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OBJECTIVE: The objective of this study was to investigate the effectiveness and tolerance of the ketogenic diet (KD) in children who have drug-resistant epilepsy (DRE) caused by neonatal hypoglycemia. METHODS: We conducted a retrospective analysis of the data from pediatric patients who were diagnosed with neonatal hypoglycemia-related DRE and initiated a KD at Xi'an Children's Hospital between May 2014 and March 2023. RESULTS: Nine patients were enrolled in this study. The mean age of seizure onset was 6.16 ± 3.97 months, with a mean age of dietary therapy initiation at 21.56 ± 10.94 months and a median diet duration of nine months (range: 3-39.6 months). All of the nine patients (seven males) had daily seizures, and the most common seizure type was epileptic spasms. Magnetic resonance imaging (MRI) of the brain in all nine patients revealed bilateral atrophy of the occipital-parietal cortex, with or without gliosis. Of the patients studied, 22.2 % were classified as definite KD responders. These individuals achieved seizure freedom after one month of starting KD treatment and maintained a seizure-free state for over 22 months. One patient (11.1 %) was a partial KD responder who had a > 50 % seizure reduction within three months from KD initiation and continued the diet therapy for more than one year. None of the patients stopped taking KD because they could not tolerate the majority of the adverse effects, which were mild. At the last follow-up, six patients (66.7 %) had stopped their diet therapy with lack of efficacy being the leading cause. CONCLUSIONS: KD is a safe and tolerable alternative treatment in pediatric patients with DRE secondary to neonatal hypoglycaemia. Most of the time, KD has minimal efficacy; however, diet therapy may be quite helpful for some patients. Thus, for DRE associated with neonatal hypoglycemia, KD treatment is appropriate to consider.
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Yam is a dual-purpose crop used in both medicine and food that is commonly used as a dietary supplement in food processing. Since yam proteins are often lost during the production of yam starch, elucidating the functionally active value of yam proteins is an important guideline for fully utilizing yam in industrial production processes. This study aimed to explore the potential protective effect of yam protein (YP) on cyclophosphamide (CTX)-induced immunosuppression in mice. The results showed that YP can reduce immune damage caused by CTX by reversing immunoglobulins (IgA, IgG and IgM), cytokines (TNF-α, IL-6, etc.) in the intestines of mice. Moreover, YPs were found to prevent CTX-induced microbiota dysbiosis by enhancing the levels of beneficial bacteria within the microbiome, such as Lactobacillus, and lowering those of Desulfovibrio_R and Helicobacter_A. Metabolomics analyses showed that YP significantly altered differential metabolites (tryptophan, etc.) and metabolic pathways (ABC transporter protein, etc.) associated with immune responses in the gut. Furthermore, important connections were noted between particular microbiomes and metabolites, shedding light on the immunoprotective effects of YPs by regulating gut flora and metabolism. These findings deepen our understanding of the functional properties of YPs and lay a solid foundation for the utilization of yam.
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Ciclofosfamida , Dioscorea , Microbioma Gastrointestinal , Ciclofosfamida/farmacología , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Ratones , Dioscorea/química , Proteínas de Plantas/farmacología , Masculino , Intestinos/efectos de los fármacos , Intestinos/microbiología , Intestinos/inmunología , Citocinas/metabolismo , Terapia de Inmunosupresión , Disbiosis/inducido químicamenteRESUMEN
BACKGROUND: Methylmalonic acidemia (MMA) is the most common organic acidemia in China, with cblC (cblC-MMA) and mut (mut-MMA) being the predominant subtypes. The present study aimed to investigate the prognostic manifestations and their possible influence in patients with these two subtypes. METHODS: A national multicenter retrospective study of patients with cblC-MMA and mut-MMA between 2004 and 2022 was performed. We compared the clinical features between patients with two subtypes or diagnosed with or without newborn screening (NBS) and further explored the potentially influential factors on the prognosis. RESULTS: The 1617 enrolled MMA patients included 81.6% cblC-MMA patients and 18.4% mut-MMA patients, with an overall poor prognosis rate of 71.9%. These two subtypes of patients showed great differences in poor prognostic manifestations. The role of NBS in better outcomes was more pronounced in cblC-MMA patients. Predictors of outcomes are "pre-treatment onset", "NBS", variants of c.80A > G and c.482G > A and baseline levels of propionylcarnitine and homocysteine for cblC-MMA; "pre-treatment onset", "responsive to vitB12", variants of c.914T > C and baseline propionylcarnitine and propionylcarnitine/acetylcarnitine ratio for mut-MMA. Besides, prognostic biochemical indicators have diagnostic value for poor outcomes in mut-MMA. CONCLUSIONS: The study provided potential predictors of the long-term outcome of patients with cblC-MMA and mut-MMA. IMPACT: Predictors of outcomes are "pre-treatment onset", "NBS", MMACHC variants of c.80A > G and c.482G > A and baseline propionylcarnitine and homocysteine for cblC-MMA, "pre-treatment onset", "responsive to vitB12", MMUT variants of c.914T > C and baseline propionylcarnitine and propionylcarnitine/acetylcarnitine ratio for mut-MMA. This study with larger sample sizes effectively validated the prediction power and emphasized the importance of NBS in improving the outcomes of both MMA subtypes. The study enhances understanding of the phenotypic and prognostic variations of MMA disease and the predictors will help in the improvement of diagnosis and treatment strategies to achieve a better prognosis for MMA.
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Netrin-G2 is a membrane-anchored protein known to play critical roles in neuronal circuit development and synaptic organization. In this study, we identify compound heterozygous mutations of c.547delC, p.(Arg183Alafs∗186) and c.605G > A, p.(Trp202X) in NTNG2 causing a syndrome exhibiting developmental delay, intellectual disability, hypotonia, and facial dysmorphism. To elucidate the underlying cellular and molecular mechanisms, CRISPR-Cas9 technology is employed to generate a knock-in mouse model expressing the R183Afs and W202X mutations. We report that the Ntng2R183Afs/W202X mice exhibit hypotonia and impaired learning and memory. We find that the levels of CaMKII and p-GluA1Ser831 are decreased, and excitatory postsynaptic transmission and long-term potentiation are impaired. To increase the activity of CaMKII, the mutant mice receive intraperitoneal injections of DCP-LA, a CaMKII agonist, and show improved cognitive function. Together, our findings reveal molecular mechanisms of how NTNG2 deficiency leads to impairments of cognitive ability and synaptic plasticity.
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Low accuracy of diagnosing prostate cancer (PCa) was easily caused by only assaying single prostate specific antigen (PSA) biomarker. Although conventional reported methods for simultaneous detection of two specific PCa biomarkers could improve the diagnostic efficiency and accuracy, low detection sensitivity restrained their use in extreme early-stage PCa clinical assay applications. In order to overcome above drawbacks, this paper herein proposed a multiplexed dual optical microfibers separately functionalized with gold nanorods (GNRs) and Au nanobipyramids (Au NBPs) nanointerfaces with strong localized surface plasmon resonance (LSPR) effects. The sensors could simultaneously detect PSA protein biomarker and long noncoding RNA prostate cancer antigen 3 (lncRNA PCA3) with ultrahigh sensitivity and remarkable specificity. Consequently, the proposed dual optical microfibers multiplexed biosensors could detect the PSA protein and lncRNA PCA3 with ultra-low limit-of-detections (LODs) of 3.97 × 10-15 mol/L and 1.56 × 10-14 mol/L in pure phosphorus buffer solution (PBS), respectively, in which the obtained LODs were three orders of magnitude lower than existed state-of-the-art PCa assay technologies. Additionally, the sensors could discriminate target components from complicated physiological environment, that showing noticeable biosensing specificity of the sensors. With good performances of the sensors, they could successfully assay PSA and lncRNA PCA3 in undiluted human serum and urine simultaneously, respectively. Consequently, our proposed multiplexed sensors could real-time high-sensitivity simultaneously detect complicated human samples, that providing a novel valuable approach for the high-accurate diagnosis of early-stage PCa individuals.
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Antígenos de Neoplasias , Técnicas Biosensibles , Oro , Límite de Detección , Nanotubos , Antígeno Prostático Específico , Neoplasias de la Próstata , ARN Largo no Codificante , Resonancia por Plasmón de Superficie , Humanos , Antígeno Prostático Específico/sangre , Masculino , Oro/química , ARN Largo no Codificante/genética , ARN Largo no Codificante/sangre , ARN Largo no Codificante/orina , Antígenos de Neoplasias/orina , Antígenos de Neoplasias/sangre , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/orina , Nanotubos/química , Nanopartículas del Metal/química , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/orinaRESUMEN
To date, NH3 synthesis under mild conditions is largely confined to precious Ru catalysts, while nonprecious metal (NPM) catalysts are confronted with the challenge of low catalytic activity due to the inverse relationship between the N2 dissociation barrier and NHx (x = 1-3) desorption energy. Herein, we demonstrate NPM (Co, Ni, and Re)-mediated Mo2CTx MXene (where Tx denotes the OH group) to achieve efficient NH3 synthesis under mild conditions. In particular, the NH3 synthesis rate over Re/Mo2CTx and Ni/Mo2CTx can reach 22.4 and 21.5 mmol g-1 h-1 at 400 °C and 1 MPa, respectively, higher than that of NPM-based catalysts and Cs-Ru/MgO ever reported. Experimental and theoretical studies reveal that Mo4+ over Mo2CTx has a strong ability for N2 activation; thus, the rate-determining step is shifted from conventional N2 dissociation to NH2* formation. NPM is mainly responsible for H2 activation, and the high reactivity of spillover hydrogen and electron transfer from NPM to the N-rich Mo2CTx surface can efficiently facilitate nitrogen hydrogenation and the subsequent desorption of NH3. With the synergistic effect of the dual active sites bridged by H-spillover, the NPM-mediated Mo2CTx catalysts circumvent the major obstacle, making NH3 synthesis under mild conditions efficient.
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BACKGROUND: Isolated methylmalonic acidemia, an autosomal recessive disorder of propionate metabolism, is usually caused by mutations in the methylmalonyl-CoA mutase gene (mut-type). Because no universal consensus was made on whether mut-type methylmalonic acidemia should be included in newborn screening (NBS), we aimed to compare the outcome of this disorder detected by NBS with that detected clinically and investigate the influence of NBS on the disease course. DESIGN & METHODS: In this study, 168 patients with mut-type methylmalonic acidemia diagnosed by NBS were compared to 210 patients diagnosed after disease onset while NBS was not performed. Clinical data of these patients from 7 metabolic centers in China were analyzed retrospectively, including initial manifestations, biochemical metabolites, the responsiveness of vitamin B12 therapy, and gene variation, to explore different factors on the long-term outcome. RESULTS: By comparison of the clinically-diagnosed patients, NBS-detected patients showed younger age at diagnosis, less incidence of disease onset, better responsiveness of vitamin B12, younger age at start of treatment, lower levels of biochemical features before and after treatment, and better long-term prognosis (P < 0.01). Onset of disease, blood C3/C2 ratio and unresponsiveness of vitamin B12 were more positively associated with poor outcomes of patients whether identified by NBS. Moreover, the factors above as well as older age at start of treatment were positively associated with mortality. CONCLUSIONS: This research highly demonstrated NBS could prevent major disease-related events and allow an earlier treatment initiation. As a key prognostic factor, NBS is beneficial for improving the overall survival of infants with mut-type methylmalonic acidemia.
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Errores Innatos del Metabolismo de los Aminoácidos , Metilmalonil-CoA Mutasa , Tamizaje Neonatal , Vitamina B 12 , Humanos , Errores Innatos del Metabolismo de los Aminoácidos/genética , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/patología , Errores Innatos del Metabolismo de los Aminoácidos/sangre , Recién Nacido , Metilmalonil-CoA Mutasa/genética , China/epidemiología , Masculino , Femenino , Vitamina B 12/sangre , Vitamina B 12/genética , Lactante , Estudios Retrospectivos , Mutación/genética , Pronóstico , Resultado del Tratamiento , PreescolarRESUMEN
CONTEXT: Genetic testing for 21-hydroxylase deficiency (21-OHD) is always challenging. Current approaches, short-read sequencing and multiplex ligation-dependent probe amplification (MLPA), are insufficient for the detection of chimeric genes or complicated variants from multiple copies. Recently developed long-read sequencing (LRS) can solve this problem. OBJECTIVE: To investigate the clinical utility of LRS in precision diagnosis of 21-hydroxylase deficiency. METHODS: In the cohort of 832 patients with 21-OHD, the current approaches provided the precise molecular diagnosis for 81.7% (680/832) of cases. LRS was performed to solve the remaining 144 cases with complex chimeric variants and eight cases with variants from multiple copies. Clinical manifestations in patients with continuous deletions of CYP21A2 extending to TNXB (namely CAH-X) were further evaluated. RESULTS: Using LRS in combination with previous genetic test results, a total of 16.9% (281/1664) CYP21A1P/CYP21A2 or TNXA/TNXB chimeric alleles were identified in 832 patients, with CYP21A1P/CYP21A2 accounting for 10.4% and TNXA/TNXB for 6.5%. The top three common chimeras were CYP21 CH-1, TNX CH-1 and TNX CH-2, accounting for 77.2% (217/281) of all chimeric alleles. The eight patients with variants on multiple copies of CYP21A2 were accurately identified with LRS. The prevalence of CAH-X in our cohort was 12.1%, and a high frequency of connective tissue-related symptoms was observed in CAH-X patients. CONCLUSION: LRS can detect all types of CYP21A2 variants, including complex chimeras and pathogenic variants on multiple copies in patients with 21-OHD, which could be utilized as a first-tier routine test for the precision diagnosis and categorization of congenital adrenal hyperplasia.
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Prolonged drought conditions are a critical challenge for agricultural advancement, threatening food security and environmental equilibrium. To overcome these issues, enhancing plant resilience to drought is essential for plant growth and sustainable agriculture. In this study, blue-emitting antioxidant carbon dots (B-CDs), synthesized from citric acid and ascorbic acid, emerged as a promising solution to enhance the drought resistance of peas (Pisum sativum L.). B-CDs can efficiently scavenge reactive oxygen species (ROS), which are harmful in excess to plants under stress conditions. Through detailed experimental analyses and density functional theory (DFT) studies, it is found that these B-CDs possess structures featuring eight-membered aromatic rings with abundant oxygen-containing functional groups, providing active sites for reactions with ROS. The practical benefits of the B-CDs are evident in tests with pea plants exposed to drought conditions. These plants show a remarkable reduction in ROS accumulation, an increase in photosynthetic efficiency due to improved electron transfer rates, and significant growth enhancement. Compared to untreated controls under drought stress, the application of B-CDs results in an impressive increase in the fresh and dry weights of both the shoots and roots of pea seedlings by 39.5 and 43.2% for fresh weights and 121.0 and 73.7% for dry weights, respectively. This suggests that B-CDs can significantly mitigate the negative effects of drought on plants. Thus, leveraging B-CDs opens a novel avenue for enhancing plant resilience to abiotic stressors through nanotechnology, thereby offering a sustainable pathway to counter the challenges of drought in agriculture.
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Antioxidantes , Carbono , Resistencia a la Sequía , Pisum sativum , Puntos Cuánticos , Especies Reactivas de Oxígeno , Antioxidantes/química , Antioxidantes/metabolismo , Ácido Ascórbico/química , Carbono/química , Ácido Cítrico/química , Fotosíntesis/efectos de los fármacos , Pisum sativum/efectos de los fármacos , Pisum sativum/metabolismo , Puntos Cuánticos/química , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Programmed cell death ligand 1 (PD-L1) interacts with programmed cell death 1 (PD-1), leading to T cell exhaustion and promoting tumor cell survival, ultimately mediating immunosuppression. While FDA-approved monoclonal antibodies targeting the PD-1/PD-L1 interaction have shown success in cancer treatment, some patients experience limited and short-lived therapeutic outcomes. Recent studies have identified PD-L1 expression not only on tumor cell surfaces but also on exosomes, with secretion pathways including both conventional and unconventional endocytosis routes, presenting a unique therapeutic opportunity. Emerging evidence suggests that exosomal PD-L1 contributes to systemic immunosuppression, potentially counteracting the effects of anti-PD-1 checkpoint therapies. However, the significance of exosomal PD-L1 in clinical cancer patients unresponsive to anti-PD-1/PD-L1 immunotherapy, as well as the factors regulating its generation, remain unclear. Moreover, the mechanisms underlying PD-L1 expression on exosomes and its regulation in cancer are yet to be fully elucidated. This review primarily focuses on the mechanisms modulating exosomal PD-L1 generation in cancer, while also outlining its involvement in immunosuppression, tumor proliferation, and response to cancer immunotherapy. Additionally, we explore the potential of exosomal PD-L1 as a cancer biomarker and therapeutic target, aiming to provide a comprehensive overview of this emerging field and its implications for cancer treatment and diagnosis.
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Antígeno B7-H1 , Exosomas , Neoplasias , Humanos , Exosomas/metabolismo , Exosomas/inmunología , Antígeno B7-H1/metabolismo , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Animales , Inmunoterapia , Biomarcadores de Tumor/metabolismo , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacologíaRESUMEN
Strip steel plays a crucial role in modern industrial production, where enhancing the accuracy and real-time capabilities of surface defect classification is essential. However, acquiring and annotating defect samples for training deep learning models are challenging, further complicated by the presence of redundant information in these samples. These issues hinder the classification of strip steel surface defects. To address these challenges, this paper introduces a high real-time network, ODNet (Orthogonal Decomposition Network), designed for few-shot strip steel surface defect classification. ODNet utilizes ResNet as its backbone and incorporates orthogonal decomposition technology to reduce the feature redundancies. Furthermore, it integrates skip connection to preserve essential correlation information in the samples, preventing excessive elimination. The model optimizes the parameter efficiency by employing Euclidean distance as the classifier. The orthogonal decomposition not only helps reduce redundant image information but also ensures compatibility with the Euclidean distance requirement for orthogonal input. Extensive experiments conducted on the FSC-20 benchmark demonstrate that ODNet achieves superior real-time performance, accuracy, and generalization compared to alternative methods, effectively addressing the challenges of few-shot strip steel surface defect classification.
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Currently, the subfamily Meconematinae encompasses 1029 species, but whole-mitochondrial-genome assemblies have only been made available for 13. In this study, the whole mitochondrial genomes (mitogenomes) of nine additional species in the subfamily Meconematinae were sequenced. The size ranged from 15,627 bp to 17,461 bp, indicating double-stranded circular structures. The length of the control region was the main cause of the difference in mitochondrial genome length among the nine species. All the mitogenomes including 13 protein-coding genes (PCGs), 22 transfer RNA genes (tRNAs), 2 ribosomal RNA genes (rRNAs) and a control region (CR). The majority strand encoded 23 genes, and the minority strand encoded 14 genes. A phylogenetic analysis reaffirmed the monophyletic status of each subfamily, but the monophysitism of Xizicus, Xiphidiopsis and Phlugiolopsis was not supported.
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Oridonin (Ori) is a naturally existing diterpenoid substance that mainly exists in the Chinese medicinal plant Rabdosia rubescens. It was previously found to possess intriguing biological properties; however, the quick clearance from plasma and limited solubility in water restricts its use as a drug. Several metal-organic frameworks (MOFs), having big surfaces and large pores, have recently been considered promising drug transporters. The zeolitic imidazolate framework-8 (ZIF-8), a form of MOF consisting of 2-methylimidazole with zinc ions, is structurally stable under physiologically neutral conditions, while it can degrade at low pH values such as in tumor cells. Herein, a nanosized drug delivery system, Ori@ZIF-8, was successfully designed for encapsulating and transporting oridonin to the tumor site. The drug loading of the prepared Ori@ZIF-8 was 26.78%, and the particles' mean size was 240.5 nm. In vitro, the release of Ori@ZIF-8 exhibited acid sensitivity, with a slow release under neutral conditions and rapid release of the drug under weakly acidic conditions. According to the in vitro anti-tumor experiments, Ori@ZIF-8 produced higher cytotoxicity than free Ori and induced apoptosis in A549 cancer cells. In conclusion, Ori@ZIF-8 could be a potential pH-responsive carrier to accurately release more oridonins at the tumor site.
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Diterpenos de Tipo Kaurano , Estructuras Metalorgánicas , Diterpenos de Tipo Kaurano/química , Diterpenos de Tipo Kaurano/farmacología , Estructuras Metalorgánicas/química , Humanos , Concentración de Iones de Hidrógeno , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Portadores de Fármacos/química , Células A549 , Línea Celular Tumoral , Zeolitas/química , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Antineoplásicos/farmacología , Antineoplásicos/química , Supervivencia Celular/efectos de los fármacos , ImidazolesRESUMEN
Angiogenesis is extensively involved in embryonic development and requires complex regulation networks, whose defects can cause a variety of vascular abnormalities. Cis-regulatory elements control gene expression at all developmental stages, but they have not been studied or profiled in angiogenesis yet. In this study, we exploited public DNase-seq and RNA-seq datasets from a VEGFA-stimulated in vitro angiogenic model, and carried out an integrated analysis of the transcriptome and chromatin accessibility across the entire process. Totally, we generated a bank of 47,125 angiogenic cis-regulatory elements with promoter (marker by H3K4me3) and/or enhancer (marker by H3K27ac) activities. Motif enrichment analysis revealed that these angiogenic cis-regulatory elements interacted preferentially with ETS family TFs. With this tool, we performed an association study using our WES data of TAPVC and identified rs199530718 as a cis-regulatory SNP associated with disease risk. Altogether, this study generated a genome-wide bank of angiogenic cis-regulatory elements and illustrated its utility in identifying novel cis-regulatory SNPs for TAPVC, expanding new horizons of angiogenesis as well as vascular abnormality genetics.
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Polimorfismo de Nucleótido Simple , Humanos , Secuencias Reguladoras de Ácidos Nucleicos , Factor A de Crecimiento Endotelial Vascular/genética , Estudio de Asociación del Genoma Completo , Neovascularización Patológica/genéticaRESUMEN
Two acylhydrazone based zinc(II) complexes [Zn(HL)2Cl2(CH3OH)2] (Zn1) and [ZnL(AC)]2 (Zn2) were synthesized from 3-(1-(salicyloylhydrazono)ethyl) pyridine (HL). Single crystal X-ray structure analyses showed that complexes Zn1 and Zn2 have a zero-dimensional monomer or dimer structure. Antiproliferative activity studies revealed that Zn1 and Zn2 are both more effective against A549 cells than cisplatin. The results of the reactive oxygen species (ROS) generation assay on A549 cells showed that both Zn1 and Zn2 induced apoptosis through ROS accumulation. The apoptosis-inducing and cell cycle arrest effects of Zn1 and Zn2 on A549 cells indicated that the antitumor effect was achieved through apoptosis induction and inhibition of DNA synthesis by blocking the G0/G1 phase of the cell cycle. What's more, the results of wound-healing assay showed that Zn1 and Zn2 could inhibit the migration of A549 cells. Western blot analysis further demonstrated that Zn1 and Zn2 induced cell apoptosis through the mitochondrial pathway, in which process, the expression level of cytochrome C, cleaved-PARP, cleaved-caspase 3 and cleaved-caspase 9 proteins increased while pro-caspase 3 and pro-caspase 9 expression decreased. In vivo anticancer evaluation demonstrated that both Zn1 and Zn2 complexes effectively inhibited tumor growth without causing significant toxicity in systemic organs.
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Antineoplásicos , Apoptosis , Proliferación Celular , Complejos de Coordinación , Ensayos de Selección de Medicamentos Antitumorales , Hidrazonas , Neoplasias Pulmonares , Zinc , Animales , Ratones , Células A549 , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Relación Dosis-Respuesta a Droga , Hidrazonas/química , Hidrazonas/farmacología , Hidrazonas/síntesis química , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Ratones Endogámicos BALB C , Ratones Desnudos , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Neoplasias Experimentales/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Relación Estructura-Actividad , Zinc/química , Zinc/farmacologíaRESUMEN
Small-molecule positive allosteric modulator 1 (SPAM1), which targets pituitary adenylate cyclase-activating polypeptide receptor 1 (PAC1-R), has been found to have a neuroprotective effect, and the underlying mechanism was explored in this study. First, using a D-galactose (D-gal)-induced aging mouse model, we confirmed that SPAM1 improves the structure of the hippocampal dentate gyrus and restores the number of neurons. Compared with D-gal model mice, SPAM1-treated mice showed up-regulated expression of Sirtuin 6 (SIRT6) and Lamin B1 and down-regulated expression of YinYang 1 (YY1) and p16. A similar tendency was observed in senescent RGC-5 cells induced by long-term culture, indicating that SPAM1 exhibits significant in vitro and in vivo anti-senescence activity in neurons. Then, using whole-transcriptome sequencing and proteomic analysis, we further explored the mechanism behind SPAM1's neuroprotective effects and found that SPAM is involved in the longevity-regulating pathway. Finally, the up-regulation of neurofilament light and medium polypeptides indicated by the proteomics results was further confirmed by Western blotting. These results help to lay a pharmacological network foundation for the use of SPAM1 as a potent anti-aging therapeutic drug to combat neurodegeneration with anti-senescence, neuroprotective, and nerve regeneration activity.
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Proteómica , Transcriptoma , Animales , Ratones , Perfilación de la Expresión Génica , Envejecimiento/genética , Longevidad , Galactosa/farmacologíaRESUMEN
BACKGROUND: Obesity is associated with a wide variety of metabolic disorders that impose significant burdens on patients and society. The "browning" phenomenon in white adipose tissue (WAT) has emerged as a promising therapeutic strategy to combat metabolic disturbances. However, though the anti-diabetic drug dapagliflozin (DAPA) is thought to promote "browning," the specific mechanism of this was previously unclear. METHODS: In this study, C57BL/6 J male mice were used to establish an obesity model by high-fat diet feeding, and 3T3-L1 cells were used to induce mature adipocytes and to explore the role and mechanism of DAPA in "browning" through a combination of in vitro and in vivo experiments. RESULTS: The results show that DAPA promotes WAT "browning" and improves metabolic disorders. Furthermore, we discovered that DAPA activated "browning" through the fibroblast growth factor receptors 1-liver kinase B1-adenosine monophosphate-activated protein kinase signaling pathway. CONCLUSION: These findings provide a rational basis for the use of DAPA in treating obesity by promoting the browning of white adipose tissue.
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Tejido Adiposo Blanco , Compuestos de Bencidrilo , Glucósidos , Proteínas Serina-Treonina Quinasas , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos , Transducción de Señal , Animales , Masculino , Ratones , Células 3T3-L1 , Adipocitos/metabolismo , Adipocitos/efectos de los fármacos , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/efectos de los fármacos , Proteínas Quinasas Activadas por AMP/metabolismo , Compuestos de Bencidrilo/farmacología , Dieta Alta en Grasa , Glucósidos/farmacología , Ratones Endogámicos C57BL , Obesidad/metabolismo , Obesidad/tratamiento farmacológico , Proteínas Serina-Treonina Quinasas/metabolismo , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Transducción de Señal/efectos de los fármacosRESUMEN
Aiming at the realization of learning continually from an online data stream, replay-based methods have shown superior potential. The main challenge of replay-based methods is the selection of representative samples which are stored in the buffer and replayed. In this paper, we propose the Cross-entropy Contrastive Replay (CeCR) method in the online class-incremental setting. First, we present the Class-focused Memory Retrieval method that proceeds the class-level sampling without replacement. Second, we put forward the class-mean approximation memory update method that selectively replaces the mistakenly classified training samples with samples of current input batch. In addition, the Cross-entropy Contrastive Loss is proposed to implement the model training with obtaining more solid knowledge to achieve effective learning. Experiments show that the CeCR method has comparable or improved performance in two benchmark datasets in comparison with the state-of-the-art methods.
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Educación a Distancia , Entropía , Aprendizaje , Benchmarking , ConocimientoRESUMEN
The surface chemical composition of materials is essential for regulating their charge trapping and storage capabilities, which directly affect their electret performance. Although chemical modification of materials to alter electret performance has been investigated, the mechanism through which electret properties are regulated more systematically via chemical customization has not been elucidated in detail. Herein, p-phenylenediamine, benzidine and 4,4'-diaminotriphenyl, which have different conjugated strength functional groups, were selected to chemically tailor the surface of bamboo pulp fibers to regulate the electret properties and elucidate the regulatory mechanism more systematically. The results showed that the charge trapping and storage properties of materials could be regulated by introducing functional groups with different conjugated strengths to their surfaces, realizing the regulation of the electret properties. Moreover, the charge trapping and storage ability could be tailored more specifically by regulating the number of functional groups. By chemical customization to provide electrostatic effects to the materials, the purification time was reduced by approximately 45 %-52 %. More importantly, a relatively systematic mechanism was proposed to elucidate the effect of the conjugate group strength on the charge trapping and charge storage properties of the material. These findings will provide guidance for the investigation of chemical modifications to regulate the electret performance of materials.