RESUMEN
Bifunctional chiral squaramide-catalyzed highly enantioselective Michael addition of nitromethane to diverse 2-enoylazaarenes was successfully performed. This protocol provided a set of chiral azaarene-containing γ-nitroketones with up to 98% yield and 98% ee in a solvent-free catalytic system under mild conditions. Furthermore, gram-scale synthetic utility was also showcased.
RESUMEN
Dehydroabietane-type bifunctional organocatalysts derived from rosane-type diterpenes of dehydroabietic acid (DHAA) and dehydroabietylamine (DA) have been utilized in a wide variety of highly enantioselective reactions. Since one well-documented review exclusively reported on the development of terpene-derived bifunctional thioureas in asymmetric organocatalysis in 2013, fragmentary progress on the dehydroabietane-type bifunctional thioureas and squaramides has been mentioned in other reviews. In this mini-review, we systematically analyze and reorganize the published literature on dehydroabietane-type bifunctional organocatalysts in the recent decade according to the type of catalysts. Our aim is for this review to provide helpful research information and serve as a foundation for further design and application of rosin-based organocatalysts.
RESUMEN
BACKGROUND: O-GlcNAcylation is a highly dynamic post-translational modification that plays a key role in regulating phosphorylation of protein and cell survival. The proteins O-GlcNAcylation level is regulated dynamically by O-GlcNAc transferase (OGT) and ß-N-acetylglucosaminidase (O-GlcNAcase, OGA). Although previous studies have suggested the role of O-GlcNAcylation in neurodegenerative diseases, the mechanism of O-GlcNAcylation in Alzheimer's disease (AD) remains unclear. METHODS: The decrease of O-GlcNAcylation by alloxan, an OGT inhibitor, and increase by NAG-thiazolines (NAG-Ae), an O-GlcNAcase inhibitor were tested to investigate the effects of O-GlcNAc alteration on AD like neurodegeneration in SK-N-SH cells. RESULTS: The level of O-GlcNAcylation was decreased in alloxan treated cells and increased in NAG-Ae treated cells. Meanwhile, it was observed that both abnormal phosphorylation of NFs in cell bodies and apoptosis induced by alloxan treatment can be resisted by pretreatment or simultaneous treatment with appropriate NAG-Ae. CONCLUSION: These results demonstrated that increasing O-GlcNAc with NAG-Ae protected AD like neurodegeneration from NFs hyperphosphorylation and the cell loss, suggesting the role of O-GlcNAc in the pathogenesis and therapy of AD.
Asunto(s)
Enfermedad de Alzheimer/enzimología , N-Acetilglucosaminiltransferasas/metabolismo , Acetilación , Aloxano/farmacología , Enfermedad de Alzheimer/etiología , Apoptosis/fisiología , Muerte Celular/fisiología , Línea Celular Tumoral , Inhibidores Enzimáticos/farmacología , Humanos , N-Acetilglucosaminiltransferasas/antagonistas & inhibidores , Fosforilación/fisiología , beta-N-Acetilhexosaminidasas/antagonistas & inhibidoresRESUMEN
Long non-coding RNAs (lncRNAs) are widely accepted as key players in various biological processes. However, the roles of lncRNA in peripheral nerve regeneration remain completely unknown. Thus, in this study, we performed microarray analysis to measure lncRNA expression in the distal segment of the sciatic nerve at 0, 3, 7 and 14 days following injury. We identified 5,354 lncRNAs that were differentially expressed: 3,788 lncRNAs were differentially expressed between days 0 and 3; 3,314 lncRNAs were differentially expressed between days 0 and 7; and 2,400 lncRNAs were differentially expressed between days 0 and 14. The results of RT-qPCR of two dysregulated lncRNAs were consistent with those of microarray analysis. Bioinformatics approaches, including lncRNA classification, gene ontology (GO) analysis and target prediction, were utilized to investigate the functions of these dysregulated lncRNAs in peripheral nerve damage. Importantly, we predicted that several lncRNA-mRNA pairs may participate in biological processes related to peripheral nerve injury. RT-qPCR was performed for the preliminary verification of three lncRNAmRNA pairs. The overexpression of NONMMUG014387 promoted the proliferation of mouse Schwann cells. Thus, the findings of our study may enhance our knowledge of the role of lncRNAs in nerve injury.
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Perfilación de la Expresión Génica , Traumatismos de los Nervios Periféricos/genética , ARN Largo no Codificante/genética , Animales , Proliferación Celular , Regulación de la Expresión Génica , Ontología de Genes , Redes Reguladoras de Genes , Genómica , Ratones Endogámicos C57BL , ARN Mensajero/genética , Nervio Ciático/lesiones , Nervio Ciático/metabolismoRESUMEN
This study is to investigate the protective effect of rosiglitazone (RSG) against learning and memory impairment of APP/PS1/tau transgenic mice. AD mice model was replicated by using 6-month APP/PS1/tau transgenic mice. The learning and memory ability of mice was evaluated by Morris water maze and Western blotting assays was applied to measure the phosphorylation and O-glycosylation of Tau and neurofilaments (NFs) protein. The results demonstrated that RSG could reverse the learning and memory deficits of 3 x Tg mice significantly. It was also found that RSG could suppress the hyperphosphorylation of Tau and NFs protein levels and increase the glycosylation expression of Tau and NFs proteins in 3 x Tg mice brain. Together, RSG ameliorates cognitive impairments of 3 x Tg mice via the alleviation of the hyperphosphorylated Tau and NFs proteins burden in the brain.
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Aprendizaje/efectos de los fármacos , Memoria/efectos de los fármacos , Tiazolidinedionas/farmacología , Enfermedad de Alzheimer , Péptidos beta-Amiloides , Animales , Encéfalo/efectos de los fármacos , Modelos Animales de Enfermedad , Glicosilación , Trastornos de la Memoria/tratamiento farmacológico , Ratones , Ratones Transgénicos , Proteínas de Neurofilamentos/metabolismo , Fosforilación , Rosiglitazona , Proteínas tau/metabolismoRESUMEN
The design and synthesis of a new series of N-trisubstituted (at C2, C4 and C6 respectively) pyrimidine derivatives were reported, their in vitro structure-activity relationships vs. aurora A kinase were also discussed. Our results demonstrated that the introduction of characteristic N-substituted side chain at C2 of pyrimidines possessed a potent aurora A inhibitory activity, the position and the nature of the substituents on the phenyl ring of aniline side chain played key roles in cellular kinase inhibitory potency. Most tested compounds exhibited good inhibitory activities against aurora A kinase and various human tumor cell lines. Compounds 7j, 7m-n and 7p showed strong growth-inhibitory activities in the solid CNE-2 tumor cell and selectively blocked cell-cycle progression at the G2/M phase.
Asunto(s)
Antineoplásicos/farmacología , Aurora Quinasa A/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Aurora Quinasa A/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HL-60 , Humanos , Células K562 , Células MCF-7 , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-Actividad , Células U937RESUMEN
The mol-ecule of the title compound, C(35)H(27)N(3)O(2), lies on a twofold rotation axis passing through the pyridine ring. The five-membered ring is approximately flat (r.m.s. deviation = 0.065â Å) and is essentially coplanar [dihedral angle = 4.2â (2)°] with the pyridine ring.
RESUMEN
The five-membered ring in the the title mol-ecule, C(24)H(25)NO, fused with the phenyl-ene ring, is almost planar (r.m.s. deviation = 0.023â Å), with the methyl-ene C atom deviating most from this mean plane [0.031â (1)â Å]. The tertiary N atom shows a flattened pyramidal configuration [Σ(angles at N) = 350.3â (6)°].
RESUMEN
OBJECTIVE: To explore the effect of Chlamydia pneumoniae (C.pn) infection on human laryngeal carcinoma cell line HEp-2 cell adhesion and migration, to further clarify the role and mechanism of C.pn infection in tumor metastasis. METHODS: HEp-2 cells were infected with C.pn after the culture and propagation of C.pn. The cytopathic effect was observed by microscopy. Morphological characteristics of C.pn inclusions in HEp-2 cells were examined by fluorescence microscopy and acridine orange staining. The ultrastructural changes of C.pn inclusions in the HEp-2 cells were examined by transmission electron microscopy (TEM). Cell adhesion assay was performed to investigate the effect of C.pn infection on the adhesion of HEp-2 cells to collagen I. Wound-healing assay and transwell assay were performed to explore the effect of C.pn infection on HEp-2 cell migration. RESULTS: At 72 h post-infection, C.pn infected-HEp-2 cells were swollen and partially desquamated. Numerous vacuoles (inclusions) were observed and C.pn inclusions occupied almost the whole cytoplasm of the HEp-2 cells. Grape-like C.pn inclusions were observed in the HEp-2 cells stained with acridine orange under a fluorescence microscope at 72 h after infection. Under TEM, there were more mature pear-shaped elementary bodies, but less larger and round reticulate bodies in the HEp-2 cells infected with C.pn for 72 h. In the cell adhesion assay, the A value in C.pn infection group was 0.669 ± 0.011, significantly higher than that in the control group (0.558 ± 0.005) at 2 h after infection (P < 0.001). The cell adhesion ratio in the C.pn infection group was 119.89%. The migration distance of C.pn infected-HEp-2 cells in the wound-healing assay was significantly longer than that of control cells at 24 h after infection (P < 0.05). HEp-2 cells infected with C.pn for 12 h migrated more than the control cells in the transwell assay (23.40 ± 2.41 vs 10.40 ± 1.67) (P < 0.001). CONCLUSIONS: C.pn infection can significantly promote HEp-2 cell adhesion to collagen I and migration of HEp-2 cells, indicating that C.pn infection may play an important role in promoting the metastasis of laryngeal cancer.
Asunto(s)
Carcinoma de Células Escamosas/patología , Adhesión Celular , Movimiento Celular , Infecciones por Chlamydophila , Neoplasias Laríngeas/patología , Carcinoma de Células Escamosas/microbiología , Línea Celular Tumoral , Infecciones por Chlamydophila/microbiología , Infecciones por Chlamydophila/fisiopatología , Chlamydophila pneumoniae , Humanos , Neoplasias Laríngeas/microbiologíaRESUMEN
Hyperphosphorylated tau is the major protein subunit of neurofibrillary tangles in Alzheimer's disease (AD) and related tauopathies. It is not understood, however, why the neurofibrillary tangle-containing neurons seen in the AD brains do not die of apoptosis but rather degeneration even though they are constantly awash in a proapoptotic environment. Here, we show that cells overexpressing tau exhibit marked resistance to apoptosis induced by various apoptotic stimuli, which also causes correlated tau hyperphosphorylation and glycogen synthase kinase 3 (GSK-3) activation. GSK-3 overexpression did not potentiate apoptotic stimulus-induced cell apoptosis in the presence of high levels of tau. The resistance of neuronal cells bearing hyperphosphorylated tau to apoptosis was also evident by the inverse staining pattern of PHF-1-positive tau and activated caspase-3 or fragmented nuclei in cells and the brains of rats or tau-transgenic mice. Tau hyperphosphorylation was accompanied by decreases in beta-catenin phosphorylation and increases in nuclear translocation of beta-catenin. Reduced levels of beta-catenin antagonized the antiapoptotic effect of tau, whereas overexpressing beta-catenin conferred resistance to apoptosis. These results reveal an antiapoptotic function of tau hyperphosphorylation, which likely inhibits competitively phosphorylation of beta-catenin by GSK-3beta and hence facilitates the function of beta-catenin. Our findings suggest that tau phosphorylation may lead the neurons to escape from an acute apoptotic death, implying the essence of neurodegeneration seen in the AD brains and related tauopathies.
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Enfermedad de Alzheimer/metabolismo , Apoptosis/fisiología , Ovillos Neurofibrilares/metabolismo , beta Catenina/metabolismo , Proteínas tau/metabolismo , Animales , Western Blotting , Línea Celular , Técnica del Anticuerpo Fluorescente , Glucógeno Sintasa Quinasa 3/metabolismo , Ratones , Ratones Transgénicos , Ovillos Neurofibrilares/fisiología , Fosforilación , RatasRESUMEN
Co-injection of wortmannin (inhibitor of phosphatidylinositol-3 kinase, PI3K) and GF109203X (inhibitor of protein kinase C, PKC) into the rat brain was found to induce spatial memory deficiency and enhance tau hyperphosphorylation in the hippocampus of rat brain. To establish a cell model with durative Alzheimer-like tau hyperphosphorylation in this study, we treated N2a neuroblastoma cells with wortmannin and GF109203X separately and simultaneously, and measured the glycogen synthase kinase 3 (GSK-3) activity by gamma-32P-labeling and the level of tau phosphorylation by Western blotting. It was found that the application of wortmannin alone only transitorily increased the activity of GSK-3 (about 1 h) and the level of tau hyperphosphorylation at Ser396/Ser404 and Ser199/Ser202 sites (no longer than 3 h); however, a prolonged and intense activation of GSK-3 (over 12 h) and enhanced tau hyperphosphorylation (about 24 h) were observed when these two selective kinase inhibitors were applied together. We conclude that the simultaneous inhibition of PI3K and PKC can induce GSK-3 overactivation, and further strengthen and prolong the Alzheimer-like tau hyperphosphorylation in N2a cells, suggesting the establishment of a cell model with early pathological events of Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Glucógeno Sintasa Quinasa 3/metabolismo , Neuroblastoma/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteína Quinasa C/antagonistas & inhibidores , Proteína Quinasa C/metabolismo , Proteínas tau/metabolismo , Amiloide/metabolismo , Androstadienos/farmacología , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Indoles/farmacología , Maleimidas/farmacología , Fosforilación/efectos de los fármacos , Ratas , WortmaninaRESUMEN
AIM: To explore the underlying mechanism of tau hyperphosphorylation in an Alzheimeros-affected brain and the possible arresting strategies. METHODS: MTT(3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide), crystal violet assay, phase-contrast, dead end colorimetric apoptosis detection system (TUNEL) and electron microscopy were used to detect cell viability, morphology and apoptosis. Western blot, 32P-labeling and the detection of malondialdehyde level and superoxide dismutase activity were used respectively for the phosphorylation level of tau, the activity of glycogen synthase kinase (GSK-3), and oxidative stress measurement. RESULTS: Exposure of the cells to wortmannin resulted in an obvious lipid peroxidation, reduction of cell viability, cell process retraction, and plasma vacuolation, but with no obvious cell apoptosis. We also found that preincubation of the cells with melatonin or vitamin E attenuated differentially wortmannin-induced oxidative stress as well as GSK-3 overactivation and tau hyperphosphorylation. CONCLUSION: Wortmannin is an effective tool for reproducing Alzheimer-like tau hyperphosphorylation cell model and melatonin/vitamin E can effectively protect the cells from wortmannin-induced impairments.
Asunto(s)
Androstadienos/antagonistas & inhibidores , Melatonina/farmacología , Neuroblastoma/metabolismo , Proteínas tau/metabolismo , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Humanos , Peroxidación de Lípido/efectos de los fármacos , Malondialdehído/metabolismo , Neuroblastoma/patología , Fosforilación/efectos de los fármacos , Superóxido Dismutasa/metabolismo , Vitamina E/farmacología , WortmaninaRESUMEN
Hyperphosphorylation of cytoskeletal proteins seen in Alzheimer's disease is most probably the result of an imbalanced regulation in protein kinases and protein phosphatases (PP) in the affected neurons. Previous studies have revealed that PP-2A and PP-1 play important roles in the pathogenesis. Employing human neuroblastoma cells, we found that 10 nM calyculin A (CA), a selective inhibitor of PP-2A and PP-1, significantly increased phosphorylation and accumulation of neurofilament (NF) in the cells. Levels of NF-M (middle chain) and NF-L (light chain) mRNA decreased after CA treatment. Additionally, CA led to a decreased cell viability determined by MTT and crystal violet assay. Melatonin efficiently protects the cell from CA-induced alterations in NF hyperphosphorylation and accumulation, suppressed NF gene expression as well as decreased cell viability. It is concluded that inhibition of PP-2A/PP-1 by CA induces abnormalities in NF metabolism and cell survival, and melatonin efficiently arrests the lesions.