RESUMEN

Researchers continue to explore drug targets to treat the characteristic pathologies of Alzheimer's disease (AD). Some drugs relieve the pathological processes of AD to some extent, but the failed clinical trials indicate that multifunctional agents seem more likely to achieve the therapy goals for this neurodegenerative disease. Herein, a novel compound named melatonin-trientine (TM) has been covalently synthesized with the natural antioxidant compounds melatonin and the metal ion chelator trientine. After toxicological and pharmacokinetic verification, we elucidated the effects of intraperitoneal administration of TM on AD-like pathology in 6-month-old mice that express both the ß-amyloid (Aß) precursor protein and presenilin-1 (APP/PS1). We found that TM significantly decreased Aß deposition and neuronal degeneration in the brains of the APP/PS1 double transgenic mice. This result may be due to the upregulation of iron regulatory protein-2 (IRP2), insulin degrading enzyme (IDE), and low density lipoprotein receptor related protein 1 (LRP1), which leads to decreases in APP and Aß levels. Additionally, TM may promote APP non-amyloidogenic processing by activating the melatonin receptor-2 (MT2)-dependent signaling pathways, but not MT1. In addition, TM plays an important role in blocking γ-secretase, tau hyperphosphorylation, neuroinflammation, oxidative stress, and metal ion dyshomeostasis. Our results suggest that TM may effectively maximize the therapeutic efficacy of targeting multiple mechanisms associated with AD pathology.

Asunto(s)

Enfermedad de Alzheimer , Melatonina , Enfermedades Neurodegenerativas , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Quelantes/farmacología , Modelos Animales de Enfermedad , Melatonina/farmacología , Melatonina/uso terapéutico , Ratones , Ratones Transgénicos , Trientina/uso terapéutico

RESUMEN

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

RESUMEN

Two-dimensional materials provide extraordinary opportunities for exploring phenomena arising in atomically thin crystals. Beginning with the first isolation of graphene, mechanical exfoliation has been a key to provide high-quality two-dimensional materials, but despite improvements it is still limited in yield, lateral size and contamination. Here we introduce a contamination-free, one-step and universal Au-assisted mechanical exfoliation method and demonstrate its effectiveness by isolating 40 types of single-crystalline monolayers, including elemental two-dimensional crystals, metal-dichalcogenides, magnets and superconductors. Most of them are of millimeter-size and high-quality, as shown by transfer-free measurements of electron microscopy, photo spectroscopies and electrical transport. Large suspended two-dimensional crystals and heterojunctions were also prepared with high-yield. Enhanced adhesion between the crystals and the substrates enables such efficient exfoliation, for which we identify a gold-assisted exfoliation method that underpins a universal route for producing large-area monolayers and thus supports studies of fundamental properties and potential application of two-dimensional materials.

RESUMEN

Enantioselective alkynylation of cyclic N-sulfonyl α-ketiminoesters with terminal alkynes was developed by using an Ni(ClO4)2/(R)-DTBM-Segphos complex as a catalyst. A range of propargylic amides bearing quaternary stereocenters were afforded in excellent enantioselectivities (up to 97% ee). Theoretical studies revealed that this reaction proceeded via a Friedel-Crafts-type reaction pathway.

RESUMEN

A Ni(ClO4)2-catalyzed enantioselective [2 + 2] cycloaddition of N-allenamides with cyclic N-sulfonylketimines was developed, which regioselectively occurred at the proximal C[double bond, length as m-dash]C bonds of the N-allenamides. Broad substrate scope of N-allenamides and cyclic N-sulfonylketimines was observed. A range of fused polysubstituted azetidines bearing quaternary stereocenters were afforded in good yields and with excellent enantioselectivities (up to 99%).

RESUMEN

A number of epidemiological studies have established a link between Alzheimer's disease (AD) and diabetes mellitus (DM). So, nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) plays an important role in the treatment of AD. However, current PPARγ-targeting drugs such as thiazolidinediones (TZDs) are associated with undesirable side effects. We identified herbal extract with a small molecular, astragaloside IV (AS-IV), as a selective PPARγ natural agonist in nervous cells by developing a PPAR-PPRE pathway regulatory system. Cultured SH-SY5Y cells transfected with pEGFP-N1-BACE1 were treated with AS-IV for 24 h or AS-IV plus the PPAR-γ antagonist GW9662 in vitro. APP/PS1 mice were intragastrically treated with AS-IV or AS-IV plus the GW9662 every 48 h for 3 months. Immunofluorescence, western blotting, and real-time PCR were used to examine the expression of PPARγ and BACE1. Immunohistochemical staining was performed to analyze the distribution of Aß plaques in the APP/PS1 mouse brain. The levels of Aß were determined using ELISA kits. AS-IV was shown to be a PPARγ agonist by establishing a high-throughput screening model for PPARγ agonists. The results showed that AS-IV treatment increased activity of PPARγ and inhibited BACE1 in vitro. As a result, Aß levels decreased significantly. GW9662, which is a PPARγ antagonist, significantly blocked the beneficial role of AS-IV. In vivo, AS-IV treatment increased PPARγ and BACE1 expression and reduced neuritic plaque formation and Aß levels in the brains of APP/PS1 mice. These effects of AS-IV could be effectively inhibited by GW9662. These results indicate that AS-IV may be a natural PPARγ agonist that suppressed activity of BACE1 and ultimately attenuates generation of Aß. Therefore, AS-IV may be a promising agent for modulating Aß-related pathology in AD.

Asunto(s)

Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Péptidos beta-Amiloides/biosíntesis , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , PPAR gamma/agonistas , Saponinas/uso terapéutico , Triterpenos/uso terapéutico , Enfermedad de Alzheimer/complicaciones , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Línea Celular Tumoral , Genes Reporteros , Humanos , Ligandos , Luciferasas/metabolismo , Ratones Endogámicos C57BL , Ratones Transgénicos , PPAR gamma/metabolismo , Placa Amiloide/complicaciones , Placa Amiloide/metabolismo , Placa Amiloide/patología , Plásmidos/metabolismo , Presenilina-1/metabolismo , Elementos de Respuesta/genética , Saponinas/farmacología , Transfección , Triterpenos/farmacología

RESUMEN

We performed angle-resolved photoemission spectroscopy studies on a series of FeTe1-xSex monolayer films grown on SrTiO3. The superconductivity of the films is robust and rather insensitive to the variations of the band position and effective mass caused by the substitution of Se by Te. However, the band gap between the electron- and hole-like bands at the Brillouin zone center decreases towards band inversion and parity exchange, which drive the system to a nontrivial topological state predicted by theoretical calculations. Our results provide a clear experimental indication that the FeTe1-xSex monolayer materials are high-temperature connate topological superconductors in which band topology and superconductivity are integrated intrinsically.

RESUMEN

OBJECTIVE: Amyloid-beta (Abeta) is a 36-43 amino acid peptide that is derived by processing of the beta-amyloid precursor protein (APP). Abeta plays a central role in the development of Alzheimer's disease (AD). Although growing evidence suggests that insulin has important functions in Abeta metabolism, the underlying mechanisms are still unknown. METHODS: Using an SH-SY5Y cell line overexpressing human APP Swedish mutant (APPsw), we evaluated the effect of insulin on APP processing and Abeta production by using western blot analysist. RESULTS: Our data showed that administration of insulin reduced the Abeta generation in culture media with a concomitant decreases in the levels of beta-secretase BACE1, secreted extracellular domain (sAPPbeta) and a fragment of 99 amino acids (C99) in APPsw cells. We further showed that insulin increased the levels of alpha-secretase ADAM10, a secreted extracellular domain secreted (sAPPa) and a fragment of 83 amino acids (C83) in APPsw cells. CONCLUSION: Our present data suggest that insulin could inhibit Abeta production through modulation of APP processing by increasing cleavage at the a-secretase site and decreased cleavage at the beta-secretase sites.

Asunto(s)

Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Precursor de Proteína beta-Amiloide/metabolismo , Insulina/farmacología , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Enfermedad de Alzheimer/genética , Secretasas de la Proteína Precursora del Amiloide/genética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Células Cultivadas , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Humanos , Modelos Biológicos

RESUMEN

BACKGROUND: An increasing number of studies have demonstrated of that diabetes mellitus (DM) is associated with an increased prevalence of Alzheimer disease (AD), the underlying mechanisms are still obscure. METHODS: We developed a streptozotocin (STZ)-induced diabetic AD transgenic mouse model and evaluated the effect of hyperglycemia on senile plaque formation. RESULTS: Our data showed that administration of STZ increased the level of blood glucose and increased the advanced glycation end products (AGEs) in brain tissue, and further enhanced the expression levels of the receptor for AGEs (RAGE) and the nuclear factor-kappa B (NF-κB) in the brain, and accelerated the senile plaque formation in the transgenic mice. Our results showed that STZ-induced insulin-deficient hyperglycemia caused the pathophysiology of AD in APP/PS1 transgenic mice by modulating the AGEs/RAGE/NF-κB pathway. CONCLUSIONS: Our study suggests that there is a close linkage of DM and cerebral amyloidosis in the pathogenesis of AD.

Asunto(s)

Enfermedad de Alzheimer/metabolismo , Diabetes Mellitus Experimental/metabolismo , Productos Finales de Glicación Avanzada/metabolismo , FN-kappa B/biosíntesis , Placa Amiloide/metabolismo , Receptores Inmunológicos/biosíntesis , Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/patología , Animales , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/patología , Masculino , Ratones , Ratones Transgénicos , Placa Amiloide/etiología , Placa Amiloide/patología , Receptor para Productos Finales de Glicación Avanzada

RESUMEN

We elucidate the existing controversies in the newly discovered K-doped iron selenide (K(x)Fe(2-y)Se(2-z)) superconductors. The stoichiometric KFe(2)Se(2) with √2 × âˆš2 charge ordering was identified as the parent compound of K(x)Fe(2-y)Se(2-z) superconductor using scanning tunneling microscopy and spectroscopy. The superconductivity is induced in KFe(2)Se(2) by either Se vacancies or interacting with the antiferromagnetic K(2)Fe(4)Se(5) compound. In total, four phases were found to exist in K(x)Fe(2-y)Se(2-z): parent compound KFe(2)Se(2), superconducting KFe(2)Se(2) with √2 × âˆš5 charge ordering, superconducting KFe(2)Se(2-z) with Se vacancies, and insulating K(2)Fe(4)Se(5) with √5 × âˆš5 Fe vacancy order. The phase separation takes place at the mesoscopic scale under standard molecular beam epitaxy conditions.

RESUMEN

Valproate (VPA) is a widely used anticonvulsant and mood-stabilizing drug. Recent studies have shown that VPA could reduce amyloid-ß generation, and improve memory deficits in transgenic mouse models of Alzheimer's disease (AD). However, whether VPA affects tau phosphorylation and the underlying mechanism has not been established. Here, we showed that systemic treatment of APP and presenilin 1 double transgenic mice with VPA (50mg/kg, once a day for 12 weeks), significantly reduced the levels of tau phosphorylation at the sites of Thr205, Ser396 and Thr231. Meanwhile, VPA treatment markedly reduced the activities of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3ß (GSK3ß), two protein kinases involved in abnormal hyperphosphorylation of tau. In an okadaic acid-induced tau hyperphosphorylation SH-SY5Y cell model, the anti-tau-phosphorylation effect of VPA was further confirmed, accompanied by a marked decrease in the activities of CDK5 and GSK3ß. Our present data suggest that the inhibitory effects of VPA on tau hyperphosphorylation might be mediated through both CDK5 and GSK3ß signaling pathways.

Asunto(s)

Quinasa 5 Dependiente de la Ciclina/metabolismo , Inhibidores Enzimáticos/farmacología , Glucógeno Sintasa Quinasa 3/metabolismo , Transducción de Señal/efectos de los fármacos , Ácido Valproico/farmacología , Proteínas tau/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Calpaína/farmacología , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Humanos , Ratones , Ratones Transgénicos , Neuroblastoma , Fosforilación/efectos de los fármacos , Presenilina-1/genética , Treonina/metabolismo

RESUMEN

The spin-3/2 fermion models with contact interactions have a generic SO5 symmetry without any fine-tuning of parameters. Its physical consequences are discussed in both the continuum and lattice models. A Monte Carlo algorithm free of the sign problem at any doping and lattice topology is designed when the singlet and quintet interactions satisfy U0< or = U2< or = -3/5 U0 (U0< or = 0), thus making it possible to study different competing orders with high numerical accuracy. This model can be accurately realized in ultracold atomic systems.

RESUMEN

We propose a microscopic state for the vortex phase of BSCO superconductors. Around the vortex core or above H(c2), the d wave hole pairs form a checkerboard localized in the antiferromagnetic background. We discuss this theory in connection with recent STM experiments.