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1.
Carcinogenesis ; 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33417668

RESUMO

Impairment of genome instability drives the development of cancer by disrupting anti-cancer barriers. Upon genotoxic insults, DNA damage responsive factors, notably ATM kinase, is crucial to protect genomic integrity while promoting cell death. Meanwhile, cytotoxic therapy inducing DNA lesions is double-edged sword by causing cancer metastasis based on animal models and clinical observations. The underlying mechanisms for the procancer effect of cytotoxic therapies are poorly understood. Here we report that cancer cells subjected to cytotoxic treatments elicit dramatic alteration of gene expression controlling the potential of epithelium-mesenchyme transition (EMT). Resultantly, EMT-dependent cell mobility is potently induced upon DNA damage. This stimulation of EMT is mainly Ataxia-Telangiectasia-mutated (ATM)-dependent, as the chemical inhibitor specifically inhibiting ATM kinase activity can suppress the EMT gene expression and thus cell mobility. At last, we show that cancer cells with ATM activation display increased metastatic potential in ovarian cancer tissues. Taken together, we reveal a novel role of ATM in promoting metastatic potential of cancer cells by favoring EMT gene expression.

2.
Sensors (Basel) ; 21(2)2021 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-33435444

RESUMO

With the rapid development of artificial intelligence and fifth-generation mobile network technologies, automatic instrument reading has become an increasingly important topic for intelligent sensors in smart cities. We propose a full pipeline to automatically read watermeters based on a single image, using deep learning methods to provide new technical support for an intelligent water meter reading. To handle the various challenging environments where watermeters reside, our pipeline disentangled the task into individual subtasks based on the structures of typical watermeters. These subtasks include component localization, orientation alignment, spatial layout guidance reading, and regression-based pointer reading. The devised algorithms for orientation alignment and spatial layout guidance are tailored to improve the robustness of our neural network. We also collect images of watermeters in real scenes and build a dataset for training and evaluation. Experimental results demonstrate the effectiveness of the proposed method even under challenging environments with varying lighting, occlusions, and different orientations. Thanks to the lightweight algorithms adopted in our pipeline, the system can be easily deployed and fully automated.

3.
Ecotoxicol Environ Saf ; 208: 111391, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33039869

RESUMO

Hexavalent chromium [Cr(VI)] is a pervasive environmental pollutant that can enter the body through a variety of routes and cause organ toxicity, genetic damage, and cancer. Cr(VI)-induced apoptosis is a toxicant mechanism of Cr(VI). Studies have shown that Cr(VI) can induce p53-independent apoptosis, but the mechanisms are not fully understood. The intracellular calcium concentration affects cellular life. Apoptosis-inducing factor (AIF), a caspase-independent apoptotic effector, can induce DNA degradation. Using p53-null Hep3B cells, we investigated the effects of cytoplasmic calcium homeostasis and AIF on Cr(VI)-induced apoptosis. We found that 20 µM of Cr(VI) induced DNA damage and mitochondrial permeability transition pore (MPTP) openings, causing calcium overload that was accompanied by decreased Ca2+-Mg2+-ATPase and Na+-K+-ATP activities, downregulation of calmodulin (CaM) and Ca2+/CaM-dependent protein kinase II (CAMKII) mRNA, and increased expression of p-CaMKII/CaMKII protein. After treatment with calcium chelating agent BAPTA-AM, Cr(VI)-induced DNA damage, calcium overload, and apoptosis were reduced. AIF was released from the mitochondria and translocated into the nuclei. As the Cr(VI) treatment time progressed, the mRNA and protein expression of B cell lymphoma 2 (Bcl-2) and heat-shock protein 70 (HSP70) decreased, whereas the mRNA and protein expression of Bcl-2-associated X (Bax), cyclophilin A (CypA), and endonuclease G (EndoG) were upregulated. These results indicated that Cr(VI)-induced apoptosis of Hep3B cells (p53-null) was closely associated with calcium overload, and was accompanied by the activation of Ca2+/CaM/CaMKII signaling pathway. Besides, Cr(VI) triggered AIF nuclear translocation in Hep3B cells, accompanied by the changes in the levels of apoptosis-associated factors. These results provide additional experimental evidence of the molecular mechanisms involved in Cr(VI)-induced p53-independent apoptosis.


Assuntos
Cromo/toxicidade , Substâncias Perigosas/toxicidade , Apoptose/efeitos dos fármacos , Fator de Indução de Apoptose/metabolismo , Fator de Indução de Apoptose/farmacologia , Cálcio/metabolismo , Morte Celular , Ácido Egtázico/análogos & derivados , Humanos , Mitocôndrias/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
4.
Br J Radiol ; 94(1117): 20200634, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33296222

RESUMO

OBJECTIVES: To identify the value of radiomics method derived from CT images to predict prognosis in patients with COVID-19. METHODS: A total of 40 patients with COVID-19 were enrolled in the study. Baseline clinical data, CT images, and laboratory testing results were collected from all patients. We defined that ROIs in the absorption group decreased in the density and scope in GGO, and ROIs in the progress group progressed to consolidation. A total of 180 ROIs from absorption group (n = 118) and consolidation group (n = 62) were randomly divided into a training set (n = 145) and a validation set (n = 35) (8:2). Radiomics features were extracted from CT images, and the radiomics-based models were built with three classifiers. A radiomics score (Rad-score) was calculated by a linear combination of selected features. The Rad-score and clinical factors were incorporated into the radiomics nomogram construction. The prediction performance of the clinical factors model and the radiomics nomogram for prognosis was estimated. RESULTS: A total of 15 radiomics features with respective coefficients were calculated. The AUC values of radiomics models (kNN, SVM, and LR) were 0.88, 0.88, and 0.84, respectively, showing a good performance. The C-index of the clinical factors model was 0.82 [95% CI (0.75-0.88)] in the training set and 0.77 [95% CI (0.59-0.90)] in the validation set. The radiomics nomogram showed optimal prediction performance. In the training set, the C-index was 0.91 [95% CI (0.85-0.95)], and in the validation set, the C-index was 0.85 [95% CI (0.69-0.95)]. For the training set, the C-index of the radiomics nomogram was significantly higher than the clinical factors model (p = 0.0021). Decision curve analysis showed that radiomics nomogram outperformed the clinical model in terms of clinical usefulness. CONCLUSIONS: The radiomics nomogram based on CT images showed favorable prediction performance in the prognosis of COVID-19. The radiomics nomogram could be used as a potential biomarker for more accurate categorization of patients into different stages for clinical decision-making process. ADVANCES IN KNOWLEDGE: Radiomics features based on chest CT images help clinicians to categorize the patients of COVID-19 into different stages. Radiomics nomogram based on CT images has favorable predictive performance in the prognosis of COVID-19. Radiomics act as a potential modality to supplement conventional medical examinations.


Assuntos
/diagnóstico por imagem , Nomogramas , Tomografia Computadorizada por Raios X , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Distribuição Aleatória , Estudos Retrospectivos
5.
J Neurosci Methods ; 347: 108953, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33007344

RESUMO

BACKGROUND: The classification of epileptiform electroencephalogram (EEG) signals has been treated as an important but challenging issue for realizing epileptic seizure detection. In this work, combing gray recurrence plot (GRP) and densely connected convolutional network (DenseNet), we developed a novel classification system named GRP-DNet to identify seizures and epilepsy from single-channel, long-term EEG signals. NEW METHODS: The proposed GRP-DNet classification system includes three main modules: 1) input module takes an input long-term EEG signal and divides it into multiple short segments using a fixed-size non-overlapping sliding window (FNSW); 2) conversion module transforms short segments into GRPs and passes them to the DenseNet; 3) fusion and decision, the predicted label of each GRP is fused using a majority voting strategy to make the final decision. RESULTS: Six different classification experiments were designed based on a publicly available benchmark database to evaluate the effectiveness of our system. Experimental results showed that the proposed GRP-DNet achieved an excellent classification accuracy of 100 % in each classification experiment, Furthermore, GRP-DNet gave excellent computational efficiency, which indicates its tremendous potential for developing an EEG-based online epilepsy diagnosis system. COMPARISON WITH EXISTING METHODS: Our GRP-DNet system was superior to the existing competitive classification systems using the same database. CONCLUSIONS: The GRP-DNet is a potentially powerful system for identifying and classifying EEG signals recorded from different brain states.

6.
Am J Rhinol Allergy ; : 1945892420982236, 2020 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-33348995

RESUMO

BACKGROUND: Although subsequent anti-inflammatory treatments are indispensable for patients with chronic rhinosinusitis (CRS) undergoing sinus surgery, few studies have explored the factors influencing the efficacy of postoperative anti-inflammatory treatment. OBJECTIVE: We aimed to develop prediction models for the response to glucocorticoid- and macrolide-based postoperative therapy in CRS patients. METHODS: We performed a post-hoc analysis of our previous study comparing the efficacy of fluticasone propionate and clarithromycin in the postoperative treatment of CRS patients. Clinical characteristics and treatment outcome information were collected. In addition, diseased sinonasal mucosal tissues obtained during surgery were processed for Bio-Plex analysis of protein levels of 34 biomarkers. Classification trees were built to predict refractory CRS based on clinical characteristics and biological markers for patients treated with fluticasone propionate or clarithromycin. A random forest algorithm was used to confirm the discriminating factors that formed the classification trees. RESULTS: One year after surgery, 22.7% of the patients (17/75) treated with fluticasone propionate, and 24.3% of those (18/74) treated with clarithromycin were diagnosed with refractory CRS. Nasal tissue IL-8 and IgG3 levels and headache VAS scores in the fluticasone propionate group, and nasal tissue IgG4 levels and overall burden of symptoms VAS scores in the clarithromycin group, were identified as discriminating factors forming the classification tree to predict refractory CRS. The overall predictive accuracy of the model was 89.3% and 87.8% for fluticasone propionate- and clarithromycin-based postsurgical treatment, respectively. CONCLUSIONS: Classification trees built using clinical and biological parameters could be helpful in identifying patients with poor response to fluticasone propionate- and clarithromycin-based postoperative treatment.

7.
Artigo em Inglês | MEDLINE | ID: mdl-33340608

RESUMO

BACKGROUND: Stimulator of interferon genes (STING) activation favors effective innate immune responses against viral infections. Its role in chronic rhinosinusitis with nasal polyps (CRSwNP) remains unknown. OBJECTIVE: To explore the expression, regulation, and function of STING in CRSwNP. METHODS: STING expression in sinonasal mucosal samples was analyzed by means of quantitative RT-PCR, immunohistochemistry, flow cytometry and western blotting. STING expression regulation and function were explored by using cultured primary human nasal epithelial cells (HNECs) and BEAS-2B cell lines in vitro. RESULTS: STING expression was reduced in eosinophilic nasal polyps compared with that in noneosinophilic nasal polyps and control tissues. STING was predominantly expressed by epithelial cells in nasal tissue and was downregulated by IL-4 and IL-13 in a STAT6-dependent manner. HNECs derived from eosinophilic polyps displayed compromised STING-dependent type I interferon production, whereas heightened IL-13-induced STAT6 activation and CCL26 production as compared to those from noneosinophilic polyps and control tissues, which were rescued by exogenous STING overexpression. Knocking down or overexpressing STING decreased or enhanced SOCS1 expression in BEAS-2B cells, respectively, independent of canonical STING pathway elements, TBK1 and IRF3. Knocking down SOCS1 abolished the inhibitory effect of STING on IL-13 signaling in BEAS-2B cells. STING expression positively correlated with SOCS1 expression, but negatively correlated with CCL26 expression in nasal epithelial cells in CRSwNP patients. CONCLUSIONS: Reduced STING expression caused by the type 2 milieu not only impairs STING-dependent type I interferon production, but also amplifies IL-13 signaling by decreasing SOCS1 expression in nasal epithelial cells in eosinophilic CRSwNP.

8.
Ying Yong Sheng Tai Xue Bao ; 31(9): 3216-3226, 2020 Sep 15.
Artigo em Chinês | MEDLINE | ID: mdl-33345523

RESUMO

In recent years, Chinese scientists have made remarkable achievements in on mycorrhizal molecular biology, nutrition, taxonomy, and ecology, with arbuscular mycorrhizal fungus (AMF) having been mostly studied. AMF can form symbiotic relationship with roots of most terrestrial plants, promote plant growth and development, improve plant stress resistance, maintain ecological balance, and protect ecological environment. This review mainly introduced the ecological function and mechanism of AMF in plant rhizosphere stress from the aspects of abiotic (drought stress, heavy metal pollution, saline-alkali stress) and biotic stresses (pathogenic bacteria and nematode infection). We proposed the remaining deficiencies and research prospects in this field to provide refe-rence for future research of AMF.


Assuntos
Micorrizas , Raízes de Plantas , Plantas , Rizosfera , Simbiose
9.
Chemistry ; 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33231936

RESUMO

Herein, the reaction of (1-methyl-1 H-benzo[d]imidazol-2-yl)methanamine (L1) with Co(H2 O)6 Cl2 , in CH3 CN at 120 °C, leading to the 2,3,5,6-tetrakis(1-methyl-1 H-benzo[d]imidazol-2-yl)pyrazine (3), isolated as a dimeric cluster {[CoII 2 (3)Cl4 ]⋅2 CH3 CN} (2), is reported. When O2 and H2 O are present, (1-methyl-1 H-benzo[d]imidazole-2-carbonyl)amide (HL1') is first formed and crystallized as [CoIII (L1)2 (L1')]Cl2 ⋅2 H2 O (4) before fusion of HL1' with L1, giving 1-methyl-N-(1-methyl-1 H-benzo[d]imidazol-2-carbonyl)-1 H-benzo[d]imidazol-2-carboxamide (HL2'') forming a one-dimensional (1D) chain of [CoII 3 (L2'')2 Cl4 ]n (5). The combination of crystallography and mass spectrometry (ESI-MS) of isolated crystals and the solutions taken from the reaction as a function time reveal seven intermediate steps leading to 2, but six steps for 5, for which a different sequence takes place. Control and isotope labeling experiments confirm the two carbonyl oxygen atoms in 5 originate from both air and water. The dependence on the metals, compared with FeCl3 ⋅6 H2 O leading to a stable triheteroarylmethyl radical, is quite astounding, which could be attributed to the different oxidation states of the metals and coordination modes confirmed by DFT calculations. This metal and valence dependent process is a very useful way for selectively obtaining these large molecules, which are unachievable by common organic synthesis.

10.
Dalton Trans ; 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33232433

RESUMO

An unexpected dominance of the coordination affinity of the sulfate anion over those of two organic chelating ligands, (1-methyl-1H-benzo[d]imidazol-2-yl)methanol (Hmbm) and pyridin-2-ylmethanamine (pma), was observed during the study of the solvothermal assembly of [Co11(mbm)6(pma)2(SO4)8(H2O)6(CH3OH)6]·5CH3OH (1), from CoSO4·7H2O at 100 °C in methanol. ESI-MS of solutions at different periods of the assembly reveal a hierarchical sequence, [Co1] → [Co2] → [Co3] → [Co4] → [Co5] → [Co9], where the lower nuclearity species are richer in Co2+ and SO42- before the inclusion of more mbm ligands at the last step. Its crystal structure consists of an almost symmetrical wheel of nine cobalt atoms, [Co9(mbm)6(SO4)8(H2O)6] in edge-sharing octahedral coordination arranged in triangles with two peripheral dangling [Co(pma)(CH3OH)3]. The sulfate ions exhibit three different coordination modes, two in µ6-, two in µ3- and four as µ2-bridging. Its thermal, optical and magnetic properties are also reported.

11.
EuroIntervention ; 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33164894

RESUMO

AIMS: To test whether a non-stenting anti-thrombotic strategy was still effective at 4-year follow-up in patients enrolled in the EROSION study and to explore potential predictors of long-term prognosis. METHODS AND RESULTS: Out of 55 patients who completed 1-month follow-up, 52 patients finished 4-year follow-up. The median duration was 4.8 years (4.2 - 5.8 years). The majority of patients remained free from events, and all patients were free from hard endpoints (death, myocardial infarction, stroke, bypass surgery, or heart failure). Only 1 patient had gastrointestinal bleeding, and 11 patients underwent elective target lesion revascularization (TLR). Patients in the non-TLR group had more optical coherence tomography (OCT) thrombus reduction from baseline to 1 month; 95% patients in the non-TLR group versus 45% in the TLR group (p=0.001) met the primary endpoint (thrombus volume reduction >50%). Consistent with the OCT findings, angiographic results showed that the TLR group had less improvement in diameter stenosis (p=0.014) at 1 month compared with non-TLR group. CONCLUSIONS: Four-year follow-up findings reconfirmed the safety of an anti-thrombotic therapy without stenting for erosion-caused acute coronary syndrome. Patients with better response to anti-thrombotic therapy in the first month were less likely to require stent implantation during the next four years.

12.
J Pharm Sci ; 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33035537

RESUMO

Commercial specifications for a new biotherapeutic product are a critical component of the product's overall control strategy that ensures safety and efficacy. This paper describes strategies for setting commercial specifications as proposed by a consortium of industry development scientists. The specifications for some attributes are guided by compendia and regulatory guidance. For other product quality attributes (PQAs), product knowledge and the understanding of attribute criticality built throughout product development should drive specification setting. The foundation of PQA knowledge is an understanding of potential patient impact through an assessment of potency, PK, immunogenicity and safety. In addition to PQA knowledge, the ability of the manufacturing process to consistently meet specifications, typically assessed through statistical analyses, is an important consideration in the specification-setting process. Setting acceptance criteria that are unnecessarily narrow can impact the ability to supply product or prohibit consideration of future convenient dosage forms. Patient-centric specifications enable appropriate control over higher risk PQAs to ensure product quality for the patient, and flexibility for lower risk PQAs for a sustainable supply chain. This paper captures common strategic approaches for setting specifications for standard biotherapeutic products such as monoclonal antibodies and includes considerations for ensuring specifications are patient centric.

14.
J Phys Chem B ; 124(43): 9570-9578, 2020 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-33073576

RESUMO

There is no doubt that electric fields of a specific frequency and intensity could excite certain vibrational modes of a macromolecule, which alters its mode coupling and conformation. Motivated by recent experiments and theories, we study the mode coupling between the Fe-CO mode and CO-stretch mode and vibration energy transfer among the active site and proteins in carboxyhemoglobin (HbCO) under different electric fields using the quasi-static two-dimensional infrared spectra. This study uses iron-porphyrin-imidazole-CO and two distal histidines in HbCO as the subsystem. The potential energy and dipole moment surfaces of the subsystem are calculated using an all-electron ab initio (B3LYP-D3(BJ)) method with the basis set Lanl2dz for the Fe atom and 6-31G(d,p) for C, H, O, and N atoms. Although the subsystem is reduced dimensionally, the anharmonic frequency and anharmonicity of the CO-stretch mode show excellent agreement with experimental values. We use the revealing noncovalent interaction method to confirm the hydrogen bond between the Hε atom of the His63 and the CO molecule. Our study confirms that the mode coupling between the Fe-CO mode and CO-stretch mode does not exist when the subsystem is free of electric field perturbation, which is coupled when the electric field is -0.5142 V/nm. In addition, with the increases of distance between the active site and the His92, there is no vibrational energy transfer between them when the electric field is 1.028 V/nm. We believe that our work could provide new ideas for increasing the dissociation efficiency of the Fe-CO bond and theoretical references for experimental research.

16.
FASEB J ; 34(11): 14200-14216, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32918762

RESUMO

Glucocorticoids (GCs), stress-induced steroid hormones, are released by adrenal cortex and essential for stress adaptation. Recently, there has been renewed interest in the relationship between GCs and pregnancy following the discovery that glucocorticoid receptor is necessary for implantation. It has been widely recognized that stress is detrimental to pregnancy. However, effects of stress-induced GC exposure on uterine receptivity and decidualization are still poorly understood. This study aims to explore the effects of GCs exposure on uterine receptivity, decidualization, and their underlying mechanisms in mice. Single prolonged stress (SPS) and corticosterone (Cort) injection models were used to analyze effects of GC exposure on early pregnancy, respectively. SPS or Cort injection inhibits embryo implantation by interfering Lif signaling and stimulating the uterine deposition of collagen types I, III, and IV on day 4 of pregnancy. Uterine decidualization is also attenuated by SPS or Cort injection through suppressing Cox-2 expression. Cort-induced collagen disorder also suppresses decidualization through regulating mesenchymal-epithelial transition. Our data should shed lights for a better understanding for the effects of GCs on embryo implantation for clinical research.

17.
Adv Mater ; 32(42): e2002940, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32881121

RESUMO

Recent years have seen enormous advances in nanovaccines for both prophylactic and therapeutic applications, but most of these technologies employ chemical or hybrid semi-biosynthetic production methods. Thus, production of nanovaccines has to date failed to exploit biology-only processes like complex sequential post-translational biochemical modifications and scalability, limiting the realization of the initial promise for offering major performance advantages and improved therapeutic outcomes over conventional vaccines. A Nano-B5 platform for in vivo production of fully protein-based, self-assembling, stable nanovaccines bearing diverse antigens including peptides and polysaccharides is presented here. Combined with the self-assembly capacities of pentamer domains from the bacterial AB5 toxin and unnatural trimer peptides, diverse nanovaccine structures can be produced in common Escherichia coli strains and in attenuated pathogenic strains. Notably, the chassis of these nanovaccines functions as an immunostimulant. After showing excellent lymph node targeting and immunoresponse elicitation and safety performance in both mouse and monkey models, the strong prophylactic effects of these nanovaccines against infection, as well as their efficient therapeutic effects against tumors are further demonstrated. Thus, the Nano-B5 platform can efficiently combine diverse modular components and antigen cargos to efficiently generate a potentially very large diversity of nanovaccine structures using many bacterial species.

18.
Cell Death Dis ; 11(8): 679, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32826848

RESUMO

Local renin-angiotensin system (RAS) in female reproductive system is involved in many physiological and pathological processes, such as follicular development, ovarian angiogenesis, ovarian, and endometrial cancer progress. However, studies on the functional relevance of RAS in human endometrium are limited, especially for renin-angiotensin-aldosterone system (RAAS). In this study, we defined the location of RAS components in human endometrium. We found that angiotensin II type-1 receptor (AT1R) and aldosterone synthase (CYP11B2), major components of RAAS, are specifically expressed in endometrial gland during mid-secretory phase. Aldosterone receptor, mineralocorticoid receptor (MR), is elevated in stroma in mid-secretory endometrium. In vitro, MR is also activated by aldosterone during decidualization. Activated MR initiates LKB1 expression, followed by phosphorylating of AMPK that stimulates PDK4 expression. The impact of PDK4 on decidualization is independent on PDHE1α inactivation. Based on co-immunoprecipitation, PDK4 interacts with p-CREB to prevent its ubiquitination for facilitating decidualization via FOXO1. Restrain of MR activation interrupts LKB1/p-AMPK/PDK4/p-CREB/FOXO1 pathway induced by aldosterone, indicating that aldosterone action on decidualization is mainly dependent on MR stimulation. Aldosterone biosynthesized in endometrial gland during mid-secretory phase promotes decidualization via activating MR/LKB1/p-AMPK/PDK4/p-CREB/FOXO1 signaling pathway. This study provides the valuable information for understanding the underlying mechanism during decidualization.

19.
Reproduction ; 160(4): 491-500, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32817586

RESUMO

Embryo implantation and decidualization are crucial steps during early pregnancy. We recently showed that nucleolar stress is involved in embryo implantation. This study was to explore whether nucleolar stress participates in mouse and human decidualization. Our data demonstrated that a low dose of actinomycin D (ActD) could induce nucleolar stress in stroma cells. Nucleolar stress promotes the stromal-epithelial transition during mouse in vitro decidualization through nucleophosmin1 (NPM1). Under nucleolar stress, Wnt family member 4 (Wnt4), a decidualization marker, is significantly increased, but decidua/trophoblast prolactin-related protein (Dtprp/Prl8a2) expression remains unchanged. For translational significance, we also examined the effects of nucleolar stress on human decidualization. Nucleolar stress stimulated by a low dose of ActD enhances human stromal-epithelial transition during human decidualization, but has no effects on the expression of insulin-like growth factor-binding protein 1 (IGFBP1). Our study indicates that nucleolar stress may promote only the mesenchymal-epithelial transition (MET), but not for all the molecular changes during decidualization.

20.
Sci Signal ; 13(646)2020 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-32843542

RESUMO

Embryo implantation involves a sterile inflammatory reaction that is required for the invasion of the blastocyst into the decidua. Adenosine triphosphate (ATP) released from stressed or injured cells acts as an important signaling molecule to regulate many key physiological events, including sterile inflammation. We found that the amount of ATP in the uterine luminal fluid of mice increased during the peri-implantation period, and this depended on the presence of an embryo. We further showed that the release of ATP from receptive epithelial cells was likely stimulated by lactate released from the blastocyst through connexin hemichannels. The ATP receptor P2y2 was present on uterine epithelial cells during the preimplantation period and increased in the stromal cells during the time at which decidualization began. Pharmacological inhibition of P2y2 compromised decidualization and implantation. ATP-P2y2 signaling stimulated the phosphorylation of Stat3 in uterine luminal epithelial cells and the expression of early growth response 1 (Egr1) and prostaglandin-endoperoxide synthase 2 (Ptgs2, also known as Cox-2), all of which are required for decidualization and/or implantation, in stromal cells. Short exposure to high concentrations of ATP promoted decidualization of primary stromal cells, but longer exposures or lower ATP concentrations did not. The expression of genes encoding ATP-degrading ectonucleotidases increased in the decidua during the peri-implantation period, suggesting that they may limit the duration of the ATP signal. Together, our results indicate that the blastocyst-induced release of ATP from uterine epithelial cells during the peri-implantation period may be important for the initiation of stromal cell decidualization.

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