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1.
Eur Heart J ; 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34570211

RESUMO

AIMS: Our previous study demonstrated that Ca2+ influx through the Orai1 store-operated Ca2+ channel in macrophages contributes to foam cell formation and atherosclerosis via the calcineurin-ASK1 pathway, not the classical calcineurin-nuclear factor of activated T-cell (NFAT) pathway. Moreover, up-regulation of NFATc3 in macrophages inhibits foam cell formation, suggesting that macrophage NFATc3 is a negative regulator of atherogenesis. Hence, this study investigated the precise role of macrophage NFATc3 in atherogenesis. METHODS AND RESULTS: Macrophage-specific NFATc3 knockout mice were generated to determine the effect of NFATc3 on atherosclerosis in a mouse model of adeno-associated virus-mutant PCSK9-induced atherosclerosis. NFATc3 expression was decreased in macrophages within human and mouse atherosclerotic lesions. Moreover, NFATc3 levels in peripheral blood mononuclear cells from atherosclerotic patients were negatively associated with plaque instability. Furthermore, macrophage-specific ablation of NFATc3 in mice led to the atherosclerotic plaque formation, whereas macrophage-specific NFATc3 transgenic mice exhibited the opposite phenotype. NFATc3 deficiency in macrophages promoted foam cell formation by potentiating SR-A- and CD36-meditated lipid uptake. NFATc3 directly targeted and transcriptionally up-regulated miR-204 levels. Mature miR-204-5p suppressed SR-A expression via canonical regulation. Unexpectedly, miR-204-3p localized in the nucleus and inhibited CD36 transcription. Restoration of miR-204 abolished the proatherogenic phenotype observed in the macrophage-specific NFATc3 knockout mice, and blockade of miR-204 function reversed the beneficial effects of NFATc3 in macrophages. CONCLUSION: Macrophage NFATc3 up-regulates miR-204 to reduce SR-A and CD36 levels, thereby preventing foam cell formation and atherosclerosis, indicating that the NFATc3/miR-204 axis may be a potential therapeutic target against atherosclerosis.

2.
Medicine (Baltimore) ; 100(35): e27125, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34477155

RESUMO

ABSTRACT: We aimed to investigate the genetic and demographic differences and interactions between areas where observed genomic variations in Mycobacterium tuberculosis (M. tb) were distributed uniformly in cold and hot spots.The cold and hot spot areas were identified using the reported incidence of TB over the previous 5 years. Whole genome sequencing was performed on 291 M. tb isolates between January and June 2018. Analysis of molecular variance and a multifactor dimensionality reduction (MDR) model was applied to test gene-gene-environment interactions. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were computed to test the extent to which genetic mutation affects the TB epidemic using a multivariate logistic regression model.The percentage of the Beijing family strain in hot spots was significantly higher than that in cold spots (64.63% vs 50.69%, P = .022), among the elderly, people with a low BMI, and those having a history of contact with a TB patient (all P < .05). Individuals from cold spot areas had a higher frequency of out-of-town traveling (P < .05). The mutation of Rv1186c, Rv3900c, Rv1508c, Rv0210, and an Intergenic Region (SNP site: 3847237) showed a significant difference between cold and hot spots. (P < .001). The MDR model displayed a clear negative interaction effect of age groups with BMI (interaction entropy: -3.55%) and mutation of Rv0210 (interaction entropy: -2.39%). Through the mutations of Rv0210 and BMI had a low independent effect (interaction entropy: -1.46%).Our data suggests a statistically significant role of age, BMI and the polymorphisms of Rv0210 genes in the transmission and development of M. tb. The results provide clues for the study of susceptibility genes of M. tb in different populations. The characteristic strains showed a local epidemic. Strengthening genotype monitoring of strains in various regions can be used as an early warning signal of epidemic spillover.


Assuntos
Interações Hospedeiro-Patógeno/genética , Mycobacterium tuberculosis/genética , Tuberculose/microbiologia , Adulto , China/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tuberculose/epidemiologia
3.
BMC Infect Dis ; 21(1): 840, 2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34412585

RESUMO

BACKGROUND: Tuberculosis (TB) is caused by a bacterium called Mycobacterium tuberculosis (Mtb). China is the third in top 8 high TB burden countries and Guangxi is one of the high incidence areas in South China. Determine bacterial factors that affected TB incidence rate is a step toward Ending the TB epidemic. RESULTS: Genomes of M. tuberculosis cultures from a relatively high and low incidence region in Guangxi have been sequenced. 347 of 358(96.9%) were identified as M. tuberculosis. All the strains belong to Lineage 2 and Lineage 4, except for one in Lineage 1. We found that the genetic structure of the M. tuberculosis population in each county varies enormously. Low incidence rate regions have a lower prevalence of Beijing genotypes than other regions. Four isolates which harbored mutT4-48 also had mutT2-58 mutations. It is suggested that strains from the ancestors of modern Beijing lineage is circulating in Guangxi. Strains of modern Beijing lineage (OR=2.04) were more likely to acquire drug resistances than Lineage 4. Most of the lineage differentiation SNPs are related to cell wall biosynthetic pathways. CONCLUSIONS: These results provided a higher resolution to better understand the history of transmission of M. tuberculosis from/to South China. And the incidence rate of tuberculosis might be affected by bacterial population structure shaped by demographic history. Our findings also support the hypothesis that Modern Beijing lineage originated in South China.


Assuntos
Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose , Antituberculosos/uso terapêutico , China/epidemiologia , Genótipo , Humanos , Incidência , Mycobacterium tuberculosis/genética , Tuberculose/tratamento farmacológico , Tuberculose/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico
4.
Ear Nose Throat J ; : 1455613211031024, 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34233486

RESUMO

We describe a case of nasal non-Hodgkin's lymphoma in a 79-year-old Chinese patient accompany with nasal myiasis. The first 2 biopsies in this case were false negative. Subsequently, nasal maggots developed in this patient. After removing all maggots under nasal endoscopy, the patient continued to have recurrent fever and was transferred to a higher hospital for further treatment, in which he received a third biopsy. Unfortunately, several hours after the biopsy, the patient died for severe nasal bleeding. The final biopsy result indicated the neoplasm of the left nasal cavity was non-Hodgkin's lymphoma. This case illustrates the importance of repeated biopsies for nasal non-Hodgkin's lymphoma if necessary. Nasal myiasis is a secondary disease of nasal non-Hodgkin's lymphoma in this case.

5.
Medicine (Baltimore) ; 100(27): e26557, 2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34232198

RESUMO

ABSTRACT: Radiomics transforms the medical images into high-dimensional quantitative features and provides potential information about tumor phenotypes and heterogeneity. We conducted a retrospective analysis to explore and validate radiomics model based on contrast-enhanced computed tomography (CECT) to predict recurrence of locally advanced oesophageal squamous cell cancer (SCC) within 2 years after trimodal therapy. This study collected CECT and clinical data of consecutive 220 patients with pathology-confirmed locally advanced oesophageal SCC (154 in the training cohort and 66 in the validation cohort). Univariate statistical test and the least absolute shrinkage and selection operator method were performed to select the optimal radiomics features. Logistic regression was conducted to build radiomics model, clinical model, and combined model of both the radiomics and clinical features. Predictive performance was judged by the area under receiver operating characteristics curve (AUC), accuracy, and F1-score in the training and validation cohorts. Ten optimal radiomics features and/or 7 clinical features were selected to build radiomics model, clinical model, and the combined model. The integrated model of radiomics and clinical features was superior to radiomics model or clinical model in predicting recurrence of locally advanced oesophageal SCC within 2 years in the training (AUC: 0.879 vs 0.815 or 0.763; accuracy: 0.844 vs 0.773 or 0.740; and F1-score: 0.886 vs 0.839 or 0.815, respectively) and validation (AUC: 0.857 vs 0.720 or 0.750; accuracy: 0.788 vs 0.700 or 0.697; and F1-score: 0.851 vs 0.800 or 0.787, respectively) cohorts. The combined model of radiomics and clinical features shows better performance than the radiomics or clinical model to predict the recurrence of locally advanced oesophageal SCC within 2 years after trimodal therapy.


Assuntos
Neoplasias Esofágicas/diagnóstico , Carcinoma de Células Escamosas do Esôfago/diagnóstico , Recidiva Local de Neoplasia/diagnóstico , Estadiamento de Neoplasias , Tomografia Computadorizada por Raios X/métodos , Terapia Combinada , Neoplasias Esofágicas/terapia , Carcinoma de Células Escamosas do Esôfago/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Estudos Retrospectivos , Fatores de Tempo
6.
Free Radic Biol Med ; 172: 530-540, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34174395

RESUMO

Vascular calcification is very commonly observed in patients with chronic kidney disease (CKD), but there is no efficient therapy available. Oxidative stress plays critical roles in the progression of vascular calcification. Celastrol (Cel), a natural constituent derived from Chinese herbals, exhibits anti-oxidative stress activity. Here, we investigated the effect of celastrol on vascular calcification using vascular smooth muscle cells (VSMCs), arterial rings and CKD rats. Alizarin red staining and gene expression analysis showed that Cel dose-dependently inhibited rat VSMC calcification and osteogenic differentiation. Similarly, ex vivo study revealed that Cel inhibited calcification of rat and human arterial rings. In addition, micro-computed tomography, alizarin red staining and calcium content analysis confirmed that Cel inhibited aortic calcification in CKD rats. Interestingly, Cel treatment increased the mRNA and protein levels of heme oxygenase-1 (HMOX-1), and reduced the levels of reactive oxygen species (ROS) in VSMCs. Furthermore, both pharmacological inhibition of HMOX-1 and knockdown of HMOX-1 by siRNA independently counteracted the inhibitory effect of Cel on vascular calcification. Moreover, knockdown of HMOX-1 prevented Cel treatment-mediated reduction in ROS levels. Finally, Cel treatment reduced Vitamin D3-induced aortic calcification in mice and this effect was blocked by HMOX-1 inhibitor ZnPP9. Collectively, our results suggest that up-regulation of HMOX-1 is required for the inhibitory effect of Cel on vascular calcification. Modulation of HMOX-1 may provide a novel strategy for the treatment of vascular calcification in CKD.


Assuntos
Insuficiência Renal Crônica , Calcificação Vascular , Animais , Células Cultivadas , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Camundongos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso , Osteogênese , Estresse Oxidativo , Triterpenos Pentacíclicos , Ratos , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo , Regulação para Cima , Calcificação Vascular/etiologia , Calcificação Vascular/genética , Microtomografia por Raio-X
7.
Atherosclerosis ; 328: 83-91, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34118596

RESUMO

BACKGROUND AND AIMS: The apolipoprotein A-I mimetic peptide D-4F, among its anti-atherosclerotic effects, improves vasodilation through mechanisms not fully elucidated yet. METHODS: Low-density lipoprotein (LDL) receptor null (LDLr-/-) mice were fed Western diet with or without D-4F. We then measured atherosclerotic lesion formation, endothelial nitric oxide synthase (eNOS) phosphorylation and its association with heat shock protein 90 (HSP90), nitric oxide (NO) and superoxide anion (O2•-) production, and tetrahydrobiopterin (BH4) and GTP-cyclohydrolase 1 (GCH-1) concentration in the aorta. Human umbilical vein endothelial cells (HUVECs) and aortas were treated with oxidized LDL (oxLDL) with or without D-4F; subsequently, BH4 and GCH-1 concentration, NO and O2•- production, eNOS association with HSP90, and endothelium-dependent vasodilation were measured. RESULTS: Unexpectedly, eNOS phosphorylation, eNOS-HSP90 association, and O2•- production were increased, whereas BH4 and GCH-1 concentration and NO production were reduced in atherosclerosis. D-4F significantly inhibited atherosclerosis, eNOS phosphorylation, eNOS-HSP90 association, and O2•- generation but increased NO production and BH4 and GCH-1 concentration. OxLDL reduced NO production and BH4 and GCH-1 concentration but enhanced O2•- generation and eNOS association with HSP90, and impaired endothelium-dependent vasodilation. D-4F inhibited the overall effects of oxLDL. CONCLUSIONS: Hypercholesterolemia enhanced uncoupled eNOS activity by decreasing GCH-1 concentration, thereby reducing BH4 levels. D-4F reduced uncoupled eNOS activity by increasing BH4 levels through GCH-1 expression and decreasing eNOS phosphorylation and eNOS-HSP90 association. Our findings elucidate a novel mechanism by which hypercholesterolemia induces atherosclerosis and D-4F inhibits it, providing a potential therapeutic approach.


Assuntos
Aterosclerose , Óxido Nítrico Sintase Tipo III , Animais , Apolipoproteína A-I , Aterosclerose/tratamento farmacológico , Aterosclerose/prevenção & controle , Biopterina/análogos & derivados , Células Endoteliais , Endotélio Vascular , GTP Cicloidrolase , Guanosina Trifosfato , Camundongos , Óxido Nítrico , Peptídeos , Superóxidos
8.
Aging Cell ; 20(6): e13377, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33969611

RESUMO

Vascular calcification is a common pathologic condition in patients with chronic kidney disease (CKD) and aging individuals. It has been established that vascular calcification is a gene-regulated biological process resembling osteogenesis involving osteogenic differentiation. However, there is no efficient treatment available for vascular calcification so far. The natural polyamine spermidine has been demonstrated to increase life span and protect against cardiovascular disease. It is unclear whether spermidine supplementation inhibits vascular calcification in CKD. Alizarin red staining and quantification of calcium content showed that spermidine treatment markedly reduced mineral deposition in both rat and human vascular smooth muscle cells (VSMCs) under osteogenic conditions. Additionally, western blot analysis revealed that spermidine treatment inhibited osteogenic differentiation of rat and human VSMCs. Moreover, spermidine treatment remarkably attenuated calcification of rat and human arterial rings ex vivo and aortic calcification in rats with CKD. Furthermore, treatment with spermidine induced the upregulation of Sirtuin 1 (SIRT1) in VSMCs and resulted in the downregulation of endoplasmic reticulum (ER) stress signaling components, such as activating transcription factor 4 (ATF4) and CCAAT/enhancer-binding protein homologous protein (CHOP). Both pharmacological inhibition of SIRT1 by SIRT1 inhibitor EX527 and knockdown of SIRT1 by siRNA markedly blocked the inhibitory effect of spermidine on VSMC calcification. Consistently, EX527 abrogated the inhibitory effect of spermidine on aortic calcification in CKD rats. We for the first time demonstrate that spermidine alleviates vascular calcification in CKD by upregulating SIRT1 and inhibiting ER stress, and this may develop a promising therapeutic treatment to ameliorate vascular calcification in CKD.

9.
Cancer Imaging ; 21(1): 38, 2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34039403

RESUMO

BACKGROUND: Early recurrence of oesophageal squamous cell carcinoma (SCC) is defined as recurrence after surgery within 1 year, and appears as local recurrence, distant recurrence, and lymph node positive and disseminated recurrence. Contrast-enhanced computed tomography (CECT) is recommended for diagnosis of primary tumor and initial staging of oesophageal SCC, but it cannot be used to predict early recurrence. It is reported that radiomics can help predict preoperative stages of oesophageal SCC, lymph node metastasis before operation, and 3-year overall survival of oesophageal SCC patients following chemoradiotherapy by extracting high-throughput quantitative features from CT images. This study aimed to develop models based on CT radiomics and clinical features of oesophageal SCC to predict early recurrence of locally advanced cancer. METHODS: We collected electronic medical records and image data of 197 patients with confirmed locally advanced oesophageal SCC. These patients were randomly allocated to 137 patients in the training cohort and 60 in the test cohort. 352 radiomics features were extracted by delineating region-of-interest (ROI) around the lesion on CECT images and clinical signature was generated by medical records. The radiomics model, clinical model, the combined model of radiomics and clinical features were developed by radiomics features and/or clinical characteristics. Predicting performance of the three models was assessed with area under receiver operating characteristic curve (AUC), accuracy and F-1 score. RESULTS: Eleven radiomics features and/or six clinical signatures were selected to build prediction models related to recurrence of locally advanced oesophageal SCC after trimodal therapy. The AUC of integration of radiomics and clinical models was better than that of radiomics or clinical model for the training cohort (0.821 versus 0.754 or 0.679, respectively) and for the validation cohort (0.809 versus 0.646 or 0.658, respectively). Integrated model of radiomics and clinical features showed good performance in predicting early recurrence of locally advanced oesophageal SCC for both the training and validation cohorts (accuracy = 0.730 and 0.733, and F-1score = 0.730 and 0.778, respectively). CONCLUSIONS: The integrated model of CECT radiomics and clinical features may be a potential imaging biomarker to predict early recurrence of locally advanced oesophageal SCC after trimodal therapy.


Assuntos
Meios de Contraste/uso terapêutico , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/radioterapia , Radiometria/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico por imagem , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Tomografia Computadorizada por Raios X/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
10.
Eur J Hum Genet ; 29(7): 1129-1138, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33824467

RESUMO

Thoracic aortic aneurysm with or without dissection (TAAD) can be broadly categorized as syndromic TAAD (sTAAD) and isolated TAAD (iTAAD). sTAAD and is highly correlated with genetics. However, although the incidence of iTAAD is much higher, its monogenic contribution is not yet clear. Here, we sequenced 15 known TAAD genes for 578 iTAAD cases from four cardiac centers in China and found that 10.6% patients with a pathogenic/likely pathogenic (P/LP) variant. Other 7.27% of patients carried variants of uncertain significance in these target genes. We further investigated the correlations among genetics, clinical features, and long-term outcomes. Genetic patients showed younger onset ages (P = 1.31E-13) and larger aortic diameter (P = 1.00E-6), with the youngest age in patients with FBN1 P/LP variants. Monogenic variants were also associated with more aortic segments involved (P = 0.043) and complicated with initial dissection (P = 4.50E-5), especially for genetic patients with non-FBN1 P/LP variants. MACEs occurred in 14.9% patients during follow-up of median 55 months. Genetic status (P = 0.001) and initial dissection (P = 3.00E-6) were two major risk factors for poor prognosis. Early onset age was associated with MACEs in non-genetic cases without initial dissection (P = 0.005). Our study revealed the monogenic contribution in known TAAD genes to iTAAD patients. The genotype-phenotype correlations may complement the risk stratification of iTAAD patients and identification of higher risk subgroups, as well as assist the development of tailored precision medicine in iTAAD.

11.
J Lipid Res ; 62: 100066, 2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33711324

RESUMO

Endothelial-to-mesenchymal transition (EndMT), the process by which an endothelial cell (EC) undergoes a series of molecular events that result in a mesenchymal cell phenotype, plays an important role in atherosclerosis. 1-Palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC), derived from the oxidation of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphatidylcholine, is a proinflammatory lipid found in atherosclerotic lesions. Whether POVPC promotes EndMT and how simvastatin influences POVPC-mediated EndMT remains unclear. Here, we treated human umbilical vein ECs with POVPC, simvastatin, or both, and determined their effect on EC viability, morphology, tube formation, proliferation, and generation of NO and superoxide anion (O2•-). Expression of specific endothelial and mesenchymal markers was detected by immunofluorescence and immunoblotting. POVPC did not affect EC viability but altered cellular morphology from cobblestone-like ECs to a spindle-like mesenchymal cell morphology. POVPC increased O2- generation and expression of alpha-smooth muscle actin, vimentin, Snail-1, Twist-1, transforming growth factor-beta (TGF-ß), TGF-ß receptor II, p-Smad2/3, and Smad2/3. POVPC also decreased NO production and expression of CD31 and endothelial NO synthase. Simvastatin inhibited POVPC-mediated effects on cellular morphology, production of O2•- and NO, and expression of specific endothelial and mesenchymal markers. These data demonstrate that POVPC induces EndMT by increasing oxidative stress, which stimulates TGF-ß/Smad signaling, leading to Snail-1 and Twist-1 activation. Simvastatin inhibited POVPC-induced EndMT by decreasing oxidative stress, suppressing TGF-ß/Smad signaling, and inactivating Snail-1 and Twist-1. Our findings reveal a novel mechanism of atherosclerosis that can be inhibited by simvastatin.

12.
Int J Mol Sci ; 22(3)2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33499186

RESUMO

Autophagy is a catabolic process that is important for maintaining cellular homeostasis. It is also known to possess other functions including protein trafficking and anti-microbial activities. Hepatitis C virus (HCV) is known to co-opt cellular autophagy pathway to promote its own replication. HCV regulates autophagy through multiple mechanisms to control intracellular protein and membrane trafficking to enhance its replication and suppress host innate immune response. In this review, we discuss the current knowledge on the interplay between HCV and autophagy and the crosstalk between HCV-induced autophagy and host innate immune responses.


Assuntos
Autofagia/fisiologia , Hepacivirus/fisiologia , Hepatite C/virologia , Transporte Proteico , Replicação Viral , Membrana Celular/metabolismo , Hepatite C/patologia , Hepatócitos/virologia , Homeostase , Humanos , Imunidade Inata , Microdomínios da Membrana , Mitocôndrias/metabolismo , Mitofagia , RNA Viral/metabolismo , Transdução de Sinais
13.
Acta Pharmacol Sin ; 42(1): 10-17, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32457416

RESUMO

Atherosclerosis (AS) is the main pathological cause of coronary heart disease (CHD). Current clinical interventions including statin drugs can effectively reduce acute myocardial infarction and stroke to some extent, but residual risk remains high. The current clinical treatment regimens are relatively effective for early atherosclerotic plaques and can even reverse their progression. However, the effectiveness of these treatments for advanced AS is not ideal, and advanced atherosclerotic plaques-the pathological basis of residual risk-can still cause a recurrence of acute cardiovascular and cerebrovascular events. Recently, nanomedicine-based treatment strategies have been extensively used in antitumor therapy, and also shown great potential in anti-AS therapy. There are many microstructures in late-stage atherosclerotic plaques, such as neovascularization, micro-calcification, and cholesterol crystals, and these have become important foci for targeted nanomedicine delivery. The use of targeted nanoparticles has become an important strategy for the treatment of advanced AS to further reduce the residual risk of cardiovascular events. Furthermore, the feasibility and safety of nanotechnology in clinical treatment have been preliminarily confirmed. In this review, we summarize the application of nanomedicine delivery in the treatment of advanced AS and the clinical value of several promising nanodrugs.

14.
Recent Results Cancer Res ; 217: 47-70, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33200361

RESUMO

Hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC). There are approximately 250 million people in the world that are chronically infected by this virus, resulting in nearly 1 million deaths every year. Many of these patients die from severe liver diseases, including HCC. HBV may induce HCC through the induction of chronic liver inflammation, which can cause oxidative stress and DNA damage. However, many studies also indicated that HBV could induce HCC via the alteration of hepatocellular physiology that may involve genetic and epigenetic changes of the host DNA, the alteration of cellular signaling pathways, and the inhibition of DNA repair mechanisms. This alteration of cellular physiology can lead to the accumulation of DNA damages and the promotion of cell cycles and predispose hepatocytes to oncogenic transformation.


Assuntos
Carcinoma Hepatocelular , Vírus da Hepatite B , Hepatite B , Neoplasias Hepáticas , Carcinoma Hepatocelular/virologia , Reparo do DNA , Hepatite B/complicações , Hepatite B/genética , Vírus da Hepatite B/genética , Vírus da Hepatite B/patogenicidade , Humanos , Neoplasias Hepáticas/virologia , Oncogenes
15.
Redox Biol ; 36: 101642, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32863238

RESUMO

Normal high-density lipoprotein (nHDL) in normal, healthy subjects is able to promote angiogenesis, but the mechanism remains incompletely understood. HDL from patients with coronary artery disease may undergo a variety of oxidative modifications, rendering it dysfunctional; whether the angiogenic effect is mitigated by such dysfunctional HDL (dHDL) is unknown. We hypothesized that dHDL compromises angiogenesis. The angiogenic effects of nHDL and dHDL were assessed using endothelial cell culture, endothelial sprouts from cardiac tissue from C57BL/6 mice, zebrafish model for vascular growth and a model of impaired vascular growth in hypercholesterolemic low-density lipoprotein receptor null(LDLr-/-)mice. MiRNA microarray and proteomic analyses were used to determine the mechanisms. Lipid hydroperoxides were greater in dHDL than in nHDL. While nHDL stimulated angiogenesis, dHDL attenuated these responses. Protein and miRNA profiles in endothelial cells differed between nHDL and dHDL treatments. Moreover, nHDL suppressed miR-24-3p expression to increase vinculin expression resulting in nitric oxide (NO) production, whereas dHDL delivered miR-24-3p to inhibit vinculin expression leading to superoxide anion (O2•-) generation via scavenger receptor class B type 1. Vinculin was required for endothelial nitric oxide synthase (eNOS) expression and activation and modulated the PI3K/AKT/eNOS and ERK1/2 signaling pathways to regulate nHDL- and VEGF-induced angiogenesis. Vinculin overexpression or miR-24-3p inhibition reversed dHDL-impaired angiogenesis. The expressions of vinculin and eNOS and angiogenesis were decreased, but the expression of miR-24-3p and lipid hydroperoxides in HDL were increased in the ischemic lower limbs of hypercholesterolemic LDLr-/- mice. Overexpression of vinculin or miR-24-3p antagomir restored the impaired-angiogenesis in ischemic hypercholesterolemic LDLr-/- mice. Collectively, nHDL stimulated vinculin and eNOS expression to increase NO production by suppressing miR-24-3p to induce angiogenesis, whereas dHDL inhibited vinculin and eNOS expression to enhance O2•- generation by delivering miR-24-3p to impair angiogenesis, and that vinculin and miR-24-3p may be therapeutic targets for dHDL-impaired angiogenesis.


Assuntos
Doença da Artéria Coronariana , MicroRNAs , Animais , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/genética , Células Endoteliais , Voluntários Saudáveis , Humanos , Lipoproteínas HDL , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Neovascularização Fisiológica , Óxido Nítrico Sintase Tipo III/genética , Fosfatidilinositol 3-Quinases , Proteômica , Peixe-Zebra
16.
Eur J Radiol ; 130: 109201, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32738462

RESUMO

PURPOSE: To build a radiomics model of liver contrast-enhanced computed tomography (CT) to predict hepatic encephalopathy secondary to Hepatitis B related cirrhosis. MATERIALS AND METHODS: This study consisted of 304 consecutive patients with first-diagnosed hepatitis B related cirrhosis. 212 and 92 patients were randomly computer-generated into training and testing cohorts, among which 38 and 21 patients endured HE, respectively. 356 radiomics features of liver were extracted from portal venous-phase CT data, and 3 clinical features were collected from medical record. After data were standardized by Z-score, we used least absolute shrinkage and selection operator to choose useful radiomics features. Ultimately, three predictive models including a radiomics model, a clinical model and an integrated model of radiomics and clinical features were built by analysis of R-software. Predictive performance was tested by multivariable logistic regression, and evaluated by area under receiver-operating characteristic curve (AUC), and accuracy. RESULTS: 19 radiomics features of liver CT were selected. The selected radiomics features and 3 relevant clinical features were applied to develop a radiomics model, a clinical model, and an integrated model of both radiomics and clinical features. The integrated model showed better performance than the radiomics model or clinical model to predict HE (AUC = 0.94 vs. 0.91 or 0.76, and 0.87 vs. 0.86 or 0.73; accuracy = 0.93 vs. 0.89 or 0.83, and 0.83 vs. 0.84 or 0.77) in the training and testing cohorts, respectively. CONCLUSION: The integrated model of radiomics and clinical features could well predict HE secondary to hepatitis B related cirrhosis.


Assuntos
Encefalopatia Hepática/diagnóstico por imagem , Hepatite B/diagnóstico por imagem , Cirrose Hepática/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Feminino , Humanos , Neoplasias Hepáticas , Masculino , Pessoa de Meia-Idade , Veia Porta , Curva ROC , Estudos Retrospectivos , Risco , Tomografia Computadorizada por Raios X/métodos
17.
Radiol Infect Dis ; 7(3): 123-129, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32838010

RESUMO

Objective: To investigate changes in CT manifestations and results of reverse transcription polymerase chain reaction (RT-PCR) testing between afferent and second-generation coronavirus disease 2019 (COVID-19) outside the original city (Wuhan) until recovery. Methods: We collected 26 consecutive COVID-19 patients undergoing initial and follow-up CT scans together with RT-PCR until recovery from 2 hospitals outside the original city. Seventeen patients with afferent infection and 9 with second-generation infection were assigned to Group A and B, respectively. By observing CT manifestations, we scored COVID-19, and statistically analyzed numbers of patients with changes in CT scores and RT-PCR results between stages. Results: The total score of COVID-19 on initial CT manifestations was higher in Group A than in Group B (P < 0.05). COVID-19 progressed more frequently from stage 1-2, and relieved from stage 3-4 in Group A (P < 0.05). The similar trend in Group A could not be found in Group B. Results of RT-PCR in most of patients in Group A turned negative at stage 4 while those in Group B turned negative at stage 3 (P < 0.05). Conclusion: Changes in CT manifestation and RT-PCR result can be different between afferent and second-generation COVID-19 until recovery.

18.
BMC Infect Dis ; 20(1): 462, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32611396

RESUMO

BACKGROUND: At present, there are few studies on polymorphism of Mycobacterium tuberculosis (Mtb) gene and how it affects the TB epidemic. This study aimed to document the differences of polymorphisms between tuberculosis hot and cold spot areas of Guangxi Zhuang Autonomous Region, China. METHODS: The cold and hot spot areas, each with 3 counties, had been pre-identified by TB incidence for 5 years from the surveillance database. Whole genome sequencing analysis was performed on all sputum Mtb isolates from the detected cases during January and June 2018. Single nucleotide polymorphism (SNP) of each isolate compared to the H37Rv strain were called and used for lineage and sub-lineage identification. Pairwise SNP differences between every pair of isolates were computed. Analyses of Molecular Variance (AMOVA) across counties of the same hot or cold spot area and between the two areas were performed. RESULTS: As a whole, 59.8% (57.7% sub-lineage 2.2 and 2.1% sub-lineage 2.1) and 39.8% (17.8% sub-lineage 4.4, 6.5% sub-lineage 4.2 and 15.5% sub-lineage 4.5) of the Mtb strains were Lineage 2 and Lineage 4 respectively. The percentages of sub-lineage 2.2 (Beijing family strains) are significantly higher in hot spots. Through the MDS dimension reduction, the genomic population structure in the three hot spot counties is significantly different from those three cold spot counties (T-test p = 0.05). The median of SNPs distances among Mtb isolates in cold spots was greater than that in hot spots (897 vs 746, Rank-sum test p < 0.001). Three genomic clusters, each with genomic distance ≤12 SNPs, were identified with 2, 3 and 4 consanguineous strains. Two clusters were from hot spots and one was from cold spots. CONCLUSION: Narrower genotype diversity in the hot area may indicate higher transmissibility of the Mtb strains in the area compared to those in the cold spot area.


Assuntos
Temperatura Baixa , Epidemias , Temperatura Alta/efeitos adversos , Mycobacterium tuberculosis/genética , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/epidemiologia , China/epidemiologia , Análise por Conglomerados , Genótipo , Humanos , Incidência , Mycobacterium tuberculosis/isolamento & purificação , Filogenia , Polimorfismo de Nucleotídeo Único , Escarro/microbiologia , Tuberculose Pulmonar/transmissão , Sequenciamento Completo do Genoma
19.
Am J Physiol Endocrinol Metab ; 319(1): E217-E231, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32516026

RESUMO

We previously demonstrated that circulating extracellular vesicles (EVs) from patients with valvular heart disease (VHD; vEVs) contain inflammatory components and inhibit endothelium-dependent vasodilation. Neutrophil chemotaxis plays a key role in renal dysfunction, and dexmedetomidine (DEX) can reduce renal dysfunction in cardiac surgery. However, the roles of vEVs in neutrophil chemotaxis and effects of DEX on vEVs are unknown. Here, we investigated the impact of vEVs on neutrophil chemotaxis in kidneys and the influence of DEX on vEVs. Circulating EVs were isolated from healthy subjects and patients with VHD. The effects of EVs on chemokine generation, forkhead box protein O3a (FOXO3a) pathway activation and neutrophil chemotaxis on cultured human umbilical vein endothelial cells (HUVECs) and kidneys in mice and the influence of DEX on EVs were detected. vEVs increased FOXO3a expression, decreased phosphorylation of Akt and FOXO3a, promoted FOXO3a nuclear translocation, and activated the FOXO3a signaling pathway in vitro. DEX pretreatment reduced vEV-induced CXCL4 and CCL5 expression and neutrophil chemotaxis in cultured HUVECs via the FOXO3a signaling pathway. vEVs were also found to suppress Akt phosphorylation and activate FOXO3a signaling to increase plasma levels of CXCL4 and CCL5 and neutrophil accumulation in kidney. The overall mechanism was inhibited in vivo with DEX pretreatment. Our data demonstrated that vEVs induced CXCL4-CCL5 to stimulate neutrophil infiltration in kidney, which can be inhibited by DEX via the FOXO3a signaling. Our findings reveal a unique mechanism involving vEVs in inducing neutrophils chemotaxis and may provide a novel basis for using DEX in reducing renal dysfunction in valvular heart surgery.


Assuntos
Quimiotaxia de Leucócito/imunologia , Vesículas Extracelulares/imunologia , Doenças das Valvas Cardíacas/imunologia , Células Endoteliais da Veia Umbilical Humana/imunologia , Rim/imunologia , Neutrófilos/imunologia , Insuficiência Renal/imunologia , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Adulto , Animais , Estudos de Casos e Controles , Quimiocina CCL5/efeitos dos fármacos , Quimiocina CCL5/imunologia , Quimiocina CCL5/metabolismo , Quimiotaxia de Leucócito/efeitos dos fármacos , Dexmedetomidina/farmacologia , Vesículas Extracelulares/efeitos dos fármacos , Vesículas Extracelulares/metabolismo , Feminino , Proteína Forkhead Box O3/efeitos dos fármacos , Proteína Forkhead Box O3/imunologia , Proteína Forkhead Box O3/metabolismo , Doenças das Valvas Cardíacas/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamação , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Fosforilação , Fator Plaquetário 4/efeitos dos fármacos , Fator Plaquetário 4/imunologia , Fator Plaquetário 4/metabolismo , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Insuficiência Renal/metabolismo , Vasodilatação
20.
Adv Sci (Weinh) ; 7(10): 1903657, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32440483

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease, and the mechanisms underpinning its pathogenesis have not been completely established. Transmembrane member 16A (TMEM16A), a component of the Ca2+-activated chloride channel (CaCC), has recently been implicated in metabolic events. Herein, TMEM16A is shown to be responsible for CaCC activation in hepatocytes and is increased in liver tissues of mice and patients with NAFLD. Hepatocyte-specific ablation of TMEM16A in mice ameliorates high-fat diet-induced obesity, hepatic glucose metabolic disorder, steatosis, insulin resistance, and inflammation. In contrast, hepatocyte-specific TMEM16A transgenic mice exhibit the opposite phenotype. Mechanistically, hepatocyte TMEM16A interacts with vesicle-associated membrane protein 3 (VAMP3) to induce its degradation, suppressing the formation of the VAMP3/syntaxin 4 and VAMP3/synaptosome-associated protein 23 complexes. This leads to the impairment of hepatic glucose transporter 2 (GLUT2) translocation and glucose uptake. Notably, VAMP3 overexpression restrains the functions of hepatocyte TMEM16A in blocking GLUT2 translocation and promoting lipid deposition, insulin resistance, and inflammation. In contrast, VAMP3 knockdown reverses the beneficial effects of TMEM16A downregulation. This study demonstrates a role for TMEM16A in NAFLD and suggests that inhibition of hepatic TMEM16A or disruption of TMEM16A/VAMP3 interaction may provide a new potential therapeutic strategy for NAFLD.

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