RESUMO
Factors affecting the probability of hepatocellular carcinoma (HCC) development even after sustained virological response (SVR) following anti-hepatitis C virus (HCV) therapy remain unelucidated. This study characterized the role of 16 soluble (s) immune checkpoint proteins in 168 HCV-SVR patients, with 47 developing HCC at the study end point. At baseline, high concentrations of 10 immune checkpoint proteins were found in the sera of the HCC group. At the study end point, levels of sCD27, sCD28, sCD40, and sCD86 in the HCC group, which were depleted following SVR, returned to higher levels than those in the non-HCC group. More importantly, patients with baseline levels of sCD27 ≥ 4104 pg/mL, sCD28 ≥ 1530 pg/mL, and sCD40 ≥ 688 pg/mL predicted a significantly greater HCC cumulative rate. Although sCD27 was elevated in patient sera, its membrane-bound form, mCD27, accumulated in the tumor and peritumor area, mainly localized in T cells. Interestingly, T-cell activation time dependently induced sCD27. Furthermore, CD70, the ligand of CD27, was robustly expressed in HCC area in which CD70 promoter methylation analysis indicated the hypomethylation compared with the nontumor pairs. Recombinant human CD27 treatment induced the proliferation of CD70-bearing HepG2 cells via the mitogen-activated protein kinase (MEK)-extracellular signal-regulated kinase pathway, but not NF-κB or p38 pathway. In conclusion, these data indicate that baseline sCD27, sCD28, and sCD40 levels could be used as HCC prognostic markers in HCV-SVR patients. sCD27 likely promotes HepG2 cell growth via the CD27-CD70 axis.
Assuntos
Carcinoma Hepatocelular , Hepatite C , Proteínas de Checkpoint Imunológico , Neoplasias Hepáticas , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral , Antivirais , Biomarcadores , Carcinoma Hepatocelular/tratamento farmacológico , MAP Quinases Reguladas por Sinal Extracelular , Hepacivirus , Hepatite C/complicações , Hepatite C/tratamento farmacológico , Humanos , Proteínas de Checkpoint Imunológico/metabolismo , Ligantes , Neoplasias Hepáticas/tratamento farmacológico , Quinases de Proteína Quinase Ativadas por Mitógeno , Prognóstico , Resposta Viral Sustentada , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismoRESUMO
BACKGROUND AND AIMS: Antifibrotic therapy remains an unmet medical need in human chronic liver disease. We report the antifibrotic properties of cytoglobin (CYGB), a respiratory protein expressed in hepatic stellate cells (HSCs), the main cell type involved in liver fibrosis. APPROACH AND RESULTS: Cygb-deficient mice that had bile duct ligation-induced liver cholestasis or choline-deficient amino acid-defined diet-induced steatohepatitis significantly exacerbated liver damage, fibrosis, and reactive oxygen species (ROS) formation. All of these manifestations were attenuated in Cygb-overexpressing mice. We produced hexa histidine-tagged recombinant human CYGB (His-CYGB), traced its biodistribution, and assessed its function in HSCs or in mice with advanced liver cirrhosis using thioacetamide (TAA) or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). In cultured HSCs, extracellular His-CYGB was endocytosed and accumulated in endosomes through a clathrin-mediated pathway. His-CYGB significantly impeded ROS formation spontaneously or in the presence of ROS inducers in HSCs, thus leading to the attenuation of collagen type 1 alpha 1 production and α-smooth muscle actin expression. Replacement the iron center of the heme group with cobalt nullified the effect of His-CYGB. In addition, His-CYGB induced interferon-ß secretion by HSCs that partly contributed to its antifibrotic function. Momelotinib incompletely reversed the effect of His-CYGB. Intravenously injected His-CYGB markedly suppressed liver inflammation, fibrosis, and oxidative cell damage in mice administered TAA or DDC mice without adverse effects. RNA-sequencing analysis revealed the down-regulation of inflammation- and fibrosis-related genes and the up-regulation of antioxidant genes in both cell culture and liver tissues. The injected His-CYGB predominantly localized to HSCs but not to macrophages, suggesting specific targeting effects. His-CYGB exhibited no toxicity in chimeric mice with humanized livers. CONCLUSIONS: His-CYGB could have antifibrotic clinical applications for human chronic liver diseases.
Assuntos
Citoglobina/metabolismo , Fígado Gorduroso , Células Estreladas do Fígado , Cirrose Hepática , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Colestase/tratamento farmacológico , Colestase/metabolismo , Descoberta de Drogas , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Cirrose Hepática/prevenção & controle , Camundongos , Camundongos Knockout , Substâncias Protetoras/farmacologia , Proteínas Recombinantes/farmacologia , Resultado do TratamentoRESUMO
INTRODUCTION: Emergency departments (EDs) at public hospitals in Vietnam typically face problems with overcrowding, as well as being populated by a wide variety of illnesses, resulting in increasing dissatisfaction from patients. To alleviate these problems, we used the increasingly popular value-stream mapping (VSM) and lean strategy approaches to (1) evaluate the current patient flow in EDs; (2) identify and eliminate the non-valued-added components; and (3) modify the existing process in order to improve waiting times. METHODS: Data from a total of 742 patients who presented at the ED of 108 Military Central Hospital in Hanoi, Vietnam, were collected. A VSM was developed where improvement possibilities were identified and attempts to eliminate non-value-added activities were made. A range of issues that were considered as a resource waste were highlighted, which led to a re-design process focusing on prioritizing blood tests and ultrasound procedures. On the administrative side, various measures were considered, including streamlining communication with medical departments, using QR codes for healthcare insurance payments, and efficient management of X-ray and CT scan online results. RESULTS: By implementing a lean approach, the following reductions in delay and waiting time were incurred: (1) pre-operative test results (for patients requiring medical procedures/operations) by 33.3% (from 134.4 to 89.4 min); (2) vascular interventions by 10.4% (from 54.6 to 48.9 min); and (3) admission to other hospital departments by 49.5% (from 118.3 to 59.8 min). Additionally, prior to the implementation of the lean strategy approach, only 22.9% of patients or their proxies (family members or friends), who responded to the survey, expressed satisfaction with the ED services. This percentage increased to 76.5% following the curtailment of non-value-added activities. Through statistical inferential test analyses, it can be confidently concluded that applying lean strategy and tools can improve patient flow in public/general hospital EDs and achieve better staff coordination within the various clinical and administrative hospital departments. To the authors' knowledge, such analysis in a Vietnamese hospital's ED context has not been previously undertaken.
Assuntos
Hospitais Gerais , Listas de Espera , Povo Asiático , Serviço Hospitalar de Emergência , Hospitais Públicos , HumanosRESUMO
In this study, total phosphorus (P) and P released forms were measured in core sediments from the areas affected by human settlement and shrimp farming activities and the core zone of the Can Gio Biosphere Reserve, a coastal district in south Vietnam. Furthermore, ecological risk assessment and parameters controlling P release from sediments were investigated, including pH, major elements (Al-Ca-Mg-Fe), and fine fraction. The average total amount of P in the sediments varied from 287 to 669 mg/kg, with significantly lower values being observed in the mangrove biosphere reserve area. According to the results of the correlation analysis, organic matter was the primary source of P in the sediments, but the majority of the P released was inorganic. Positive correlations were found between Fe and non-apatite inorganic P (NAIP) and apatite P (AP), as well as intercorrelations between P fractions (r = 0.40-0.79, p < 0.05), suggesting that Fe might be the controlling factor of P release in the investigated sediments. The rank orders of concentrations of P forms were significantly different between the areas. The range of P forms was AP (35-248 mg/kg) > NAIP (63-201 mg/kg) > LP (labile P) (4-25 mg/kg) in the human settlement and aquaculture areas and NAIP (84-99 mg/kg) > AP (20-38 mg/kg) > LP (7-12 mg/kg) in the mangrove biosphere reserve area. Risk assessment based on the total concentration of P and the availability of P from a single extraction suggested a relatively low risk of P from sediment as an internal load in the studied areas.
Assuntos
Fósforo , Poluentes Químicos da Água , China , Monitoramento Ambiental , Sedimentos Geológicos/análise , Humanos , Fósforo/análise , Medição de Risco , Vietnã , Poluentes Químicos da Água/análiseRESUMO
BACKGROUND: Despite the poor prognosis in patients with type 2 myocardial infarction (MI), no prospective data on risk stratification exists. The aim of this study was to develop and validate a model for prediction of 18-month mortality of among patients with type 2 MI (T2MI) and compare its performance with GRACE and TARRACO scores. METHODS: The prospective observational study included 712 consecutive patients diagnosed with MI undergoing coronary angiography <24 h between January 2017 and December 2018. Diagnosis of T2MI was adjusted according to Third universal definition. A prognostic model was developed by using Bayesian approach and logistic regression analysis with identifying predictors for mortality. The model was validated by bootstrap validation. Comparison performance between scores using Delong test. RESULTS: T2MI was identified in 174 (24.4%) patients. The median age of patients was 69 years, 52% were female. The mortality rate was 20.1% at 18 months. Prior MI, presence of ST elevation, hemoglobin level at admission, Charlson comorbidity index and were independently associated with 18-month mortality. The model to predict 18-month mortality showed excellent discrimination (optimism corrected c-statistic = 0.822) and calibration (corrected slope = 0.893). GRACE and TARRACO scores had moderate discrimination [c-statistic = 0.748 (95% CI 0.652-0.843) and 0.741, 95% CI 0.669-0.805), respectively] and inferior compared with model (p = 0.043 and 0.037, respectively). CONCLUSIONS: The risk of mortality among T2MI patients could be accurately predicted by using common clinical characteristics and laboratory tests. Further studies are required with external validation of nomogram prior to clinical implementation.
Assuntos
Infarto do Miocárdio/diagnóstico , Idoso , Teorema de Bayes , Comorbidade , Angiografia Coronária , Feminino , Hemoglobinas/metabolismo , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Mortalidade , Infarto do Miocárdio/classificação , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio sem Supradesnível do Segmento ST/classificação , Infarto do Miocárdio sem Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio sem Supradesnível do Segmento ST/metabolismo , Reprodutibilidade dos Testes , Infarto do Miocárdio com Supradesnível do Segmento ST/classificação , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/metabolismoRESUMO
One major goal of organometallic chemists is the direct functionalization of the bonds most recurrent in organic molecules: C-H, C-C, C-O, and C-N. An even grander challenge is C-C bond formation when both precursors are of this category. Parallel to this is the synthetic goal of achieving reaction selectivity that contrasts with conventional methods. Electrophilic aromatic substitution (EAS) via Friedel-Crafts acylation is the most renowned method for the synthesis of aryl ketones, a common structural motif of many pharmaceuticals, agrochemicals, fragrances, dyes, and other commodity chemicals. However, an EAS synthetic strategy is only effective if the desired site for acylation is in accordance with the electronic-controlled regioselectivity of the reaction. Herein we report steric-controlled regioselective arene acylation with salicylate esters via iridium catalysis to access distinctly substituted benzophenones. Experimental and computational data indicate a unique reaction mechanism that integrates C-O activation and C-H activation with a single iridium catalyst without an exogenous oxidant or base. We disclose an extensive exploration of the synthetic scope of both the arene and the ester components, culminating in the concise synthesis of the potent anticancer agent hydroxyphenstatin.
RESUMO
Kawasaki disease (KD) is a multisystem vasculitis that predominantly targets the coronary arteries in children. Phenotypic similarities between KD and recurrent fever syndromes point to the potential role of inflammasome activation in KD. Mutations in NLRP3 are associated with recurrent fever/autoinflammatory syndromes. We show that the KD-associated genetic polymorphism in inositol-triphosphate 3-kinase C (ITPKC) (rs28493229) has important functional consequences, governing ITPKC protein levels and thereby intracellular calcium, which in turn regulates NLRP3 expression and production of IL-1ß and IL-18. Analysis of transcript abundance, protein levels, and cellular response profiles from matched, serial biospecimens from a cohort of genotyped KD subjects points to the critical role of ITPKC in mediating NLRP3 inflammasome activation. Treatment failure in those with the high-risk ITPKC genotype was associated with the highest basal and stimulated intracellular calcium levels and with increased cellular production of IL-1ß and IL-18 and higher circulating levels of both cytokines. Mechanistic studies using Itpkc-deficient mice in a disease model support the genomic, cellular, and clinical findings in affected children. Our findings provide the mechanism behind the observed efficacy of rescue therapy with IL-1 blockade in recalcitrant KD, and we identify that regulation of calcium mobilization is fundamental to the underlying immunobiology in KD.
Assuntos
Vasos Coronários/patologia , Síndrome de Linfonodos Mucocutâneos/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Animais , Pré-Escolar , Estudos de Coortes , Vasos Coronários/metabolismo , Genótipo , Humanos , Inflamassomos/metabolismo , Interleucina-18/genética , Interleucina-18/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Síndrome de Linfonodos Mucocutâneos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Polimorfismo de Nucleotídeo Único , Risco , Resultado do TratamentoRESUMO
MED13L is a component subunit of the Mediator complex, an important regulator of transcription that is highly conserved across eukaryotes. Here, we report MED13L disruption in a translocation t(12;19) breakpoint of a patient with Pierre-Robin syndrome, moderate intellectual disability, craniofacial anomalies, and muscular defects. The phenotype is similar to previously described patients with MED13L haploinsufficiency. Knockdown of MED13L orthologue in zebrafish, med13b, showed early defective migration of cranial neural crest cells (NCCs) that contributed to cartilage structure deformities in the later stage, recapitulating craniofacial anomalies seen in human patients. Notably, we observed abnormal distribution of developing neurons in different brain regions of med13b morphant embryos, which could be rescued upon introduction of full-length human MED13L mRNA. To compare with mammalian system, we suppressed MED13L expression by short-hairpin RNA in ES-derived human neural progenitors, and differentiated them into neurons. Transcriptome analysis revealed differential expression of components of Wnt and FGF signaling pathways in MED13L-deficient neurons. Our finding provides a novel insight into the mechanism of overlapping phenotypic outcome targeting NCCs derivatives organs in patients with MED13L haploinsufficiency, and emphasizes a clinically recognizable syndromic phenotype in these patients.
Assuntos
Haploinsuficiência , Deficiência Intelectual/genética , Complexo Mediador/genética , Crista Neural/metabolismo , Animais , Diferenciação Celular/genética , Movimento Celular/genética , Pré-Escolar , Pontos de Quebra do Cromossomo , Modelos Animais de Doenças , Células-Tronco Embrionárias/metabolismo , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Silenciamento de Genes , Estudos de Associação Genética , Humanos , Deficiência Intelectual/diagnóstico , Complexo Mediador/metabolismo , Crista Neural/embriologia , Neurônios/citologia , Neurônios/metabolismo , Fenótipo , RNA Mensageiro/genética , Análise de Sequência de DNA , Transcriptoma , Translocação Genética , Peixe-ZebraRESUMO
BACKGROUND: Two previous surveys conducted in Ho Chi Minh City revealed an increasing prevalence of overweight and obese adolescents, from 5.9% in 2002 to 11.7% in 2004. From 2004 to 2010, the government set up and implemented health promotion programs to promote physical activity and good nutritional habits in order to prevent overweight and obesity in children and adolescents. Our study aimed to estimate the prevalence of overweight and obesity among adolescents in urban areas of Ho Chi Minh City in 2010. METHODS: A representative sample of 1,989 students aged 11-14 years was selected using a multistage cluster sampling method. 23 schools were randomly selected from the full list of all public junior high schools. In each selected school, 2 classes were chosen at random and all students from the class were examined. Age- and sex-adjusted overweight and obesity were defined using International Obesity Taskforce cut-offs. RESULTS: The prevalences of overweight and obesity were 17.8% and 3.2%, respectively. Prevalences of overweight and obesity were significantly higher in boys (22%, 5.4% ) than in girls (13.3%, 1.3%, p<0.001) and higher in children from districts with a high economic level (20.5% , 3.8% ) than in those from districts with a low economic level (12.1%, 3.8%, p<0.001). Additionally, children living in wealthier families were more overweight and obese than those living in less wealthy families. When using WHO cutoffs, the overall prevalences of overweight and obesity reached 19.6% and 7.9%, respectively. CONCLUSION: Our study's findings suggest that the prevalence of overweight and obesity among secondary school students remains high, especially among boys living in wealthier families. Public health programs should therefore be developed or improved in order to promote good eating habits and physical activity among youth in HCMC.
Assuntos
Sobrepeso/epidemiologia , Saúde da População Urbana/estatística & dados numéricos , Adolescente , Criança , Estudos Transversais , Feminino , Humanos , Masculino , Obesidade/epidemiologia , Prevalência , Fatores de Risco , Distribuição por Sexo , Fatores Socioeconômicos , Vietnã/epidemiologiaRESUMO
BACKGROUND: There currently exists no data on birth defects from population-based studies in Vietnam. Our study's aim was to assess external birth defect (EBD) prevalence among live newborns in Binh Thuan Province in Vietnam with the help of health workers at all levels of the health system. METHODS: A 2-month training session for 452 health professionals (HP) practicing delivery care in 127 Commune Health Stations (CHS) and in 12 provincial or district hospitals (DH) was setup in 2006. After a successful 6-month pilot study, a one-year registry of EBDs was established in 2008. All live newborns were screened for EBDs within 24 hours after birth in all DH obstetric departments and in all CHSs. Trained local HPs collected information by filling out a predesigned form and by photographing the affected newborn. EBDs were coded using the International Classification of Diseases system-10, Clinical Modification. The study was repeated in 2010. RESULTS: Throughout 2010, out of a total of 13,954 newborns, 84 cases with one or more EBDs were reported, representing an overall prevalence rate of 60.2 per 10,000 live births. The most common groups of EBDs were limbs (27.2/10,000), orofacial clefts (20.1/10,000) and the central nervous system (7.9/10,000). CONCLUSIONS: This first population-based study in Vietnam, which required coordination efforts at the local level, provides baseline prevalences of external birth defects. Data on EBDs from this study in southern Vietnam may be useful for setting up a regional population-based registry of birth defects in Vietnam.
Assuntos
Anormalidades Congênitas/epidemiologia , Adolescente , Adulto , Anormalidades Congênitas/diagnóstico , Anormalidades Congênitas/etiologia , Feminino , Humanos , Recém-Nascido , Masculino , Idade Materna , Triagem Neonatal , Prevalência , Sistema de Registros , Fatores de Risco , Fatores Socioeconômicos , Vietnã/epidemiologia , Adulto JovemRESUMO
Aims: Cell-cell interactions between hepatocytes (Hep) and other liver cells are key to maintaining liver homeostasis. Cytoglobin (CYGB), expressed exclusively by hepatic stellate cells (HSC), is essential in mitigating mitochondrial oxidative stress. CYGB absence causes Hep dysfunction and evokes hepatocarcinogenesis through an elusive mechanism. CYGB deficiency is speculated to hinder nitric oxide dioxygenase (NOD) activity, resulting in the elevated formation and release of nitric oxide (NO). Hence, we hypothesized that NO accumulation induced by the loss of NOD activity in CYGB-deficient HSC could adversely affect mitochondrial function in Hep, leading to disease progression. Results: NO, a membrane-permeable gas metabolite overproduced by CYGB-deficient HSC, diffuses into the neighboring Hep to reversibly inhibit cytochrome c oxidase (CcO), resulting in the suppression of respiratory function in an electron transport chain (ETC). The binding of NO to CcO is proved using purified CcO fractions from Cygb knockout (Cygb-/-) mouse liver mitochondria. Its inhibitory action toward CcO-specific activity is fully reversed by the external administration of oxyhemoglobin chasing away the bound NO. Thus, these findings indicate that the attenuation of respiratory function in ETC causes liver damage through the formation of excessive reactive oxygen species. Treating Cygb-/- mice with an NO synthase inhibitor successfully relieved NO-induced inhibition of CcO activity in vivo. Innovation and Conclusion: Our findings provide a biochemical link between CYGB-absence in HSC and neighboring Hep dysfunction; mechanistically the absence of CYGB in HSC causes mitochondrial dysfunction of Hep via the inhibition of CcO activity by HSC-derived NO. Antioxid. Redox Signal. 38, 463-479.
Assuntos
Células Estreladas do Fígado , Óxido Nítrico , Camundongos , Animais , Citoglobina/metabolismo , Células Estreladas do Fígado/metabolismo , Óxido Nítrico/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Globinas , Hepatócitos/metabolismoRESUMO
This paper presents a deep learning framework for detecting COVID-19 positive subjects from their cough sounds. In particular, the proposed approach comprises two main steps. In the first step, we generate a feature representing the cough sound by combining an embedding extracted from a pre-trained model and handcrafted features extracted from draw audio recording, referred to as the front-end feature extraction. Then, the combined features are fed into different back-end classification models for detecting COVID-19 positive subjects in the second step. Our experiments on the Track-2 dataset of the Second 2021 DiCOVA Challenge achieved the second top ranking with an AUC score of 81.21 and the top F1 score of 53.21 on a Blind Test set, improving the challenge baseline by 8.43% and 23.4% respectively and showing deployability, robustness and competitiveness with the state-of-the-art systems.
Assuntos
COVID-19 , Aprendizado Profundo , COVID-19/diagnóstico , Tosse/diagnóstico , Humanos , SomRESUMO
This paper evaluates a range of deep learning frameworks for detecting respiratory anomalies from input audio. Audio recordings of respiratory cycles collected from patients are transformed into time-frequency spectrograms to serve as front-end two-dimensional features. Cropped spectrogram segments are then used to train a range of back-end deep learning networks to classify respiratory cycles into predefined medically-relevant categories. A set of those trained high-performance deep learning frameworks are then fused to obtain the best score. Our experiments on the ICBHI benchmark dataset achieve the highest ICBHI score to date of 57.3%. This is derived from a late fusion of inception based and transfer learning based deep learning frameworks, easily outperforming other state-of-the-art systems. Clinical relevance--- Respiratory disease, wheeze, crackle, inception, convolutional neural network, transfer learning.
Assuntos
Aprendizado Profundo , Humanos , Redes Neurais de Computação , Taxa RespiratóriaRESUMO
Pancreatic cancer is a highly challenging malignancy with extremely poor prognosis. Cytoglobin (CYGB), a hemeprotein involved in liver fibrosis and cancer development, is expressed in pericytes of all organs. Here, we examined the role of CYGB in the development of pancreatic cancer. CYGB expression appeared predominately in the area surrounding adenocarcinoma and negatively correlated with tumor size in patients with pancreatic cancer. Directly injecting 7, 12-dimethylbenz[a]anthracene into the pancreatic tail in wild-type mice resulted in time-dependent induction of severe pancreatitis, fibrosis, and oxidative damage, which was rescued by Cygb overexpression in transgenic mice. Pancreatic cancer incidence was 93% in wild-type mice but only 55% in transgenic mice. Enhanced CYGB expression in human pancreatic stellate cells in vitro reduced cellular collagen synthesis, inhibited cell activation, increased expression of antioxidant-related genes, and increased CYGB secretion into the medium. Cygb-overexpressing or recombinant human CYGB (rhCYGB) -treated MIA PaCa-2 cancer cells exhibited dose-dependent cell cycle arrest at the G1 phase, diminished cell migration, and reduction in colony formation. RNA sequencing in rhCYGB-treated MIA PaCa-2 cells revealed downregulation of cell cycle and oxidative phosphorylation pathways. An increase in MIA PaCa-2 cell proliferation and reactive oxygen species production by H2O2 challenge was blocked by rhCYGB treatment or Cygb overexpression. PANC-1, OCUP-A2, and BxPC-3 cancer cells showed similar responses to rhCYGB. Known antioxidants N-acetyl cysteine and glutathione also inhibited cancer cell growth. These results demonstrate that CYGB suppresses pancreatic stellate cell activation, pancreatic fibrosis, and tumor growth, suggesting its potential therapeutic application against pancreatic cancer.
RESUMO
BACKGROUND & AIMS: Hepatic stellate cells (HSCs) are the primary cell type in liver fibrosis, a significant global health care burden. Cytoglobin (CYGB), a globin family member expressed in HSCs, inhibits HSC activation and reduces collagen production. We studied the antifibrotic properties of globin family members hemoglobin (HB), myoglobin (MB), and neuroglobin (NGB) in comparison with CYGB. APPROACH & RESULTS: We characterized the biological activities of globins in cultured human HSCs (HHSteCs) and their effects on carbon tetrachloride (CCl4)-induced cirrhosis in mice. All globins demonstrated greater antioxidant capacity than glutathione in cell-free systems. Cellular fractionation revealed endocytosis of extracellular MB, NGB, and CYGB, but not HB; endocytosed globins localized to intracellular membranous, cytoplasmic, and cytoskeletal fractions. MB, NGB, and CYGB, but not HB, scavenged reactive oxygen species generated spontaneously or stimulated by H2O2 or transforming growth factor ß1 in HHSteCs and reduced collagen 1A1 production via suppressing COL1A1 promoter activity. Disulfide bond-mutant NGB displayed decreased heme and superoxide scavenging activity and reduced collagen inhibitory capacity. RNA sequencing of MB- and NGB-treated HHSteCs revealed downregulation of extracellular matrix-encoding and fibrosis-related genes and HSC deactivation markers. Upregulation of matrix metalloproteinase (MMP)-1 was observed following MB and NGB treatment, and MMP-1 knockdown partially reversed globin-mediated effects on secreted collagen. Importantly, administration of MB, NGB, and CYGB suppressed CCl4-induced mouse liver fibrosis. CONCLUSIONS: These findings revealed unexpected roles for MB and NGB in deactivating HSCs and inhibiting liver fibrosis development, suggesting that globin therapy may represent a new strategy for combating fibrotic liver disease.
Assuntos
Globinas , Metaloproteinase 1 da Matriz , Animais , Citoglobina , Globinas/genética , Globinas/metabolismo , Hemoglobinas , Peróxido de Hidrogênio , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/genética , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Neuroglobina , Espécies Reativas de OxigênioRESUMO
Intracellular gap (iGap) formation in liver sinusoidal endothelial cells (LSECs) is caused by the destruction of fenestrae and appears under pathological conditions; nevertheless, their role in metastasis of cancer cells to the liver remained unexplored. We elucidated that hepatotoxin-damaged and fibrotic livers gave rise to LSECs-iGap formation, which was positively correlated with increased numbers of metastatic liver foci after intrasplenic injection of Hepa1-6 cells. Hepa1-6 cells induced interleukin-23-dependent tumor necrosis factor-α (TNF-α) secretion by LSECs and triggered LSECs-iGap formation, toward which their processes protruded to transmigrate into the liver parenchyma. TNF-α triggered depolymerization of F-actin and induced matrix metalloproteinase 9 (MMP9), intracellular adhesion molecule 1, and CXCL expression in LSECs. Blocking MMP9 activity by doxycycline or an MMP2/9 inhibitor eliminated LSECs-iGap formation and attenuated liver metastasis of Hepa1-6 cells. Overall, this study revealed that cancer cells induced LSEC-iGap formation via proinflammatory paracrine mechanisms and proposed MMP9 as a favorable target for blocking cancer cell metastasis to the liver.
Assuntos
Células Endoteliais , Neoplasias Hepáticas , Actinas/metabolismo , Animais , Doxiciclina/metabolismo , Células Endoteliais/metabolismo , Humanos , Interleucina-23/metabolismo , Fígado/metabolismo , Neoplasias Hepáticas/patologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Atherothrombosis is the principal mechanism of type 1 (T1) myocardial infarction (MI), while type 2 (T2) MI is typically diagnosed in the presence of triggers (anemia, arrhythmia, etc.). We aimed to evaluate the proportions of T1 vs. T2 MI based on angiographic and clinical definitions, their concordance and prognosis. METHODS: Consecutive MI patients [n = 712, 61% male; age 64.6 ± 12.3 years] undergoing coronary angiography were classified according to the presence of atherothrombosis and identifiable triggers. Association of angiographic and clinical MI type criteria with adverse outcomes (Time follow-up was 1.5 years) was evaluated. Predictive ability of GRACE risk score for all-cause mortality was then assessed. RESULTS: Atherothrombosis and clinical triggers were identified in 397 (55.6%) and 324 (45.5%) subjects, respectively. Only 247 (34.7%) patients had "true" T1MI (atherothrombosis+ / triggers-); 174 (24.4%) were diagnosed with "true" T2MI (atherothrombosis- / triggers+), while 291 (40.9%) had discordant clinical and angiographic characteristics. All-cause mortality in T2MI (20.1%) patients was higher than in T1MI (9.3%), P = 0.002. Presence of triggers [odds ratio (OR) 2.4, 95% CI 1.5-3.6, P < 0.0001] but not atherothrombosis [OR 0.8, 95% confidence interval (CI) 0.5-1.3, P = 0.26] was associated with worse prognosis. GRACE score is a better predictor of death in T1MI vs. T2MI: area under curve 0.893 (95% CI 0.830-0.956) vs 0.748 (95% CI 0.652-0.843), P = 0.013. CONCLUSION: Angiographic and clinical definitions of MI type are discordant in a substantial proportion of patients. Clinical triggers are associated with all-cause mortality. Predictive performance of GRACE score is worse in T2MI patients.
Assuntos
Trombose Coronária/diagnóstico por imagem , Infarto do Miocárdio/classificação , Infarto do Miocárdio/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Angiografia Coronária , Trombose Coronária/complicações , Trombose Coronária/epidemiologia , Feminino , Fatores de Risco de Doenças Cardíacas , Cardiopatias , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/complicações , Infarto do Miocárdio/mortalidade , Placa Aterosclerótica/complicações , Placa Aterosclerótica/diagnóstico por imagem , Prognóstico , Federação Russa/epidemiologia , Índice de Gravidade de DoençaRESUMO
While atherosclerotic plaque disruption remains the hallmark of type 1 myocardial infarction (T1MI), multiple other mechanisms provoking myocardial supply/demand mismatch (eg, anemia and tachyarrhythmias) are recognized as the potential causes of type 2 myocardial infarction (T2MI). In clinical practice, angiography is underutilized in patients with MI that have typical T2MI triggers, although the presence of these triggers and various forms of atherosclerotic coronary artery disease is not mutually exclusive. We describe a 70-year-old man that developed MI during hospitalization for gastrointestinal bleeding. He was treated conservatively without angiography due to posthemorrhagic anemia, which is a recognized T2MI trigger, and subsequently developed refractory cardiogenic shock. Autopsy revealed atherothrombosis, which is characteristic of T1MI.
RESUMO
In the present work, we reported the fabrication of a novel electrochemical sensing platform to detect 2,4-dichlorophenol (2,4-DCP) by using a copper benzene-1,3,5-tricarboxylate-graphene oxide (Cu-BTC/GO) composite. The sensor was prepared by drop-casting Cu-BTC/GO suspension onto the electrode surface followed by electrochemical reduction, leading to the generation of an electrochemically reduced graphene oxide network (ErGO). By combining the large specific area of the Cu-BTC matrix with the electrical percolation from the graphene network, the number of accessible reaction sites was strongly increased, which consequently improved the detection performance. The electrochemical characteristics of the composite were revealed by cyclic voltammetry and electrochemical impedance spectroscopy. For the detection of 2,4-DCP, differential pulse voltammetry was used to emphasize the faradaic reaction related to the oxidation of the analyte. The results displayed a low detection limit (83 × 10-9 M) and a linear range from 1.5 × 10-6 M to 24 × 10-6 M alongside high reproducibility (RSD = 2.5% for eight independent sensors) and good stability. Importantly, the prepared sensors were sufficiently selective against interference from other pollutants in the same electrochemical window. Notably, the presented sensors have already proven their ability in detecting 2,4-DCP in real field samples with high accuracy (recovery range = 97.17-104.15%).
RESUMO
Can Gio district is located in the coastal area of Ho Chi Minh City, southern Vietnam. Discharge of wastewater from Ho Chi Minh City and neighboring provinces to the rivers of Can Gio has led to concerns about the accumulation of trace metals (As, Cu, Cr, Ni, Pb, and Zn) in the coastal sediments. The main objective of this study was to assess the distribution of As, Cu, Cr, Ni, Pb, and Zn in surface and core sediments and to evaluate the contamination status in relation to local background values, as well as the potential release of these selected trace metals from sediments to the water environment. Sediment characteristization, including determination of fine fraction, pH, organic matter, and major elements (Al, Fe, Ca, K, Mg, and S), was carried out to investigate which parameters affect the trace metal enrichment. Fine fraction and Al contents were found to be the controlling proxies affecting the distribution of trace metals while other sediment characteristics did not show any clear influence on trace metals' distribution. Although As concentrations in the sediments were much higher compared to its reference value in other areas, the enrichment factor based on local background values suggests minor contamination of this element as well as for Cr, Cu, and Pb. Risk assessment suggested a medium to very high risk of Mn, Zn, and Ni under acidification. Of importance is also that trace metals in sediments were not easily mobilized by organic complexation based on their low extractabilities by ammonium-EDTA extraction.