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BACE1 is essential for the generation of amyloid-ß (Aß) that likely initiates the toxicity in Alzheimer's disease (AD). BACE1 activity is mainly regulated by post-translational modifications, but the relationship between these modifications is not fully characterized. Here, we studied the effects of BACE1 SUMOylation on its phosphorylation and ubiquitination. We demonstrate that SUMOylation of BACE1 inhibits its phosphorylation at S498 and its ubiquitination in vitro. Conversely, BACE1 phosphorylation at S498 suppresses its SUMOylation, which results in promoting BACE1 degradation in vitro. Furthermore, an increase in BACE1 SUMOylation is associated with the progression of AD pathology, while its phosphorylation and ubiquitination are decreased in an AD mouse model. Our findings suggest that BACE1 SUMOylation reciprocally influences its phosphorylation and competes against its ubiquitination, which might provide a new insight into the regulations of BACE1 activity and Aß accumulation.
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Enfermedad de Alzheimer , Secretasas de la Proteína Precursora del Amiloide , Animales , Ratones , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Fosforilación , Sumoilación , Ubiquitinación , HumanosRESUMEN
Although oviductal sperm storage are essential steps in reproduction for female animals with internal fertilisation, no systematic study on the identification of genes involving sperm storage has been performed in crocodilian species. In the present research, the relationship between morphological variation related to sperm storage in the oviduct and gene expression patterns derived from RNA sequencing analyses between active period (AP), breeding period (BP), and hibernation period (HP) were investigated. The corresponding results indicated that sperm were observed not only in the ciliated cells within infundibulum and mucosal layer of uterus during BP, but also been detected in the spermatosperm storage tube (SST) in the anterior uterus at HP stage. The further transmission electron microscopy analysis indicated that the differences in the number and activity of the secretory cells likely to attributed to the seasonal variation of microenvironment related to the sperm storage. Based on the RNA-sequecing, 13147 DEGs related to the Peroxisome proliferator-activated receptors (PPARs) and FOXO signalling were identified, including these, the down-regulated ATG12 and BCL2L11 in the HP group may thus constitute an important point of convergence between autophagy and apoptosis involving the FOXO1 pathway. The genes involved in the PPARs pathway might modulate the immune response and thereby contribute to prolong the life span of stored spermatozoa in Alligator sinensis . The outcomes of this study provide fundamental insights into the mechanism of sperm storage in A. sinensis .
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Caimanes y Cocodrilos , Oviductos , Caimanes y Cocodrilos/fisiología , Animales , China , Femenino , Expresión Génica , Masculino , Oviductos/fisiología , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Estaciones del Año , Semen , Espermatozoides/fisiologíaRESUMEN
The key cyclin-dependent kinase Cdk1 (Cdc2) promotes irreversible mitotic entry, mainly by activating the phosphatase Cdc25 while suppressing the tyrosine kinase Wee1. Wee1 needs to be downregulated at the onset of mitosis to ensure rapid activation of Cdk1. In human somatic cells, one mechanism of suppressing Wee1 activity is mediated by ubiquitylation-dependent proteolysis through the Skp1/Cul1/F-box protein (SCF) ubiquitin E3 ligase complex. This mechanism is believed to be conserved from yeasts to humans. So far, the best-characterized human F-box proteins involved in recognition of Wee1 are ß-TrCP (BTRCP) and Tome-1 (CDCA3). Although fission yeast Wee1 was the first identified member of its conserved kinase family, the F-box proteins involved in recognition and ubiquitylation of Wee1 have not been identified in this organism. In this study, our screen using Wee1-Renilla luciferase as the reporter revealed that two F-box proteins, Pof1 and Pof3, are required for downregulating Wee1 and are possibly responsible for recruiting Wee1 to SCF. Our genetic analyses supported a functional relevance between Pof1 and Pof3 and the rate of mitotic entry, and Pof3 might play a major role in this process.
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Proteínas de Ciclo Celular/metabolismo , Proteínas F-Box/metabolismo , Mitosis , Proteínas Nucleares/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Proteolisis , Proteínas de Schizosaccharomyces pombe/metabolismo , Schizosaccharomyces/citología , Schizosaccharomyces/metabolismo , Proteínas Mutantes/metabolismo , Mutación/genética , Unión Proteica , Estabilidad ProteicaRESUMEN
Vibrio fluvialis is considered as a human pathogen in developing countries. This bacterium is widely distributed in seawater and harbors that contains traces of salt. V. fluvialis can cause human enteritis and diarrhea, which has broken out at a global scale. Lipopolysaccharide (LPS) is a key bacterial antigen used to classify V. fluvialis serogroups. In this research, phage display technology was adopted to isolate nanobodies from a naïve phage library by using LPS as the target antigen. The isolated nanobody was tested in LPS ELISA and bacterial enzyme-linked immunosorbent assay Nanobody V23 had a high affinity toward the pathogen and was utilized to synthesize immunomagnetic beads for the enrichment of V. fluvialis. The capture efficiency of the immunomagnetic beads against V. fluvialis was 90.7⯱â¯3.2% (Nâ¯=â¯3) through the plate-counting method. We generated a high-affinity nanobody against LPS from V. fluvialis and developed a rapid method of enriching V. fluvialis by using immunomagnetic beads.
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Lipopolisacáridos/inmunología , Anticuerpos de Dominio Único/inmunología , Vibrio/inmunología , Vibrio/aislamiento & purificación , Técnicas de Visualización de Superficie Celular , Ensayo de Inmunoadsorción Enzimática , Humanos , Separación Inmunomagnética , Vibriosis/microbiologíaRESUMEN
Choroidal neovascularization (CNV) is a hallmark of exudative age-related macular degeneration (exAMD) and a major cause of visual loss in AMD. Despite the widespread use of anti-VEGF therapy, serious adverse effects arise from repeated intravitreal injection of anti-VEGF antibodies, which warrant alternative strategy. We report herein that in a CNV murine model created by krypton red laser, intravenous injection of a serine racemase inhibitor, l-Aspartic acid ß-hydroxamate (L-ABH), significantly reduced CNV at the dose 6â¯mg/kg on the first day before and followed by 3â¯mg/kg on the third day after laser injury. The CNV volumes were analyzed with isolectin GS-IB4 staining on choroidal/RPE flat mounts on the seventh day after laser injury. Injection of L-ABH did not produce negative effects on retinal function and visual behavior. To dissect the mechanism in vitro, pretreatment with L-ABH in primary RPE cultures significantly reduced production of vascular endothelial growth factor (VEGF) and macrophage chemotactic protein 1 (MCP-1) by TNFα-primed RPEs. Consistent with these observations, L-ABH pretreatment significantly attenuated macrophage migration mediated by TNFα-primed RPE. Collectively, intravenous injection of L-ABH significantly reduced CNV volumes via reducing production of VEGF and MCP-1 by inflammation-primed RPEs.
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Inhibidores de la Angiogénesis/administración & dosificación , Asparagina/análogos & derivados , Neovascularización Coroidal/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Animales , Antineoplásicos/administración & dosificación , Asparagina/administración & dosificación , Células Cultivadas , Coroides/patología , Neovascularización Coroidal/metabolismo , Neovascularización Coroidal/patología , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Inflamación/metabolismo , Inflamación/patología , Inyecciones Intravenosas , Inyecciones Intravítreas , Ratones , Ratones Endogámicos C57BL , Epitelio Pigmentado de la Retina/metabolismo , Epitelio Pigmentado de la Retina/patología , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Agudeza VisualRESUMEN
Consistent results suggest the promoting roles of serine racemase (SR)/D-serine in retinal neurodegeneration in diabetic retinopathy (DR). However, the direct evidence connecting SR deficiency with retinal neuroprotection in genetic model of diabetes mellitus has not been reported. In this investigation, we explore the effect of absence of functional SR on the degeneration of retinal ganglion cells (RGCs) with a diabetic murine model, Ins2Akita mice. We established a murine strain with double mutation, termed Ins2Akita-Srr, by mating heterozygous Ins2Akita mice with homozygous Srrochre269 mice. Ins2Akita retained less RGC in posterior, middle, and peripheral retinae than the counterpart from non-diabetic sibling mice at the age of five or seven months. Ins2Akita-Srr mice retained more RGC in middle and peripheral--but not in posterior-- retinae than the counterpart from Ins2Akita sibling mice at the age of five months. By contrast, at the age of seven months, Ins2Akita-Srr mice contained more RGC in peripheral, middle, and posterior retinae than the counterpart from Ins2Akita. RGCs were identified with retrograde labeling in vivo or with immunolabeling against a RGC-specific transcription factor, Brn3a, in retinal flat mounts. Correspondingly, the aqueous humor of Ins2Akita-Srr contained less amount of D-serine than sibling Ins2Akita mice. Thus, SR deficiency significantly prevented RGC loss in diabetic mice. We conclude that D-serine is a critical factor in the degeneration of RGC in DR. Targeting SR expression or activity may be a strategy for ameliorating RGC loss in DR.
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Retinopatía Diabética/prevención & control , Modelos Animales de Enfermedad , Mutación con Pérdida de Función/genética , Racemasas y Epimerasas/genética , Degeneración Retiniana/prevención & control , Células Ganglionares de la Retina/metabolismo , Animales , Glucemia/metabolismo , Recuento de Células , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/prevención & control , Retinopatía Diabética/metabolismo , Retinopatía Diabética/patología , Técnica del Anticuerpo Fluorescente Indirecta , Técnicas de Genotipaje , Hiperglucemia/metabolismo , Hiperglucemia/patología , Etiquetado Corte-Fin in Situ , Insulina/genética , Ratones , Ratones Endogámicos C57BL , Microscopía Fluorescente , Reacción en Cadena de la Polimerasa , Degeneración Retiniana/metabolismo , Células Ganglionares de la Retina/patologíaRESUMEN
Inward migration of cerebellar granule cells (CGCs) after birth is critical for lamination in the cerebellar cortex. N-methyl-d-aspartate (NMDA) subtype of glutamate receptor (NMDAR) tethering CGCs into Bergmann glial fibers mediates the inward movement during the glial-dependent migratory phase. Activation of NMDAR depends on simultaneous binding of the GluN2 subunit by glutamate, and of the GluN1 subunit by d-serine or glycine; d-serine is believed to be an endogenous ligand of NMDAR. We hypothesized that lamination of the cerebellar cortex may be compromised in Srr (the gene for serine racemase (SR)) mutated mice (Srrnull) because of significantly low levels of d-serine per se. Indeed, the external germinal cell layer (EGL) in Srrnull was thicker than in sibling wild-type (WT) mice on postnatal day7 (P7), which accords with decreased CGC migration in Srrnull mice. However, the cerebellar laminar structure in Srrnull mice was normal on P12 and later. Feeding d-serine to pregnant mice abrogated the increased EGL thickness in Srrnull mice on P7. To determine the underlying mechanism of abnormal laminar structure during cerebellar development in Srrnull mice, we examined NMDAR subunits and their ligands. We found increased GluN2B on P10 and increased glycine during P7-12 in the cerebellar homogenates from Srrnull mice compared with the corresponding values from sibling WT mice. In summary, the study revealed how the potential defect in early cerebellar development caused by Srr mutation is circumvented by a compensatory mechanism. This knowledge advances understanding of the adaptation of cerebellar development under the condition of Srr mutation.
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Cerebelo/crecimiento & desarrollo , Cerebelo/metabolismo , Neurogénesis/fisiología , Racemasas y Epimerasas/deficiencia , Receptores de N-Metil-D-Aspartato/biosíntesis , Animales , Movimiento Celular/fisiología , Ratones , Ratones Mutantes , Mutación , Racemasas y Epimerasas/genética , Receptores de N-Metil-D-Aspartato/agonistasRESUMEN
Choroidal neovascularization (CNV) is a leading cause of blindness in age-related macular degeneration. Production of vascular endothelial growth factor (VEGF) and macrophage recruitment by retinal pigment epithelial cells (RPE) significantly contributes to the process of CNV in an experimental CNV model. Serine racemase (SR) is expressed in retinal neurons and glial cells, and its product, d-serine, is an endogenous co-agonist of N-methyl-d-aspartate receptor. Activation of the receptor results in production of nitric oxide (. NO), a molecule that promotes retinal and choroidal neovascularization. These observations suggest possible roles of SR in CNV. With laser-injured CNV mice, we found that inactivation of SR-coding gene (Srrnull ) significantly reduced CNV volume, neovascular density, and invading macrophages. We exploited the underlying mechanism in vivo and ex vivo. RPE from wild-type (WT) mice expressed SR. To explore the possible downstream target of SR inactivation, we showed that choroid/RPE homogenates extracted from laser-injured Srrnull mice contained less inducible nitric oxide synthase and decreased phospho-VEGFR2 compared to amounts in WT mice. In vitro, inflammation-primed WT RPEs expressed more inducible NOS, produced more. NO and VEGF than did inflammation-primed Srrnull RPEs. When co-cultured with inflammation-primed Srrnull RPE, significantly fewer RF/6A-a cell line of choroidal endothelial cell, migrated to the opposite side of the insert membrane than did cells co-cultured with pre-treated WT RPE. Altogether, SR deficiency reduces RPE response to laser-induced inflammatory stimuli, resulting in decreased production of a cascade of pro-angiogenic cytokines, including. NO and VEGF, and reduced macrophage recruitment, which contribute synergistically to attenuated angiogenesis.
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Ceguera/patología , Neovascularización Coroidal/genética , Regulación de la Expresión Génica/genética , Óxido Nítrico/metabolismo , Racemasas y Epimerasas/deficiencia , Epitelio Pigmentado de la Retina/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Ceguera/etiología , Ceguera/genética , Células Cultivadas , Neovascularización Coroidal/patología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de la radiación , Rayos Láser/efectos adversos , Lipopolisacáridos/farmacología , Macrófagos/fisiología , Macrófagos/efectos de la radiación , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mutación/genética , ARN Mensajero/metabolismo , Racemasas y Epimerasas/genética , Epitelio Pigmentado de la Retina/efectos de los fármacos , Serina/metabolismoRESUMEN
BACKGROUND: Recently genome-wide association studies identified that NCAN rs2228603 polymorphism was associated with non-alcoholic fatty liver disease (NAFLD) mainly in subjects of European ancestry. While no research have been conducted to demonstrate the relationship between NCAN rs2228603 and NAFLD in Chinese Han adults. The aim of this study was to investigate whether NCAN rs2228603 is associated with NAFLD in Chinese population. METHODS: Gene NCAN rs2228603 was genotyped in 182 patients with NAFLD and 195 healthy controls. The expression of NCAN was tested according to polymerase chain reaction analysis (PCR) and serum lipids were performed by biology techniques. RESULTS: No significant difference was found in genotype and allele frequencies of NCAN rs2228603 between the NAFLD group and the controls (P > 0.05). Subjects with the NCAN rs2228603 CT genotype showed a higher level of alkaline phosphatase (AKP) (P = 0.017) and a higher high-density lipoprotein (HDL) (P < 0.05). CONCLUSIONS: Our study for the first time identified that the gene NCAN rs2228603 is not a risk factor for the incidence of NAFLD in Chinese population. Also we found the dual and opposite role of T variant in protecting liver with a higher level of HDL and conferring risk for liver damage with a higher level of AKP. TRIAL REGISTRATION: Chinese Clinical Trial Register.gov Identifier: ChiCTR-ROC-15006447 .
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Proteoglicanos Tipo Condroitín Sulfato/genética , Predisposición Genética a la Enfermedad , Lectinas Tipo C/genética , Proteínas del Tejido Nervioso/genética , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Enfermedad del Hígado Graso no Alcohólico/genética , Polimorfismo de Nucleótido Simple , Adulto , Pueblo Asiatico/genética , Estudios de Casos y Controles , Femenino , Humanos , Incidencia , Lipoproteínas HDL/sangre , Lipoproteínas HDL/genética , Masculino , Persona de Mediana Edad , Neurocano , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/metabolismoRESUMEN
Objective: To assess the effectiveness and clinical value of case-cohort design and determine prognostic factors of breast cancer patients in Xinjiang on the basis of case-cohort design. Methods: The survival data with different sample characteristics were simulated by using Cox proportional risk models. To evaluate the effectiveness for the case-cohort, entire cohort, and simple random sampling design by comparing the mean, coefficient of variation, etc., of covariate parameters. Furthermore, the prognostic factors of breast cancer patients in Xinjiang were determined based on case-cohort sampling designs. The models were comprehensively evaluated by likelihood ratio test, the area under the receiver operating characteristic curve (AUC), and Akaike Information Criterion (AIC). Results: In a simulations study, the case-cohort design shows better stability and improves the estimation efficiency when the censored rate is high. In the breast cancer data, molecular subtypes, T-stage, N-stage, M-stage, types of surgery, and postoperative chemotherapy were identified as the prognostic factors of patients in Xinjiang. These models based on the different sampling designs both passed the likelihood ratio test (p<0.05). Moreover, the model constructed under the case-cohort design had better fitting effect (AIC=3,999.96) and better discrimination (AUC=0.807). Conclusion: Simulations study confirmed the effectiveness of case-cohort design and further determined the prognostic factors of breast cancer patients in Xinjiang based on this design, which presented the practicality of case-cohort design in actual data.
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Alzheimer's disease (AD) is a progressive neurodegenerative disorder, and moderate exercise holds promise in ameliorating the ongoing neurodegeneration and cognitive decline. Here, we investigated whether exercise-enriched blood plasm could yield a beneficial therapeutic effect on AD pathologies and cognitive decline in transgenic AD (P301S) mice. In this investigation, a cohort of 2-month-old C57BL/6 mice were granted continuous access to either a running wheel or a fixed wheel for 6 weeks. After that, their plasmas were extracted and subsequently injected intravenously into 4.5-month-old P301S mice biweekly over a 6-week period. A comprehensive methodology was then employed, integrating behavioral tests, pathology assessments, and biochemical analyses to unveil the potential anti-dementia implications of exercise-enriched blood plasma in P301S mice. Upon systemic administration, the findings revealed a noteworthy attenuation of hippocampus-dependent behavioral impairments in P301S mice. Conversely, blood plasma from sedentary counterparts exhibited no discernible impact. These effects were intricately associated with the mitigation of neuroinflammation, the augmentation of hippocampal adult neurogenesis, and a reduction of synaptic impairments following the administration of exercise-enriched blood plasma. These findings advance the proposition that administering exercise-enriched blood plasma may serve as an effective prophylactic measure against AD, opening avenues for further exploration and potential therapeutic interventions.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Modelos Animales de Enfermedad , Hipocampo , Ratones Endogámicos C57BL , Ratones Transgénicos , Condicionamiento Físico Animal , Animales , Enfermedad de Alzheimer/terapia , Enfermedad de Alzheimer/sangre , Hipocampo/metabolismo , Hipocampo/patología , Condicionamiento Físico Animal/métodos , Disfunción Cognitiva/terapia , Disfunción Cognitiva/sangre , Ratones , Plasma/metabolismo , Masculino , NeurogénesisRESUMEN
Xinjiang has been one of the high incidence areas of pulmonary tuberculosis (PTB) in China. Besides being infected by direct contacting with active PTB individuals (direct infection), the susceptible would be infected because of the exposure to the environment contaminated by Mycobacterium tuberculosis (indirect infection). Active PTB individuals include not only the smear-positive PTB (PTB+) but also the smear-negative PTB (PTB-) who are infectious due to their ability to release tiny Mycobacterium tuberculosis particles even in the absence of visible Mycobacterium tuberculosis in sputum. By taking account of direct/indirect infection and the difference between PTB+ and PTB- individuals in transmission capability, a periodic dynamical PTB transmission model is proposed. The model is fitted to the newly monthly PTB+ and PTB- cases in Xinjiang from 2008 to 2017 by Markov Chain Monte Carlo algorithm. Moreover, global sensitivity analysis is constructed to address the uncertainty of some key parameters by using Latin hypercube sampling and partial rank correlation coefficient methods. Basic reproduction number R0 for PTB transmission in Xinjiang is estimated to be 2.447 (95% CrI:(1.203, 3.844)), indicating that PTB has been prevalent in Xinjiang over the study period. Our results suggest that reducing the direct/indirect transmission rates, early screening, isolating and treating the latent, PTB+ and PTB- individuals, and enhancing the clearance of Mycobacterium tuberculosis in the environment could more effectively control PTB transmission in Xinjiang. The model fits the reported PTB data well and achieves acceptable prediction accuracy. We believe that our model can provide heuristic support for controlling PTB transmission in Xinjiang.
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Mycobacterium tuberculosis , Esputo , Tuberculosis Pulmonar , China/epidemiología , Humanos , Mycobacterium tuberculosis/aislamiento & purificación , Tuberculosis Pulmonar/transmisión , Tuberculosis Pulmonar/epidemiología , Tuberculosis Pulmonar/microbiología , Esputo/microbiología , Número Básico de Reproducción , Adulto , Masculino , Femenino , Persona de Mediana Edad , Método de MontecarloRESUMEN
HYPOTHESIS: Ice accretion on component surfaces often causes severe impacts or accidents. Liquid-infused surfaces (LIS) have drawn much attention as icephobic materials for ice mitigation in recent years due to their outstanding icephobicity. However, the durability of LIS constructions remains a big challenge, including mechanical vulnerability and rapid depletion of lubricants. The practical applications of LIS materials are significantly restrained, and the full potential of LIS for ice prevention has yet to be demonstrated. EXPERIMENTS: A universal approach was proposed to introduce microporous metallic scaffolds in the LIS construction to increase the applicability and durability, and to prompt the potential of LIS for ice mitigation. Microporous Ni scaffolds were chosen to integrate with polydimethylsiloxane modified by silicone oil addition. FINDINGS: The new LIS construction demonstrated significantly improved durability in icing/de-icing cyclic test, and it also offered a solution for the rapid oil depletion by restraining the deformation of the matrix material. Low ice adhesion strength could be maintained via a micro-crack initiation mechanism. The results indicated that the multi-phase LIS construction consisting of microporous Ni scaffolds effectively addressed the shackles of the icephobicity deterioration of LIS materials, confirming a new design strategy for the R&D of icephobic surfaces.
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OBJECTIVE: Post-stroke cognitive impairment (PSCI) develops in approximately one-third of stroke survivors and is associated with ingravescence. Nonetheless, the biochemical mechanisms underlying PSCI remain unclear. The study aimed to establish an ischemic mouse model by means of transient unilateral middle cerebral artery occlusions (MCAOs) and to explore the biochemical mechanisms of p25/cyclin-dependent kinase 5 (CDK5)-mediated tau hyperphosphorylation on the PSCI behavior. METHODS: Cognitive behavior was investigated, followed by the detection of tau hyperphosphorylation, mobilization, activation of kinases and/or inhibition of phosphatases in the lateral and contralateral cerebrum of mice following ischemia in MACO mice. Finally, we treated HEK293/tau cells with oxygen-glucose deprivation (OGD) and a CDK5 inhibitor (Roscovitine) or a GSK3ß inhibitor (LiCl) to the roles of CDK5 and GSK3ß in mediating ischemia-reperfusion-induced tau phosphorylation. RESULTS: Ischemia induced cognitive impairments within 2 months, as well as causing tau hyperphosphorylation and its localization to neuronal somata in both ipsilateral and contralateral cerebra. Furthermore, p25 that promotes CDK5 hyperactivation had significantly higher expression in the mice with MCAO than in the shamoperation (control) group, while the expression levels of protein phosphatase 2 (PP2A) and the phosphorylation level at Tyr307 were comparable between the two groups. In addition, the CDK5 inhibitor rescued tau from hyperphosphorylation induced by OGD. CONCLUSION: These findings demonstrate that upregulation of CDK5 mediates tau hyperphosphorylation and localization in both ipsilateral and contralateral cerebra, contributing to the pathogenesis of PSCI.
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Cerebro , Disfunción Cognitiva , Animales , Humanos , Ratones , Cerebro/metabolismo , Cognición , Disfunción Cognitiva/etiología , Quinasa 5 Dependiente de la Ciclina/genética , Quinasa 5 Dependiente de la Ciclina/metabolismo , Glucógeno Sintasa Quinasa 3 beta/genética , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Células HEK293 , Isquemia , Proteínas tau/genética , Proteínas tau/metabolismoRESUMEN
The presence of insufficient bone volume affects the implant healing and success. The aim of this study was to evaluate osteogenic capacity of dental pulp stem cells (DPSCs) on micro-arc oxidation (MAO) titanium surface. DPSCs were challenged at MAO and smooth titanium surface separately for different durations, and the bone marrow mesenchymal stem cells (BMSCs) served as the positive controls. The osteogenic capacity of DPSCs on MAO titanium surface was assessed by using scanning electron microscopy, energy dispersive spectroscopy, biochemical tests and real-time quantitative PCR. Data showed that DPSCs differentiated into osteoblasts and expressed bone morphogenetic genes on MAO titanium surface. The results of this study revealed that DPSCs had good potential to generate mineralized tissue on MAO titanium plates. The differential potential of DPSCs may be regulated by MAO titanium surface. The osteogenesis potential of DPSCs on the MAO titanium was similar with BMSCs.
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Pulpa Dental/efectos de los fármacos , Pulpa Dental/fisiología , Osteogénesis/efectos de los fármacos , Osteogénesis/fisiología , Células Madre/efectos de los fármacos , Células Madre/parasitología , Titanio/farmacología , Animales , Células Cultivadas , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
In the work reported herein, the concise and enantioselective total synthesis of the Schizozygine alkaloid (-)-strempeliopine was developed. This synthetic strategy featured the palladium-catalyzed decarboxylative asymmetric allylic alkylation of N-benzoyl lactam to set up the absolute configuration at the C20 position, a highly diastereoselective one-pot Bischler-Napieralski/lactamization and iminium reduction sequence for the construction of the pentacyclic core structure, and the late-stage dearomative addition of indole, leading to the otherwise difficult-to-achieve hexacyclic indoline framework with complete control of four neighbouring stereocenters.
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Objective: To examine the factors that affect the prognosis and survival of breast cancer patients who were diagnosed at the Affiliated Cancer Hospital of Xinjiang Medical University between 2015 and 2021, forecast the overall survival (OS), and assess the clinicopathological traits and risk level of prognosis of patients in various subgroups. Method: First, nomogram model was constructed using the Cox proportional hazards models to identify the independent prognostic factors of breast cancer patients. In order to assess the discrimination, calibration, and clinical utility of the model, additional tools such as the receiver operating characteristic (ROC) curve, calibration curve, and clinical decision curve analysis (DCA) were used. Finally, using two-step cluster analysis (TCA), the patients were grouped in accordance with the independent prognostic factors. Kaplan-Meier survival analysis was employed to compare prognostic risk among various subgroups. Result: T-stage, N-stage, M-stage, molecular subtyping, type of operation, and involvement in postoperative chemotherapy were identified as the independent prognostic factors. The nomogram was subsequently constructed and confirmed. The area under the ROC curve used to predict 1-, 3-, 5- and 7-year OS were 0.848, 0.820, 0.813, and 0.791 in the training group and 0.970, 0.898, 0.863, and 0.798 in the validation group, respectively. The calibration curves of both groups were relatively near to the 45° reference line. And the DCA curve further demonstrated that the nomogram has a higher clinical utility. Furthermore, using the TCA, the patients were divided into two subgroups. Additionally, the two groups' survival curves were substantially different. In particular, in the group with the worse prognosis (the majority of patients did not undergo surgical therapy or postoperative chemotherapy treatment), the T-, N-, and M-stage were more prevalent in the advanced, and the total points were likewise distributed in the high score side. Conclusion: For the survival and prognosis of breast cancer patients in Xinjiang, the nomogram constructed in this paper has a good prediction value, and the clustering results further demonstrated that the selected factors were important. This conclusion can give a scientific basis for tailored treatment and is conducive to the formulation of focused treatment regimens for patients in practical practice.
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Here, we disclose the divergent total syntheses of representative C18-oxo eburnamine-vincamine alkaloids (+)-eburnaminol, (-)-larutenine, and (-)-cuanzine. Key to the approach is a substrate-controlled iridium-catalyzed asymmetric hydrogenation/lactamization cascade that leads to the formation of the common tetracyclic skeleton with essential cis-C20/C21 stereochemistry (93% yield, 98% ee, >20:1 dr, gram scale). Access to the targeted alkaloids is effected late in the synthesis by implementation of a number of diversity-oriented transformations and late-stage modifications.
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Alcaloides , Vincamina , Imidazoles , Iridio , Estereoisomerismo , Sulfonamidas , TiofenosRESUMEN
Tangeretin (TAN) exhibits many bioactivities, including neuroprotective effects. However, the efficacy of TAN in Alzheimer's disease (AD) has not been sufficiently investigated. In the present study, we integrated behavioral tests, pathology assessment, and biochemical analyses to elucidate the antidementia activity of TAN in APPswe/PSEN1dE9 transgenic (Tg) mice. At supplementation levels of 100 mg/kg body weight per day, TAN significantly attenuated the cognitive impairment of Tg mice in behavioral tests. These effects were associated with less synaptic impairments and fewer ß-amyloid accumulations after TAN administration. Furthermore, our study revealed that TAN possessed powerful inhibitory activity against ß-secretase both in vitro and in vivo, which played a crucial role in the process of Aß generation. These findings indicate that TAN is a potential drug for preventing AD pathology. The key mechanism underlying the antidementia effect of TAN may include its inhibitory activity against ß-secretase.
Asunto(s)
Enfermedad de Alzheimer , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Disfunción Cognitiva , Flavonas/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Secretasas de la Proteína Precursora del Amiloide/genética , Péptidos beta-Amiloides , Precursor de Proteína beta-Amiloide/genética , Animales , Ácido Aspártico Endopeptidasas/genética , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/genética , Modelos Animales de Enfermedad , Ratones , Ratones TransgénicosRESUMEN
BACKGROUND: Alzheimer's disease (AD), with cognitive impairment as the main clinical manifestation, is a progressive neurodegenerative disease. The assembly of amyloid-ß (Aß) as senile plaques is one of the most well-known histopathological alterations in AD. Several studies reported that cognitive training reduced Aß deposition and delayed memory loss. However, the long-term benefits of spatial training and the underlying neurobiological mechanisms have not yet been elucidated. OBJECTIVE: To explore the long-term effects of spatial training on AD-related pathogenic processes in APP/PS1 mice. METHODS: We used Morris water maze (MWM), Open Field, Barnes Maze, western blotting, qPCR, and immunofluorescence. RESULTS: One-month MWM training in APP/PS1 mice at 2.5 months of age could attenuate Aß deposition and decrease the expression of ß-secretase (BACE1) and amyloid-ß protein precursor (AßPP) with long-term effects. Simultaneously, regular spatial training increased the expression of synapse-related proteins in the hippocampus. Moreover, MWM training increased adult hippocampal neurogenesis in AD model mice. Nonetheless, cognitive deficits in APP/PS1 transgenic mice at 7 months of age were not attenuated by MWM training at an early stage. CONCLUSION: Our study demonstrates that MWM training alleviates amyloid plaque burden and adult hippocampal neurogenesis deficits with long-term effects in AD model mice.