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BACKGROUND: Casein kinase 1α (CK1α), expressed in both ovarian germ and somatic cells, is involved in the initial meiosis and primordial follicle formation of mouse oocytes. Using in vitro and in vivo experiments in this study, we explored the function and mechanism of CK1α in estrogen synthesis in mice ovarian granulosa cells. METHODS: A CK1α knockout (cKO) mouse model, targeted specifically to ovarian granulosa cells (GCs), was employed to establish the influence of CK1α on in vivo estrogen synthesis. The influence of CK1α deficiency on GCs was determined in vivo and in vitro by immunofluorescence analysis and Western blot assay. Transcriptome profiling, differentially expressed genes and gene functional enrichment analyses, and computation protein-protein docking, were further employed to assess the CK1α pathway. Furthermore, wild-type female mice were treated with the CK1α antagonist D4476 to elucidate the CK1α's role in estrogen regulation. RESULTS: Ovarian GCs CK1α deficiency impaired fertility and superovulation of female mice; also, the average litter size and the estradiol (E2) level in the serum of cKO female mice were decreased by 57.3% and 87.4% vs. control mice, respectively. This deficiency disrupted the estrous cycle and enhanced the apoptosis in the GCs. We observed that CK1α mediated the secretion of estradiol in mouse ovarian GCs via the cytochrome P450 subfamily 19 member 1 (CYP19A1). CONCLUSIONS: These findings improve the existing understanding of the regulation mechanism of female reproduction and estrogen synthesis. TRIAL REGISTRATION: Not applicable.
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Aromatase , Estradiol , Células da Granulosa , Camundongos Knockout , Animais , Feminino , Camundongos , Aromatase/metabolismo , Aromatase/genética , Caseína Quinase Ialfa/metabolismo , Caseína Quinase Ialfa/genética , Estradiol/metabolismo , Células da Granulosa/metabolismoRESUMO
Uterine glands and their secretions are crucial for conceptus survival and implantation in rodents and humans. In mice, the development of uterine gland known as adenogenesis occurs after birth, whereas the adenogenesis in humans initiates from fetal life and completed at puberty. Uterine adenogenesis involves dynamic epithelial cell proliferation, differentiation, and apoptosis. However, it is largely unexplored about the mechanisms governing adenogenesis. CK1α plays important roles in regulating cell division, differentiation, and death, but it is unknown whether CK1α affects adenogenesis. In the current study, uterus-specific CK1α knockout female mice (Csnk1a1d/d) were infertile resulted from lack of uterine glands. Subsequent analysis revealed that CK1α deletion induced massive apoptosis in uterine epithelium by activating GSK3ß, which was confirmed by injections of GSK3ß inhibitor SB216763 to Csnk1a1d/d females, and the co-treatment of SB216763 and CK1 inhibitor d4476 on cultured epithelial cells. Another important finding was that our results revealed CK1α deficiency activated p53, which then blocked the expression of Foxa2, an important factor for glandular epithelium development and function. This was confirmed by that Foxa2 expression level was elevated in p53 inhibitor pifithrin-α injected Csnk1a1d/d mouse uterus and in vitro dual-luciferase reporter assay between p53 and Foxa2. Collectively, these studies reveal that CK1α is a novel factor regulating uterine adenogenesis by inhibiting epithelial cell apoptosis through GSK3ß pathway and regulating Foxa2 expression through p53 pathway. Uncovering the mechanisms of uterine adenogenesis is expected to improve pregnancy success in humans and other mammals.
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Indóis , Maleimidas , Proteína Supressora de Tumor p53 , Útero , Gravidez , Animais , Feminino , Camundongos , Humanos , Glicogênio Sintase Quinase 3 beta/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Útero/metabolismo , Apoptose , Células Epiteliais/metabolismo , Camundongos Knockout , Mamíferos/metabolismo , Fator 3-beta Nuclear de Hepatócito/genética , Fator 3-beta Nuclear de Hepatócito/metabolismoRESUMO
Atherosclerosis is a major underlying cause of cardiovascular disease. Genome wide association studies have predicted that GalNAc-T4 (GALNT4), which responsible for initiating step of mucin-type O-glycosylation, plays a causal role in the susceptibility to cardiovascular diseases, whereas the precise mechanism remains obscure. Thus, we sought to determine the role and mechanism of GALNT4 in atherosclerosis. Firstly, we found the expression of GALNT4 and protein O-glycosylation were both increased in plaque as atherosclerosis progressed in ApoE-/- mice by immunohistochemistry. And the expression of GALNT4 was also increased in human monocytes treated with ACS (acute coronary syndrome) sera and subjected to LPS and ox-LDL in vitro. Moreover, silencing expression of GALNT4 by shRNA lentivirus alleviated atherosclerotic plaque formation and monocyte/macrophage infiltration in ApoE-/- mice. Functional investigations demonstrate that GALNT4 knockdown inhibited P-selectin-induced activation of ß2 integrin on the surface of monocytes, decreased monocytes adhesion under flow condition with P-selectin stimulation, as well as suppressed monocytes transmigration triggered by monocyte chemotactic protein- 1(MCP-1). In contrast, GALNT4 overexpression enhanced monocytes adhesion and transmigration. Furthermore, Vicia Villosa Lectin (VVL) pull down and PSGL-1 immunoprecipitation assays showed that GALNT4 overexpression increased O-Glycosylation of PSGL-1 and P-selectin induce phosphorylation of Akt/mTOR and IκBα/NFκB on monocytes. Conversely, knockdown of GALNT4 decreased VVL binding and attenuated the activation of Akt/mTOR and IκBα/NFκB. Additionally, mTOR inhibitor rapamycin blocked these effects of GALNT4 overexpression on monocytes. Collectively, GALNT4 catalyzed PSGL-1 O-glycosylation that involved in P-selectin induced monocytes adhesion and transmigration via Akt/mTOR and NFκB pathway. Thus, GALNT4 may be a potential therapeutic target for atherosclerosis.
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Aterosclerose , Placa Aterosclerótica , Animais , Apolipoproteínas E/metabolismo , Aterosclerose/metabolismo , Adesão Celular , Estudo de Associação Genômica Ampla , Glicosilação , Camundongos , Monócitos/metabolismo , N-Acetilgalactosaminiltransferases , Inibidor de NF-kappaB alfa/genética , Inibidor de NF-kappaB alfa/metabolismo , Selectina-P/metabolismo , Placa Aterosclerótica/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Polipeptídeo N-AcetilgalactosaminiltransferaseRESUMO
Unmanned aerial vehicles (UAVs) require data-link system to link ground data terminals to the real-time controls of each UAV. Consequently, the ability to predict the health status of a UAV data-link system is vital for safe and efficient operations. The performance of a UAV data-link system is affected by the health status of both the hardware and UAV data-links. This paper proposes a method for predicting the health state of a UAV data-link system based on a Bayesian network fusion of information about potential hardware device failures and link failures. Our model employs the Bayesian network to describe the information and uncertainty associated with a complex multi-level system. To predict the health status of the UAV data-link, we use the health status information about the root node equipment with various life characteristics along with the health status of the links as affected by the bit error rate. In order to test the validity of the model, we tested its prediction of the health of a multi-level solar-powered unmanned aerial vehicle data-link system and the result shows that the method can quantitatively predict the health status of the solar-powered UAV data-link system. The results can provide guidance for improving the reliability of UAV data-link system and lay a foundation for predicting the health status of a UAV data-link system accurately.
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Nível de Saúde , Tecnologia de Sensoriamento Remoto/métodos , Robótica/métodos , Aeronaves , Teorema de Bayes , Humanos , Energia SolarRESUMO
BACKGROUND: Myocardial infarction (MI) is a major cause of mortality and morbidity worldwide. The intercellular communication in post-infarction angiogenesis remains unclear. METHODS: In this study, we explored the role and mechanism of action of M2 macrophage-derived exosomes (M2-exos) in angiogenesis after MI. M2-exos were harvested and injected intramyocardially at the onset of MI. Two distinct endothelial cells (ECs) were cultured with M2-exos to explore the direct effects on angiogenesis. RESULTS: We showed that M2-exos improved cardiac function, reduced infarct size, and enhanced angiogenesis after MI. Moreover, M2-exos promoted angiogenesis in vitro; the molecules loaded in the vesicles were responsible for its proangiogenic effects. We further validated that higher abundance of miR-132-3p in M2-exos, which recapitulate their functions, was required for the cardioprotective effects exerted by M2-exos. Mechanistically, miR-132-3p carried by M2-exos down-regulate the expression of THBS1 through direct binding to its 3´UTR and the proangiogenic effects of miR-132-3p were largely reversed by THBS1 overexpression. CONCLUSION: Our findings demonstrate that M2-exos promote angiogenesis after MI by transporting miR-132-3p to ECs, and by binding to THBS1 mRNA directly and negatively regulating its expression. These findings highlight the role of M2-exos in cardiac repair and provide novel mechanistic understanding of intercellular communication in post-infarction angiogenesis.
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Exossomos , Macrófagos , MicroRNAs , Infarto do Miocárdio , Neovascularização Fisiológica , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/terapia , Infarto do Miocárdio/genética , Exossomos/metabolismo , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , Macrófagos/metabolismo , Camundongos , Masculino , Humanos , Células Endoteliais/metabolismo , Trombospondina 1/metabolismo , Trombospondina 1/genética , Camundongos Endogâmicos C57BL , AngiogêneseRESUMO
Taurine (Tau) is a semiessential amino acid in mammals with preventive and therapeutic effects on several intestinal disorders. However, the exact function of taurine in ulcerative colitis (UC) is still largely unclear. In this study, we used two taurine-deficient mouse models (CSAD-/- and TauT-/- mice) to explore the influence of taurine on the progression of UC in both dextran sulfate sodium (DSS)-induced colitis and LPS-stimulated Caco-2 cells. We found that cysteine sulfinic acid decarboxylase (CSAD) and taurine transporter (TauT) expressions and taurine levels were markedly reduced in colonic tissues of mice treated with DSS. The CSAD and TauT knockouts exacerbated DSS-induced clinical symptoms and pathological damage and aggravated the intestinal barrier dysfunction and the colonic mucosal inflammatory response. Conversely, taurine pretreatment enhanced the intestinal barrier functions by increasing goblet cells and upregulating tight junction protein expression. Importantly, taurine bound with TLR4 and inhibited the TLR4/NF-κB pathway, ultimately reducing proinflammatory factors (TNF-α and IL-6) and oxidative stress. Our findings highlight the essential role of taurine in maintaining the intestinal barrier integrity and inhibiting intestinal inflammation, indicating that taurine is a promising supplement for colitis treatment.
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Colite , Mucosa Intestinal , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B , Transdução de Sinais , Taurina , Receptor 4 Toll-Like , Animais , Taurina/farmacologia , Taurina/administração & dosagem , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Camundongos , Humanos , NF-kappa B/genética , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Colite/tratamento farmacológico , Colite/metabolismo , Colite/induzido quimicamente , Colite/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Células CACO-2 , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Sulfato de Dextrana/efeitos adversos , Carboxiliases/genética , Carboxiliases/metabolismo , Função da Barreira IntestinalRESUMO
Casein kinase 1α (CK1α) is a main component of the Wnt/ß-catenin signaling pathway, which participates in multiple biological processes. Our recent study demonstrated that CK1α is expressed in both germ cells and somatic cells of mouse testes and regulates spermatogenesis. However, little information is known about the role of CK1α in regulating the development of somatic cells in mouse testes. Our results demonstrated that conditional disruption of CK1α in murine Leydig cells sharply decreased testosterone levels; markedly affected testis development, sperm motility, and sperm morphology; and caused subfertility. The germ cell population was partially decreased in CK1α conditional knockout (cKO) mice, while the proliferation of Leydig cells and Sertoli cells was not affected. Furthermore, in vitro results verified that luteinizing hormone upregulates CK1α through the luteinizing hormone/protein kinase/Epidermal Growth Factor Receptor/extracellular regulated protein kinases/2 signaling pathway and that CK1α interacts with and phosphorylates EGFR, which subsequently activates the phosphorylation of ERK1/2, thereby promoting testosterone synthesis. In addition, high-dose testosterone propionate partially rescued the phenotype observed in cKO mice. This study provides new insights into the role of CK1α in steroidogenesis and male reproduction.
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Caseína Quinase Ialfa , Testículo , Camundongos , Masculino , Animais , Testículo/metabolismo , Testosterona/metabolismo , Caseína Quinase Ialfa/genética , Caseína Quinase Ialfa/metabolismo , Sêmen/metabolismo , Motilidade dos Espermatozoides , Células Intersticiais do Testículo/metabolismo , Hormônio Luteinizante/metabolismoRESUMO
BACKGROUND: Taurine performs multiple physiological functions, and the maintenance of taurine level for most mammals relies on active uptake from diet and endogenous taurine synthesis through its synthesis enzymes, including cysteine dioxygenase (CDO). In addition, uterus tissue and uterus fluid are rich in taurine, and taurine synthesis is regulated by estrogen (E2) and progesterone (P4), the key hormones priming embryo-uterine crosstalk during embryo implantation, but the functional interactions and mechanisms among which are largely unknown. The present study was thus proposed to identify the effects of CDO and taurine on embryo implantation and related mechanisms by using Cdo knockout (KO) and ovariectomy (OVX) mouse models. RESULTS: The uterine CDO expression was assayed from the first day of plugging (d 1) to d 8 and the results showed that CDO expression level increased from d 1 to d 4, followed by a significant decline on d 5 and persisted to d 8, which was highly correlated with serum and uterine taurine levels, and serum P4 concentration. Next, Cdo KO mouse was established by CRISPER/Cas9. It was showed that Cdo deletion sharply decreased the taurine levels both in serum and uterus tissue, causing implantation defects and severe subfertility. However, the implantation defects in Cdo KO mice were partly rescued by the taurine supplementation. In addition, Cdo deletion led to a sharp decrease in the expressions of P4 receptor (PR) and its responsive genes Ihh, Hoxa10 and Hand2. Although the expression of uterine estrogen receptor (ERα) had no significant change, the levels of ERα induced genes (Muc1, Ltf) during the implantation window were upregulated after Cdo deletion. These accompanied by the suppression of stroma cell proliferation. Meanwhile, E2 inhibited CDO expression through ERα and P4 upregulated CDO expression through PR. CONCLUSION: The present study firstly demonstrates that taurine and CDO play prominent roles in uterine receptivity and embryo implantation by involving in E2-ERα and P4-PR signaling. These are crucial for our understanding the mechanism of embryo implantation, and infer that taurine is a potential agent for improving reproductive efficiency of livestock industry and reproductive medicine.
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Background: The v-raf-leukemia viral oncogene 1 (RAF1) plays an essential physiological role in reproduction and development through the mediation of steroid hormone synthesis. Follicle-stimulating hormone (FSH) signaling pathway was not involved in the majority of RAF1 studies, whether RAF1 takes part in the signaling events of gonadotropic hormones such as FSH in ovarian tissue is unknown. Methods: The process is blocked by treating granulosa cells (GCs) with the RAF1 inhibitor, RAF709. Inhibition of RAF1 activity by RAF709 decreased extracellular regulated protein kinases (ERK) phosphorylation and suppressed the expression of the cytochrome P450 subfamily 19 member 1 (CYP19A1), which is a major rate-limiting enzyme that participates in the last step of E2 biosynthesis. Results: We found that RAF1, acting as a downstream molecule, mediates FSH signalling to stimulate estradiol (E2) synthesis and secretion in mouse ovarian GCs. Gene expression of RAF1 was induced by FSH and the secretion of E2 increased into the bloodstream of mice and into the supernatant of primary GCs. Our in vitro and in vivo studies clearly illustrate RAF1 plays an important medium adjusting role in the FSH signaling pathway, and RAF1 acting as a downstream molecule to trigger ERK phosphorylation to stimulate GC E2 synthesis and secretion. Conclusions: RAF1 plays a pivotal mediating role in the FSH signaling pathway by inducing the phosphorylation of ERK and promoting E2 synthesis.
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Background: Chronic total occlusion (CTO) is a critical and unique subgroup of coronary lesions. This study aimed to investigate the correlation between the Selvester QRS score and late gadolinium enhancement cardiac magnetic resonance imaging (LGE-CMRI) in quantifying myocardial scarring to provide a simple and feasible method for treating CTO. Methods: The medical records of 134 patients with absolute CTO who underwent coronary angiography between May 1, 2014 and December 30, 2017 were retrospectively reviewed. All patients were grouped according to the CTO location (right coronary artery [RCA] CTO, left artery descending [LAD] CTO, left circumflex [LCX] CTO, and multivessel CTO groups). The degree of myocardial scarring was determined according to the Selvester QRS score and using the LGE-CMRI. All patients were followed up for at least 12 months. Results: Among the 62 CTO patients, 55 had occlusion of a single vessel and seven had occlusion of multiple vessels, of which 27 (43.55%) were in the RCA CTO group, 16 (25.81%) in the LAD CTO group, 12 (19.35%) in the LCX CTO group, and 7 (11.29%) in the multivessel CTO group. The area under the receiver operating characteristic curve for the QRS score that was used to determine the degree of myocardial scarring was 0.806, with a sensitivity and specificity of 94.7% and 42.1%, respectively. The Selvester QRS score and LGE-CMRI measures of scar size were correlated in the RCA CTO, LCX CTO, and multivessel CTO groups (r = 0.466, 0.593, and 0.775, respectively). Conclusion: The Selvester QRS score was feasible for detecting myocardial scarring in patients with CTO.
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In aqueous zinc-based batteries, the reaction by-product Zn4SO4(OH)6·xH2O is commonly observed when cycling vanadium-based and manganese-based cathodes. This by-product obstructs ion transport paths, resulting in enhanced electrochemical impedance. In this work, we report a hybrid aqueous battery based on a Na0.44MnO2 cathode and a metallic zinc foil anode. The surfactant sodium lauryl sulfate is added to the electrolyte as a modifier, and the performance before and after modification is compared. The results show that sodium lauryl sulfate can generate an artificial passivation film on the electrode surface. This passivation film reduces the generation of Zn4SO4(OH)6·xH2O and inhibits the dissolution of Na0.44MnO2 in the electrolyte. Therefore, the reaction kinetics and cycle stability of the battery are significantly enhanced. A battery with this electrolyte additive delivers an initial discharge capacity of 235 mA h g-1 at a current density of 0.1 A g -1. At the same time, the battery has excellent rate performance. Under the high-rate condition of 1 A g-1, the battery still maintains a capacity retention rate of 93% after 1500 cycles. Finally, the functional mechanism of by-product inhibition by the electrolyte additive is discussed.
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BACKGROUND: Miscellaneous cardiovascular risk factors have been defined, but the contribution of environmental pollutants exposure on cardiovascular disease (CVD) remains underappreciated. OBJECTIVE: We investigated the potential impact of typical environmental pollutant exposure on atherogenesis and its underlying mechanisms. METHODS: We used human umbilical vein endothelial cells (HUVECs) and apolipoprotein E knockout (ApoE-/-) mice to investigate how 2,3,5-trichloro-6-phenyl-[1,4]-benzoquinone (PCB29-pQ, a toxic polychlorinated biphenyl metabolite) affects atherogenesis and identified early biomarkers of CVD associated with PCB29-pQ exposures. Then, we used long noncoding RNAs (lncRNAs) HDAC7-AS1-overexpressing ApoE-/- mice and apolipoprotein E/caveolin 1 double-knockout (ApoE-/-/CAV1-/-) mice to address the role of these early biomarkers in PCB29-pQ-induced atherogenesis. Plasma samples from patients with coronary heart disease (CHD) were also used to confirm our findings. RESULTS: Our data indicate that lncRNA HDAC7-AS1 bound to MIR-7-5p via argonaute 2 in PCB29-pQ-challenged HUVECs. Our mRNA sequencing assay identified transforming growth factor-ß2 (TGF-ß2) as a possible target gene of MIR-7-5p; HDAC7-AS1 sponged MIR-7-5p and inhibited the binding of TGF-ß2 to MIR-7-5p. The effect of PCB29-pQ-induced endothelial injury, vascular inflammation, development of plaques, and atherogenesis in ApoE-/- mice was greater with MIR-7-5p-mediated TGF-ß2 inhibition, whereas HDAC7-AS1-overexpressing ApoE-/- mice and ApoE-/-/CAV1-/- mice showed the opposite effect. Consistently, plasma levels of HDAC7-AS1 and MIR-7-5p were found to be significantly associated individuals diagnosed with CHD. DISCUSSIONS: These findings demonstrated that a mechanism-based, integrated-omics approach enabled the identification of potentially clinically relevant diagnostic indicators and therapeutic targets of CHD mediated by environmental contaminants using in vitro and in vivo models of HUVECs and ApoE-/- and ApoE-/-/CAV1-/- mice. https://doi.org/10.1289/EHP9833.
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Aterosclerose , Bifenilos Policlorados , RNA Longo não Codificante , Animais , Aterosclerose/induzido quimicamente , Biomarcadores , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Camundongos , Bifenilos Policlorados/toxicidade , RNA Longo não Codificante/genéticaRESUMO
The mild electrolyte working environment of rechargeable aqueous Zn-ion batteries (AZIBs) features its promising characteristic and potential application for large-scale energy storage system. However, the poor cycling stability significantly hinders the broad application of AZIBs due to the complex electrochemical conversion reactions during charge-discharge process. Herein, we propose a strategy to improve the electrochemical performance of AZIB by enhancing the successive electrochemical conversion reactions. With a rational design of electrode, an even homogeneous electric field can be achieved in the cathode side, resulting to significantly enhanced efficiency of successive electrochemical conversion reactions. Charge storage mechanism studies reveal that the reversibility behaviors of byproducts alkaline zinc sulfate (ZHS) can dramatically determine the H+/Zn2+ de/intercalation process, and a high reversibility characteristic ensures the facilitated electrochemical kinetics. As expected, the resultant AZIB possesses outstanding electrochemical performance with a high specific capacity of 425.08 mAhâ g-1 at 0.1 Aâ g-1, an excellent rate capacity of about 60% (246.6 mAhâ g-1 at 1 Aâ g-1) and superior cycling stability of 93.7% after 3000 cycles (at 3 Aâ g-1). This effective strategy and thinking proposed here may open a new avenue for the development of high-performing AZIBs.
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Background: The safety and efficacy associated with the use of proton pump inhibitors (PPIs) by patients with coronary artery disease receiving dual antiplatelet therapy (DAPT) remain unclear. Methods: The evaluated outcomes included combined major adverse cardiovascular events (MACEs), myocardial infarction (MI), all-cause mortality, and gastrointestinal (GI) bleeding. A random effects meta-analysis, stratified by study design, was performed and heterogeneity was assessed using the I2 statistic. Results: In total, 6 randomized controlled trials (RCTs) (6930 patients) and 16 observational studies (183,546 patients) were included. Analysis of RCTs showed that there were no significant differences in the incidences of MACEs (risk ratio [RR] = 0.89 [95% confidence interval (CI) = 0.75-1.05]), MI (RR = 0.93 [95% CI = 0.76-1.15]), and all-cause mortality (RR = 0.79 [95% CI = 0.50-1.23]) in the PPI groups vs. the non-PPI groups. Pooled data from observational studies revealed an inconsistent association between the use of each PPI subtype and the increased risks of MACEs during clopidogrel treatment. There was no increased risk of MACEs or all-cause mortality associated with the use of PPIs (as a class) and other P2Y12 inhibitors. Both the RCTs and observational studies revealed that the use of PPIs significantly reduced the risks of GI bleeding. Conclusion: The use of PPIs was associated with a reduced risk of GI bleeding in patients treated with DAPT after percutaneous coronary intervention or acute coronary syndrome. There was no clear evidence of an association between the use of PPIs and adverse cardiovascular events. Clinical Trial Registration: identifier [CRD42020190315].
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Cyclin-dependent kinase inhibitor 1B (Cdkn1b, p27) plays important regulatory roles in many cellular processes. p27 is highly expressed in the mouse testis, but its roles and underlying mechanisms for testosterone synthesis and secretion remain not well understood. In the current study, we found that p27 located in Leydig cells and Sertoli cells of adult mouse testis. To explore the function of p27 in Leydig cells, p27 inhibitor and activator were injected into the adult mice, primary Leydig cells and TM3 cells. Our in vivo and in vitro results showed that change in the expression of p27 significantly alters the testosterone in both globe serum and culture medium. Meanwhile, the steroidogenesis-related gene expression was significantly regulated too. Moreover, our in vitro study showed that luteinizing hormone (LH) significantly increased p27 mRNA levels. Furthermore, our results proved that altering the mRNA expression of p27 leads to the synchronized changes of Lhcgr, Star, Cyp11a1, Hsd3b6, Cyp11a1, and Hsd17b3. Alterations of p27 also result in synchronously changes of RAF1 and ERK1/2 phosphorylation. These findings indicate that p27 plays vital roles in LH-induced testosterone production, providing a novel mechanism that p27 acts as an upstream molecule to elevate ERK1/2 phosphorylation to promote the expression of StAR and other cholesterol-metabolizing enzymes.
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Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Células Intersticiais do Testículo/metabolismo , Hormônio Luteinizante/metabolismo , Testosterona/metabolismo , Animais , Células Cultivadas , Inibidor de Quinase Dependente de Ciclina p27/genética , Regulação da Expressão Gênica , Masculino , Camundongos Endogâmicos ICR , Fosforilação , Proteínas Proto-Oncogênicas c-raf/metabolismo , Transdução de Sinais , Testículo/metabolismo , Testosterona/biossínteseRESUMO
Inflammation and pyroptosis play a deleterious role in cardiac dysfunction after myocardial infarction (MI). NLRP3/caspase-1 is a well-established axis in pyroptosis and inflammation. In this study, we examined the effects of TN-C on pyroptosis through NLRP3 is unclear. We constructed 18 TN-C-knockout and 38 WT male mice model and divided into WT sham (n = 16), WT MI (n = 22), TNKO sham (n = 6), TNKO MI (n = 12). Elisa, immunostaining, TTC, qPCR, CCK8, flow cytometry, and western blot, echocardiographic, TUNEL staining technologies were applied. Here, we found a positive correlation between TN-C and NLRP3 in heart tissue via the GEPIA database (r = 0.52, p < 0.05). The findings indicate that TN-C was elevated and peaked on the fifth day after MI. TN-C deficiency alleviated cardiac dysfunction (LVEF, FS, LVIDd, and LVIDs) and cardiomyocyte death. Though the intracellular levels of pyroptosis-related cytokine caspase-1, cleaved caspase-1, NLRP3, IL-18, IL-1ß were upregulated both in MI and H2O2 stimulation, knockout of TN-C resisted such injury and alleviated cardiac pyroptosis, which further decreased IL-6, TNF-α, MCP-1 expression. TN-C knockdown inhibited TLR4 expression, reduces the release of downstream factors by inactivating the TLR4/NF-kB pathway, while protects the cardiomyocytes. And TLR4 inhibitor TAK-242 significantly reduced NLRP3 expression levels after MI. We demonstrated for the first time a direct link between MI-induced TN-C upregulation and caspase-1-dependent cardiomyocyte pyroptosis, a process mediated, at least in part, by TLR4/NF-kB/NLRP3 and IL-18, IL-1ß signaling pathways. These findings provide new insights into the role of TN-C in post-MI cardiomyocytes' pyroptosis and inflammation.
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Infarto do Miocárdio , Proteína 3 que Contém Domínio de Pirina da Família NLR , Animais , Caspase 1 , Peróxido de Hidrogênio , Inflamassomos/metabolismo , Masculino , Camundongos , Infarto do Miocárdio/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Tenascina , Receptor 4 Toll-LikeRESUMO
A power supply with the characteristics of portability and safety will be one of the dominating mainstreams for future wearable electronics and implantable biomedical devices. The conventional energy storage devices with typical sandwich structures have complicated components and low mechanical properties, suffering from the apparent performance degradation during deformation and hindering the possibility of implanting biomedical units. Herein, a novel all-in-one structure â³paper-likeâ³ zinc ion battery (ZIB) was designed and assembled from an electrospun polyacrylonitrile (PAN) nanomembrane (as the separator) with in situ deposited anode (zinc nanosheets) and cathode (MnO2 nanosheets), which ensures the monolith under different bending states by avoiding the relative sliding and detaching between the integrated layers. Benefiting from the well-designed all-in-one construction and electrodes, the resultant all-in-one ZIB (AZIB) features an ultrathin thickness (about 97 µm), superior specific capacity of 353.8 mAh g-1 (at 0.1 mA cm-2), and outstanding cycling stability (98.7% capacity retention after 500 cycles at 1 A cm-2). And the achieved volumetric energy density is as high as 17.5 mWh cm-3 at a power density of 116.4 mW cm-3. Impressively, the concept of wearable electronic applications of the obtained AZIB was fully demonstrated with excellent flexibility and remarkable temperature resistance under various severe conditions. Our AZIB may provide a versatile strategy for applying and developing flexible wearable electronics and implantable biomedical devices.