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Atherosclerotic plaque formation is largely attributed to the impaired efferocytosis, which is known to be associated with the pathologic upregulation of cluster of differentiation 47 (CD47), a key antiphagocytic molecule. By gene expression omnibus (GEO) datasets analysis, we identified that four miRNAs are aberrantly downregulated in atherosclerosis, coronary artery disease, and obesity. Of them, hsa-miR-299-3p (miR-299-3p) was predicted to target the 3'UTR of human CD47 mRNA by bioinformatics analysis. Further, we demonstrated that miR-299-3p negatively regulates CD47 expression by binding to the target sequence "CCCACAU" in the 3'UTR of CD47 mRNA through luciferase reporter assay and site-directed mutagenesis. Additionally, we found that miR-299-3p was downregulated by ~32% in foam cells in response to oxidized low-density lipoprotein (ox-LDL) stimulation, thus upregulating CD47 and contributing to the impaired efferocytosis. Whereas, restoration of miR-299-3p reversed the ox-LDL-induced upregulation of CD47, thereby facilitating efferocytosis. In high-fat diet (HFD) fed ApoE-/- mice, we discovered that miR-299-3p was downregulated thus leading to upregulation of CD47 in abdominal aorta. Conversely, miR-299-3p restoration potently suppressed HFD-induced upregulation of CD47 and promoted phagocytosis of foam cells by macrophages in atherosclerotic plaques, thereby reducing necrotic core, increasing plaque stability, and mitigating atherosclerosis. Conclusively, we identify miR-299-3p as a negative regulator of CD47, and reveal a molecular mechanism whereby the ox-LDL-induced downregulation of miR-299-3p leads to the upregulation of CD47 in foam cells thus contributing to the impaired efferocytosis in atherosclerosis, and propose miR-299-3p can potentially serve as an inhibitor of CD47 to promote efferocytosis and ameliorate atherosclerosis.
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Aterosclerosis , Antígeno CD47 , Eferocitosis , MicroARNs , Animales , Humanos , Ratones , Regiones no Traducidas 3' , Aterosclerosis/metabolismo , Aterosclerosis/genética , Aterosclerosis/patología , Antígeno CD47/metabolismo , Antígeno CD47/genética , Dieta Alta en Grasa/efectos adversos , Células Espumosas/metabolismo , Células Espumosas/patología , Lipoproteínas LDL/metabolismo , Ratones Endogámicos C57BL , MicroARNs/genética , MicroARNs/metabolismoRESUMEN
Parental histone recycling is vital for maintaining chromatin-based epigenetic information during replication, yet its underlying mechanisms remain unclear. Here, we uncover an unexpected role of histone chaperone FACT and its N-terminus of the Spt16 subunit during parental histone recycling and transfer in budding yeast. Depletion of Spt16 and mutations at its middle domain that impair histone binding compromise parental histone recycling on both the leading and lagging strands of DNA replication forks. Intriguingly, deletion of the Spt16-N domain impairs parental histone recycling, with a more pronounced defect observed on the lagging strand. Mechanistically, the Spt16-N domain interacts with the replicative helicase MCM2-7 and facilitates the formation of a ternary complex involving FACT, histone H3/H4 and Mcm2 histone binding domain, critical for the recycling and transfer of parental histones to lagging strands. Lack of the Spt16-N domain weakens the FACT-MCM interaction and reduces parental histone recycling. We propose that the Spt16-N domain acts as a protein-protein interaction module, enabling FACT to function as a shuttle chaperone in collaboration with Mcm2 and potentially other replisome components for efficient local parental histone recycling and inheritance.
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Histonas , Proteínas de Saccharomyces cerevisiae , Factores de Elongación Transcripcional , Cromatina/genética , ADN Helicasas/genética , Chaperonas de Histonas/genética , Chaperonas de Histonas/metabolismo , Histonas/metabolismo , Chaperonas Moleculares/genética , Nucleosomas/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Factores de Elongación Transcripcional/metabolismo , Complejos Multiproteicos/metabolismoRESUMEN
Developmental arsenic exposure has been associated with cognitive deficits in epidemiological studies, but the underlying mechanisms remain poorly understood. Here, we establish a mouse model of developmental arsenic exposure exhibiting deficits of recognition and spatial memory in the offspring. These deficits are associated with genome-wide DNA hypomethylation and abnormal expression of cognition-related genes in the hippocampus. Arsenic atoms directly bind to the cysteine-rich ADD domain of DNA methyltransferase 3A (DNMT3A), triggering ubiquitin- and proteasome-mediated degradation of DNMT3A in different cellular contexts. DNMT3A degradation leads to genome-wide DNA hypomethylation in mouse embryonic fibroblasts but not in non-embryonic cell lines. Treatment with metformin, a first-line antidiabetic agent reported to increase DNA methylation, ameliorates the behavioral deficits and normalizes the aberrant expression of cognition-related genes and DNA methylation in the hippocampus of arsenic-exposed offspring. Our study establishes a DNA hypomethylation effect of developmental arsenic exposure and proposes a potential treatment against cognitive deficits in the offspring of pregnant women in arsenic-contaminated areas.
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Arsénico , Metilación de ADN , ADN Metiltransferasa 3A , Animales , Arsénico/toxicidad , Cognición , Femenino , Fibroblastos/metabolismo , Humanos , Ratones , EmbarazoRESUMEN
BACKGROUND: There is a contradiction in the use of microbiota-therapies, including probiotics, prebiotics, and synbiotics, to improve the condition of patients with nonalcoholic fatty liver disease (NAFLD). The aim of this review was to evaluate the effect of microbiota-therapy on liver injury, inflammation, and lipid levels in individuals with NAFLD. METHODS: Using Pubmed, Embase, Cochrane Library, and Web of Science databases were searched for articles on the use of prebiotic, probiotic, or synbiotic for the treatment of patients with NAFLD up to March 2024. RESULTS: Thirty-four studies involving 12,682 individuals were included. Meta-analysis indicated that probiotic, prebiotic, and synbiotic supplementation significantly improved liver injury (hepatic fibrosis, SMD = -0.31; 95% CI: -0.53, -0.09; aspartate aminotransferase, SMD = -0.35; 95% CI: -0.55, -0.15; alanine aminotransferase, SMD = -0.48; 95% CI: -0.71, -0.25; alkaline phosphatase, SMD = -0.81; 95% CI: -1.55, -0.08), lipid profiles (triglycerides, SMD = -0.22; 95% CI: -0.43, -0.02), and inflammatory factors (high-density lipoprotein, SMD = -0.47; 95% CI: -0.88, -0.06; tumour necrosis factor alpha, SMD = -0.86 95% CI: -1.56, -0.56). CONCLUSION: Overall, supplementation with probiotic, prebiotic, or synbiotic had a positive effect on reducing liver enzymes, lipid profiles, and inflammatory cytokines in patients with NAFLD.
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Enfermedad del Hígado Graso no Alcohólico , Prebióticos , Probióticos , Simbióticos , Humanos , Alanina Transaminasa/sangre , Inflamación , Lípidos/sangre , Hígado , Enfermedad del Hígado Graso no Alcohólico/terapia , Probióticos/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Simbióticos/administración & dosificaciónRESUMEN
BACKGROUND: The image quality of computed tomography angiography (CTA) images following endovascular aneurysm repair (EVAR) is not satisfactory, since artifacts resulting from metallic implants obstruct the clear depiction of stent and isolation lumens, and also adjacent soft tissues. However, current techniques to reduce these artifacts still need further advancements due to higher radiation doses, longer processing times and so on. Thus, the aim of this study is to assess the impact of utilizing Single-Energy Metal Artifact Reduction (SEMAR) alongside a novel deep learning image reconstruction technique, known as the Advanced Intelligent Clear-IQ Engine (AiCE), on image quality of CTA follow-ups conducted after EVAR. MATERIALS: This retrospective study included 47 patients (mean age ± standard deviation: 68.6 ± 7.8 years; 37 males) who underwent CTA examinations following EVAR. Images were reconstructed using four different methods: hybrid iterative reconstruction (HIR), AiCE, the combination of HIR and SEMAR (HIR + SEMAR), and the combination of AiCE and SEMAR (AiCE + SEMAR). Two radiologists, blinded to the reconstruction techniques, independently evaluated the images. Quantitative assessments included measurements of image noise, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), the longest length of artifacts (AL), and artifact index (AI). These parameters were subsequently compared across different reconstruction methods. RESULTS: The subjective results indicated that AiCE + SEMAR performed the best in terms of image quality. The mean image noise intensity was significantly lower in the AiCE + SEMAR group (25.35 ± 6.51 HU) than in the HIR (47.77 ± 8.76 HU), AiCE (42.93 ± 10.61 HU), and HIR + SEMAR (30.34 ± 4.87 HU) groups (p < 0.001). Additionally, AiCE + SEMAR exhibited the highest SNRs and CNRs, as well as the lowest AIs and ALs. Importantly, endoleaks and thrombi were most clearly visualized using AiCE + SEMAR. CONCLUSIONS: In comparison to other reconstruction methods, the combination of AiCE + SEMAR demonstrates superior image quality, thereby enhancing the detection capabilities and diagnostic confidence of potential complications such as early minor endleaks and thrombi following EVAR. This improvement in image quality could lead to more accurate diagnoses and better patient outcomes.
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Artefactos , Angiografía por Tomografía Computarizada , Procedimientos Endovasculares , Humanos , Estudios Retrospectivos , Femenino , Angiografía por Tomografía Computarizada/métodos , Anciano , Masculino , Procedimientos Endovasculares/métodos , Persona de Mediana Edad , Aneurisma de la Aorta Abdominal/cirugía , Aneurisma de la Aorta Abdominal/diagnóstico por imagen , Aprendizaje Profundo , Interpretación de Imagen Radiográfica Asistida por Computador/métodos , Stents , Reparación Endovascular de AneurismasRESUMEN
Hepatotoxicity is frequently observed following acute cadmium (Cd) exposure in chicken. Oxidative stress and subsequent inflammation are regarded as the main reasons for cadmium-induced liver injury. NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome-induced pyroptosis is involved in various inflammatory diseases, including liver injury. Poultry are more susceptible to harmful effects of heavy metals. However, the mechanism of cadmium-induced liver injury in chicken is still elusive. In this study, the effect of cadmium on chicken liver cells and the underlying mechanisms were investigated. The results showed mitochondria was damaged and excessive reactive oxygen species (ROS) were generated in chicken liver cell line LMH after cadmium exposure. Furthermore, cadmium-induced NLRP3 inflammasome activation and the cell membrane rupture indicated LMH cells pyroptosis. The ROS scavengers, acetylcysteine (NAC) and Mito-TEMPO prevented pyroptosis in LMH cells, suggesting that ROS were responsible for the activation of the NLRP3 inflammasome induced by cadmium. Additionally, anti-oxidative transcription factor Nrf2 was inhibited after cadmium exposure, explaining the excessive ROS generation. In summary, our study showed that cadmium leads to ROS generation by inducing mitochondrial damage and inhibiting Nrf2 activity, which promotes NLRP3 inflammasome activation and eventually induces pyroptosis in LMH cells.
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Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Proteína con Dominio Pirina 3 de la Familia NLR , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Inflamasomas/metabolismo , Piroptosis , Cadmio/toxicidad , Pollos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Factor 2 Relacionado con NF-E2 , Inflamación/inducido químicamenteRESUMEN
Chemical investigation of bioactive components from the whole plant of Euphorbia helioscopia resulted in the isolation and identification of 17 new jatrophane diterpenoids, namely, heliojatrone D (1) and helioscopids A-P (2-17), along with 11 known analogues (18-28). The structural elucidation of the new diterpenoids was achieved by the comprehensive analysis of HRESIMS, NMR, and X-ray crystallographic data, as well as using electronic circular dichroism. Structurally, heliojatone D (1) is the fourth natural diterpenoid with a rare bicyclo[8.3.0]tridecane skeleton. The inhibitory effect of the isolated diterpenoids against Kv1.3 ion channels was evaluated in a human embryonic kidney 293 cell model transfected with plasmid encoding Kv1.3, resulting in the identification of a series of potent Kv1.3 ion channel inhibitors, with the most active ones (2 and 15) showing IC50 values of 0.9 µM.
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Diterpenos , Euphorbia , Cristalografía por Rayos X , Diterpenos/química , Diterpenos/farmacología , Euphorbia/química , Humanos , Estructura MolecularRESUMEN
Extensive phytochemical investigation on the methanol extract of the inflorescences, twigs, and leaves of Brucea javanica led to the isolation and identification of 27 triterpenoids, including 21 previously undescribed ones, named brujavanoids A-U (1-21). Their structures were determined based on comprehensive spectroscopic analysis and single-crystal X-ray diffraction. Of these compounds, brujavanoid A (1) represents the first apotirucallane-type triterpenoid with a novel 19(10 â 9)abeo motif, and brujavanoids B and C (2-3) are the first apotirucallane-type triterpenoids with a rarely occurring 14-hydorxy-15,16-epoxy fragment. All the isolates were evaluated for their anti-inflammatory effect in an LPS-activated RAW264.7 cells model. Furthermore, the most active one, brujavanoid E (5), can suppress the transcriptional expression of typical pro-inflammatory mediators and inhibit the nuclear translocation of NF-κB p65 in the LPS- activated RAW264.7 cells.
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Brucea , Triterpenos , Antiinflamatorios/farmacología , Brucea/química , Brucea javanica , Lipopolisacáridos/farmacología , Triterpenos/química , Triterpenos/farmacologíaRESUMEN
The most frequently mutated protein in human cancer is p53, a transcription factor (TF) that regulates myriad genes instrumental in diverse cellular outcomes including growth arrest and cell death. Cell context-dependent p53 modulation is critical for this life-or-death balance, yet remains incompletely understood. Here we identify sequence signatures enriched in genomic p53-binding sites modulated by the transcription cofactor iASPP. Moreover, our p53-iASPP crystal structure reveals that iASPP displaces the p53 L1 loop-which mediates sequence-specific interactions with the signature-corresponding base-without perturbing other DNA-recognizing modules of the p53 DNA-binding domain. A TF commonly uses multiple structural modules to recognize its cognate DNA, and thus this mechanism of a cofactor fine-tuning TF-DNA interactions through targeting a particular module is likely widespread. Previously, all tumor suppressors and oncoproteins that associate with the p53 DNA-binding domain-except the oncogenic E6 from human papillomaviruses (HPVs)-structurally cluster at the DNA-binding site of p53, complicating drug design. By contrast, iASPP inhibits p53 through a distinct surface overlapping the E6 footprint, opening prospects for p53-targeting precision medicine to improve cancer therapy.
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ADN/genética , ADN/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas Represoras/metabolismo , Elementos de Respuesta , Proteína p53 Supresora de Tumor/metabolismo , Secuencia de Bases , Sitios de Unión , Línea Celular Tumoral , ADN/química , Perfilación de la Expresión Génica , Humanos , Péptidos y Proteínas de Señalización Intracelular/química , Modelos Moleculares , Motivos de Nucleótidos , Proteínas Oncogénicas Virales/química , Proteínas Oncogénicas Virales/metabolismo , Unión Proteica , Conformación Proteica , Proteínas Represoras/química , Relación Estructura-Actividad , Proteína p53 Supresora de Tumor/químicaRESUMEN
INTRODUCTION: The aim of this study was to investigate for possible associations between an early increase in body temperature within 24 hours of endovascular therapy (EVT) for large vessel occlusion stroke and the presence of symptomatic intracranial hemorrhage (sICH) and other clinical outcomes. METHODS: This was a retrospective study of consecutive patients with large vessel occlusion stroke who were treated with EVT from August 2018 to June 2021. Patients were divided into two groups based on the presence of fever, as defined by a Peak Body Temperature (PBT) of ≥37.3 °C. The presence of sICH and other clinical outcomes were compared between the two groups. RESULTS: The median NIHSS admission score (IQR) was 16.0 (12.0, 21.0), with higher NIHSS scores in the PBT ≥37.3 °C group than in the PBT <37.3 °C group (18 vs 14, respectively; p = 0.002). There were no differences in clinical outcomes at 3 months between patients with PBT <37.3 °C and patients with PBT between 37.3 °C and 38 °C. However, patients with PBT ≥38 °C had an increased risk of sICH (adjusted odds ratio (OR) = 8.8, 95% confidence interval (95% CI): 1.7-46.0; p = 0.01), increased inpatient death or hospice discharge (OR = 10.5, 95% CI: 2.0-53.9; p = 0.005), poorer clinical outcome (OR = 25.6, 95% CI: 5.2-126.8; p < 0.001), and increased 3-month mortality (OR = 6.6, 95% CI: 1.8-24.6; p = 0.01). CONCLUSIONS: Elevated PBT (≥38 °C) within 24 hours of EVT was significantly associated with an increased incidence of symptomatic intracranial hemorrhage, discharge to hospice or inpatient death, poorer clinical outcome and 3-month mortality, and with less functional independence. Further large-scale, prospective and multicenter trials are needed to confirm these findings.
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Isquemia Encefálica , Procedimientos Endovasculares , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Isquemia Encefálica/complicaciones , Accidente Cerebrovascular/terapia , Estudios Retrospectivos , Temperatura Corporal , Estudios Prospectivos , Procedimientos Endovasculares/efectos adversos , Resultado del Tratamiento , Hemorragias Intracraneales/etiologíaRESUMEN
OBJECTIVE: We aimed to evaluate door-to-puncture time (DPT) and door-to-recanalization time (DRT) without directing healthcare by neuro-interventionalist support in the emergency department (ED) by workflow optimization and improving patients' outcomes. METHODS: Records of 98 consecutive ischemic stroke patients who had undergone endovascular therapy (EVT) between 2018 to 2021 were retrospectively reviewed in a single-center study. Patients were divided into three groups: pre-intervention (2018-2019), interim-intervention (2020), and post-intervention (January 1st 2021 to August 16th, 2021). We compared door-to-puncture time, door-to-recanalization time (DRT), puncture-to-recanalization time (PRT), last known normal time to-puncture time (LKNPT), and patient outcomes (measured by 3 months modified Rankin Scale) between three groups using descriptive statistics. RESULTS: Our findings indicate that process optimization measures could shorten DPT, DRT, PRT, and LKNPT. Median LKNPT was shortened by 70 min from 325 to 255 min(P < 0.05), and DPT was shortened by 119 min from 237 to 118 min. DRT shortened by 132 min from 338 to 206 min, and PRT shortened by 33 min from 92 to 59 min from the pre-intervention to post-intervention groups (all P < 0.05). Only 21.4% of patients had a favorable outcome in the pre-intervention group as compared to 55.6% in the interventional group (P= 0.026). CONCLUSION: This study demonstrated that multidisciplinary cooperation was associated with shortened DPT, DRT, PRT, and LKNPT despite challenges posed to the healthcare system such as the COVID-19 pandemic. These practice paradigms may be transported to other stroke centers and healthcare providers to improve endovascular time metrics and patient outcomes.
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COVID-19 , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Accidente Cerebrovascular Isquémico/cirugía , Pandemias , Punciones , Estudios Retrospectivos , Accidente Cerebrovascular/terapia , Trombectomía , Tiempo de Tratamiento , Resultado del Tratamiento , Flujo de TrabajoRESUMEN
With the increasing digitalization and informatization of distribution network systems, distribution networks have gradually developed into distribution network cyber physical systems (CPS) which are deeply integrated with traditional power systems and cyber systems. However, at the same time, the network risk problems that the cyber systems face have also increased. Considering the possible cyber attack vulnerabilities in the distribution network CPS, a dynamic Bayesian network approach is proposed in this paper to quantitatively assess the security risk of the distribution network CPS. First, the Bayesian network model is constructed based on the structure of the distribution network and common vulnerability scoring system (CVSS). Second, a combination of the fuzzy analytic hierarchy process (FAHP) and entropy weight method is used to correct the selectivity of the attacker to strike the target when cyber attack vulnerabilities occur, and then after considering the defense resources of the system, the risk probability of the target nodes is obtained. Finally, the node loads and node risk rates are used to quantitatively assess the risk values that are applied to determine the risk level of the distribution network CPS, so that defense strategies can be given in advance to counter the adverse effects of cyber attack vulnerabilities.
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Structurally diverse acylations have been identified as post-translational modifications (PTMs) on histone lysine residues, but their functions and regulations remain largely unknown. Interestingly, in nature, a lysine acylation analog, pyrrolysine, is introduced as a co-translational modification (CTM) through genetic encoding. To explore this alternative life form, we created a model organism Saccharomyces cerevisiae containing site-specific lysine CTMs (acetyl-lysine, crotonyl-lysine, or another synthetic analog) at histone H3K56 using non-canonical amino acid mutagenesis to afford a chemically modified nucleosome in lieu of their own in vivo. We further demonstrated that acetylation of histone H3K56 partly tends to provide a more favorable chromatin environment for DNA repair in yeast compared to crotonylation and crosstalk with other PTMs differently. This study provides a potentially universal approach to decipher the consequences of different histone lysine PTMs in eukaryotes.
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Histonas , Nucleosomas , Acetilación , Histonas/química , Lisina/química , Nucleosomas/metabolismo , Procesamiento Proteico-Postraduccional , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismoRESUMEN
A time-economical TfOH-catalyzed N-H insertion between anilines and α-alkyl and α-aryl-α-diazoacetates provides a straightforward approach to access unnatural α-amino esters, which readily undergo various transformations and can thus be used for the synthesis of pharmaceutically relevant molecules. The α-amino esters were obtained in moderate to excellent yields.
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Compuestos de Anilina , Ésteres , Catálisis , EstereoisomerismoRESUMEN
Thirteen previously undescribed guaiane-type sesquiterpenoids based on [5,7] bicyclic system, stelleranoids A-M (1-13), along with six known analogues (14-20), were isolated from the roots of Stellera chamaejasme with chromatographic techniques. Their structures including absolute configurations were determined by HRESIMS and spectroscopic data, quantum chemical calculations, as well as X-ray crystallographic analysis. Cytotoxicity test in three cell lines indicated that compound 14 had relatively stronger cytotoxic effect against MKN-45, SKOV3, and Du145 cell lines with IC50 of 9.8, 17.4 and 7.3 µM, respectively; compounds 3 and 8 displayed moderate cytotoxic effect against MKN-45 and Du145 cell lines with IC50 ranged from 14.5 to 18.8 µM, comparable to those of the positive control. As determined by fluorescent microscopy and flow cytometry in Du145 cell line, compound 14 could promote cell apoptosis and cause cell cycle arrest at the G0/G1 phase, leading to the inhibition of cell proliferation. Further Western blot analysis revealed that this inhibitory effect was accompanied by upregulating pro-apoptosis proteins cleaved-PARP, cleaved-Caspase-9 and tumor suppressor protein p53 while downregulating anti-apoptotic protein Bcl-2 in 14-treated Du145 cells.
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Antineoplásicos Fitogénicos/farmacología , Sesquiterpenos/farmacología , Thymelaeaceae/química , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Modelos Moleculares , Estructura Molecular , Raíces de Plantas/química , Sesquiterpenos/química , Sesquiterpenos/aislamiento & purificación , Relación Estructura-ActividadRESUMEN
Two new series of betulin derivatives with semicarbazone (7a-g) or thiosemicarbazone (8a-g) groups at the C-28 position were synthesized. All compounds were evaluated for their in vitro cytotoxicities in human hepatocellular carcinoma cells (HepG2), human breast carcinoma cells (MCF-7), human lung carcinoma cells (A549), human colorectal cells (HCT-116) and normal human gastric epithelial cells (GES-1). Among these compounds, 8f displayed the most potent cytotoxicity with an IC50 value of 5.86 ± 0.61 µM against MCF-7 cells. Furthermore, the preliminary mechanism studies in MCF-7 cells showed that compound 8f could trigger the intracellular mitochondrial-mediated apoptosis pathway by losing MMP level, which was related with the upregulation of Bax, P53 and cytochrome c expression; the downregulation of Bcl-2 expression; activation of the expression levels of caspase-3, caspase-9, cleaved caspase-3 and cleaved caspase-9; and an increase in the amounts of intracellular reactive oxygen species. These results indicated that compound 8f may be used as a valuable skeleton structure for developing novel antitumor agents.
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Apoptosis/efectos de los fármacos , Técnicas de Química Sintética , Diseño de Fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Semicarbazonas/química , Semicarbazonas/farmacología , Triterpenos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Biomarcadores , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Citometría de Flujo , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Redes y Vías Metabólicas/efectos de los fármacos , Estructura Molecular , Especies Reactivas de Oxígeno/metabolismo , Semicarbazonas/síntesis químicaRESUMEN
Aryl benzofuranones are privileged structural units present in natural products and pharmaceutically relevant compounds with high bioactivity and therapeutic value; synthetic access to these scaffolds remains an area of intensive interest. A new and efficient TfOH-catalyzed cascade ortho C-H activation/lactonization of phenols with α-aryl-α-diazoacetates is reported. This metal-free protocol provides an operationally simple and rapid method for the one-pot assembly of diverse α-aryl benzofuranones in high yields with broad substrate scope, a readily starting material, good chemo-regioselectivity, and excellent functional group compatibility.
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BACKGROUND This study was designed to investigate the role of long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in the proliferation as well as apoptosis of human umbilical vein endothelial cells (HUVECs), to offer a basis for therapy of hypertension. MATERIAL AND METHODS The lncRNA MALAT1 expression, hsa-miR-124-3p, hsa-miR-135a-5p, hsa-miR-135b-5p, and hsa-miR-455-5p in plasma were measured from 230 patients with hypertension and 230 non-hypertensive controls. The mechanism for lncRNA MALAT1 modulating the proliferation and apoptosis of HUVECs was explored by cell transfection, Cell Counting Kit-8 (CCK-8), quantitative real-time polymerase chain reaction (qRT-PCR), western blot, and dual-luciferase reporter assays. RESULTS The expression of hsa-miR-124-3p and hsa-miR-135a-5p was reduced and the expression of lncRNA MALAT1 was increased in the plasma of hypertensive patients. Moreover, the plasma levels of hsa-miR-124-3p and hsa-miR-135a-5p of hypertensive patients were negatively correlated with lncRNA MALAT1 (r=-0.64, -0.72; P<0.01, P<0.01, respectively). The level of nuclear receptor subfamily 3, group C, member 2 (NR3C2) protein was negatively correlated with hsa-miR-124-3p and hsa-miR-135a-5p (r=-0.74, -0.84; P<0.01, P<0.01, respectively). The proliferation of HUVECs was inhibited after the inhibition of MALAT. Additionally, after knocking down MALAT, the levels of hsa-miR-124-3p and hsa-miR-135a-5p in HUVECs were markedly increased, while the expression level of NR3C2 protein was decreased. The apoptotic rate of HUVECs after the transfection of MALAT1 small interfering RNA (si-MALAT1) (3.64±0.21%) was significantly reduced compared to that of transfected si-MALAT1 no template control (NC) (3.76±0.19%) and the control group (10.51±1.24%). CONCLUSIONS LncRNA MALAT1 regulates proliferation and apoptosis of HUVECs through the hsa-miR-124-3p/NR3C2 and/or hsa-miR-135a-5p/NR3C2 axis.
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Hipertensión Esencial/genética , MicroARNs/metabolismo , ARN Largo no Codificante/metabolismo , Receptores de Mineralocorticoides/genética , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis/genética , Estudios de Casos y Controles , Proliferación Celular/genética , Endotelio Vascular/citología , Endotelio Vascular/patología , Hipertensión Esencial/patología , Femenino , Células HEK293 , Células Endoteliales de la Vena Umbilical Humana , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The gene encoding the novel amylolytic enzyme designated CoMA was cloned from Corallococcus sp. strain EGB. The deduced amino acid sequence contained a predicted lipoprotein signal peptide (residues 1 to 18) and a conserved glycoside hydrolase family 13 (GH13) module. The amino acid sequence of CoMA exhibits low sequence identity (10 to 19%) with cyclodextrin-hydrolyzing enzymes (GH13_20) and is assigned to GH13_36. The most outstanding feature of CoMA is its ability to catalyze the conversion of maltooligosaccharides (≥G3) and soluble starch to maltose as the sole hydrolysate. Moreover, it can hydrolyze γ-cyclodextrin and starch to maltose and hydrolyze pullulan exclusively to panose with relative activities of 0.2, 1, and 0.14, respectively. CoMA showed both hydrolysis and transglycosylation activities toward α-1,4-glycosidic bonds but not to α-1,6-linkages. Moreover, glucosyl transfer was postulated to be the major transglycosidation reaction for producing a high level of maltose without the attendant production of glucose. These results indicated that CoMA possesses some unusual properties that distinguish it from maltogenic amylases and typical α-amylases. Its physicochemical properties suggested that it has potential for commercial development.IMPORTANCE The α-amylase from Corallococcus sp. EGB, which was classified to the GH13_36 subfamily, can catalyze the conversion of maltooligosaccharides (≥G3) and soluble starch to maltose as the sole hydrolysate. An action mechanism for producing a high level of maltose without the attendant production of glucose has been proposed. Moreover, it also can hydrolyze γ-cyclodextrin and pullulan. Its biochemical characterization suggested that CoMA may be involved the accumulation of maltose in Corallococcus media.
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ADN Bacteriano/aislamiento & purificación , Glicósido Hidrolasas/genética , Myxococcales/genética , Oligosacáridos/metabolismo , Clonación Molecular , ADN Bacteriano/genética , Regulación Bacteriana de la Expresión Génica , Glucanos/metabolismo , Glicósido Hidrolasas/metabolismo , Concentración de Iones de Hidrógeno , Hidrólisis , Maltosa/metabolismo , Myxococcales/metabolismo , Análisis de Secuencia de ADN , Almidón/metabolismo , Temperatura , alfa-Amilasas/genética , alfa-Amilasas/metabolismo , gamma-Ciclodextrinas/metabolismoRESUMEN
A highly efficient palladium-catalyzed oxidative cross-coupling of arylhydrazines and arenethiols with molecular oxygen as the sole oxidant to afford unsymmetrical diaryl sulfides has been developed. The only byproducts are nitrogen and water. A broad range of functional groups, even the reactive iodides, are tolerated and thus offer the opportunity for further functionalization.