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Intrauterine infection during pregnancy can enhance uterine contractions. A two-pore K+ channel TREK1 is crucial for maintaining uterine quiescence and reducing contractility, with its properties regulated by pH changes in cell microenvironment. Meanwhile, the sodium hydrogen exchanger 1 (NHE1) plays a pivotal role in modulating cellular pH homeostasis, and its activation increases smooth muscle tension. By establishing an infected mouse model of Escherichia coli (E. coli) and lipopolysaccharide (LPS), we used Western blotting, real-time quantitative polymerase chain reaction, and immunofluorescence to detect changes of TREK1 and NHE1 expression in the myometrium, and isometric recording measured the uterus contraction. The NHE1 inhibitor cariporide was used to explore the effect of NHE1 on TREK1. Finally, cell contraction assay and siRNA transfection were performed to clarify the relationship between NHE1 and TREK1 in vitro. We found that the uterine contraction was notably enhanced in infected mice with E. coli and LPS administration. Meanwhile, TREK1 expression was reduced, whereas NHE1 expression was upregulated in infected mice. Cariporide alleviated the increased uterine contraction and promoted myometrium TREK1 expression in LPS-injected mice. Furthermore, suppression of NHE1 with siRNA transfection inhibited the contractility of uterine smooth muscle cells and activated the TREK1. Altogether, our findings indicate that infection increases the uterine contraction by downregulating myometrium TREK1 in mice, and the inhibition of TREK1 is attributed to the activation of NHE1.NEW & NOTEWORTHY Present work found that infection during pregnancy will increase myometrium contraction. Infection downregulated NHE1 and followed TREK1 expression and activation decrease in myometrium, resulting in increased myometrium contraction.
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Guanidinas , Lipopolisacáridos , Miometrio , Canales de Potasio de Dominio Poro en Tándem , Intercambiador 1 de Sodio-Hidrógeno , Sulfonas , Animales , Femenino , Ratones , Embarazo , Escherichia coli , Lipopolisacáridos/toxicidad , Miometrio/metabolismo , ARN Interferente Pequeño/metabolismo , Contracción Uterina/fisiología , Canales de Potasio de Dominio Poro en Tándem/metabolismo , Intercambiador 1 de Sodio-Hidrógeno/metabolismoRESUMEN
In brief: During pregnancy and delivery, the myometrium was affected by hypoxia stress, which acts as a regulator of cell proliferation. The proliferation of uterine smooth muscle cells in pregnant mice was inhibited under hypoxia, which was related to the up-regulated autophagy through the mTOR pathway. Abstract: Hypoxia is closely associated with physiological and pathological conditions in the human body, and the myometrium is affected by hypoxic stress during pregnancy and delivery. Autophagy is a catabolic pathway involved in the regulation of apoptosis, proliferation, and migration of a variety of cells, which can be activated under hypoxia. However, the mechanism and function of autophagy in uterine smooth muscle cells remained unclear. The aim of this study was to investigate the changes in autophagy in pregnant uterine smooth muscle cells (pUSMCs) under hypoxia and the effect of autophagy on myometrial cellscell proliferation during pregnancy. In this study, primary uterine smooth muscle cells were isolated from mice in late pregnancy and cultured under normoxic and hypoxic conditions, respectively. Western blotting and immunofluorescence were used to detect the expression levels of autophagy-related proteins LC3B, P62, mTOR, and p-mTOR under different culture conditions. Cell proliferation was assessed by CCK-8 assay. In addition, 3-methyladenine (3-MA) was used to inhibit autophagy in hypoxia-treated pUSMCs, and MHY1485 was used to activate mTOR. Studies have confirmed that under hypoxic conditions, autophagy is enhanced and cell proliferative viability is reduced in pUSMCs. The autophagy inhibitor 3-MA restored cell proliferation inhibited by hypoxia. Furthermore, hypoxia in pUSMCs led to a downregulation of p-mTOR/mTOR levels. The mTOR activator MHY1485 inhibited autophagy by preventing the binding of autophagosomes to lysosomes and reversed the hypoxia-induced inhibition of cell proliferation. Collectively, our results indicate that hypoxia upregulates autophagy through the mTOR pathway in pUSMCs, thereby inhibiting cell proliferation during pregnancy.
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Autofagia , Proliferación Celular , Miometrio , Transducción de Señal , Serina-Treonina Quinasas TOR , Femenino , Animales , Embarazo , Serina-Treonina Quinasas TOR/metabolismo , Ratones , Miometrio/metabolismo , Miometrio/citología , Miometrio/patología , Miocitos del Músculo Liso/metabolismo , Hipoxia/metabolismo , Células Cultivadas , Hipoxia de la CélulaRESUMEN
Implementation of efficient terahertz (THz) wave control is essential for THz technology development for applications including sixth-generation communications and THz sensing. Therefore, realization of tunable THz devices with large-scale intensity modulation capabilities is highly desirable. By integrating perovskite and graphene with a metallic asymmetric metasurface, two ultrasensitive devices for dynamic THz wave manipulation through low-power optical excitation are demonstrated experimentally here. The perovskite-based hybrid metadevice offers ultrasensitive modulation with a maximum modulation depth for the transmission amplitude reaching 190.2% at the low optical pump power of 5.90â mW/cm2. Additionally, a maximum modulation depth of 227.11% is achieved in the graphene-based hybrid metadevice at a power density of 18.87â mW/cm2. This work paves the way toward design and development of ultrasensitive devices for optical modulation of THz waves.
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Microbial metabolic products play a vital role in maintaining ecosystem multifunctionality, such as soil physical structure and soil organic carbon (SOC) preservation. Afforestation is an effective strategy to restore degraded land. Glomalin-related soil proteins (GRSP) and amino sugars are regarded as stable microbial-derived C, and their distribution within soil aggregates affects soil structure stability and SOC sequestration. However, the information about how afforestation affects the microbial contribution to SOC pools within aggregates is poorly understood. We assessed the accumulation and contribution of GRSP and amino sugars within soil aggregates along a restoration chronosequence (Bare land, Eucalyptus exserta plantation, native species mixed forest, and native forest) in tropical coastal terraces. Amino sugars and GRSP concentrations increased, whereas their contributions to the SOC pool decreased along the restoration chronosequence. Although microaggregates harbored greater microbial abundances, amino sugars and GRSP concentrations were not significantly affected by aggregate sizes. Interestingly, the contributions of amino sugars and GRSP to SOC pools decreased with decreasing aggregate size which might be associated with increased accumulation of plant-derived C. However, the relative change rate of GRSP was consistently greater in all restoration chronosequences than that of amino sugars. The accumulation of GRSP and amino sugars in SOC pools was closely associated with the dynamics of soil fertility and the microbial community. Our findings suggest that GRSP accumulates faster and contributes more to SOC pools during restoration than amino sugars did which was greatly affected by aggregate sizes. Afforestation substantially enhanced soil quality with native forest comprising species sequestering more SOC than the monoculture plantation did. Such information is invaluable for improving our mechanistic understanding of microbial control over SOC preservation during degraded ecosystem restoration. Our findings also show that plantations using arbuscular mycorrhizal plants can be an effective practice to sequester more soil carbon during restoration.
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Carbono , Suelo , Suelo/química , Carbono/análisis , Ecosistema , Amino Azúcares , Proteínas Fúngicas/metabolismo , Secuestro de Carbono , ChinaRESUMEN
In brief: During pregnancy, uterine kept quiescence along with uterine overdistention before labor. Prolonged stretching induced uterus myometrial hypoxia, increased TREK1 expression, and relaxed the myometrium, which may contribute to uterine quiescence and atony during pregnancy. Abstract: The mechanisms underlying pre-labor uterine quiescence and uterine atony during overdistention are unclear. TREK1 (a two-pore domain potassium channel) and hypoxia-inducible factor-1α (HIF-1α) are activated by mechanical stretch, and their expression is upregulated by decreased uterine contractility. HIF-1α is a nuclear factor which regulates numerous target proteins, but whether it regulates TREK1 during the uterine stretch to cause uterine quiescence and/or atony is unclear. We investigated uterine contractility at different gestational stages in rats, as well as in non-pregnant uteri, which were induced by prolonged stretching and hypoxia. We also assessed the effects of incubating the uteri with or without echinomycin or l-methionine. Moreover, we analyzed HIF-1α and TREK1 expression levels in each group, as well as at various gestational stages of pregnant human uteri. We found that contractility was significantly decreased in pregnant uteri when compared with non-pregnant uteri, and this decrease was associated with increases in HIF-1α and TREK1 expression levels. HIF-1α and TREK1 expression levels in human uteri increased with the gestational length. Decreased uterine contractility and increased HIF-1α and TREK1 expression levels were also observed in non-pregnant rat uteri under 8 g of stretching tension or hypoxia. Inhibition of hypoxia with echinomycin restored normal uterine contractility, while HIF-1α and TREK1 protein expression remained reduced. TREK1 inhibition with l-methionine also restored uterine contractility under tension or hypoxia. In conclusion, we demonstrated that prolonged stretching induces myometrial hypoxia, increases TREK1 expression, and relaxes the myometrium, which may contribute to uterine quiescence and atony.
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Equinomicina , Trabajo de Parto , Canales de Potasio de Dominio Poro en Tándem , Animales , Femenino , Humanos , Embarazo , Ratas , Equinomicina/farmacología , Hipoxia , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Trabajo de Parto/fisiología , Miometrio/fisiología , Útero , Canales de Potasio de Dominio Poro en Tándem/fisiologíaRESUMEN
Due to the lack of engine reference torque and the accumulated work of reference transient cycle, the work based window (WBW) method for portable emission measurement system test data processing cannot be used for vehicle emission assessment in the current on-board diagnostics (OBD) system in China. In this work, a fuel-consumption based window (FBW) method was proposed to imitate a WBW method procedure by using fuel consumption rate as an alternative parameter to scale the window so the entire procedure can be based on the attainable data items in the OBD system. Some key issues regarding converting WBW method to FBW method, including window separation, window average power ratio calculation and specific NOx emission conversion from mg/kg. fuel to mg/kW.h, were solved by linking the 100-km fuel consumption and the average vehicle specific power of China World Transient Vehicle Cycle test. The comparison between the FBW and WBW methods on the NOx emission calculation results shows that the number of all windows, the number of valid windows, and the thresholds for >50% valid windows are quite similar for WBW and FBW methods. The estimation accuracy of average power ratio for the FBW method depends on the value of transmission efficiency of vehicle driveline. The deviations of 90% specific NOx emission in mg/kW.h between the two methods are smaller than 6% for the cases investigated in the present work.
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Dipeptidyl peptidase-4 (DPP4) plays a crucial role in regulating the bioactivity of glucagon-like peptide-1 (GLP-1) that enhances insulin secretion and pancreatic ß-cell proliferation, making it a therapeutic target for type 2 diabetes. Although the crystal structure of DPP4 has been determined, its structure-function mechanism is largely unknown. Here, we examined the biochemical properties of sporadic human DPP4 mutations distal from its catalytic site, among which V486M ablates DPP4 dimerization and causes loss of enzymatic activity. Unbiased molecular dynamics simulations revealed that the distal V486M mutation induces a local conformational collapse in a ß-propeller loop (residues 234-260, defined as the flap) and disrupts the dimerization of DPP4. The "open/closed" conformational transitions of the flap whereby capping the active site, are involved in the enzymatic activity of DPP4. Further site-directed mutagenesis guided by theoretical predictions verified the importance of the conformational dynamics of the flap for the enzymatic activity of DPP4. Therefore, the current studies that combined theoretical modeling and experimental identification, provide important insights into the biological function of DPP4 and allow for the evaluation of directed DPP4 genetic mutations before initiating clinical applications and drug development.
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Diabetes Mellitus Tipo 2 , Dipeptidil Peptidasa 4 , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dipeptidil Peptidasa 4/genética , Péptido 1 Similar al Glucagón , Humanos , MutaciónRESUMEN
BACKGROUND: To determine the optimal delivery time for women with diet-controlled gestational diabetes mellitus by comparing differences in adverse maternal-fetal outcome and cesarean section rates. METHODS: This real-world retrospective study included 1,050 patients with diet-controlled gestational diabetes mellitus who delivered at 35-42 weeks' gestation. Data on patient characteristics, maternal-fetal outcomes, and cesarean section rate based on fetal gestational age were collected and analyzed. Differences between deliveries with and without iatrogenic intervention were also analyzed. RESULTS: The cesarean section rate at ≥ 41 weeks' gestation was significantly higher than that at 39-39 + 6 weeks (56% vs. 39%, p = 0.031). There were no significant differences in multiple adverse maternal or neonatal outcomes at delivery before and after 39 weeks. Vaginal delivery rates were increased significantly at 39-39 + 6 weeks due to iatrogenic intervention (p = 0.005) and 40-40 + 6 weeks (p = 0.003) in patients without and with spontaneous uterine contractions, respectively. CONCLUSIONS: It's recommended that optimal delivery time for patients with diet-controlled gestational diabetes mellitus should be between 39- and 40 + 6 weeks' gestation. Patients who have Bishop scores higher than 4 can undergo iatrogenic intervention at 39-39 + 6 weeks. However iatrogenic interventions are not recommended for patients with low Bishop scores.
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Cesárea , Diabetes Gestacional , Dieta , Femenino , Edad Gestacional , Humanos , Enfermedad Iatrogénica , Recién Nacido , Embarazo , Estudios RetrospectivosRESUMEN
Breast cancer is a common malignancy that is highly lethal. Due to the poor prognosis, more effective and efficient treatment methods are urgently needed. Rutin (RUT) is a traditional Chinese medicine reported to have a variety of pharmacological properties, including anticancer properties. However, the effects of RUT on breast cancer and its underlying molecular mechanism of action remain unclear. In the present study, we observed a significant downregulation of microRNA (miR)-129-1-3p in mouse breast cancer cells (4T1) compared with the expression in mouse normal breast epithelial cells (HC11). We also found that RUT could increase the expression of miR-129-1-3p in 4T1 cells and suppress cell proliferation. To elucidate the molecular mechanism of action of RUT, miR-129-1-3p mimics and its inhibitor were transfected into 4T1 cells. miR-129-1-3p overexpression could inhibit the proliferation, invasion, migration, and calcium overload of mouse breast cancer cells and also enhance apoptosis, whereas miR-129-1-3p knockdown had the opposite effects. Taken together, cell-based experiments indicated that RUT restrains the growth of mouse breast cancer cells by regulating the miR-129-1-3p/Ca2+ signaling pathway. This study also revealed the inhibitory effect of RUT on breast cancer cells at the noncoding RNA level and provided a theoretical foundation for the application of RUT as a drug to inhibit tumor growth.
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Señalización del Calcio/efectos de los fármacos , Neoplasias Mamarias Animales/metabolismo , MicroARNs/metabolismo , ARN Neoplásico/metabolismo , Rutina/farmacología , Animales , Línea Celular , Femenino , Neoplasias Mamarias Animales/genética , Neoplasias Mamarias Animales/patología , Ratones , MicroARNs/genética , Metástasis de la Neoplasia , ARN Neoplásico/genéticaRESUMEN
Our experiments have previously demonstrated that rutin (RUT) can improve myocardial damage caused by pirarubicin (THP). However, the underlying molecular mechanisms remain uncertain. In this study, we developed an microRNA (miRNA) chip by replicating the rat model of THP-induced myocardial injury and identified miR-22-5p and the RAP1-member of RAS oncogene family/extracellular regulated protein kinases (RAP1/ERK) signaling pathway as an object of study. Also, in vivo experiments demonstrated that THP caused abnormal changes in the electrocardiogram, cardiac function, and histomorphology in rats (P < .01). THP also reduces the expression of miR-22-5p (P < .01) and increases the levels of RAP1/ERK signaling pathway-related proteins (P < .01, P < .05). RUT significantly improved THP-induced myocardial damage (P < .01), increased the expression of miR-22-5p (P < .01), and decreased the levels of RAP1/ERK signaling pathway-related proteins (P < .01, P < .05). In vitro studies confirmed that Rap1a is one of the target genes of miR-22-5p. miR-22-5p overexpression in cardiomyocytes can affect the RAP1/ERK pathway and reduce reactive oxygen species production and cardiomyocyte apoptosis caused by THP (P < .01), which is consistent with the effect of RUT. Our results indicate that RUT treats THP-induced myocardial damage, which may be achieved by upregulating miR-22-5p, causing changes in its target gene Rap1a and the RAP1/ERK pathway.
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Doxorrubicina/análogos & derivados , Lesiones Cardíacas , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , MicroARNs/metabolismo , Miocardio/metabolismo , Rutina/farmacología , Proteínas de Unión al GTP rap1/metabolismo , Animales , Doxorrubicina/efectos adversos , Doxorrubicina/farmacología , Lesiones Cardíacas/inducido químicamente , Lesiones Cardíacas/tratamiento farmacológico , Lesiones Cardíacas/metabolismo , Lesiones Cardíacas/patología , Miocardio/patología , Ratas , Ratas WistarRESUMEN
Dyslipidemia is a chronic metabolic disease characterized by elevated levels of lipids in plasma. Recently, various studies demonstrate that the increased activity of adenosine 5'-monophosphate-activated protein kinase (AMPK) causes health benefits in energy regulation. Thus, great efforts have been made to develop AMPK activators as a metabolic syndrome treatment. In the present study, we investigated the effects of the AMPK activator C24 on dyslipidemia and the potential mechanisms. We showed that C24 (5-40 µM) dose-dependently increased the phosphorylation of AMPKα and acetyl-CoA carboxylase (ACC), and inhibited lipogenesis in HepG2 cells. Using compound C, an AMPK inhibitor, or hepatocytes isolated from liver tissue-specific AMPK knockout AMPKα1α2fl/fl;Alb-cre mice (AMPK LKO), we demonstrated that the lipogenesis inhibition of C24 was dependent on hepatic AMPK activation. In rabbits with high-fat and high-cholesterol diet-induced dyslipidemia, administration of C24 (20, 40, and 60 mg · kg-1· d-1, ig, for 4 weeks) dose-dependently decreased the content of TG, total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) in plasma and played a role in protecting against hepatic dysfunction by decreasing lipid accumulation. A lipid-lowering effect was also observed in high-fat and high-cholesterol diet-fed hamsters. In conclusion, our results demonstrate that the small molecular AMPK activator C24 alleviates hyperlipidemia and represents a promising compound for the development of a lipid-lowering drug.
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Proteínas Quinasas Activadas por AMP/metabolismo , Dislipidemias/tratamiento farmacológico , Activadores de Enzimas/uso terapéutico , Hipolipemiantes/uso terapéutico , Lipogénesis/efectos de los fármacos , Oxindoles/uso terapéutico , Animales , Dieta Alta en Grasa , Dislipidemias/enzimología , Células Hep G2 , Humanos , Hígado/efectos de los fármacos , Masculino , Mesocricetus , Ratones Endogámicos C57BL , ConejosRESUMEN
BACKGROUND: Low risk pregnancy ending in a vaginal birth is best served and guided by a midwife. Utilizing a midwife in such cases offers many emotional and economic advantages and does not increase the risks for mother or neonate. However, women's experience and satisfaction of midwife-led maternity care is rarely reported in China. The primary objective of this study is to describe the experience of Chinese women receiving midwife-led maternity care, and to report their satisfaction level of the experience. METHODS: The study is a cross-sectional survey of 4192 women who had natural birth from March-June 2019 in a maternity care center, Shanghai, China. We used a self-administered questionnaire addressing items related to women's experience during childbirth, as well as their satisfaction with midwife-led maternity care. We also included demographic and perinatal characteristics of each participant. Descriptive statistics and correlations analysis between groups of different experience and satisfaction were used. RESULTS: In this sample, 87.7% of women had a Doula and a family member present during childbirth. Epidural anesthesia was used in 75.6% and episiotomy was needed in 23.2%. Free positioning during the first stage of labor and free positioning during the second stage of labor and delivery were adopted in 84.3 and 67.9% of the cases, respectively. Moderate to severe perineal pain and moderate to severe perineal edema were reported in 43.1 and 12.2% of the participants, respectively. High satisfaction level was found when there was midwife-led prenatal counseling and presence of Doula and family member, Lamaze breathing techniques, warm perineal compresses, epidural anesthesia, free positioning during the first stage of labor, and midwifes' postpartum guidance. Negative satisfaction was seen with perineal pain and edema. CONCLUSION: Women in this survey generally had high satisfaction with midwife-led maternity care. This satisfaction is probably felt because of the prenatal counseling by the midwife and allowing a Doula and a family member in the room during childbirth. Other intangible factors to improve the satisfaction level were Lamaze breathing techniques, warm perineal compresses, epidural anesthesia, free positioning during first stage of labor, and early skin to skin contact.
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Parto Obstétrico/métodos , Trabajo de Parto , Servicios de Salud Materna , Partería/métodos , Satisfacción del Paciente , Adulto , China , Continuidad de la Atención al Paciente , Estudios Transversales , Femenino , Humanos , Recién Nacido , Parto , Atención Perinatal/métodos , EmbarazoRESUMEN
The attempt to integrate the applications of conventional structural deformation reconstruction strategies and vibration-based damage identification methods is made in this study, where, more specifically, the inverse finite element method (iFEM) and pseudo-excitation approach (PE) are combined for the first time, to give rise to a novel structural health monitoring (SHM) framework showing various advantages, particularly in aspects of enhanced adaptability and robustness. As the key component of the method, the inverse finite element method (iFEM) enables precise reconstruction of vibration displacements based on measured dynamic strains, which, as compared to displacement measurement, is much more adaptable to existing on-board SHM systems in engineering practice. The PE, on the other hand, is applied subsequently, relying on the reconstructed displacements for the identification of structural damage. Delamination zones in a carbon fibre reinforced plastic (CFRP) laminate are identified using the developed method. As demonstrated by the damage detection results, the iFEM-PE method possesses apparently improved accuracy and significantly enhanced noise immunity compared to the original PE approach depending on displacement measurement. Extensive parametric study is conducted to discuss the influence of a variety of factors on the effectiveness and accuracy of damage identification, including the influence of damage size and position, measurement density, sensor layout, vibration frequency and noise level. It is found that different factors are highly correlated and thus should be considered comprehensively to achieve optimal detection results. The application of the iFEM-PE method is extended to better adapt to the structural operational state, where multiple groups of vibration responses within a wide frequency band are used. Hybrid data fusion is applied to process the damage index (DI) constructed based on the multiple responses, leading to detection results capable of indicating delamination positions precisely.
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Owning to the unique optical and electronic properties, organic-inorganic hybrid perovskites have made impressive progress in photodetection applications. However, achieving ultrabroadband detection over the ultraviolet (UV) to terahertz (THz) range remains a major challenge for perovskite photodetectors. Here, we report an ultrabroadband (UV-THz) dual-mechanism photodetector based on CH3NH3PbI3 films. The photoresponse of the PD in the UV-visible (vis) and near-infrared (NIR)-THz bands is mainly caused by the photoconductive (PC) effect and bolometric effect, respectively. High responsivities ranging from 105 to 102 mA W-1 are acquired within UV-THz bands under 1 V bias voltage at room temperature. Moreover, the device also shows fast rise and decay times of 76 and 126 ns under 1064 nm laser illumination, respectively. This work provides insight into the thermoelectric characteristics of perovskite and offers a new way to realize ultrabroadband photodetectors notably for THz detector at room temperature.
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Pirarubicin (THP), an anthracycline anticancer drug, is a first-line therapy for various solid tumours and haematologic malignancies. However, THP can cause dose-dependent cumulative cardiac damage, which limits its therapeutic window. The mechanisms underlying THP cardiotoxicity are not fully understood. We previously showed that MiR-129-1-3p, a potential biomarker of cardiovascular disease, was down-regulated in a rat model of THP-induced cardiac injury. In this study, we used Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway enrichment analyses to determine the pathways affected by miR-129-1-3p expression. The results linked miR-129-1-3p to the Ca2+ signalling pathway. TargetScan database screening identified a tentative miR-129-1-3p-binding site at the 3'-UTR of GRIN2D, a subunit of the N-methyl-D-aspartate receptor calcium channel. A luciferase reporter assay confirmed that miR-129-1-3p directly regulates GRIN2D. In H9C2 (rat) and HL-1 (mouse) cardiomyocytes, THP caused oxidative stress, calcium overload and apoptotic cell death. These THP-induced changes were ameliorated by miR-129-1-3p overexpression, but exacerbated by miR-129-1-3p knock-down. In addition, miR-129-1-3p overexpression in cardiomyocytes prevented THP-induced changes in the expression of proteins that are either key components of Ca2+ signalling or important regulators of intracellular calcium trafficking/balance in cardiomyocytes including GRIN2D, CALM1, CaMK⠡δ, RyR2-pS2814, SERCA2a and NCX1. Together, these bioinformatics and cell-based experiments indicate that miR-129-1-3p protects against THP-induced cardiomyocyte apoptosis by down-regulating the GRIN2D-mediated Ca2+ pathway. Our results reveal a novel mechanism underlying the pathogenesis of THP-induced cardiotoxicity. The miR-129-1-3p/Ca2+ signalling pathway could serve as a target for the development of new cardioprotective agents to control THP-induced cardiotoxicity.
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Apoptosis/genética , Señalización del Calcio/genética , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , MicroARNs/genética , Miocitos Cardíacos/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Regiones no Traducidas 3'/genética , Animales , Apoptosis/efectos de los fármacos , Señalización del Calcio/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Muerte Celular/genética , Línea Celular , Biología Computacional/métodos , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacología , Ratones , Miocitos Cardíacos/efectos de los fármacos , Ratas , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genéticaRESUMEN
Pirarubicin (THP), an anthracycline drug, is widely used as a basic therapeutic agent for the treatment of carcinoma and lymphatic malignant tumor. However, it exerts irreversible cardiotoxicity in varying degrees. At present, dexrazoxane (DZR) is the only cardioprotective agent used to treat anthracycline drug-induced cardiotoxicity, but it may reduce the anticancer effect of anthracycline drugs, causing severe granulocytopenia and other adverse reactions. Therefore, it is necessary to discover more effective and less toxic drugs for the treatment of THP-induced cardiotoxicity. The present study aimed to investigate the effects and possible mechanisms of rutin (RUT) against THP-induced cardiomyocyte injury. An in vitro cardiomyocyte injury model of THP-treated murine immortalized cardiomyocytes (HL-1) was used in this study. The results showed that RUT markedly increased the viability of HL-1 cells through protection against THP-induced cardiomyocyte injury. Furthermore, RUT significantly inhibited myocardial oxidative insult by adjusting the levels of intracellular reactive oxygen species (ROS). Our data also indicated that RUT activated JunD signaling pathways, thereby affecting the expression levels of some apoptotic proteins by decreasing miR-125b-1-3p expression level. In addition, intracellular ROS level significantly increased in HL-1 cells treated with THP after miR-125b-1-3p mimic transfection, whereas the expression of JunD was downregulated and that of some apoptotic proteins was upregulated. However, this effect was markedly reversed by RUT. Therefore, we inferred that the protective effect of RUT on THP cardiotoxicity was achieved through regulation of the JunD gene by miR-125b-1-3p. This experiment revealed the protective effect of RUT on THP-induced cardiotoxicity at the non-coding RNA level and provided a theoretical foundation for the application of RUT as a protective agent against THP cardiotoxicity.
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Cardiotoxicidad , Doxorrubicina/análogos & derivados , MicroARNs/metabolismo , Miocitos Cardíacos , Proteínas Proto-Oncogénicas c-jun/metabolismo , Rutina/farmacología , Transducción de Señal/efectos de los fármacos , Animales , Cardiotoxicidad/metabolismo , Cardiotoxicidad/patología , Cardiotoxicidad/prevención & control , Doxorrubicina/efectos adversos , Doxorrubicina/farmacología , Ratones , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patologíaRESUMEN
Self-driven photodetectors are widely used in communication and imaging. As a newly developed semiconductor material, perovskite quantum dots (QDs) are not only bandgap tunable, but also easily combined with other materials. In this paper, a vertical structure self-driven photodetector based on heterojunction of CsPbBr3 QDs and PbS QDs is proposed, and the device is prepared by solution spin coating method. The device can work in visible and near infrared (400-1130 nm) regions, and has excellent performance, such as ultrafast response speed (rise and decay time are 0.4 µs/0.73 µs under 532 nm laser irradiation in self-driven mode, the estimated response time under 1064 nm laser irradiation is about 11.5 µs), more than 100 dB linear dynamic range for both visible and infrared regions, and good stability. Similarly, the responsivity of the photodetector can also reach an average of 10 mA W-1, and the detectivity is 1.13 × 1010 Jones at 0 V bias for 1064 nm laser irradiation. The device combines two kinds of QDs revealing its good prospects and great advantages in self-driven photodetectors and high-speed optical communication devices.
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The use of multipronged measures, including traditional Chinese medicine (TCM), has greatly increased in response to the COVID-19 pandemic, and we found the use of TCM and is positively correlated with the regional cure rate in China (R=0.77, P<10-5). We analyzed 185 commonly administered TCM recipes comprised of 210 herbs nationwide to reveal mechanistic insight. Eight out of the 10 most commonly used herbs showed anti-coronavirus potential by intersecting with COVID-19 targets. Intriguingly, 17 compounds from the 5 most commonly used herbs were revealed to have direct anti-SARS-CoV-2 potential by docking with the two core structures [CoV spike (S) glycoprotein (6SVB) and CoV 3CL hydrolase (6LU7)]. Seven reported COVID-19 drugs served as positive controls; among them, retionavir (-7.828 kcal/mol) and remdesivir (-8.738 kcal/mol) performed best with 6VSB and 6LU7, respectively. The top candidate was madreselvin B (6SVB: -8.588 kcal/mol and 6LU7: -9.017 kcal/mol), an appreciable component of Flos Lonicerae. Eighty-six compounds from 22 unlisted herbs were further identified among 2,042 natural compounds, completing our arsenal for TCM formulations. The mechanisms have been implicated as multifactorial, including activation of immunoregulation (Th2, PPAR and IL10), suppression of acute inflammatory responses (IL-6, IL-1α/ß, TNF, COX2/1, etc.), enhancement of antioxidative activity (CAT and SOD1), and modulation of apoptosis (inhibited CASP3). It is of interest to understand the biological mechanisms of TCM recipes. We then analyzed 18 representative remedies based on molecular targets associated with 14 medical conditions over the disease course, e.g., pyrexia, coughing, asthenia, lymphopenia, cytokine storm, etc. The significant level of coherence (SLC) revealed, in part, the potential uses and properties of corresponding TCMs. Thus, herbal plants coordinate to combat COVID-19 in multiple dimensions, casting a light of hope before effective vaccines are developed.
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Infecciones por Coronavirus/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Medicina Tradicional China/métodos , Fitoterapia/métodos , Neumonía Viral/tratamiento farmacológico , Algoritmos , Antivirales/aislamiento & purificación , Antivirales/farmacología , Antivirales/uso terapéutico , Betacoronavirus/efectos de los fármacos , Betacoronavirus/fisiología , COVID-19 , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/genética , Desarrollo de Medicamentos , Medicamentos Herbarios Chinos/clasificación , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Simulación del Acoplamiento Molecular , Pandemias , Fitoterapia/clasificación , Neumonía Viral/epidemiología , Neumonía Viral/genética , SARS-CoV-2 , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Tratamiento Farmacológico de COVID-19RESUMEN
Light enhanced low-voltage nonvolatile memory was prepared using all-inorganic perovskite quantum dots (QDs) as a semiconductor layer and Ag nanoparticles (NPs) as a floating gate layer. The photo-induced carriers can be produced in CsPbBr3 QDs under ultraviolet light and trapped in Ag NPs under the action of an external electric field. With the assistance of light, the device exhibited a significantly larger memory window (ΔV th) under low programming and erasing voltages of ±5 V owing to the use of CsPbBr3 QDs. Furthermore, we proved that the ΔV th of the memory strongly depended on the applied bias voltage (V DS) as well as still remaining at 79.3% after 105 s at V DS of 1.4 V. The facile memory provides a new approach to trap a photo-induced charge and reduce operating voltages by combining QDs with metal NPs.
RESUMEN
An end-pumped actively $Q$Q-switched ${\rm Nd}\!:\!{{\rm YVO}_4}/{{\rm YVO}_4}$Nd:YVO4/YVO4 Raman laser with a folded coupled cavity is demonstrated to study the evolution of Raman beam quality. The theoretical mechanism of the beam cleanup effect of stimulated Raman scattering is analyzed. The beam quality ($M^2$M2) of the Raman beam and the fundamental beams before and after the Raman conversion are measured experimentally. The results show that with the incident pump power increasing, the ${M^2}$M2 of the fundamental beam increases from 1.85 to 3.08, while the ${M^2}$M2 of the Raman beam increases from 1.21 to 1.69. The beam quality of the Raman laser and its degradation are better than that of the fundamental laser.