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1.
Nat Commun ; 12(1): 5989, 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34645818

RESUMO

Liquid-liquid phase separation promotes the formation of membraneless condensates that mediate diverse cellular functions, including autophagy of misfolded proteins. However, how phase separation participates in autophagy of dysfunctional mitochondria (mitophagy) remains obscure. We previously discovered that nuclear receptor Nur77 (also called TR3, NGFI-B, or NR4A1) translocates from the nucleus to mitochondria to mediate celastrol-induced mitophagy through interaction with p62/SQSTM1. Here, we show that the ubiquitinated mitochondrial Nur77 forms membraneless condensates capable of sequestrating damaged mitochondria by interacting with the UBA domain of p62/SQSTM1. However, tethering clustered mitochondria to the autophagy machinery requires an additional interaction mediated by the N-terminal intrinsically disordered region (IDR) of Nur77 and the N-terminal PB1 domain of p62/SQSTM1, which confers Nur77-p62/SQSTM1 condensates with the magnitude and liquidity. Our results demonstrate how composite multivalent interaction between Nur77 and p62/SQSTM1 coordinates to sequester damaged mitochondria and to connect targeted cargo mitochondria for autophagy, providing mechanistic insight into mitophagy.

2.
Microbiol Immunol ; 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34491597

RESUMO

Schistosomiasis is a zoonotic parasitic disease that is endemic in Asia. Macrophages are mainly involved in the inflammatory response of late schistosoma infection. Our previous study found that C/EBP homologous protein (CHOP) expression significantly increased, and M2 macrophages are activated in schistosome-induced liver fibrosis mice. However, the role of CHOP in the regulation of macrophage polarization remains to be further studied.Western blotting or qPCR revealed that interleukin-4 (IL-4) increased the expression of arginase-1 (Arg-1), macrophage mannose receptor 1 (Mrc-1), phosphorylation signal transducer and activator of transcription 6 (p-STAT6), Krüppel-like factor 4 (KLF4), CHOP, and interleukin-13 receptor alpha (IL-13Rα) and induced M2 polarization in RAW264.7 as measured by flow cytometry. Inhibiting STAT6 phosphorylation (AS1517499) reduced the IL-4-induced expression of KLF4, CHOP, and IL-13Rα and also the number of M2 macrophages. The overexpression of CHOP stimulated M2 polarization, but AS1517499 inhibited this effect. CHOP increased the protein expression of KLF4 but did not change the expression of p-STAT6. Soluble egg antigen (SEA) could promote the IL-4-induced protein expression of p-STAT6, CHOP, and KLF4.Overall, the findings show that SEA can promote the activation of M2 macrophages by causing increased CHOP-induced KLF4 levels and activation of STAT6 phosphorylation. This article is protected by copyright. All rights reserved.

3.
Arthritis Rheumatol ; 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34569725

RESUMO

OBJECTIVE: Protein tyrosine kinases (PTKs) regulate osteoarthritis (OA) progression by activating a series of signal transduction pathways. However, the roles of protein tyrosine phosphatases (PTPs) in OA remain obscure. METHODS: The expression of 107 PTP genes in human OA cartilage was analyzed based on a single-cell sequencing dataset. The enzyme activity of the PTP SHP2 was detected in primary chondrocytes after interleukin (IL)-1ß treatment and in human OA cartilage. Destabilized medial meniscus (DMM) model and IL-1ß-stimulated primary mouse chondrocytes were treated with an SHP2 inhibitor and celecoxib (a clinical drug for the treatment of OA). The function of SHP2 in OA pathogenesis was further verified in Aggrecan-CreERT ; SHP2 flox/flox mice. The downstream protein expression profile and dephosphorylated substrate of SHP2 were examined by tandem mass tag (TMT) labeling-based global proteomic and stable isotope labeling using amino acids in cell culture (SILAC)-labeled tyrosine phosphoproteomic analysis, respectively. RESULTS: SHP2 enzyme activity significantly increased in human OA samples with serious articular cartilage injury and in IL-1ß-stimulated chondrocytes. Pharmacological inhibition or genetic deletion of SHP2 ameliorated OA progression. SHP2 inhibitors dramatically reduced the expression of cartilage degradation-related genes and simultaneously promoted the expression of cartilage synthesis-related genes. Mechanistically, SHP2 inhibition suppressed the dephosphorylation of DOK1 and subsequently reduced the expression of uridine phosphorylase 1 and increased uridine level, thereby contributing to the homeostasis of cartilage metabolism. CONCLUSIONS: SHP2 is a novel accelerator of the imbalance in the cartilage homeostasis. Specific inhibition of SHP2 may ameliorate OA by maintaining the anabolic and catabolic balance.

4.
Dev Cell ; 56(18): 2592-2606.e7, 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34508658

RESUMO

Membrane contact between intracellular organelles is important in mediating organelle communication. However, the assembly of molecular machinery at membrane contact site and its internal organization correlating with its functional activity remain unclear. Here, we demonstrate that a gel-like condensation of Cidec, a crucial protein for obesity development by facilitating lipid droplet (LD) fusion, occurs at the LD-LD contact site (LDCS) through phase separation. The homomeric interaction between the multivalent N terminus of Cidec is sufficient to promote its phase separation both in vivo and in vitro. Interestingly, Cidec condensation at LDCSs generates highly plastic and lipid-permeable fusion plates that are geometrically constrained by donor LDs. In addition, Cidec condensates are distributed unevenly in the fusion plate generating stochastic sub-compartments that may represent unique lipid passageways during LD fusion. We have thus uncovered the organization and functional significance of geometry-constrained Cidec phase separation in mediating LD fusion and lipid homeostasis.

5.
Channels (Austin) ; 15(1): 516-527, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34414859

RESUMO

Estradiol regulates thyroid function, and chloride channels are involved in the regulation of thyroid function. However, little is known about the role of chloride channels in the regulation of thyroid functions by estrogen. In this study, the effects of estrogen on chloride channel activities in human thyroid Nthy-ori3-1 cells were therefore investigated using the whole cell patch-clamp technique. The results showed that the extracellular application of 17ß-estradiol (E2) activated Cl- currents, which reversed at a potential close to Cl- equilibrium potential and showed remarkable outward rectification and an anion permeability of I- > Br- > Cl- > gluconate. The Cl- currents were inhibited by the chloride channel blockers, NPPB and tamoxifen. Quantitative Real-time PCR results demonstrated that ClC-3 expression was highest in ClC family member in Nthy-ori3-1 cells. The down-regulation of ClC-3 expression by ClC-3 siRNA inhibited E2-induced Cl- current. The Cl- current was blocked by the estrogen receptor antagonist, ICI 182780 (fulvestrant). Estrogen receptor alpha (ERα) and not estrogen receptor beta was the protein expressed in Nthy-ori3-1 cells, and the knockdown of ERα expression with ERα siRNA abolished E2-induced Cl- currents. Estradiol can promote the accumulation of ClC-3 in cell membrane. ERα and ClC-3 proteins were partially co-localized in the cell membrane of Nthy-ori3-1 cells after estrogen exposure. The results suggest that estrogen activates chloride channels via ERα in normal human thyroid cells, and ClC-3 proteins play a pivotal role in the activation of E2-induced Cl- current.

6.
Gastric Cancer ; 2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34370147

RESUMO

The tumor suppressor gene phosphatase and tensin homolog (PTEN) in PI3K/Akt/mTOR pathway is essential in inhibiting tumor growth and metastasis. However, whether the mutation of PTEN gene could induce tumorigenesis and impact the treatment of gastric cancer is still unclear. The purpose of the study was to investigate the combined treatment of gastric tumorigenesis using Rapamycin and Fluorouracil (5-Fu) through interfering with the Akt/mTOR pathway in a mouse model with PTEN conditional deletion. Three groups of mice were exposed for 5 days to Rapamycin and 5-Fu separately and together. The gene expression of the Akt/mTOR pathway, the protein expression of caspase-3 and p-Akt, p-S6K and p-4EBP1, and the pathological changes in stomachs were analyzed. Our study demonstrates that the conditional PTEN deletion in the cells of glandular stomach induces hyperplastic gastric tumors in mice. The combined Rapamycin administration with 5-Fu resulted in better outcomes than their separate administration for the treatment of gastric cancer by inhibiting the mTOR signal pathway. Our study indicates that Rapamycin has a synergistic interaction with chemotherapeutic 5-Fu, and demonstrates a potential therapeutic combination treatment on glandular stomach tumor with PTEN functional absence or aberrantly activated Akt/mTOR pathway. It provides important insights into the inhibition of the Akt/mTOR pathway in gastric cancer clinical therapy.

7.
Comput Intell Neurosci ; 2021: 5107034, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34326867

RESUMO

Cross-modal hashing encodes heterogeneous multimedia data into compact binary code to achieve fast and flexible retrieval across different modalities. Due to its low storage cost and high retrieval efficiency, it has received widespread attention. Supervised deep hashing significantly improves search performance and usually yields more accurate results, but requires a lot of manual annotation of the data. In contrast, unsupervised deep hashing is difficult to achieve satisfactory performance due to the lack of reliable supervisory information. To solve this problem, inspired by knowledge distillation, we propose a novel unsupervised knowledge distillation cross-modal hashing method based on semantic alignment (SAKDH), which can reconstruct the similarity matrix using the hidden correlation information of the pretrained unsupervised teacher model, and the reconstructed similarity matrix can be used to guide the supervised student model. Specifically, firstly, the teacher model adopted an unsupervised semantic alignment hashing method, which can construct a modal fusion similarity matrix. Secondly, under the supervision of teacher model distillation information, the student model can generate more discriminative hash codes. Experimental results on two extensive benchmark datasets (MIRFLICKR-25K and NUS-WIDE) show that compared to several representative unsupervised cross-modal hashing methods, the mean average precision (MAP) of our proposed method has achieved a significant improvement. It fully reflects its effectiveness in large-scale cross-modal data retrieval.


Assuntos
Destilação , Semântica , Bases de Dados Factuais , Humanos , Gestão da Informação , Armazenamento e Recuperação da Informação
8.
Plant Physiol Biochem ; 167: 42-48, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34332253

RESUMO

Grafting is a technique that provides a substantial way to enhance nutrient utilization thereby improves plant growth and yield quality. Although it is commonly practised in horticultural crops, the impact of scion-rootstock interaction on nutrient distribution is still unclear. Here, 'Newhall' navel orange plants grafted on Trifoliate orange (T) as the original rootstock were inarched with trifoliate orange (N/Tt combination) or carrizo citrange (N/Tc combination) rootstock seedlings. The experimental plants were treated with isotope 10B solution for 7 weeks to investigate the effect of different inarched rootstocks on B distribution and translocation by using a two-root system. From this study, the original rootstock played a more dominant role in B distribution to scion tissues than the inarching rootstock either in N/Tt or N/Tc combination. From inarched combinations, the carrizo citrange in the N/Tc combination had a higher ability to distribute B to new leaves, new twigs and old twigs than trifoliate orange in the N/Tt combination. However, the original rootstock of N/Tt distributed more B to scion tissues than N/Tc and the B concentration in old leaves and new leaves of N/Tt plants was significantly higher than that of N/Tc plants. These results suggest that scion B status is influenced by the B distribution of two inarching rootstocks in an inarching plant, as well as the affinity between the inarching rootstock and grafted plant. In addition, by either adding 10B to the inarching rootstock or original rootstock, we could detect 10B in the other rootstock root in both N/Tt and N/Tc combinations. The results further suggest that B can translocate from rootstock to leaves and then, re-translocate from scion to rootstock through the cycling of B transportation.


Assuntos
Citrus sinensis , Citrus , Boro , Folhas de Planta , Raízes de Plantas
9.
Nutr J ; 20(1): 50, 2021 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-34092243

RESUMO

BACKGROUND: Arterial stiffness is an independent cardiovascular risk factor. However, the association between sodium/potassium intake and vascular stiffness was inconsistent. Therefore, a large community-based cross-sectional study was performed to try and achieve more definitive conclusion. METHODS: Urinary sodium, potassium, and creatinine levels were tested in spot urine samples during physical examinations of each recruited participant. The 24-h estimated urinary sodium excretion (eUNaE) and estimated urinary potassium excretion (eUKE) levels were determined using the Kawasaki formula (used as a surrogate for intake). Carotid intima-media thickness (IMT) and plaques were measured using ultrasound. RESULTS: In 13,523 subjects aged 18-80 years, the relationships between carotid plaques and IMT with eUNaE, eUKE and their ratios were analyzed. Overall, 30.2% of participants were diagnosed with carotid artery plaques. The ratio of estimated sodium vs. potassium excretion (Na/K ratio) of the individuals with carotid artery plaques was significantly higher than that of participants without plaque (2.14 ± 0.73 vs. 2.09 ± 0.61, P < 0.01). After adjusting for age, gender, and other lifestyle covariates, a significant positive relation was found between carotid plaque and Na/K ratios (OR = 1.06, P < 0.05). In participants without plaque, a similar positive association was observed between Na/K ratios and increased bifurcation carotid IMT (ß = 0.008, P < 0.01), especially in the females (Pinteraction < 0.01). CONCLUSIONS: In this study, in which sodium intake was estimated on the basis of measured urinary excretion, high estimated excretion levels of urinary sodium and/or low estimated excretion levels of urinary potassium might be associated with an increased presence of carotid atherosclerosis in Chinese individuals.


Assuntos
Aterosclerose , Doenças das Artérias Carótidas , Sódio na Dieta , Adulto , Aterosclerose/epidemiologia , Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/diagnóstico por imagem , Espessura Intima-Media Carotídea , China/epidemiologia , Estudos Transversais , Feminino , Humanos , Potássio , Sódio
11.
Physiol Rev ; 101(4): 1691-1744, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33949875

RESUMO

This review deals with the roles of calcium ions and ATP in the control of the normal functions of the different cell types in the exocrine pancreas as well as the roles of these molecules in the pathophysiology of acute pancreatitis. Repetitive rises in the local cytosolic calcium ion concentration in the apical part of the acinar cells not only activate exocytosis but also, via an increase in the intramitochondrial calcium ion concentration, stimulate the ATP formation that is needed to fuel the energy-requiring secretion process. However, intracellular calcium overload, resulting in a global sustained elevation of the cytosolic calcium ion concentration, has the opposite effect of decreasing mitochondrial ATP production, and this initiates processes that lead to necrosis. In the last few years it has become possible to image calcium signaling events simultaneously in acinar, stellate, and immune cells in intact lobules of the exocrine pancreas. This has disclosed processes by which these cells interact with each other, particularly in relation to the initiation and development of acute pancreatitis. By unraveling the molecular mechanisms underlying this disease, several promising therapeutic intervention sites have been identified. This provides hope that we may soon be able to effectively treat this often fatal disease.


Assuntos
Trifosfato de Adenosina/fisiologia , Cálcio/fisiologia , Pâncreas Exócrino/fisiologia , Pancreatopatias/fisiopatologia , Animais , Sinalização do Cálcio , Humanos , Pâncreas Exócrino/fisiopatologia
12.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 52(3): 423-429, 2021 May.
Artigo em Chinês | MEDLINE | ID: mdl-34018360

RESUMO

Objective: To investigate the differences in the osteogenic capacity of osteoporotic adipose-derived stem cells (OP-ASCs) and normal control adipose-derived stem cells (Ctrl-ASCs), and to examine the expression levels of RNA methyltransferase like 14 (Mettl14) and the Notch signaling molecule 1 (Notch1). Methods: The osteoporosis (OP) model of SD rats was established with ovariectomy (OVX). Micro-CT, HE staining and Masson staining were performed to identify the successful establishment of the OP model, OP-ASCs and Ctrl-ASCs were isolated and cultured adherently. Then, the three-way differentiation capacity of the adipose-derived stem cells (ASCs) was determined through alizarin red staining, alcian blue staining and oil red O staining and flow cytometry was conducted to examine the surface antigens CD29, CD44, CD90, CD31, CD34, and CD45. Alizarin red staining and comparison of the mRNA and protein expression of Run-related transcription factor 2 (Runx2) were done to explore the differences in osteogenic potential of OP-ASCs and Ctrl-ASCs. Real-time PCR and Western blot were performed to explore the expression differences of Mettl14 and Notch1 at mRNA and protein levels between OP-ASCs and Ctrl-ASCs. Results: Micro-CT, HE and Masson staining results showed that the number of trabecular bone decreased and the spacing increased in the tibias of the osteoporosis group (OP group) compared with those of the control group (Ctrl group), indicating that the OP model was established successfully. Three-way differentiation and flow cytometry results confirmed the successful isolation and culture of ASCs. After osteogenic induction, alizarin red staining showed that OP-ASCs had fewer number and more scattered distribution of mineralized nodules than Ctrl-ASCs did. The expression of Runx2 in OP-ASCs was lower than that in Ctrl-ASCs ( P<0.05). Mettl14 as well as Notch1 showed lower expression in OP-ASCs than they did in Ctrl-ASCs ( P<0.05). Conclusion: The osteogenic capacity of OP-ASCs was lower compared with that of Ctrl-ASCs, Mettl14 expression of OP-ASCs was decreased compared with that of Ctrl-ASCs, and the Notch signaling pathway was inhibited in OP-ASCs. The study helps build the foundation for further investigation in the specific mechanisms of Mettl14 and Notch1 during osteogenic differentiation of OP-ASCs.


Assuntos
Osteogênese , Células-Tronco , Adipócitos , Tecido Adiposo , Animais , Diferenciação Celular , Células Cultivadas , Feminino , Humanos , Metiltransferases , Ratos , Ratos Sprague-Dawley , Receptor Notch1/genética
13.
Environ Int ; 152: 106495, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33730632

RESUMO

Zinc oxide nanoparticles (ZnO NPs) have been increasingly and widely utilized in various fields, such as agriculture, food and cosmetics. However, various levels of adverse impacts of ZnO NPs on the ecological environment and public health have been associated with each stage of their production, use and disposal. ZnO NPs can be ingested by pregnant women and transferred to developing embryos/foetus through the placental barrier, however, the potential toxicity of ZnO NPs to embryonic and foetal development is largely unclear. In this study, we discovered that ZnO NPs exposure caused growth proportional failure of neural tube closure in mouse and chicken embryos and a simultaneous increase in apoptosis in the developing neural tubes of chicken embryos, which was verified in an in vitro experiment using the SH-SY5Y cell line. Furthermore, removal of free Zn2+ ions with EDTA or inhibition of Zn2+ ion absorption by CaCl2 partially alleviated the neurotoxicity induced by ZnO NPs, implying that ZnO NPs-induced developmental neurotoxicity is probably due to both ZnO NPs and the Zn2+ ions released from ZnO NPs. In addition, we found that ZnO NPs exposure caused endoplasmic reticulum stress-mediated apoptosis driven mainly by an increase in intracellular calcium (Ca2+) concentrations, rather than by the activation of three membrane protein receptors (ATF6, IRE-1 and PERK). Thus, Ca2+ imbalance-mediated apoptosis in the context of ZnO NPs exposure may lead to cellular dysfunctions in developing neural precursors, such as, abnormalities involved in neural tube closure, ultimately leading to neural tube defects (NTDs) during embryogenesis. In sum, our results revealed that ZnO NPs exposure greatly increases the risk of failure of neural tube closure through endoplasmic reticulum stress-mediated neural cell death in the developing embryos, which may further lead to the NTD in fetal stage, including failure of neural tube closure.


Assuntos
Nanopartículas , Óxido de Zinco , Animais , Cálcio , Sobrevivência Celular , Embrião de Galinha , Desenvolvimento Embrionário , Estresse do Retículo Endoplasmático , Feminino , Humanos , Camundongos , Nanopartículas/toxicidade , Tubo Neural , Estresse Oxidativo , Gravidez , Espécies Reativas de Oxigênio , Óxido de Zinco/toxicidade
14.
Hepatology ; 74(1): 458-473, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33609283

RESUMO

BACKGROUND AND AIMS: Myofibroblasts play a pivotal role in the development and progression of HCC. Here, we aimed to explore the role and mechanism of myofibroblast Musashi RNA binding protein 2 (MSI2) in HCC progression. APPROACH AND RESULTS: Myofibroblast infiltration and collagen deposition were detected and assessed in the tissues from 117 patients with HCC. Transgenic mice (Msi2ΔCol1a1 ) with floxed Msi2 allele and collagen type I alpha 1 chain (Col1a1)-ligand inducible Cre recombinases (CreER) were constructed to generate a myofibroblast-specific Msi2 knockout model. Mouse HCC cells were orthotopically transplanted into the Msi2ΔCol1a1 or the control mice (Msi2F/F ). We found that the deposition of collagen fibers, the main product of myofibroblasts, predicted a poor prognosis for HCC; meanwhile, we detected high MSI2 expression in the peritumoral infiltrated myofibroblasts. Conditional deletion of Msi2 in myofibroblasts significantly inhibited the growth of orthotopically implanted HCC, reduced both intrahepatic and lung metastasis, and prolonged the overall survival of tumor-bearing mice (P = 0.002). In vitro analysis demonstrated that myofibroblasts promoted cell proliferation, invasion, and epithelial-mesenchymal transformation of HCC cells, whereas Msi2 deletion in myofibroblasts reversed these effects. Mechanically, Msi2 knockout decreased myofibroblast-derived IL-6 and IL-11 secretion by inhibiting the extracellular signal-regulated kinase 1/2 pathway, and thus attenuated the cancer stem cell-promoting effect of myofibroblasts. Interestingly, we found that the simultaneous knockout of Msi2 in myofibroblasts and knockdown of Msi2 in HCC cells could not further attenuate the implanted HCC progression. CONCLUSIONS: Myofibroblast-specific Msi2 knockout abrogated the tumor-promoting function of myofibroblasts and inhibited HCC progression in mouse models. Targeting myofibroblast MSI2 expression may therefore prove to be a therapeutic strategy for HCC treatment in the future.

15.
J Cell Mol Med ; 25(3): 1568-1582, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33410581

RESUMO

The pro-inflammatory and pro-fibrotic liver microenvironment facilitates hepatocarcinogenesis. However, the effects and mechanisms by which the hepatic fibroinflammatory microenvironment modulates intrahepatic hepatocellular carcinoma (HCC) progression and its response to systematic therapy remain largely unexplored. We established a syngeneic orthotopic HCC mouse model with a series of persistent liver injury induced by CCl4 gavage, which mimic the dynamic effect of hepatic pathology microenvironment on intrahepatic HCC growth and metastasis. Non-invasive bioluminescence imaging was applied to follow tumour progression over time. The effect of the liver microenvironment modulated by hepatic injury on sorafenib resistance was investigated in vivo and in vitro. We found that the persistent liver injury facilitated HCC growth and metastasis, which was positively correlated with the degree of liver inflammation rather than the extent of liver fibrosis. The inflammatory cytokines in liver tissue were clearly increased after liver injury. The two indicated cytokines, tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6), both promoted intrahepatic HCC progression via STAT3 activation. In addition, the hepatic inflammatory microenvironment contributed to sorafenib resistance through the anti-apoptotic protein mediated by STAT3, and STAT3 inhibitor S3I-201 significantly improved sorafenib efficacy impaired by liver inflammation. Clinically, the increased inflammation of liver tissues was accompanied with the up-regulated STAT3 activation in HCC. Above all, we concluded that the hepatic inflammatory microenvironment promotes intrahepatic HCC growth, metastasis and sorafenib resistance through activation of STAT3.


Assuntos
Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/metabolismo , Microambiente Celular , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Citocinas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Humanos , Mediadores da Inflamação , Cirrose Hepática/complicações , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Sorafenibe/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Ultrason Sonochem ; 71: 105406, 2020 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-33310652

RESUMO

To alleviate the cavitation damage of metallic engineering components in hydrodynamic systems operating in marine environments, a NbN nanoceramic coating was synthesized on to a Ti-6Al-4V substrate via a double cathode glow discharge technique. The microstructure of the coating consisted of a ~13 µm thick deposition layer of a hexagonal δ'-NbN phase and a diffusion layer ~2 µm in thickness composed of face-centered cubic (fcc) B1-NaCl-structured (Ti,Nb)N. The NbN coating not only exhibited higher values of H/E and H2/E than those measured from NbN coatings deposited by other techniques, but also possessed good adhesion to the substrate. The cavitation erosion resistance of the NbN coating in a 3.5 wt% NaCl solution was investigated using an ultrasonic cavitation-induced apparatus combined with a range of electrochemical test methods. Potentiodynamic polarization measurements demonstrated that the NbN coated specimens demonstrated both a higher corrosion potential (Ecorr) and lower corrosion current density (icorr) than the uncoated substrate. Mott-Schottky analysis, combined with the point defect model (PDM), revealed that, for a given cavitation time, the donor density (ND) of the passive film on the NbN coating was reduced by 1 ~ 2 orders of magnitude relative to the uncoated Ti-6Al-4V, and the diffusivity of the point defects (D0) in the passive film grown on the NbN coating was nearly one order of magnitude lower than that on the uncoated substrate. In order to better understand the experimental observations obtained from Mott-Schottky analysis and double-charge layer capacitance measurements, first-principles density-functional theory was employed to calculate the energy of vacancy formation and the adsorption energy for chloride ions for the passive films present on both the NbN coating and bare Ti-6Al-4V.

17.
Chem Sci ; 11(28): 7362-7368, 2020 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-33133487

RESUMO

CRISPR-based diagnostics (CRISPR-Dx) has shown great promise in molecular diagnostics, but its utility in the sensing of microRNA (miRNA) biomarkers is limited by sensitivity, cost and robustness. Here, we describe a CRISPR-Dx method for the sensitive and cost-effective detection of miRNAs by rationally integrating CRISPR-Cas12a with DNA circuits. In this work, a modular catalytic hairpin assembly (CHA) circuit is designed to convert and amplify each target into multiple programmable DNA duplexes, which serve as triggers to initiate the trans-cleavage activity of CRISPR-Cas12a for further signal amplification. Such rational integration provides a generic assay for the effectively amplified detection of miRNA biomarkers. By simply tuning the variable regions in the CHA modules, this assay achieves sub-femtomolar sensitivity for different miRNA biomarkers, which improves the detection limit of CRISPR-Dx in the analysis of miRNA by 3-4 orders of magnitude. With the usage of the proposed assay, the sensitive assessment of miR-21 levels in different cancer cell lines and clinical serum samples has been achieved, providing a generic method for the sensitive detection of miRNA biomarkers in molecular diagnosis.

18.
J Nanosci Nanotechnol ; 20(12): 7800-7807, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32711661

RESUMO

ZnO seed layers were deposited on silicon and sapphire substrates by the pulsed laser deposition (PLD) method, and ZnO nanorod arrays with different orientation degrees were grown using the chemical vapor deposition (CVD) method. Flat-type gas sensors based on the ZnO nanorod arrays were fabricated, and their gas sensitivity properties were studied. The ZnO seed layer with a thickness of approximately 450 nm exhibits high c-axis orientation and possesses few defects. The ZnO nanorods fabricated on both of the substrates grow along the [0001] direction and contain a large number of oxygen vacancy defects. These nanorods have lengths of 8~10 µm and diameters of 200~500 nm. The ZnO nanorods grown on the silicon substrate are perpendicular to the surface of the substrate, and their areal density is approximately 3.0×108/cm², while those grown on the sapphire substrate exhibit a lower orientation degree, and their areal density is approximately 0.9×108/cm². The largest response of the gas sensor for gaseous alcohol reaches 48.2, and the optimal operating temperature for all of the sensors is approximately 280 °C. The gas sensitivity property of the silicon-based sensor is superior to that of the sapphire-based sensor, and the corresponding sensing mechanism is discussed.

19.
Oncogene ; 39(35): 5721-5733, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32712628

RESUMO

Ribonucleotide reductase (RNR) catalyzes the rate-limiting step of de novo synthesis of deoxyribonucleotide triphosphates (dNTPs) building blocks for DNA synthesis, and is a well-recognized target for cancer therapy. RNR is a heterotetramer consisting of two large RRM1 subunits and two small RRM2 subunits. RNR activity is greatly stimulated by transcriptional activation of RRM2 during S/G2 phase to ensure adequate dNTP supply for DNA replication. However, little is known about the cell-cycle-dependent regulation of RNR activity through RRM1. Here, we report that RRM1 is phosphorylated at Ser 559 by CDK2/cyclin A during S/G2 phase. And this S559 phosphorylation of RRM1enhances RNR enzymatic activity and is required for maintaining sufficient dNTPs during normal DNA replication. Defective RRM1 S559 phosphorylation causes DNA replication stress, double-strand break, and genomic instability. Moreover, combined targeting of RRM1 S559 phosphorylation and ATR triggers lethal replication stress and profound antitumor effects. Thus, this posttranslational phosphorylation of RRM1 provides an alternative mechanism to finely regulating RNR and therapeutic opportunities for cancer treatment.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Replicação do DNA/genética , Ribonucleosídeo Difosfato Redutase/isolamento & purificação , Ribonucleosídeo Difosfato Redutase/metabolismo , Ciclo Celular , Humanos , Fosforilação
20.
Exp Mol Med ; 52(7): 1062-1074, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32632241

RESUMO

Dexmedetomidine (DEX) is an anesthetic that is widely used in the clinic, and it has been reported to exhibit paradoxical effects in the progression of multiple solid tumors. In this study, we sought to explore the mechanism by which DEX regulates hepatocellular carcinoma (HCC) progression underlying liver fibrosis. We determined the effects of DEX on tumor progression in an orthotopic HCC mouse model of fibrotic liver. A coculture system and a subcutaneous xenograft model involving coimplantation of mouse hepatoma cells (H22) and primary activated hepatic stellate cells (aHSCs) were used to study the effects of DEX on HCC progression. We found that in the preclinical mouse model of liver fibrosis, DEX treatment significantly shortened median survival time and promoted tumor growth, intrahepatic metastasis and pulmonary metastasis. The DEX receptor (ADRA2A) was mainly expressed in aHSCs but was barely detected in HCC cells. DEX dramatically reinforced HCC malignant behaviors in the presence of aHSCs in both the coculture system and the coimplantation mouse model, but DEX alone exerted no significant effects on the malignancy of HCC. Mechanistically, DEX induced IL-6 secretion from aHSCs and promoted HCC progression via STAT3 activation. Our findings provide evidence that the clinical application of DEX may cause undesirable side effects in HCC patients with liver fibrosis.

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