TM4SF5-mediated SIRT1 modulation and SREBP or SOCS/STAT3 signaling axes. TM4SF5-mediated STAT3 activation in fibrotic NASH livers increased collagen I and laminin γ2. Both collagen I α1 and laminin γ2 suppression resulted in reduced SIRT1 and active STAT3, but no change in SREBP1 or SOCS, and abolished CCl4 -mediated mouse liver damage. TM4SF5-mediated signaling pathways that involve SIRT1, SREBPs and SOCS/STAT3 promoted progression to NASH. Therefore, TM4SF5 and its downstream effectors may be promising therapeutic targets to treat nonalcoholic fatty liver disease. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Matriz Extracelular/enzimologia , Metabolismo dos Lipídeos , Cirrose Hepática Experimental/enzimologia , Fígado/enzimologia , Proteínas de Membrana/metabolismo , Hepatopatia Gordurosa não Alcoólica/enzimologia , Sirtuína 1/metabolismo , Animais , Tetracloreto de Carbono , Linhagem Celular Tumoral , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Dieta Hiperlipídica , Progressão da Doença , Matriz Extracelular/patologia , Humanos , Fígado/patologia , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/genética , Cirrose Hepática Experimental/patologia , Proteínas de Membrana/genética , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Transdução de Sinais
9.
J Public Health Policy ; 42(1): 15-26, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33087849

RESUMO

In a recent report, the British Broadcasting Company (BBC) introduced South Korea's measures to manage COVID-19 as role model for the world. Screening centers serve as frontiers for preventing community transmission of infectious diseases. COVID-19 screening centers in Korea operate 24 h a day, always open for individuals with suspected COVID-19 symptoms. South Korea concentrated COVID-19 screening centers around cities with high population density. Advanced screening centers (models C, D, and E) proved more effective and efficient in the prevention of COVID-19 than the traditional screening centers (models A and B). Particularly, screening centers at Incheon Airport in South Korea prevent transmission through imported cases effectively. It will be important elsewhere, as in South Korea, to establish an infectious disease delivery system that can lead to 'Test-Treat-Track' using an adequate model of screening centers.


Assuntos
Teste para COVID-19/métodos , COVID-19/prevenção & controle , Controle de Doenças Transmissíveis/métodos , Programas de Rastreamento/métodos , Pneumonia Viral/prevenção & controle , COVID-19/epidemiologia , Humanos , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , República da Coreia/epidemiologia , SARS-CoV-2
10.
Nutrients ; 12(11)2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33105861

RESUMO

This randomized controlled study aimed to assess the efficacy and safety of an extract mixture of kudzu flower and mandarin peel (KM) on hot flashes (HFs) and markers of bone turnover in women during the menopausal transition. Healthy women aged 45-60 years with the menopausal HFs were randomly assigned in a 1:1 ratio to either KM (1150 mg/day) or placebo arms for 12 weeks (n = 84). The intent-to-treat analysis found that compared with the placebo, the KM significantly attenuated HF scores (p = 0.041) and HF severities (p < 0.001), with a mean difference from baseline to week 12. The KM also improved bone turnover markers, showing a significant reduction in bone resorption CTx (p = 0.027) and a tendency of increasing bone formation OC relative to the placebo. No serious adverse events and hormonal changes were observed in both groups. These findings suggest that KM consumption may improve the quality of life in ways that are important to symptomatic menopausal women.


Assuntos
Reabsorção Óssea/tratamento farmacológico , Citrus , Fogachos/tratamento farmacológico , Perimenopausa , Extratos Vegetais/uso terapêutico , Pós-Menopausa , Pueraria , Feminino , Flores , Humanos , Pessoa de Meia-Idade , Fitoterapia , Extratos Vegetais/administração & dosagem
11.
AJR Am J Roentgenol ; 215(3): 624-630, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32755157

RESUMO

OBJECTIVE. The purposes of this study were to evaluate the accuracy of a semiautomatic method of measuring liver surface nodularity (LSN) on contrast-enhanced MR images and to compare the LSN score with pathologic fibrosis stage. MATERIALS AND METHODS. This retrospective study included patients who had undergone gadoxetate disodium-enhanced liver MRI 6 months before or after histopathologic investigation including percutaneous parenchymal biopsy and surgical biopsy for staging of chronic liver disease between January 2010 and December 2018. Semiautomated LSN quantification software was developed to measure LSN at MRI. Aspartate aminotransferase to platelet ratio index and fibrosis-4 index were derived from serum laboratory test results. The reference standard for staging of liver fibrosis was Metavir score. The accuracy of LSN score for staging of liver fibrosis was evaluated with AUC, and the optimal cutoff value was calculated by Youden index. Spearman correlation coefficient was used for correlation analysis. RESULTS. The study included 132 patients (93 men, 39 women). LSN score was evaluated without technical failure. There was high correlation between LSN score and Metavir score (Spearman ρ = 0.713, p < 0.001). The AUCs of LSN score for distinguishing Metavir score were 0.93 for F0-F1 versus F2-F4 (95% CI, 0.88-0.97; p < 0.001), 0.98 for F0-F2 vs F3-F4 (95% CI, 0.95-1.00; p < 0.001), and 0.83 for F0-F3 versus F4 (95% CI, 0.76-0.90; p < 0.001). The optimal cutoff value for differentiating F0-F2 from F3-F4 was 0.850 with 100% sensitivity and 85.4% specificity. CONCLUSION. LSN score calculated semiautomatically from MR images of the liver has high accuracy and correlates directly with the pathologic fibrosis stage.


Assuntos
Cirrose Hepática/patologia , Imageamento por Ressonância Magnética/métodos , Biópsia , Meios de Contraste , Feminino , Gadolínio DTPA , Humanos , Interpretação de Imagem Assistida por Computador , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sensibilidade e Especificidade
12.
Sci Rep ; 10(1): 10452, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32591563

RESUMO

In sarcopenic obesity, the importance of evaluating muscle and fat mass is unquestionable. There exist diverse quantification methods for assessing muscle and fat mass by imaging techniques; thus these methods must be standardized for clinical practice. This study developed a quantification software for the body composition imaging using abdominal magnetic resonance (MR) images and compared the difference between sarcopenic obesity and healthy controls for clinical application. Thirty patients with sarcopenic obesity and 30 healthy controls participated. The quantification software was developed based on an ImageJ multiplatform and the processing steps are as follows: execution, setting, confirmation, and extraction. The variation in the muscle area (MA), subcutaneous fat area (SA), and visceral fat area (VA) was analyzed with an independent two sample T-test. There were significant differences in SA (p < 0.001) and VA (p = 0.011), whereas there was no difference in MA (p = 0.421). Regarding the ratios, there were significant differences in MA/SA (p < 0.001), MA/VA (p = 0.002), and MA/(SA + VA) (p < 0.001). Overall, intraclass correlation coefficients were higher than 0.9, indicating excellent reliability. This study developed customized sarcopenia-software for assessing body composition using abdominal MR images. The clinical findings demonstrate that the quantitative body composition areas and ratios can assist in the differential diagnosis of sarcopenic obesity or sarcopenia.


Assuntos
Composição Corporal , Obesidade/diagnóstico , Sarcopenia/diagnóstico , Abdome/diagnóstico por imagem , Estudos de Casos e Controles , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Obesidade/diagnóstico por imagem , Obesidade/patologia , Sarcopenia/patologia , Software
13.
Int J Infect Dis ; 96: 399-407, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32417247

RESUMO

OBJECTIVE: The World Health Organization (WHO) declared a COVID-19 pandemic on March 12, 2020. Several studies have indicated that densely populated urban environments and the heavy dependence on traffic could increase the potential spread of COVID-19. This study investigated the association between changes in traffic volume and the spread of COVID-19 in South Korea. METHODS: This study analyzed the daily national traffic and traffic trend for 3 months from January 1, 2020. Traffic data were measured using 6307 vehicle detection system (VDS). This study analyzed the difference in traffic levels between 2019 and 2020. Non-linear regression was performed to analyze the change in traffic trend in 2020. The relationship between traffic and confirmed COVID-19 cases was analyzed using single linear regression. RESULTS: The mean daily nationwide level of traffic for the first 3 months of 2020 was 143 655 563 vehicles, which was 9.7% lower than the same period in 2019 (159 044 566 vehicles). All regions showed a decreasing trend in traffic in February, which shifted to an increasing trend from March. In Incheon there was a positive, but insignificant, linear relationship between increasing numbers of newly confirmed cases and increasing traffic (ß = 43 146; p = 0.056). CONCLUSIONS: Numbers of newly confirmed COVID-19 patients have been decreasing since March, while the traffic has been increasing. The fact that traffic is increasing indicates greater contact between people, which in turn increases the risk of further COVID-19 spread. Therefore, the government will need to devise suitable policies, such as total social distancing.


Assuntos
Betacoronavirus , Infecções por Coronavirus/epidemiologia , Pneumonia Viral/epidemiologia , Condução de Veículo , COVID-19 , Humanos , Pandemias , Prevalência , República da Coreia/epidemiologia , SARS-CoV-2
14.
Exp Mol Med ; 52(1): 7-14, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31956272

RESUMO

Transmembrane 4 L6 family member 5 (TM4SF5) is a tetraspanin that has four transmembrane domains and can be N-glycosylated and palmitoylated. These posttranslational modifications of TM4SF5 enable homophilic or heterophilic binding to diverse membrane proteins and receptors, including growth factor receptors, integrins, and tetraspanins. As a member of the tetraspanin family, TM4SF5 promotes protein-protein complexes for the spatiotemporal regulation of the expression, stability, binding, and signaling activity of its binding partners. Chronic diseases such as liver diseases involve bidirectional communication between extracellular and intracellular spaces, resulting in immune-related metabolic effects during the development of pathological phenotypes. It has recently been shown that, during the development of fibrosis and cancer, TM4SF5 forms protein-protein complexes with amino acid transporters, which can lead to the regulation of cystine uptake from the extracellular space to the cytosol and arginine export from the lysosomal lumen to the cytosol. Furthermore, using proteomic analyses, we found that diverse amino acid transporters were precipitated with TM4SF5, although these binding partners need to be confirmed by other approaches and in functionally relevant studies. This review discusses the scope of the pathological relevance of TM4SF5 and its binding to certain amino acid transporters.

15.
Sci Rep ; 9(1): 15002, 2019 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-31628409

RESUMO

Liver biopsy is the reference standard test to differentiate between non-alcoholic steatohepatitis (NASH) and simple steatosis (SS) in non-alcoholic fatty liver disease (NAFLD), but noninvasive diagnostics are warranted. The diagnostic accuracy in NASH using MR imaging modality have not yet been clearly identified. This study was assessed the accuracy of magnetic resonance imaging (MRI) method for diagnosing NASH. Data were extracted from research articles obtained after a literature search from multiple electronic databases. Random-effects meta-analyses were performed to obtain overall effect size of the area under the receiver operating characteristic(ROC) curve, sensitivity, specificity, likelihood ratios(LR), diagnostic odds ratio(DOR) of MRI method in detecting histopathologically-proven SS(or non-NASH) and NASH. Seven studies were analyzed 485 patients, which included 207 SS and 278 NASH. The pooled sensitivity was 87.4% (95% CI, 76.4-95.3) and specificity was 74.3% (95% CI, 62.4-84.6). Pooled positive LR was 2.59 (95% CI, 1.96-3.42) and negative LR was 0.17 (95% CI, 0.07-0.38). DOR was 21.57 (95% CI, 7.27-63.99). The area under the curve of summary ROC was 0.89. Our meta-analysis shows that the MRI-based diagnostic methods are valuable additions in detecting NASH.


Assuntos
Confiabilidade dos Dados , Fígado/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Curva ROC , Sensibilidade e Especificidade
16.
Cell Death Dis ; 10(9): 645, 2019 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501417

RESUMO

Reactive oxygen species (ROS) regulate cell fate, although signaling molecules that regulate ROS hormesis remain unclear. Here we show that transmembrane 4 L six family member 5 (TM4SF5) in lung epithelial cells induced the alternatively spliced CD44v8-10 variant via an inverse ZEB2/epithelial splicing regulatory proteins (ESRPs) linkage. TM4SF5 formed complexes with the cystine/glutamate antiporter system via TM4SF5- and CD44v8-10-dependent CD98hc plasma-membrane enrichment. Dynamic TM4SF5 binding to CD98hc required CD44v8-10 under ROS-generating inflammatory conditions. TM4SF5 and CD44v8-10 upregulated cystine/glutamate antiporter activity and intracellular glutathione levels, leading to ROS modulation for cell survival. Tm4sf5-null mice exhibited attenuated bleomycin-induced pulmonary fibrosis with lower CD44v8-10 and ESRPs levels than wild-type mice. Primary mouse alveolar epithelial cells (AECs) revealed type II AECs (AECII), but not type I, to adapt the TM4SF5-mediated characteristics, suggesting TM4SF5-mediated AECII survival following AECI injury during idiopathic pulmonary fibrosis (IPF). Thus, the TM4SF5-mediated CD44v8-10 splice variant could be targeted against IPF.


Assuntos
Células Epiteliais Alveolares/metabolismo , Receptores de Hialuronatos/metabolismo , Proteínas de Membrana/metabolismo , Fibrose Pulmonar/metabolismo , Células A549 , Células Epiteliais Alveolares/patologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/fisiologia , Humanos , Receptores de Hialuronatos/genética , Masculino , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fibrose Pulmonar/genética , Fibrose Pulmonar/patologia , Splicing de RNA , Espécies Reativas de Oxigênio/metabolismo
17.
Sci Rep ; 9(1): 9994, 2019 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-31292497

RESUMO

The liver morphological changes in relation to fibrosis stage in nonalcoholic fatty liver disease (NAFLD) have not yet been clearly understood. This study was to develop a liver surface nodularity (LSN) quantification program and to compare the fibrosis grades in simple steatosis (SS) and nonalcoholic steatohepatitis (NASH). Thirty subjects (7 normal controls [NC], 12 SS and 11 NASH) were studied. LSN quantification procedure was bias correction, boundary detection, segmentation and LSN measurement. LSN scores among three groups and fibrosis grades compared using Kruskal-Wallis H test. Diagnostic accuracy was determined by calculating the area under the receiver operating characteristics (ROC) curve. Mean LSN scores were NC 1.30 ± 0.09, SS 1.54 ± 0.21 and NASH 1.59 ± 0.23 (p = 0.008). Mean LSN scores according to fibrosis grade (F) were F0 1.30 ± 0.09, F1 1.45 ± 0.17 and F2&F3 1.67 ± 0.20 (p = 0.001). The mean LSN score in F2&F3 is significantly higher than that in F1 (p = 0.019). The AUROC curve to distinguish F1 and F2&F3 was 0.788 (95% CI 0.595-0.981, p = 0.019) at a cut-off LSN score greater than 1.48, and its diagnostic accuracy had 0.833 sensitivity and 0.727 specificity. This study developed LSN program and its clinical application demonstrated that the quantitative LSN scores can help to differentially diagnose fibrosis stage in NAFLD.


Assuntos
Interpretação de Imagem Assistida por Computador/métodos , Cirrose Hepática/diagnóstico por imagem , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Adulto , Área Sob a Curva , Feminino , Fibrose , Humanos , Fígado/diagnóstico por imagem , Cirrose Hepática/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/patologia , Variações Dependentes do Observador , Sensibilidade e Especificidade
18.
Cell Metab ; 29(6): 1306-1319.e7, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-30956113

RESUMO

The mechanistic target of rapamycin complex (mTORC1) is a signaling hub on the lysosome surface, responding to lysosomal amino acids. Although arginine is metabolically important, the physiological arginine sensor that activates mTOR remains unclear. Here, we show that transmembrane 4 L six family member 5 (TM4SF5) translocates from plasma membrane to lysosome upon arginine sufficiency and senses arginine, culminating in mTORC1/S6K1 activation. TM4SF5 bound active mTOR upon arginine sufficiency and constitutively bound amino acid transporter SLC38A9. TM4SF5 binding to the cytosolic arginine sensor Castor1 decreased upon arginine sufficiency, thus allowing TM4SF5-mediated sensing of metabolic amino acids. TM4SF5 directly bound free L-arginine via its extracellular loop possibly for the efflux, being supported by mutant study and homology and molecular docking modeling. Therefore, we propose that lysosomal TM4SF5 senses and enables arginine efflux for mTORC1/S6K1 activation, and arginine-auxotroph in hepatocellular carcinoma may be targeted by blocking the arginine sensing using anti-TM4SF5 reagents.


Assuntos
Arginina/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Proteínas de Membrana/fisiologia , Animais , Arginina/química , Transporte Biológico , Células Cultivadas , Células HEK293 , Células Hep G2 , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/química , Proteínas de Membrana/química , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Quaternária de Proteína , Transdução de Sinais/genética
19.
FASEB J ; 33(3): 4341-4354, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30592630

RESUMO

Fibrosis is characterized by the increased accumulation of extracellular matrix (ECM), which drives abnormal cell proliferation and progressive organ dysfunction in many inflammatory and metabolic diseases. Studies have shown that halofuginone, a racemic halogenated derivative, inhibits glutamyl-prolyl-transfer RNA-synthetase (EPRS)-mediated fibrosis. However, the mechanism by which this occurs is unclear. We explored the mechanistic aspects of how EPRS could develop liver fibrotic phenotypes in cells and animal models. Treatment with TGF-ß1 up-regulated fibronectin and collagen I levels in LX2 hepatic stellate cells. This effect was inhibited in prolyl-transfer RNA synthetase (PRS)-suppressed LX2 cells. Using the promoter luciferase assay, TGF-ß1-mediated collagen I, α1 chain transcription and γ2 basal laminin transcription in LX2 cells were down-regulated by EPRS suppression, suggesting that EPRS may play roles in ECM production at transcriptional levels. Furthermore, signal transducer and activator of transcription (STAT) signaling activation was involved in the effects of TGF-ß1 on ECM expression in a PRS-dependent manner. This was mediated via a protein-protein complex formation consisting of TGF-ß1 receptor, EPRS, Janus kinases, and STAT6. Additionally, ECM expression in fibrotic livers overlapped with EPRS expression along fibrotic septa regions and was positively correlated with STAT6 activation in carbon tetrachloride-treated mice. This was less obvious in livers of Eprs-/+ mice. These findings suggest that, during fibrosis development, EPRS plays roles in nontranslational processes of ECM expression via intracellular signaling regulation upon TGF-ß1 stimulation.-Song, D.-G., Kim, D., Jung, J. W., Nam, S. H., Kim, J. E., Kim, H.-J., Kim, J. H., Lee, S.-J., Pan, C.-H., Kim, S., Lee, J. W. Glutamyl-prolyl-tRNA synthetase induces fibrotic extracellular matrix via both transcriptional and translational mechanisms.


Assuntos
Aminoacil-tRNA Sintetases/metabolismo , Matriz Extracelular/metabolismo , Biossíntese de Proteínas/genética , Transcrição Genética/genética , Aminoacil-tRNA Sintetases/genética , Animais , Linhagem Celular , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Regulação para Baixo/genética , Matriz Extracelular/genética , Fibrose/genética , Fibrose/metabolismo , Células Estreladas do Fígado/metabolismo , Humanos , Fígado/metabolismo , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/genética , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima/genética
20.
Front Pharmacol ; 9: 1337, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30524284

RESUMO

Idiopathic pulmonary fibrosis (IPF), a chronic disease of unknown cause, is characterized by abnormal accumulation of extracellular matrix (ECM) in fibrotic foci in the lung. Previous studies have shown that the transforming growth factor ß1 (TGFß1) and signal transducers and activators of transcription (STAT) pathways play roles in IPF pathogenesis. Glutamyl-prolyl-tRNA-synthetase (EPRS) has been identified as a target for anti-fibrosis therapy, but the link between EPRS and TGFß1-mediated IPF pathogenesis remains unknown. Here, we studied the role of EPRS in the development of fibrotic phenotypes in A549 alveolar epithelial cells and bleomycin-treated animal models. We found that EPRS knockdown inhibited the TGFß1-mediated upregulation of fibronectin and collagen I and the mesenchymal proteins α-smooth muscle actin (α-SMA) and snail 1. TGFß1-mediated transcription of collagen I-α1 and laminin γ2 in A549 cells was also down-regulated by EPRS suppression, indicating that EPRS is required for ECM protein transcriptions. Activation of STAT signaling in TGFß1-induced ECM expression was dependent on EPRS. TGFß1 treatment resulted in EPRS-dependent in vitro formation of a multi-protein complex consisting of the TGFß1 receptor, EPRS, Janus tyrosine kinases (JAKs), and STATs. In vivo lung tissue from bleomycin-treated mice showed EPRS-dependent STAT6 phosphorylation and ECM production. Our results suggest that epithelial EPRS regulates the expression of mesenchymal markers and ECM proteins via the TGFß1/STAT signaling pathway. Therefore, epithelial EPRS can be used as a potential target to develop anti-IPF treatments.

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