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BACKGROUND: Presently, the efficacy of neonatal resuscitation techniques via interventions such as oral, nasal, and endotracheal suction for preventing meconium aspiration syndrome (MAS) after delivery has not been satisfactory. OBJECTIVE: This study aimed to investigate the role of intratracheal instillation of budesonide on oxidative stress in MAS. METHODS: Sixty-two neonates with MAS admitted to Huai'an Maternity and Child Healthcare Hospital from January 2018 to June 2020 were divided into a study group (intratracheal instillation of 2 ml budesonide suspension; n = 31) and a control group (intratracheal instillation of 2 ml normal saline; n = 31). Collect data from two groups of patients and evaluate clinical outcomes, including oxygenation index (OI), as well as serum total oxidant status (TOS), total antioxidant capacity (TAC), oxidative stress index (OSI) and 8-Isoprostane before treatment and 72h after admission. RESULTS: We found no statistical differences in mortality, complication rate, total oxygen inhalation time, OI before treatment and 72h after admission between the two groups of neonates with MAS, while the duration of invasive respiratory support in the study group was significantly shorter than in the control group. Also, serum TAC, TOS, OSI and 8-isoprostane levels were not statistically different before treatment between the two groups. After 72h of admission, OSI and 8-Isoprostane in neonates with MAS in the study group were much lower than those in the control group. TOS, OSI, 8-Isoprostane in the control group and 8-Isoprostane in the study group were significantly higher than those before treatment. As for TAC and TOS, no significant differences were observed between the two groups. CONCLUSION: Intratracheal instillation of budesonide was shown to alleviate oxidative stress and shorten invasive ventilation time in neonates with MAS.
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Budesonida , Dinoprost/análogos & derivados , Síndrome de Aspiración de Meconio , Estrés Oxidativo , Humanos , Síndrome de Aspiración de Meconio/tratamiento farmacológico , Recién Nacido , Estrés Oxidativo/efectos de los fármacos , Budesonida/administración & dosificación , Femenino , Masculino , Solución Salina/administración & dosificación , Instilación de Medicamentos , Estudios de Casos y ControlesRESUMEN
BACKGROUND: The discovering of an osteoclast (OC) coupling active agent, capable of suppressing OC-mediated bone resorption while concurrently stimulating osteoblast (OB)-mediated bone formation, presents a promising strategy to overcome limitations associated with existing antiresorptive agents. However, there is a lack of research on active OC coupling agents. PURPOSE: This study aims to investigate the potential of Jiangu Formula (JGF) in inhibiting OCs while maintaining the OCOB coupling function. METHODS: The anti-osteoporosis efficacy of JGF was evaluated in osteoporosis models induced by ovariectomy in C57BL/6 mouse and SD rats. The effect of JGF on OCs was evaluated by detecting its capacity to inhibit OC differentiation and bone resorption in an in vitro osteoclastogenesis model induced by RANKL. The OCOB coupling activity of JGF was evaluated by measuring the secretion levels of OC-derived coupling factors, OB differentiation activity of MC3T3-E1 interfered with conditioned medium, and the effect of JGF on OC inhibition and OB differentiation in a C3H10T1/2-RAW264.7 co-culture system. The mechanism of JGF was studied by network pharmacology and validated using western blot, immunofluorescence (IF), and ELISA. Following that, the active ingredients of JGF were explored through a chemotype-assembly approach, activity evaluation, and LC-MS/MS analysis. RESULTS: JGF inhibited bone resorption in murine osteoporosis without compromising the OCOB coupling effect on bone formation. In vitro assays showed that JGF preserved the coupling effect of OC on OB differentiation by maintaining the secretion of OC-derived coupling factors. Network analysis predicted STAT3 as a key regulation point for JGF to exert anti-osteoporosis effect. Further validation assays confirmed that JGF upregulated p-STAT3(Ser727) and its regulatory factors IL-2 in RANKL-induced RAW264.7 cells. Moreover, 23 components in JGF with anti-OC activity identified by chemotype-assembly approach and verification experiments. Notably, six compounds, including ophiopogonin D, ginsenoside Re, ginsenoside Rf, ginsenoside Rg3, ginsenoside Ro, and ononin were identified as OC-coupling compounds. CONCLUSION: This study first reported JGF as an agent that suppresses bone loss without affecting bone formation. The potential coupling mechanism of JGF involves the upregulation of STAT3 by its regulators IL-2. Additionally, the chemotype-assembly approach elucidated the activity compounds present in JGF, offering a novel strategy for developing an anti-resorption agent that preserves bone formation.
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Resorción Ósea , Diferenciación Celular , Medicamentos Herbarios Chinos , Ratones Endogámicos C57BL , Osteoblastos , Osteoclastos , Osteoporosis , Ratas Sprague-Dawley , Animales , Osteoclastos/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Ratones , Osteoporosis/tratamiento farmacológico , Osteoblastos/efectos de los fármacos , Femenino , Células RAW 264.7 , Diferenciación Celular/efectos de los fármacos , Resorción Ósea/tratamiento farmacológico , Ovariectomía , Ligando RANK , Ratas , Osteogénesis/efectos de los fármacos , Modelos Animales de Enfermedad , Factor de Transcripción STAT3/metabolismoRESUMEN
Thoracic echocardiography (TTE) can provide sufficient cardiac structure information, evaluate hemodynamics and cardiac function, and is an effective method for atrial septal defect (ASD) examination. This paper aims to study a deep learning method based on cardiac ultrasound video to assist in ASD diagnosis. We chose four standard views in pediatric cardiac ultrasound to identify atrial septal defects; the four standard views were as follows: subcostal sagittal view of the atrium septum (subSAS), apical four-chamber view (A4C), the low parasternal four-chamber view (LPS4C), and parasternal short-axis view of large artery (PSAX). We enlist data from 300 children patients as part of a double-blind experiment for five-fold cross-validation to verify the performance of our model. In addition, data from 30 children patients (15 positives and 15 negatives) are collected for clinician testing and compared to our model test results (these 30 samples do not participate in model training). In our model, we present a block random selection, maximal agreement decision, and frame sampling strategy for training and testing respectively, resNet18 and r3D networks are used to extract the frame features and aggregate them to build a rich video-level representation. We validate our model using our private dataset by five cross-validation. For ASD detection, we achieve 89.33 ± 3.13 AUC, 84.95 ± 3.88 accuracy, 85.70 ± 4.91 sensitivity, 81.51 ± 8.15 specificity, and 81.99 ± 5.30 F1 score. The proposed model is a multiple instances learning-based deep learning model for video atrial septal defect detection which effectively improves ASD detection accuracy when compared to the performances of previous networks and clinical doctors.
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Aprendizaje Profundo , Ecocardiografía , Defectos del Tabique Interatrial , Humanos , Defectos del Tabique Interatrial/diagnóstico por imagen , Niño , Ecocardiografía/métodos , Femenino , Masculino , Preescolar , Método Doble Ciego , Lactante , Interpretación de Imagen Asistida por Computador/métodos , Grabación en Video , AdolescenteRESUMEN
Mycoplasma gallisepticum (MG) is recognized as a principal causative agent of avian chronic respiratory disease, inflicting substantial economic losses upon the poultry industry. However, the extensive use of conventional antibiotics has resulted in the emergence of drug resistance and various challenges in their clinical application. Consequently, there is an urgent need to identify effective therapeutic agents for the prevention and treatment of mycoplasma-induced respiratory disease in avian species. AMP-activated protein kinase (AMPK) holds significant importance as a regulator of cellular energy metabolism and possesses the capacity to exert an anti-inflammatory effect by virtue of its downstream protein, SIRT1. This pathway has shown promise in counteracting the inflammatory responses triggered by pathogenic infections, thus providing a novel target for studying infectious inflammation. Quercetin possesses anti-inflammatory activity and has garnered attention as a potential alternative to antibiotics. However, there exists a gap in knowledge concerning the impact of this activation on MG-induced inflammatory damage. To address this knowledge gap, we employed AlphaFold2 prediction, molecular docking, and kinetic simulation methods to perform a systematic analysis. As expected, we found that both quercetin and the AMPK activator AICAR activate the chicken AMPKγ1 subunit in a similar manner, which was further validated at the cellular level. Our project aims to unravel the underlying mechanisms of quercetin's action as an agonist of AMPK against the inflammatory damage induced by MG infection. Accordingly, we evaluated the effects of quercetin on the prevention and treatment of air sac injury, lung morphology, immunohistochemistry, AMPK/SIRT1/NF-κB pathway activity, and inflammatory factors in MG-infected chickens. The results confirmed that quercetin effectively inhibits the secretion of pro-inflammatory cytokines such as IL-1ß, TNF-α, and IL-6, leading to improved respiratory inflammation injury. Furthermore, quercetin was shown to enhance the levels of phosphorylated AMPK and SIRT1 while reducing the levels of phosphorylated P65 and pro-inflammatory factors. In conclusion, our study identifies the AMPK cascade signaling pathway as a novel cellular mediator responsible for quercetin's ability to counter MG-induced inflammatory damage. This finding highlights the potential significance of this pathway as an important target for anti-inflammatory drug research in the context of avian respiratory diseases.
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Mycoplasma gallisepticum , FN-kappa B , Animales , FN-kappa B/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Quercetina/farmacología , Quercetina/uso terapéutico , Mycoplasma gallisepticum/metabolismo , Sirtuina 1/metabolismo , Simulación del Acoplamiento Molecular , Pollos/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/prevención & control , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antibacterianos/uso terapéuticoRESUMEN
Hyperlipidemia (HLP) is one of the risk factors for memory impairment and cognitive impairment. However, its pathological molecular mechanism remained unclear. 3ß-hydroxysterol Δ24- reductase (DHCR24) is a key enzyme in cholesterol synthesis and has been reported to decrease in the affected areas in the brain of neurodegenerative disorders. In this study, hyperlipidemic mouse model was established to study the effect of high blood lipid on brain. The data obtained from HPLC analysis demonstrated that the cholesterol level in the brain of mice with hyperlipidemia was significantly elevated compared to the control group. While the pathological damages were observed in both cerebral cortex and hippocampus in the brain of hyperlipidemic mice. Furthermore, the protein level of DHCR24 was downregulated accompanied by elevated ubiquitination level in the hyperlipidemic mice brain. The mouse neuroblastoma cells N2a were exposed to the excess cholesterol loading, the cells underwent apoptosis and the mRNA and protein of DHCR24 in cholesterol-loaded N2a cells were significantly reduced. In addition, the expression level of endoplasmic reticulum stress marker protein (Bip and Chop) was markedly increased in response to the cholesterol loading. More importantly, overexpression of DHCR24 in N2a reversed neuronal apoptosis induced by the cholesterol loading. Conclusively, these findings suggested that hyperlipidemia could cause brain tissue injuries via down-regulating DHCR24, and overexpression of DHCR24 may alleviate hyperlipidemia-induced neuronal cells damage by reversing the endoplasmic reticulum stress-mediated apoptosis.
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Lesiones Encefálicas , Oxidorreductasas , Ratones , Animales , Oxidorreductasas/metabolismo , Oxidorreductasas/farmacología , Hidroxicolesteroles/farmacología , Estrés Oxidativo , Dieta Alta en Grasa , Apoptosis , Colesterol/metabolismoRESUMEN
To improve the aqueous solubility and oral bioavailability of paclitaxel (PTX), a biomimetic system for oral administration of PTX was efficiently developed as an outer membrane vesicle (OMVs) of sodium caseinate (CAS) modified zein nanoparticles (OMVs-Zein-CAS-PTX-NPs) by Escherichia coli. To verify their structure and properties, the designed nanostructures were thoroughly characterized using various characterization techniques. The results indicated that hydrogen bonds and van der Waals forces mainly drove the interaction between PTX and Zein, but the complex is unstable. The physicochemical stability of PTX-loaded zein nanoparticles was improved by the addition of CAS. The biological characteristics of biofilms are reproduced by nanoparticles cloaked with outer membrane vesicles. OMVs-Zein-CAS-PTX-NPs delayed the release of PTX under simulated gastric and intestinal fluids due to OMVs protection. OMVs-Zein-CAS-PTX-NPs exhibited remarkable antitumor ability in vitro and improved the bioavailability of oral administration of PTX in vivo. Therefore, OMVs cloaked in nanoparticles may be a suitable delivery vehicle to provide an efficient application prospect for the oral administration of PTX.
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Nanopartículas , Zeína , Paclitaxel , Zeína/química , Portadores de Fármacos/química , Membrana Externa Bacteriana , Nanopartículas/químicaRESUMEN
Nephrolithiasis is a complicated disease affected by various environmental and genetic factors. Crystal-cell adhesion is a critical initiation process during kidney stone formation. However, genes regulated by environmental and genetic factors in this process remain unclear. In the present study, we integrated the gene expression profile data and the whole-exome sequencing data of patients with calcium stones, and found that ATP1A1 might be a key susceptibility gene involved in calcium stone formation. The study showed that the T-allele of rs11540947 in the 5'-untranslated region of ATP1A1 was associated with a higher risk of nephrolithiasis and lower activity of a promoter of ATP1A1. Calcium oxalate crystal deposition decreased ATP1A1 expression in vitro and in vivo and was accompanied by the activation of the ATP1A1/Src/ROS/p38/JNK/NF-κB signaling pathway. However, the overexpression of ATP1A1 or treatment with pNaKtide, a specific inhibitor of the ATP1A1/Src complex, inhibited the ATP1A1/Src signal system and alleviated oxidative stress, inflammatory responses, apoptosis, crystal-cell adhesion, and stone formation. Moreover, the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine reversed ATP1A1 down-regulation induced by crystal deposition. In conclusion, this is the first study to show that ATP1A1, a gene modulated by environmental factors and genetic variations, plays an important role in renal crystal formation, suggesting that ATP1A1 may be a potential therapeutic target for treating calcium stones.
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Cálculos Renales , ATPasa Intercambiadora de Sodio-Potasio , Humanos , Calcio/metabolismo , Regulación hacia Abajo , Riñón/metabolismo , Cálculos Renales/química , Cálculos Renales/metabolismo , Estrés Oxidativo/genética , ATPasa Intercambiadora de Sodio-Potasio/genéticaRESUMEN
Hyperlipidemia is a risk factor for the development of fatty liver and cardiovascular diseases such as atherosclerosis and coronary heart disease, and hence, cholesterol-lowering drugs are considered important and effective in preventing cardiovascular diseases. Thus, researchers in the field of new drug development are endeavoring to identify new types of cholesterol-lowering drugs. 3ß-hydroxysterol-Δ(24)-reductase (DHCR24) catalyzes the conversion of desmosterol to cholesterol, which is the last step in the cholesterol biosynthesis pathway. We speculated that blocking the catalytic activity of DHCR24 could be a novel therapeutic strategy for treating hyperlipidemia. In the present study, by virtually screening the DrugBank database and performing molecular dynamics simulation analysis, we selected four potential DHCR24 inhibitor candidates: irbesartan, risperidone, tolvaptan, and conivaptan. All four candidates showed significant cholesterol-lowering activity in HepG2 cells. The experimental mouse model of hyperlipidemia demonstrated that all four candidates improved high blood lipid levels and fat vacuolation in the livers of mice fed with a high-fat diet. In addition, Western blot analysis results suggested that irbesartan reduced cholesterol levels by downregulating the expression of the low-density lipoprotein receptor. Finally, the immune complex activity assay confirmed the inhibitory effect of irbesartan on the enzymatic activity of DHCR24 with its half-maximal inhibitory concentration (IC50) value of 602 nM. Thus, to the best of our knowledge, this is the first study to report that blocking the enzymatic activity of DHCR24 via competitive inhibition is a potential strategy for developing new cholesterol-lowering drugs against hyperlipidemia or multiple cancers. Furthermore, considering that irbesartan is currently used to treat hypertension combined with type 2 diabetes, we believe that irbesartan should be a suitable choice for patients with both hypertension and hyperlipidemia.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Hipertensión , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH , Animales , Ratones , Oxidorreductasas , Irbesartán , Desmosterol , Colesterol/metabolismo , Proteínas del Tejido Nervioso/metabolismoRESUMEN
With the development of the economy, family wealth continues to accumulate, and more and more consumers participate in financial management affairs. As an important way to improve financial knowledge, informal financial education is vital to consumer financial capability. Utilizing data from the 2012, 2015, and 2018 US National Financial Capability Study and the approaches of ordinary least squares and ordered probit regression are employed to produce more accurate estimates. Meanwhile, the study also explores the mediating effects of financial knowledge between informal financial education and consumer financial capability. The results show that informal financial education has a positive effect on the improvement of consumer financial capability. Besides, financial knowledge partially mediates the nexus between informal financial education and consumer financial capability. Therefore, policymakers are encouraged to formulate measures to promote financial education programs not only in schools and universities but also in workplaces or communities. Companies also should offer more opportunities for their employees to receive financial education and further enhance their financial capability. Consumers should be aware of the importance of financial education and actively learn financial knowledge to improve financial capability and further enhance financial satisfaction.
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Some relationship between abnormal cholesterol content and impairment of insulin/insulin-like growth factor I (IGF-1) signaling has been reported in the pathogenesis of Alzheimer's disease (AD). However, the underlying mechanism of this correlation remains unclear. It is known that 3-ß hydroxycholesterol Δ 24 reductase (DHCR24) catalyzes the last step of cholesterol biosynthesis. To explore the function of cholesterol in the pathogenesis of AD, we depleted cellular cholesterol by targeting DHCR24 with siRNA (siDHCR24) or U18666A, an inhibitor of DHCR24, and studied the effect of the loss of cholesterol on the IGF-1-Akt signaling pathway in vitro and in vivo. Treatment with U18666A reduced the cellular cholesterol level and blocked the anti-apoptotic function of IGF-1 by impairing the formation of caveolae and the localization of IGF-1 receptor in caveolae of the PC12 cells. Downregulation of the DHCR24 expression induced by siRNA against DHCR24 also yielded similar results. Furthermore, the phosphorylation levels of IGF-1 receptor, insulin receptor substrate (IRS), Akt, and Bad in response to IGF-1 were all found to decrease in the U18666A-treated cells. Rats treated with U18666A via intracerebral injection also exhibited a significant decrease in the cholesterol level and impaired activities of IGF-1-related signaling proteins in the hippocampus region. A significant accumulation of amyloid ß and a decrease in the expression of neuron-specific enolase (NSE) was also observed in rats with U18666A. Finally, the Morris water maze experiment revealed that U18666A-treated rats showed a significant cognitive impairment. Our findings provide new evidence strongly supporting that a reduction in cholesterol level can result in neural apoptosis via the impairment of the IGF-1-Akt survival signaling in the brain.
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Encéfalo/fisiología , Colesterol/biosíntesis , Factor I del Crecimiento Similar a la Insulina/metabolismo , Neuronas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/fisiología , Androstenos/farmacología , Animales , Aprendizaje por Laberinto , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/genética , Neuronas/efectos de los fármacos , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/antagonistas & inhibidores , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/genética , Células PC12 , RatasRESUMEN
The catalytic activity of metal clusters is closely related with the support; however, knowledge on the influence of the support on the catalytic activity is scarce. We demonstrate that Pt nanoclusters (NCs) anchored on porous TiO2 nanosheets with rich oxygen vacancies (VO -rich Pt/TiO2 ) and deficient oxygen vacancies (VO -deficient Pt/TiO2 ), display significantly different catalytic activity for the hydrogen evolution reaction (HER), in which VO -rich Pt/TiO2 shows a mass activity of 45.28â A mgPt -1 at -0.1â V vs. RHE, which is 16.7 and 58.8 times higher than those of VO -deficient Pt/TiO2 and commercial Pt/C, respectively. DFT calculations and inâ situ Raman spectra suggest that porous TiO2 with rich oxygen vacancies can simultaneously achieve reversed charge transfer (electrons transfer from TiO2 to Pt NCs) and enhanced hydrogen spillover from Pt NCs to the TiO2 support, which leads to electron-rich Pt NCs being amenable to proton reduction of absorbed H*, as well as the acceleration of hydrogen desorption at Pt catalytic sites-both promoting the HER. Our work provides a new strategy for rational design of highly efficient HER catalysts.
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Since the outbreak of the novel corona virus disease 2019 (COVID-19) at the end of 2019, specific antiviral drugs have been lacking. A Chinese patent medicine Toujiequwen granules has been promoted in the treatment of COVID-19. The present study was designed to reveal the molecular mechanism of Toujiequwen granules against COVID-19. A network pharmacological method was applied to screen the main active ingredients of Toujiequwen granules. Network analysis of 149 active ingredients and 330 drug targets showed the most active ingredient interacting with many drug targets is quercetin. Drug targets most affected by the active ingredients were PTGS2, PTGS1, and DPP4. Drug target disease enrichment analysis showed drug targets were significantly enriched in cardiovascular diseases and digestive tract diseases. An "active ingredient-target-disease" network showed that 57 active ingredients from Toujiequwen granules interacted with 15 key targets of COVID-19. There were 53 ingredients that could act on DPP4, suggesting that DPP4 may become a potential new key target for the treatment of COVID-19. GO analysis results showed that key targets were mainly enriched in the cellular response to lipopolysaccharide, cytokine activity and other functions. KEGG analysis showed they were mainly concentrated in viral protein interaction with cytokine and cytokine receptors and endocrine resistance pathway. The evidence suggests that Toujiequwen granules might play an effective role by improving the symptoms of underlying diseases in patients with COVID-19 and multi-target interventions against multiple signaling pathways related to the pathogenesis of COVID-19.
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Tratamiento Farmacológico de COVID-19 , Medicamentos Herbarios Chinos/farmacología , Medicina Tradicional China , SARS-CoV-2/genética , Antivirales/química , Antivirales/farmacología , COVID-19/genética , COVID-19/virología , Ciclooxigenasa 1/genética , Ciclooxigenasa 2/genética , Dipeptidil Peptidasa 4/genética , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/clasificación , Regulación Viral de la Expresión Génica/efectos de los fármacos , Humanos , Quercetina/genética , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/patogenicidad , Transducción de Señal/efectos de los fármacosRESUMEN
Electrocatalytic reduction of CO2 is one of the most attractive approaches for converting CO2 into valuable chemical feedstocks and fuels. This work reports a catalyst comprising graphdiyne-decorated bismuth subcarbonate (denoted as BOC@GDY) for efficient electroreduction of CO2 to formate. The BOC@GDY shows a stable current density of 200 mA cm-2 at -1.1 V in a flow cell configuration, with a faradaic efficiency of 93.5% for formate. Experimental results show that the synergistic effect in BOC@GDY is beneficial for the CO2 adsorption affinity, the reaction kinetics and the selectivity for formate. In addition, in-situ X-ray absorption and Raman spectroscopy indicate that the electron-rich GDY could facilitate the reduction from Bi(III) to Bi(0), thus leading to more active sites. We also demonstrate that the promoting effect of GDY in CO2 electroreduction can be further extended to other metal catalysts. To the best of our knowledge, such general promoting functions of GDY for CO2 electroreduction have not been documented thus far.
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Bismuto , Dióxido de Carbono , FormiatosRESUMEN
There is accumulating evidence showing that apoptosis induced by endoplasmic reticulum (ER) stress plays a key role in pancreatic ß cell dysfunction and insulin resistance. 3ß-Hydroxysteroid-Δ24 Reductase (DHCR24) is a multifunctional enzyme located in the endoplasmic reticulum (ER), which has been previously shown to protect neuronal cells from ER stress-induced apoptosis. However, the role of DHCR24 in type 2 diabetes is only incompletely understood so far. In the present study, we induced ER stress by tunicamycin (TM) treatment and showed that infection of MIN6 cells with Ad-DHCR24-myc rendered these cells resistant to caspase-3-mediated apoptosis induced by TM, while cells transfected with siRNAs targeting DHCR24 were more sensitive to TM. Western blot analysis showed that TM treatment induced upregulation of Bip protein levels in both cells infected with Ad-LacZ (the control group) and Ad-DHCR24-myc, indicating substantial ER stress. Cells infected with Ad-LacZ exhibited a rapid and strong activation of ATF6 and p38, peaking at 3 h after TM exposure. Conversely, cells infected with Ad-DHCR24-myc showed a higher and more sustained activation of ATF6 and Bip than control cells. DHCR24 overexpression also inhibited the generation of intracellular reactive oxygen species (ROS) induced by ER stress and protected cells from apoptosis caused by treatment with both cholesterol and hydrogen peroxide. In summary, these data demonstrate, for the first time, that DHCR24 protects pancreatic ß cells from apoptosis induced by ER stress.
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Apoptosis/fisiología , Estrés del Retículo Endoplásmico/fisiología , Células Secretoras de Insulina/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Animales , Apoptosis/efectos de los fármacos , Línea Celular , Colesterol/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Peróxido de Hidrógeno/farmacología , Células Secretoras de Insulina/efectos de los fármacos , Ratones , Proteínas del Tejido Nervioso/genética , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/genética , Tunicamicina/farmacologíaRESUMEN
The reaction of precursors containing both nitrogen and oxygen atoms with NiII under 500 °C can generate a N/O mixing coordinated Ni-N3 O single-atom catalyst (SAC) in which the oxygen atom can be gradually removed under high temperature due to the weaker Ni-O interaction, resulting in a vacancy-defect Ni-N3 -V SAC at Ni site under 800 °C. For the reaction of NiII with the precursor simply containing nitrogen atoms, only a no-vacancy-defect Ni-N4 SAC was obtained. Experimental and DFT calculations reveal that the presence of a vacancy-defect in Ni-N3 -V SAC can dramatically boost the electrocatalytic activity for CO2 reduction, with extremely high CO2 reduction current density of 65â mA cm-2 and high Faradaic efficiency over 90 % at -0.9â V vs. RHE, as well as a record high turnover frequency of 1.35×105 â h-1 , much higher than those of Ni-N4 SAC, and being one of the best reported electrocatalysts for CO2 -to-CO conversion to date.
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Crystal-cell interactions are a vital step toward kidney stone formation. However, its mechanisms remained unclear. Here, a protein-protein interaction (PPI) network analysis of a kidney stone revealed that the proteins were enriched in a posttranslational protein modification process in the endoplasmic reticulum (ER). The in vitro study showed that the markers of ER stress, including Bip and CHOP, were upregulated, PERK and ATF6 were activated, and XBP-1 mRNA was spliced. An ER stress-specific protein, caspase-12, was activated in the apoptotic cells induced by calcium oxalate monohydrate (COM) crystals. The treatment with tunicamycin, an ER stress inducer, promoted the crystal-cell adhesion assayed by atomic absorption, reduced cell viability assayed by MTT, and downregulated the expression of proteins involved in the crystal formations. The treatment with salubrinal, an ER stress inhibitor, reversed the above effects for both tunicamycin and COM crystals. The aforementioned main observations were supported by in vivo study. These data demonstrated that ER stress was an essentially biological process of crystal-cell interactions. Our findings suggest that blocking ER stress may become a potential approach to preventing a kidney stone.
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Comunicación Celular/fisiología , Cálculos Renales/fisiopatología , Proteómica/métodos , Animales , Estrés del Retículo Endoplásmico , Humanos , Masculino , Ratones , Ratas Sprague-DawleyRESUMEN
BACKGROUND AND OBJECTIVES: Vitamin K (VK) plays a major role in modifying the binding of calcium in bones and blood vessels. Understanding the effect of VK on crystal formation in the kidney would contribute to advancing the treatment and prevention of kidney stones. METHODS: Rats were treated with vitamin K1 (VK1) for 8 weeks. VK1 levels were detected and crystal formation were observed. HK2 cells were exposed to calcium oxalate monohydrate crystals. Apoptosis and cell viability were detected. Crystal deposition was analyzed using atomic absorption assay. The adenovirus vectors expressing matrix Gla protein (MGP) and siMGP were constructed to elucidate the effect and mechanism of VK1 on crystal formation. MGP expression in vivo and in vitro was analyzed by Western blot. The mRNA levels of monocyte chemoattractant protein-1 (MCP-1) and collagen I was measured by semiquantitative RT-PCR. RESULTS: The concentrations of VK1 in whole blood and kidney tissues rose under treatment with VK1. Crystal formation was inhibited from the second to the 6th week, the frequency and quality of crystal formation decreased significantly, and the location of crystal formation was limited to a greater extent in the rats treated by VK1 compared to the control group. Warfarin treatment in the crystals-exposed HK2 cells significantly increased the number of crystals adhering to cells and the number of apoptotic cells and reduced cell viability. VK1 treatment reversed warfarin's above influence. VK1 inhibited the upregulations of MCP-1 and collagen I in kidney tissues under crystal load. VK1 treatment increased MGP expression in vivo and in vitro, and MGP is necessary for VK1 to play a role in crystal deposition in cells. CONCLUSIONS: VK1 treatment can inhibit the formation of renal crystals in vivo. VK1 increases MGP expression and functions through MGP to reduce crystal deposition in cells and provide cell protection. Our findings suggest that VK1 treatment could be a potential strategy for the treatment and prevention of nephrolithiasis.
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Proteínas de Unión al Calcio/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Cálculos Renales/prevención & control , Riñón/metabolismo , Vitamina K 1/farmacología , Animales , Apoptosis , Proteínas de Unión al Calcio/efectos de los fármacos , Línea Celular , Supervivencia Celular , Proteínas de la Matriz Extracelular/efectos de los fármacos , Humanos , Riñón/patología , Nefrolitiasis/prevención & control , Ratas , Vitamina K 1/uso terapéutico , Warfarina/farmacología , Proteína Gla de la MatrizRESUMEN
Based on network pharmacology analysis, this study was to uncover the anti-colorectal cancer (CRC) targets and molecular mechanisms exerted by puerarin. Pathological genes of CRC and therapeutic genes of puerarin were collected through well-established databases. The crucial targets of puerarin against CRC were further used for function and pathway enrichment assays to elucidate the biological processes and signaling pathways, followed by experiment-based verification. In network data, the most significant targets of tyrosyl-DNA phosphodiesterase-1 (TDP1), aldehyde dehydrogenase 1 family member A-1 (ALDH1A1), muscleblind like splicing regulator 1 (MBNL1), aldehyde dehydrogenase-2 (ALDH2), and nicotinamide adenine dinucleotide (HPGD) were screened and defined in anti-CRC effects exerted by puerarin. In further enrichment assays, the functional processes of puerarin against CRC were associated with energy pathways, metabolism, cell communication, signal transduction, aldehyde metabolism, DNA repair. Meanwhile, key ten signaling pathways from bioinformatic findings were ascertained respectively. As revealed in human data, CRC patients showed up-regulated expressions of endogenous TDP1, ALDH1A1, accompanied with visible hematoxylin-eosin (HE) and Ki-67 stains and elevated blood tumor marker expressions. In further study in vitro, puerarin-treated human CRC cells resulted in inhibited cell growth, increased cell apoptosis in a dose-dependent way. Further, down-regulated expressions of TDP1, ALDH1A1 and proliferating cell nuclear antigen (PCNA) were detected in puerarin-treated CRC cells. In conclusion, the molecular network data manifest the biotargets and signaling pathways of puerarin against CRC, followed by verification of both human and cell line studies. Furthermore, the pharmacological molecules of TDP1, ALDH1A1 seem to be the possible targets for managing CRC.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Isoflavonas/farmacología , Terapia Molecular Dirigida , Antineoplásicos/uso terapéutico , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Femenino , Células HCT116 , Humanos , Isoflavonas/uso terapéutico , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Computer-assisted drug virtual screening models the process of drug screening through computer simulation technology, by docking small molecules in some of the databases to a certain protein target. There are many kinds of small molecules databases available for drug screening, including natural product databases. METHODS: Plants have been used as a source of medication for millennia. About 80% of drugs were either natural products or related analogues by 1990, and many natural products are biologically active and have favorable absorption, distribution, metabolization, excretion, and toxicology. RESULTS: In this paper, we review the natural product databases' contributions to drug discovery based on virtual screening, focusing particularly on the introductions of plant natural products, microorganism natural product, Traditional Chinese medicine databases, as well as natural product toxicity prediction databases. CONCLUSION: We highlight the applications of these databases in many fields of virtual screening, and attempt to forecast the importance of the natural product database in next-generation drug discovery.
Asunto(s)
Productos Biológicos/farmacología , Simulación por Computador , Bases de Datos Factuales , Descubrimiento de Drogas/métodos , Evaluación Preclínica de Medicamentos/métodos , Productos Biológicos/aislamiento & purificación , HumanosRESUMEN
Existing evidence has demonstrated liposomes as the gene transporter induce the cytotoxicity during the transfection process through several known pathways. In the present study, we investigated the possibility of siRNAs targeting 3-ß-hydroxysterol â³-24-reductase (DHCR24), which encodes an enzyme catalyzing the last step of cholesterol biosynthesis, to suppress the liposome cytotoxicity induced by lipid-based transfection reagent in the neuroblastoma cell line N2A. We found that the siRNAs targeting DHCR24 mRNA protect cells from the liposome-induced cell death, probably through the effect of siDHCR24s on the reduction of the cellular cholesterol and decrease in the generation of reactive oxygen species (ROS). This suggests that siRNAs targeting DHCR24 or other methods that reduce the intracellular cholesterol levels might be a good strategy for avoiding the cytotoxicity of liposomes, without impairing its efficiency of gene-delivering.