Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 140
Filtrar
1.
Nat Commun ; 12(1): 5835, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34611149

RESUMO

Recently developed solid-state catalysts can mediate carbon dioxide (CO2) electroreduction to valuable products at high rates and selectivities. However, under commercially relevant current densities of > 200 milliamperes per square centimeter (mA cm-2), catalysts often undergo particle agglomeration, active-phase change, and/or element dissolution, making the long-term operational stability a considerable challenge. Here we report an indium sulfide catalyst that is stabilized by adding zinc in the structure and shows dramatically improved stability. The obtained ZnIn2S4 catalyst can reduce CO2 to formate with 99.3% Faradaic efficiency at 300 mA cm-2 over 60 h of continuous operation without decay. By contrast, similarly synthesized indium sulfide without zinc participation deteriorates quickly under the same conditions. Combining experimental and theoretical studies, we unveil that the introduction of zinc largely enhances the covalency of In-S bonds, which "locks" sulfur-a catalytic site that can activate H2O to react with CO2, yielding HCOO* intermediates-from being dissolved during high-rate electrolysis.

2.
Anal Chem ; 93(41): 13952-13959, 2021 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-34613709

RESUMO

Herein, we designed a dual 3D DNA nanomachine (DDNM)-mediated catalytic hairpin assembly (DDNM-CHA) to construct an electrochemical biosensor for ultrasensitive detection of miRNA, which possesses quite a faster reaction rate and much higher amplification efficiency than those of traditional catalytic hairpin assembly (CHA). Impressively, since the DDNM skillfully increases the local concentration of reactants and decreases the steric hindrance of substrates simultaneously, the DDNM-CHA could be endowed with higher collision efficiency and more effective reaction compared with traditional CHA, resulting in a hyper conversion efficiency up to 2.78 × 107 only in 25 min. This way, the developed DDNM-CHA could easily conquer the main predicaments: long reaction time and low efficiency. As a proof of the concept, we adopt the gold nanoparticles (AuNPs) and the magnetic nanoparticle (Fe3O4) as the kernel of DNM-A and DNM-B, respectively, and harness the magnetic electrode to directly adsorb the products H1-H2/Fe3O4 for constructing an immobilization-free biosensor for high-speed and ultrasensitive detection of miRNA with a detection limit of 0.14 fM. As a result, the DDNM-CHA we developed carves out a new insight to design a functional DNA nanomachine and evolve the analysis method for practical amplification in the sensing area and promotes the deeper exploration of the nucleic acid signal amplification strategy and DNA nanobiotechnology.


Assuntos
Técnicas Biossensoriais , DNA Catalítico , Nanopartículas Metálicas , MicroRNAs , DNA , Técnicas Eletroquímicas , Ouro , Limite de Detecção
4.
Int Immunopharmacol ; 100: 108066, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34492536

RESUMO

Severe acute lung injury (ALI) cause significant morbidity and mortality worldwide. MicroRNAs (miRNAs) are possible biomarkers and therapeutic targets for ALI. We aimed to explore the role of miR-762, a known oncogenic factor, in the pathogenesis of ALI. Levels of miR-762 in lung tissues of LPS-treated ALI mice and blood cells of patients with lung injury were measured. Injury of human lung epithelial cell line A549 was induced by LPS stimulation. A downstream target of miR-762, NFIX, was predicted using online tools. Their interactions were validated by luciferase reporter assay. Effects of targeted regulation of the miR-762/NFIX axis on cell proliferation, apoptosis, and inflammatory responses were tested in vitro in A549 cells in vivo with an ALI mouse model. We found that upregulation of miR-762 expression and downregulation of NFIX expression were associated with lung injury. Either miR-762 inhibition or NFIX overexpression in A549 lung cells significantly attenuated LPS-mediated impairment of cell proliferation and viability. Notably, increasing expressions of miR-762 inhibitor or NFIX in vivo via airway lentivirus infection alleviated the LPS-induced ALI in mice. Further, targeted downregulation of miR-762 expression or upregulation of NFIX expression in A549 cells markedly down-regulates NF-κB/IRF3 activation, and substantially reduces the production of inflammatory factors, including TNF-α, IL-6, and IL-8. This study reveals a novel role for the miR-762/NFIX pathway in ALI pathogenesis and sheds new light on targeting this pathway for diagnosis, prevention, and therapy.

5.
Artigo em Inglês | MEDLINE | ID: mdl-34553478

RESUMO

Electrosynthesis of hydrogen peroxide (H2 O2 ) in the acidic environment could largely prevent its decomposition to water, but efficient catalysts that constitute entirely earth-abundant elements are lacking. Here we report the experimental demonstration of narrowing the interlayer gap of metallic cobalt diselenide (CoSe2 ), which creates high-performance catalyst to selectively drive two-electron oxygen reduction toward H2 O2 in an acidic electrolyte. The enhancement of the interlayer coupling between CoSe2 atomic layers offers a favorable surface electronic structure that weakens the critical *OOH adsorption, promoting the energetics for H2 O2 production. Consequently, on the strongly coupled CoSe2 catalyst, we achieved Faradaic efficiency of 96.7 %, current density of 50.04 milliamperes per square centimeter, and product rate of 30.60 mg cm-2 h-1 . Moreover, this catalyst shows no sign of degradation when operating at -63 milliamperes per square centimeter over 100 hours.

6.
Anal Chem ; 93(27): 9568-9574, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34210120

RESUMO

In this work, an original rolling-circle strand displacement amplification (RC-SDA) was developed by introducing a circle DNA with two recognition domains as a template instead of the limited liner DNA template in traditional strand displacement amplification (SDA), which displayed much shorter reaction time down to 30 min and quite higher conversion efficiency of more than 1.77 × 108 compared with those of traditional strand displacement amplification (SDA) and could be applied to construct a label-free biosensor for ultrasensitive detection of an HIV DNA fragment. Once the target HIV DNA fragment interacts with the template circle DNA, the RC-SDA could be activated to dramatically output amounts of mimic target DNA with the assistance of the Phi29 DNA polymerase and Nb.BbvCI enzyme. In application, while the output products were captured by the DNA tetrahedral nanoprobe (DTNP) modified electrode, the electrochemical tag silver nanoclusters (AgNCs) on DTNP would be released from the electrode surface, accompanied with an obviously decreased electrochemical signal. This way, the developed signal-off biosensor was successfully applied to realize the rapid and ultrasensitive detection of target HIV DNA fragment with a detection limit down to 0.21 fM, which exploits the new generation of a universal strategy beyond the traditional ones for applications in biosensing assay, clinic diagnosis, and DNA nanobiotechnology.


Assuntos
Técnicas Biossensoriais , Técnicas Eletroquímicas , DNA/genética , Limite de Detecção , Técnicas de Amplificação de Ácido Nucleico , Prata
7.
Theranostics ; 11(13): 6427-6444, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995666

RESUMO

Background: Reportedly, nasopharyngeal carcinoma (NPC) patients with MHC I Class aberration are prone to poor survival outcomes, which indicates that the deficiency of tumor neoantigens might represent a mechanism of immune surveillance escape in NPC. Methods: To clearly delineate the landscape of neoantigens in NPC, we performed DNA and RNA sequencing on paired primary tumor, regional lymph node metastasis and distant metastasis samples from 26 patients. Neoantigens were predicted using pVACseq pipeline. Subtype prediction model was built using random forest algorithm. Results: Portraying the landscape of neoantigens in NPC for the first time, we found that the neoantigen load of NPC was above average compared to that of other cancers in The Cancer Genome Atlas program. While the quantity and quality of neoantigens were similar among primary tumor, regional lymph node metastasis and distant metastasis samples, neoantigen depletion was more severe in metastatic sites than in primary tumors. Upon tracking the clonality change of neoantigens, we found that neoantigen reduction occurred during metastasis. Building a subtype prediction model based on reported data, we observed that subtype I lacked T cells and suffered from severe neoantigen depletion, subtype II highly expressed immune checkpoint molecules and suffered from the least neoantigen depletion, and subtype III was heterogenous. Conclusions: These results indicate that neoantigens are conducive to the guidance of clinical treatment, and personalized therapeutic vaccines for NPC deserve deeper basic and clinical investigations to make them feasible in the future.


Assuntos
Antígenos de Neoplasias/imunologia , Carcinoma Nasofaríngeo/secundário , Neoplasias Nasofaríngeas/imunologia , Adulto , Antígenos de Neoplasias/genética , DNA de Neoplasias/genética , DNA Viral/análise , DNA Viral/genética , Feminino , Antígenos HLA/genética , Antígenos HLA/imunologia , Herpesvirus Humano 4/genética , Humanos , Mutação INDEL , Inibidores de Checkpoint Imunológico/uso terapêutico , Estimativa de Kaplan-Meier , Metástase Linfática/imunologia , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/imunologia , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/virologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/terapia , Neoplasias Nasofaríngeas/virologia , Polimorfismo de Nucleotídeo Único , Intervalo Livre de Progressão , RNA Neoplásico/genética , Receptores de Antígenos de Linfócitos T/imunologia , Evasão Tumoral , Microambiente Tumoral/imunologia , Infecções Tumorais por Vírus/virologia
8.
Nat Commun ; 12(1): 2686, 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976204

RESUMO

Operating fuel cells in alkaline environments permits the use of platinum-group-metal-free (PGM-free) catalysts and inexpensive bipolar plates, leading to significant cost reduction. Of the PGM-free catalysts explored, however, only a few nickel-based materials are active for catalyzing the hydrogen oxidation reaction (HOR) in alkali; moreover, these catalysts deactivate rapidly at high anode potentials owing to nickel hydroxide formation. Here we describe that a nickel-tungsten-copper (Ni5.2WCu2.2) ternary alloy showing HOR activity rivals Pt/C benchmark in alkaline electrolyte. Importantly, we achieved a high anode potential up to 0.3 V versus reversible hydrogen electrode on this catalyst with good operational stability over 20 h. The catalyst also displays excellent CO-tolerant ability that Pt/C catalyst lacks. Experimental and theoretical studies uncover that nickel, tungsten, and copper play in synergy to create a favorable alloying surface for optimized hydrogen and hydroxyl bindings, as well as for the improved oxidation resistance, which result in the HOR enhancement.

9.
J Forensic Sci ; 66(4): 1557-1563, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33904593

RESUMO

In December 2019, a buffer tank burst accident occurred in the maintenance of liquefied natural gas (LNG) bus in China. Failure analysis revealed the bus-mounted buffer tank had been subjected to an excessive internal pressurization, although the tank material met the specifications for engineering practice. The physical evidence related to the failed tank showed that a chemical explosion was impossible. As water was used to pouring the frozen pipeline prior to the accident, according to the consequences observed, the rapid phase transition (RPT) explosion of the residual LNG due to external heat from water was regarded as the main causation of incident. The explosion energy was inversely estimated by the TNT equivalent method, and the rapid expansion of natural gas produced excessive pressure, thus causing the buffer tank to explode.


Assuntos
Acidentes , Explosões , Gás Natural , Ciências Forenses , Humanos , Modelos Teóricos , Termodinâmica
10.
J Mol Neurosci ; 71(12): 2462-2467, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33791913

RESUMO

Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) is a rare mitochondrial disorder associated with mutations in the POLG gene, which encodes the DNA polymerase gamma catalytic subunit. A few POLG-related SANDO cases have been reported, but the genotype-phenotype correlation remains unclear. Here, we report a patient with SANDO carrying two novel missense variants (c.2543G>C, p.G848A and c.452 T>C, p.L151P) in POLG. We also reviewed previously reported cases to systematically evaluate the clinical and genetic features of POLG-related SANDO. A total of 35 distinct variants in the coding region of POLG were identified in 63 patients with SANDO. The most frequent variant was the p.A467T variant, followed by the p.W748S variant. The clinical spectrum of SANDO is heterogeneous. No clear correlation has been observed between the mutation types and clinical phenotypes. Our findings expand the mutational spectrum of POLG and contribute to clinical management and genetic counseling for POLG-related SANDO.

11.
J Am Chem Soc ; 143(21): 8011-8021, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-33913717

RESUMO

Copper is currently the material with the most promise as catalyst to drive carbon dioxide (CO2) electroreduction to produce value-added multicarbon (C2+) compounds. However, a copper catalyst on a carbon-based gas diffusion layer electrode often has poor stability-especially when performing at high current densities-owing to electrolyte flooding caused by the hydrophobicity decrease of the gas diffusion layer during operation. Here, we report a bioinspired copper catalyst on a gas diffusion layer that mimics the unique hierarchical structuring of Setaria's hydrophobic leaves. This hierarchical copper structure endows the CO2 reduction electrode with sufficient hydrophobicity to build a robust gas-liquid-solid triple-phase boundary, which can not only trap more CO2 close to the active copper surface but also effectively resist electrolyte flooding even under high-rate operation. We consequently achieved a high C2+ production rate of 255 ± 5.7 mA cm-2 with a 64 ± 1.4% faradaic efficiency, as well as outstanding operational stability at 300 mA cm-2 over 45 h in a flow reactor, largely outperforming its wettable copper counterparts.

12.
Nat Commun ; 12(1): 1401, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33658516

RESUMO

Effective treatments for patients suffering from heat hypersensitivity are lacking, mostly due to our limited understanding of the pathogenic mechanisms underlying this disorder. In the nervous system, activating transcription factor 4 (ATF4) is involved in the regulation of synaptic plasticity and memory formation. Here, we show that ATF4 plays an important role in heat nociception. Indeed, loss of ATF4 in mouse dorsal root ganglion (DRG) neurons selectively impairs heat sensitivity. Mechanistically, we show that ATF4 interacts with transient receptor potential cation channel subfamily M member-3 (TRPM3) and mediates the membrane trafficking of TRPM3 in DRG neurons in response to heat. Loss of ATF4 also significantly decreases the current and KIF17-mediated trafficking of TRPM3, suggesting that the KIF17/ATF4/TRPM3 complex is required for the neuronal response to heat stimuli. Our findings unveil the non-transcriptional role of ATF4 in the response to heat stimuli in DRG neurons.


Assuntos
Fator 4 Ativador da Transcrição/metabolismo , Nociceptividade/fisiologia , Células Receptoras Sensoriais/fisiologia , Canais de Cátion TRPM/metabolismo , Fator 4 Ativador da Transcrição/genética , Animais , Membrana Celular/metabolismo , Quimiocina CXCL12/metabolismo , Gânglios Espinais/citologia , Gânglios Espinais/fisiologia , Células HEK293 , Temperatura Alta , Humanos , Injeções Espinhais , Cinesina/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Técnicas de Patch-Clamp , Transporte Proteico , Receptores CXCR4/metabolismo , Canais de Cátion TRPM/genética
13.
J Immunother Cancer ; 9(2)2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33637599

RESUMO

BACKGROUND: The advent of immune checkpoint therapy has been a tremendous advance in cancer treatment. However, the responses are still insufficient in patients with soft tissue sarcoma (STS). We aimed to identify rational combinations to increase the response to immune checkpoint therapy and improve survival. METHODS: Whole-exome sequencing (WES) was performed in 11 patients with liposarcoma. Somatic copy number alterations (SCNAs) were analyzed at the gene level to identify obvious amplification patterns in drug-target genes. The expression and prognostic value of class I histone deacetylases (HDACs) was evaluated in 49 patients with sarcoma in our center and confirmed in 263 sarcoma samples from The Tumor Cancer Genome Atlas (TCGA) database. Q-PCR, flow cytometry and RNA-seq were performed to determine the correlations between class I HDACs, chidamide and PD-L1 in vitro and in vivo. The efficacy of combining chidamide with PD-1 blockade was explored in an immunocompetent murine model and a small cohort of patients with advanced sarcoma. Western blot, ChIP assay and dual luciferase assessment were applied in the mechanistic study. RESULTS: The HDAC gene family was frequently amplified in STS. SCNAs in the HDAC gene family were extensively amplified in 8 of 11 (73%) patients with liposarcoma, based on a drug-target gene set, and we verified amplification in 76.65% (197/257) of cases by analyzing TCGA sarcoma cohort. Class I HDAC expression is associated with a poor prognosis for patients with STS, and its inhibition is responsible for promoting apoptosis and upregulating of programmed cell death ligand 1 (PD-L1). The HDAC class I inhibitor chidamide significantly increases PD-L1 expression, increased the infiltration of CD8+ T cells and reduced the number of MDSCs in the tumor microenvironment. The combination of chidamide with an anti-PD-1 antibody significantly promotes tumor regression and improves survival in a murine model. Moreover, chidamide combined with the anti-PD-1 antibody toripalimab is effective in patients with advanced and metastatic sarcoma, and the side effects are tolerable. Mechanistically, chidamide increases histone acetylation at the PD-L1 gene through the activation of the transcriptional factor STAT1. CONCLUSIONS: The combination of chidamide and anti-programmed cell death 1 (PD-1) therapy represents a potentially important strategy for STS.

14.
Pain ; 162(6): 1882-1896, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33433144

RESUMO

ABSTRACT: Adults are more likely to suffer from chronic pain than minors, and its underlying mechanism remains unclear. SIRT1 an important age-related protein with function of lifespan extension; whether SIRT1 plays a role in the different pain vulnerability of adult and juvenile remains unclear. Here, we found that the expression level of SIRT1 in dorsal root ganglia (DRG) was related to the pain vulnerability. After nerve injury, the expression of SIRT1 in DRG was decreased in adult rodents whereas increased in juvenile rodents. Differential manipulation of SIRT1 abolished the different pain vulnerability between adult and juvenile rodents. Furthermore, SIRT1 interacted with ClC-3 channel and mediated ClC-3 membrane trafficking and Cl- current in DRG neurons. Differential manipulation of ClC-3 also abolished the difference in pain vulnerability between adult and juvenile rodents. The different anti-inflammatory ability determined the different change trends of SIRT1 and ClC-3 trafficking contributed to the different pain vulnerability in adult and juvenile rodents. In addition, the serum SIRT1 level was negatively correlated with the pain score in patients with chronic pain. These findings revealed the mechanism of the difference in pain vulnerability between adult and juvenile rodents and provided evidence for age-specific treatment of chronic pain.


Assuntos
Roedores , Sirtuína 1 , Animais , Gânglios Espinais , Humanos , Ratos , Ratos Sprague-Dawley , Células Receptoras Sensoriais , Sirtuína 1/genética
15.
Angew Chem Int Ed Engl ; 60(12): 6553-6560, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33438257

RESUMO

Although the Turing structures, or stationary reaction-diffusion patterns, have received increasing attention in biology and chemistry, making such unusual patterns on inorganic solids is fundamentally challenging. We report a simple cation exchange approach to produce Turing-type Ag2 Se on CoSe2 nanobelts relied on diffusion-driven instability. The resultant Turing-type Ag2 Se-CoSe2 material is highly effective to catalyze the oxygen evolution reaction (OER) in alkaline electrolytes with an 84.5 % anodic energy efficiency. Electrochemical measurements show that the intrinsic OER activity correlates linearly with the length of Ag2 Se-CoSe2 interfaces, determining that such Turing-type interfaces are more active sites for OER. Combing X-ray absorption and computational simulations, we ascribe the excellent OER performance to the optimized adsorption energies for critical oxygen-containing intermediates at the unconventional interfaces.

16.
Parkinsonism Relat Disord ; 83: 63-65, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33482438

RESUMO

Mutations in VPS16 have been identified to be responsible for generalized dystonia. We screened VPS16 variants in 53 unrelated subjects with isolated dystonia via whole-exome sequencing. A novel pathogenic frameshift mutation p.R643fs* was found in a patient with early-onset multifocal dystonia with prominent oromandibular and bulbar involvement. Our findings expanded the spectrum of VPS16-related dystonia and suggested that mutations in VPS16 should be considered in patients with progressive early-onset dystonia.

17.
Neurosci Lett ; 746: 135590, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33388357

RESUMO

INTRODUCTION: Dystonia is a movement disorder with high clinical and genetic heterogeneity. Mutations in Anoctamin-3 (ANO3) gene have been reported to cause dystonia 24 (DYT24). This study aims to clarify the spectrum and frequency of ANO3 rare variants in Chinese populations with primary dystonia and understand the clinical and genetic features of DYT24. METHODS: Sanger sequencing was used to screen all exons and exon-intron boundaries of ANO3 for rare variants in 115 primary dystonia patients. The clinical manifestations of patients with ANO3 variants in our study and previously reported literatures were further characterized. RESULTS: Four distinct variants of ANO3 (c.1127A > G, c.1235 T > A, c.1531-3T > C, c.-11G > T) were identified in six unrelated individuals. Combined with our work and literature review, a total of 35 different rare variants distributed in ANO3 were identified in 62 dystonia patients. The predominant phenotype is cranio-cervical dystonia and more than half of patients develop head/limb tremor. Most of patients presented with isolated dystonia whereas few of them showed combined dystonia. The age of onset ranged from 1 to 69 years and peaked in late adulthood, while for generalized dystonia it peaked in a young age. Half of patients with generalized dystonia experienced deep brain stimulation (DBS). And all of them showed improvement of dystonia by DBS. CONCLUSIONS: This study confirms a relatively high frequency of rare ANO3 variants in Chinese patients with dystonia and indicates that the late adulthood-onset, cranio-cervical dystonia seems to be an important feature of the ANO3 phenotype. Further functional studies are warranted to understand the role of ANO3 in dystonia.


Assuntos
Anoctaminas/genética , Grupo com Ancestrais do Continente Asiático/genética , Distúrbios Distônicos/diagnóstico , Distúrbios Distônicos/genética , Variação Genética/genética , Idoso , Sequência de Aminoácidos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
18.
Pain ; 162(2): 490-502, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32868747

RESUMO

ABSTRACT: Mechanical allodynia is a debilitating condition for millions of patients with chronic pain. Mechanical allodynia can manifest in distinct forms, including brush-evoked dynamic and filament-evoked static allodynia. In the nervous system, the forkhead protein Foxo1 plays a critical role in neuronal structures and functions. However, the role of Foxo1 in the somatosensory signal remains unclear. Here, we found that Foxo1 selectively regulated static mechanical pain. Foxo1 knockdown decreased sensitivity to static mechanical stimuli in normal rats and attenuated static mechanical allodynia in rat models for neuropathic, inflammatory, and chemotherapy pain. Conversely, Foxo1 overexpression selectively enhanced sensitivity to static mechanical stimuli and provoked static mechanical allodynia. Furthermore, Foxo1 interacted with voltage-gated sodium Nav1.7 channels and increased the Nav1.7 current density by accelerating activation rather than by changing the expression of Nav1.7 in dorsal root ganglia neurons. In addition, the serum level of Foxo1 was found to be increased in chronic pain patients and to be positively correlated with the severity of chronic pain. Altogether, our findings suggest that serum Foxo1 level could be used as a biological marker for prediction and diagnosis of chronic pain. Moreover, selective blockade of Foxo1/Nav1.7 interaction may offer a new therapeutic approach in patients with mechanical pain.


Assuntos
Dor , Canais de Sódio Disparados por Voltagem , Animais , Proteína Forkhead Box O1/genética , Gânglios Espinais/metabolismo , Humanos , Hiperalgesia , Proteínas do Tecido Nervoso/metabolismo , Ratos , Ratos Sprague-Dawley
19.
Cell Biol Int ; 45(3): 642-653, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33289184

RESUMO

Diabetic cardiomyopathy (DCM) is characterized by myocardial hypertrophy and fibrosis. This study aimed to investigate the effects of microRNA (miR)-34a on myocardial fibrosis in DCM and its potential mechanism of targeting Pin-1 signaling. Vimentin and Pin-1 proteins in mouse cardiac tissues were detected by immunohistochemical staining. Locked nucleic acid in situ hybridization was used to measure miR-34a expression in cardiac tissues. Primary mouse cardiac fibroblasts (CFs) were transfected with a mimics control/miR-34a mimics or Pin-1 plasmid and cultured in high-glucose (HG) Dulbecco's modified Eagle's medium. The miR-34a levels were measured by quantitative polymerase chain reaction. The apoptosis and viability of transfected cells were detected by the terminal deoxynucleotidyl transferase dUTP nick end labeling and Cell Counting Kit-8 assays respectively. A cell migration experiment and dual-luciferase reporter assay were also performed. The body weight and fasting blood glucose of DCM mice were significantly higher than those in the control (CTL) group. In addition, DCM mice had decreased serum insulin levels and impaired cardiac function. The number of CFs in the DCM group was higher than in the CTL group and Pin-1 expression was upregulated. The expression level of miR-34a in the cardiac tissue of mice in the DCM group was obviously downregulated compared with the CTL group. The HG stimulation of CFs for 48 h significantly downregulated the expression level of miR-34a and was associated with increased Type I collagen expression, cell viability, and migration and decreased apoptosis. However, these effects could be reversed by overexpressing miR-34a in HG-induced CFs. Furthermore, we found that Pin-1 was a direct target of miR-34a. Our results suggest that miR-34a can attenuate myocardial fibrosis in DCM by reducing Type I collagen production, cell viability, and migration and increasing the apoptosis of CFs by targeting Pin-1 signaling.


Assuntos
Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/patologia , MicroRNAs/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Peptidilprolil Isomerase de Interação com NIMA/metabolismo , Animais , Apoptose/genética , Glicemia/metabolismo , Movimento Celular/genética , Colágeno Tipo I/metabolismo , Cardiomiopatias Diabéticas/diagnóstico por imagem , Cardiomiopatias Diabéticas/fisiopatologia , Eletrocardiografia , Fibroblastos/metabolismo , Fibrose , Regulação da Expressão Gênica , Ventrículos do Coração/patologia , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética
20.
J Hepatol ; 74(4): 838-849, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33212090

RESUMO

BACKGROUND & AIMS: Little is known about Epstein-Barr virus (EBV)-associated intrahepatic cholangiocarcinoma (EBVaICC) because of its rarity. We aimed to comprehensively investigate the clinicopathology, tumor immune microenvironment (TIME) and genomic landscape of this entity in southern China. METHODS: We evaluated 303 intrahepatic cholangiocarcinomas (ICCs) using in situ hybridization for EBV. We compared clinicopathological parameters between EBVaICC and nonEBVaICC, and we analyzed EBV infection status, tumor-infiltrating lymphocytes (TILs) and genomic features of EBVaICC by immunohistochemistry, double staining, nested PCR, multiplex immunofluorescence staining, fluorescence in situ hybridization and whole-exome sequencing. RESULTS: EBVaICC accounted for 6.6% of ICCs and was associated with EBV latency type I infection and clonal EBV isolates. Patients with EBVaICC were more often female and younger, with solitary tumors, higher HBV infection rates and less frequent cirrhosis; the lymphoepithelioma-like (LEL) subtype was more common in EBVaICC. EBVaICC was associated with a significantly larger TIME component than nonEBVaICC. The LEL subtype of EBVaICC - associated with a significantly increased density and proportion of CD20+ B cells and CD8+ T cells - was associated with significantly higher 2-year survival rates than conventional EBVaICC and nonEBVaICC. Both PD-1 and PD-L1 in TILs, and PD-L1 in tumor cells, were overexpressed in EBVaICC. High PD-L1 expression in tumor cells and high CD8+ TIL densities were significantly more common in EBVaICC than in nonEBVaICC. Seven genes (MUC4, DNAH1, GLI2, LIPE, MYH7, RP11-766F14.2 and WDR36) were mutated in at least 3 patients. EBVaICC had a different mutational pattern to liver fluke-associated cholangiocarcinoma and HBV-associated ICC. CONCLUSIONS: EBVaICC, as a subset of ICC, has unique etiological, clinicopathological and genetic characteristics, with a significantly larger TIME component. Paradoxically, patients with EBVaICC could be candidates for immune checkpoint therapy. LAY SUMMARY: Epstein-Barr virus (EBV) is associated with a subtype of intrahepatic cholangiocarcinoma, with unique clinicopathological and genetic characteristics. The tumor immune microenvironment is also different in this tumor subtype and patients with EBV-associated intrahepatic cholangiocarcinoma may respond well to immune checkpoint inhibitors.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...