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1.
Chem Soc Rev ; 49(1): 32-48, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31802082

RESUMO

The radical-involved 1,2-difunctionalization of alkenes has developed into a robust tool for preparation of complex organic molecules. Despite significant advances in this area, the catalytic asymmetric version still remains a challenging task mainly due to the difficulty in the stereocontrol of the highly reactive radical intermediates. Recently, owing to the good single-electron transfer ability and coordination with chiral ligands of copper catalysts, remarkable achievements in radical-involved asymmetric alkene difunctionalization have been made via synergistic combination of copper and chiral ligands. This tutorial review highlights the recent progress in copper-catalysed radical-involved asymmetric 1,2-difunctionalization of alkenes and the mechanistic scenarios governing the stereocontrol, with an emphasis on utilization of chiral ligands.

2.
Acc Chem Res ; 53(1): 170-181, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31657546

RESUMO

Asymmetric functionalization of alkyl radicals represents a robust yet underdeveloped method for efficient construction and decoration of carbon skeletons in chiral organic molecules. In this field, we have been inspired by the excellent redox, alkyl radical trapping, and Lewis acidic properties of copper to develop several catalytic modes for asymmetric reactions involving alkyl radicals. At the beginning, we discovered tandem radical hydrotrifluoromethylation of unactivated alkenes and enantioselective alkoxylation of remote C(sp3)-H bonds by copper/chiral phosphate relay catalysis. This success has stimulated us to develop an asymmetric three-component 1,2-dicarbofunctionalization of 1,1-diarylalkenes using a similar strategy via radical intermediates. Meanwhile, we also discovered a copper/chiral secondary amine cooperative catalyst for asymmetric radical intramolecular cyclopropanation of alkenes using α-aldehyde methylene groups as C1 sources. The trapping of alkyl radical intermediates by CuII species during the reaction was essential for the chemoselectivity toward cyclopropanation. Encouraged by the efficient enantiocontrol with chiral phosphate and the effective trapping of alkyl radicals with CuII species, we then sought to develop copper/chiral phosphate as a single-electron-transfer catalyst for asymmetric reactions involving alkyl radicals. Subsequently, we successfully achieved a series of highly enantioselective 1,2-aminofluoroalkylation, -aminoarylation, -diamination, -aminosilylation, and -oxytrifluoromethylation of unactivated alkenes. The key for high enantioinduction was believed to be the effective trapping of alkyl radicals by CuII/chiral phosphate complexes. Besides, an achiral pyridine ligand was found to be indispensable for achieving high enantioselectivity, presumably via stabilization of CuIII species in the 1,2-alkoxytrifluoromethylation reaction. This discovery reminded us of tuning the redox properties and chemoreactivity of copper centers with an ancillary ligand. As a result, we subsequently identified cinchona alkaloid-derived sulfonamides as novel neutral-anionic hybrid ligands for simultaneous chemo- and enantiocontrol. We thus accomplished highly enantioselective 1,2-iminoxytrifluoromethylation of unactivated alkenes under the catalysis of copper/cinchona alkaloid-derived sulfonamide ligand, affording trifluoromethylated isoxazolines in high enantiomeric excess. Our copper-catalyzed asymmetric reactions with alkyl radicals provide expedient access to a diverse range of valuable chiral molecules with broad application potential in areas of organic synthesis, medicine, agrochemical, and material sciences.

3.
J Appl Toxicol ; 40(2): 257-269, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31599005

RESUMO

Calcium channel blocker (CCB) poisoning is a common and sometimes life-threatening emergency. Our previous studies have shown that acetyl l-carnitine (ALCAR) prevents cardiotoxicity and developmental toxicity induced by verapamil, a CCB used to treat patients with hypertension. Here, we tested whether toxicities of nifedipine, a dihydropyridine CCB used to treat hypertension, can also be mitigated by co-treatment with ALCAR. In the zebrafish embryos at three different developmental stages, nifedipine induced developmental toxicity with pericardial sac edema in a dose-dependent manner, which were surprisingly exacerbated with ALCAR co-treatment. Even with low-dose nifedipine (5 µm), when the pericardial sac looked normal, ALCAR co-treatment showed pericardial sac edema. We hypothesized that toxicity by nifedipine, a vasodilator, may be prevented by ketamine, a known vasoconstrictor. Nifedipine toxicity in the embryos was effectively prevented by co-treatment with low (subanesthetic) doses (25-100 µm added to the water) of ketamine, although a high dose of ketamine (2 mm added to the water) partially prevented the toxicity.As expected of a CCB, nifedipine either in the presence or absence of ketamine-reduced metabolic reactive oxygen species (ROS), a downstream product of calcium signaling, in the rapidly developing digestive system. However, nifedipine induced ROS in the trunk region that showed significantly stunted growth indicating that the tissues under stress potentially produced pathologic ROS. To the best of our knowledge, these studies for the first time show that nifedipine and the dietary supplement ALCAR together induce adverse effects while providing evidence on the therapeutic efficacy of subanesthetic doses of ketamine against nifedipine toxicity in vivo.

4.
Angew Chem Int Ed Engl ; 59(3): 1129-1133, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31703156

RESUMO

Radical-involved enantioselective oxidative C-H bond functionalization by a hydrogen-atom transfer (HAT) process has emerged as a promising method for accessing functionally diverse enantioenriched products, while asymmetric C(sp3 )-H bond amination remains a formidable challenge. To address this problem, described herein is a dual CuI /chiral phosphoric acid (CPA) catalytic system for radical-involved enantioselective intramolecular C(sp3 )-H amination of not only allylic positions but also benzylic positions with broad substrate scope. The use of 4-methoxy-NHPI (NHPI=N-hydroxyphthalimide) as a stable and chemoselective HAT mediator precursor is crucial for the fulfillment of this transformation. Preliminary mechanistic studies indicate that a crucial allylic or benzylic radical intermediate resulting from a HAT process is involved.

5.
Mol Neurobiol ; 57(1): 32-40, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31487003

RESUMO

One of the most abundant proteins expressed in the brain, 14-3-3 comprises about 1% of the brain's total soluble proteins. The 14-3-3 isoforms bind to specific phosphoserine- and phosphothreonine-containing motifs found on a variety of signaling proteins (kinases and transcription factors, among others) to regulate a wide array of cellular processes including cell cycling, apoptosis, and autophagy. Previously, we described the expression of different 14-3-3 isoforms in the rat frontal cortex and reported their downregulation in a rodent model of neurodegeneration. To further investigate possible roles of 14-3-3 proteins in neurodegeneration, the present study examined different 14-3-3 isoforms in the frontal cortex of postmortem Alzheimer's disease (AD) patients and control subjects. Among the different 14-3-3 isoforms in the human frontal cortex, the relative abundance of expression is in the following order: 14-3-3-eta > tau > sigma > gamma > epsilon > zeta/delta > beta/alpha. These relative abundance levels of different 14-3-3 isoforms in human frontal cortex closely resemble those in rat frontal cortex, suggesting a conserved expression pattern of different 14-3-3 isoforms in mammalian species. In the AD samples, there was a significant decrease in total 14-3-3 levels and the 14-3-3-eta and 14-3-3-gamma isoforms, while no significant difference in the expression level of other 14-3-3 isoforms between AD and control brains was detected. Together, these results demonstrate an abundance of several 14-3-3 isoforms in the frontal cortex and that a downregulation of total 14-3-3 protein levels and specific 14-3-3 isoforms is associated with neurodegeneration. Given the known function of 14-3-3 proteins as inhibitors of apoptosis, the present results suggest that 14-3-3 proteins may play an important role in neurodegeneration and deserve further investigations into AD and other neurodegenerative disorders.

6.
Nat Commun ; 10(1): 5689, 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31831750

RESUMO

Transition metal-catalyzed enantioselective Sonogashira-type oxidative C(sp3)-C(sp) coupling of unactivated C(sp3)-H bonds with terminal alkynes has remained a prominent challenge. The difficulties mainly stem from the regiocontrol in unactivated C(sp3)-H bond functionalization and the inhibition of readily occurring Glaser homocoupling of terminal alkynes. Here, we report a copper/chiral cinchona alkaloid-based N,N,P-ligand catalyst for asymmetric oxidative cross-coupling of unactivated C(sp3)-H bonds with terminal alkynes in a highly regio-, chemo-, and enantioselective manner. The use of N-fluoroamide as a mild oxidant is essential to site-selectively generate alkyl radical species while efficiently avoiding Glaser homocoupling. This reaction accommodates a range of (hetero)aryl and alkyl alkynes; (hetero)benzylic and propargylic C(sp3)-H bonds are all applicable. This process allows expedient access to chiral alkynyl amides/aldehydes. More importantly, it also provides a versatile tool for the construction of chiral C(sp3)-C(sp), C(sp3)-C(sp2), and C(sp3)-C(sp3) bonds when allied with follow-up transformations.

7.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(11): 1124-1130, 2019 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-31753096

RESUMO

OBJECTIVE: To investigate the effects of calcium-sensitive receptors (CaSR) on the expression of 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) and cortisol concentration in a neonatal mouse model of persistent pulmonary hypertension (PPH). METHODS: Fifty-six newborn C57BL/6 mice were randomly divided into a control group (n=14), a PPH group (n=14), an agonist group (n=14), and an inhibitor group (n=14). The mice in the PPH, agonist, and inhibitor groups were exposed to a 12% oxygen concentration, and the agonist group and inhibitor group were given CaSR agonist (GdCl3, 16 mg/kg) and CaSR antagonist (NPS2390, 1 mg/kg) intraperitoneally once a day, respectively. The mice in control group were exposed to air, and then injected with an equal volume of normal saline as those in the PPH group every day. All mice were treated for 14 days. Morphological examination of heart and lung tissues was performed using hematoxylin-eosin staining. The expression levels of 11ß-HSD2 mRNA and 11ß-HSD2 protein in lung tissues were measured by qRT-PCR and Western blot respectively. Brain natriuretic peptide (BNP) and cortisol levels in lung tissues were determined using ELISA. RESULTS: Compared with the control group, the PPH group had significantly increased pulmonary artery wall thickness (WT%), ratio of right to left ventricular thickness (RV/LV), alveolar mean linear intercept, and BNP concentration and a significantly reduced radial alveolar count (P<0.05); compared with the PPH group, the agonist group showed significant increases in WT% and BNP concentration, while the inhibitor group showed significant reductions in the two indicators (P<0.05). Compared with the control group, the PPH group showed significant reductions in the expression levels of 11ß-HSD2 mRNA and 11ß-HSD2 protein, but a significant increase in cortisol concentration (P<0.05); compared with the PPH group, the agonist group had significantly lower expression levels of 11ß-HSD2 mRNA and 11ß-HSD2 protein, but a significant higher cortisol concentration, while the inhibitor group showed opposite changes in these indicators (P<0.05). CONCLUSIONS: CaSR may control the development and progression of PPH in newborn mice by regulating the expression of 11ß-HSD2 and cortisol concentration.


Assuntos
Hipertensão Pulmonar , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2 , Animais , Animais Recém-Nascidos , Cálcio , Hidrocortisona , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Detecção de Cálcio
8.
Nat Chem ; 11(12): 1158-1166, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31636393

RESUMO

Continued development of the Sonogashira coupling has made it a well established and versatile reaction for the straightforward formation of C-C bonds, forging the carbon skeletons of broadly useful functionalized molecules. However, asymmetric Sonogashira coupling, particularly for C(sp3)-C(sp) bond formation, has remained largely unexplored. Here we demonstrate a general stereoconvergent Sonogashira C(sp3)-C(sp) cross-coupling of a broad range of terminal alkynes and racemic alkyl halides (>120 examples) that are enabled by copper-catalysed radical-involved alkynylation using a chiral cinchona alkaloid-based P,N-ligand. Industrially relevant acetylene and propyne are successfully incorporated, laying the foundation for scalable and economic synthetic applications. The potential utility of this method is demonstrated in the facile synthesis of stereoenriched bioactive or functional molecule derivatives, medicinal compounds and natural products that feature a range of chiral C(sp3)-C(sp/sp2/sp3) bonds. This work emphasizes the importance of radical species for developing enantioconvergent transformations.

9.
World J Pediatr ; 15(5): 454-464, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31372844

RESUMO

BACKGROUND: Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare neurological degenerative disorder caused by the mutations of MLC1 or GLIALCAM with autosomal recessive or autosomal dominant inheritance and a different prognosis, characterized by macrocephaly, delayed motor and cognitive development, and bilateral abnormal signals in cerebral white matter (WM) with or without cysts on magnetic resonance imaging (MRI). This study aimed to reveal the clinical and genetic features of MLC patients with GLIALCAM mutations and to explore the brain pathological characteristics and prognosis of mouse models with different modes of inheritance. METHODS: Clinical information and peripheral venous blood were collected from six families. Genetic analysis was performed by Sanger sequencing of GLIALCAM. GlialcamArg92Trp/+ and GlialcamLys68Met/Thr132Asn mouse models were generated based on mutations from patients (c.274C>T(p.Arg92Trp) (c.203A>T(p.Lys68Met), and c.395C>A (p.Thr132Asn))). Brain pathologies of the mouse models at different time points were analyzed. RESULTS: Six patients were clinically diagnosed with MLC. Of the six patients, five (Pt1-Pt5) presented with a heterozygous mutation in GLIALCAM (c.274C>T(p.Arg92Trp) or c.275G>C(p.Arg92Pro)) and were diagnosed with MLC2B; the remaining patient (Pt6) with two compound heterozygous mutations in GLIALCAM (c.203A>T (p.Lys68Met) and c.395C>A (p.Thr132Asn)) was diagnosed with MLC2A. The mutation c.275C>G (p.Arg92Pro) has not been reported before. Clinical manifestations of the patient with MLC2A (Pt6) progressed with regression, whereas the course of the five MLC2B patients remained stable or improved. The GlialcamArg92Trp/+ and GlialcamLys68Met/ Thr132Asn mouse models showed vacuolization in the anterior commissural WM at 1 month of age and vacuolization in the cerebellar WM at 3 and 6 months, respectively. At 9 months, the vacuolization of the GlialcamLys68Met/ Thr132Asn mouse model was heavier than that of the GlialcamArg92Trp/+ mouse model. Decreased expression of Glialcam in GlialcamArg92Trp/+ and GlialcamLys68Met/ Thr132Asn mice may contribute to the vacuolization. CONCLUSIONS: Clinical and genetic characterization of patients with MLC and GLIALCAM mutations revealed a novel mutation, expanding the spectrum of GLIALCAM mutations. The first Glialcam mouse model with autosomal recessive inheritance and a new Glialcam mouse model with autosomal dominant inheritance were generated. The two mouse models with different modes of inheritance showed different degrees of brain pathological features, which were consistent with the patients' phenotype and further confirmed the pathogenicity of the corresponding mutations.

10.
Mol Divers ; 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31309395

RESUMO

An efficient strategy for synthesizing of 3-substituted bis-isoxazole ether bearing 2-chloro-3-pyridyl under microwave radiation was reported. The reactive regioselectivity was improved by changing mainly the solvent and acid-binding agent. 3-(2-Chloropyridin-3-yl)-5-(((3-substituted phenyl isoxazol-5-yl)methoxy)methyl)isoxazoles were synthesized in 31-92% yields and were characterized by FT-IR, HRMS, 1H and 13C NMR spectroscopy. The single crystal of 3-(2-chloropyridin-3-yl)-5-(((3-(p-tolyl)isoxazol-5-yl)methoxy)methyl)isoxazole was obtained, and the structure of compound has also been determined by X-ray diffraction technique. Weak intra- and intermolecular C-H∙∙∙O interactions and a C-H∙∙∙π interaction link molecules into a three-dimensional network. The results showed that the synthesized compounds belonged to triclinic system, and their regioselectivity depended on the solvent and acid-binding agent. The merits of this method include the environmentally friendly, efficient, simple operation, and higher regional selectivity. An efficient synthesis of 3-substituted bis-isoxazole ethers was developed via 1,3-dipolar cycloaddition reaction starting from 3-substituted phenyl-5-((prop-2-yn-1-yloxy))methyl)isoxazoles and (Z)-2-chloro-N-hydroxynicotinimidoyl chloride using NaHCO3 as an acid-binding agent in THF solvent-dissolved trace water under catalyst-free microwave-assisted conditions.

11.
Int J Toxicol ; 38(5): 385-394, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31234669

RESUMO

Conventional in vitro assays are often used as initial screens to identify potential toxic effects of nanoparticles (NPs). However, many NPs have shown interference with conventional in vitro assays, resulting in either false-positive or -negative outcomes. Here, we report an alternative method for the in vitro assessment of NP-induced cytotoxicity utilizing Fluoro-Jade C (FJ-C). To provide proof of concept and initial validation data, Ag-NPs and Au-NPs were tested in 3 different cell cultures including rat brain microvessel endothelial cells, mouse neural stem cells, and the human SH-SY5Y cell line. Conventional 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) and lactate dehydrogenase (LDH) assays were run in parallel with the new method and served as references. The results demonstrate for the first time that FJ-C labeling can be a useful tool for assessing NP-induced cytotoxicity in vitro. Using these approaches, it was also demonstrated that removal of Ag-NPs-while keeping the Ag-ions that were released from the Ag-NPs in culture media-abolished the measured cytotoxicity, indicating that Ag-NPs rather than Ag-ions in solution contributed to the observed cytotoxic effects. Further, co-treatment of Ag-NPs with N-acetyl cysteine (NAC) prevented the observed cytotoxicity, suggesting a protective role of NAC in Ag-NP-induced cytotoxicity. Thus, this alternative in vitro assay is well suited for identify potential cytotoxicity associated with exposure to NPs.

12.
BMC Med Genet ; 20(1): 76, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-31064337

RESUMO

BACKGROUND: Brown-Vialetto-Van Laere Syndrome (BVVLS), a rare neurological disorder characterized by motor, sensory, and cranial neuronopathies, is mainly associated with defective riboflavin transporters encoded by SLC52A2 and SLC52A3 genes. Clinical outcomes have been shown to be improved significantly by high-dose riboflavin supplementation. The aim of this study was to identify genetic causes and further evaluate the clinical course and response to riboflavin in a Chinese pedigree with BVVLS. CASE PRESENTATION: We report the novel compound heterozygous variants c.1328G>A p.(Cys443Tyr) and c.1022_1023insC p. (Leu341Profs*103) of SLC52A2 gene in a female proband who presented in our out-patient clinic at the age of one-year-old with progressive mental and motor regression, breath holding, and brain stem dysfunction including facial weakness, hearing loss, dysphagia. Following high-dose riboflavin supplementation, the respiratory insufficiency and mental, motor, and bulbar function improved. However, sensorineural hearing loss was not improved. The missense variant site was highly conserved. Both variants were not found in the population database gnomAD. The two variants were inherited from her mother and father, respectively. Both variants were predicted to be deleterious by Polyphen2, Mutation taster, and SIFT and were classified as likely pathogenic according to the ACMG guideline. CONCLUSIONS: Two novel pathogenic variations of SLC52A2 gene were firstly found from a Chinese pedigree with BVVLS. Clinical outcomes could be improved by early diagnosis and riboflavin supplementation.


Assuntos
Paralisia Bulbar Progressiva/genética , Perda Auditiva Neurossensorial/genética , Mutação , Receptores Acoplados a Proteínas-G/genética , Sequência de Aminoácidos , China , Feminino , Humanos , Lactente , Masculino , Linhagem , Receptores Acoplados a Proteínas-G/química , Homologia de Sequência de Aminoácidos
13.
Neurosci Lett ; 706: 36-42, 2019 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-31078678

RESUMO

Ketamine, an anesthetic, is a non-competitive antagonist of the calcium-permeable N-methyl-d-aspartate (NMDA) receptor. High concentrations of ketamine have been implicated in cardiotoxicity and neurotoxicity. Often, these toxicities are thought to be mediated by reactive oxygen species (ROS). However, findings to the contrary showing ketamine reducing ROS in mammalian cells and neurons in vitro, are emerging. Here, we determined the effects of ketamine on ROS levels in zebrafish larvae in vivo. Based on our earlier studies demonstrating reduction in ATP levels by ketamine, we hypothesized that as a calcium antagonist, ketamine would also prevent ROS generation, which is a by-product of ATP synthesis. To confirm that the detected ROS in a whole organism, such as the zebrafish larva, is specific, we used diphenyleneiodonium (DPI) that blocks ROS production by inhibiting the NADPH Oxidases (NOX). Upon 20 h exposure, DPI (5 and 10 µM) and ketamine at (1 and 2 mM) reduced ROS in the zebrafish larvae in vivo. Using acetyl l-carnitine (ALCAR), a dietary supplement, that induces mitochondrial ATP synthesis, we show elevated ROS generation with increasing ALCAR concentrations. Combined, ketamine and ALCAR counter-balanced ROS generation in the larvae suggesting that ketamine and ALCAR have opposing effects on mitochondrial metabolism, which may be key to maintaining ROS homeostasis in the larvae and affords ALCAR the ability to prevent ketamine toxicity. These results for the first time show ketamine's antioxidative and ALCAR's prooxidative effects in a live vertebrate.


Assuntos
Acetilcarnitina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ketamina/farmacologia , Neurônios/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Animais , Embrião não Mamífero/efeitos dos fármacos , Microscopia de Fluorescência , Neurônios/metabolismo , Oniocompostos/farmacologia , Peixe-Zebra
14.
BMC Med Genet ; 20(1): 80, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088393

RESUMO

BACKGROUND: Intellectual disability/developmental delay is a complex condition with extraordinary heterogeneity. A large proportion of patients lacks a specific diagnosis. Next generation sequencing, enabling identification of genetic variations in multiple genes, has become an efficient strategy for genetic analysis in intellectual disability/developmental delay. METHODS: Clinical data of 112 Chinese families with unexplained intellectual disability/developmental delay was collected. Targeted next generation sequencing of 454 genes related to intellectual disability/developmental delay was performed for all 112 index patients. Patients with promising variants and their other family members underwent Sanger sequencing to validate the authenticity and segregation of the variants. RESULTS: Fourteen promising variants in genes EFNB1, MECP2, ATRX, NAA10, ANKRD11, DHCR7, LAMA1, NFIX, UBE3A, ARID1B and PTPRD were identified in 11 of 112 patients (11/112, 9.82%). Of 14 variants, eight arose de novo, and 13 are novel. Nine patients (9/112, 8.03%) got definite molecular diagnoses. It is the first time to report variants in EFNB1, NAA10, DHCR7, LAMA1 and NFIX in Chinese intellectual disability/developmental delay patients and first report about variants in NAA10 and LAMA1 in affected individuals of Asian ancestry. CONCLUSIONS: Targeted next generation sequencing of 454 genes is an effective test strategy for patients with unexplained intellectual disability/developmental delay. Genetic heterogenicity is significant in this Chinese cohort and de novo variants play an important role in the diagnosis. Findings of this study further delineate the corresponding phenotypes, expand the mutation spectrum and support the involvement of PTPRD in the disease.


Assuntos
Deficiências do Desenvolvimento/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Deficiência Intelectual/genética , Mutação , Adolescente , Criança , Pré-Escolar , China , Cromossomos Humanos X , Feminino , Genes Dominantes , Genes Recessivos , Heterogeneidade Genética , Humanos , Lactente , Masculino , Linhagem , Fenótipo
15.
Angew Chem Int Ed Engl ; 58(21): 7092-7096, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-30919531

RESUMO

The first highly efficient and practical chiral Brønsted acid catalyzed dynamic kinetic asymmetric hydroamination (DyKAH) of racemic allenes and asymmetric hydroamination of unactivated dienes with both high E/Z selectivity and enantioselectivity are described herein. The transformation proceeds through a new catalytic asymmetric model involving a highly reactive π-allylic carbocationic intermediate, generated from racemic allenes or dienes through a proton transfer mediated by an activating/directing thiourea group. This method affords expedient access to structurally diverse enantioenriched, potentially bioactive alkenyl-containing aza-heterocycles and bicyclic aza-heterocycles.

16.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(2): 189-194, 2019 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-30782286

RESUMO

OBJECTIVE: To study the effect of calcium-sensitive receptors (CaSR) on the expression of endothelial nitric oxide synthase (eNOS) and the concentration of nitric oxide (NO) in a neonatal mouse model of persistent pulmonary hypertension (PPH). METHODS: Eighty neonatal C57BL/6 mice were randomly divided into control, PPH, agonist and antagonist groups. The control group was exposed to air, and the other three groups were exposed to 12% oxygen. The agonist and antagonist groups were intraperitoneally injected with a CaSR agonist (GdCl3 16 mg/kg) and a CaSR antagonist (NPS2390, 1 mg/kg), respectively, while the PPH and control groups were intraperitoneally injected with normal saline instead. All mice were treated for 14 days. Alveolar development and pulmonary vessels were assessed by hematoxylin-eosin staining. The protein and mRNA expression of eNOS and its localization in lung tissues were determined by Western blot, qRT-PCR and immunohistochemistry. The levels of brain natriuretic peptide (BNP) and NO in lung homogenate were determined using ELISA. RESULTS: Compared with the control group, the PPH and agonist groups showed significant increases in alveolar mean linear intercept, the percent wall thickness of pulmonary arterioles, right to left ventricular wall thickness ratio (RV/LV) and BNP concentration, but a significant reduction in radial alveolar count (P<0.05). The antagonist group had significant improvements in all the above indices except RV/LV compared with the PPH and agonist groups (P<0.05). Compared with those in the control group, the protein and mRNA expression of eNOS and NO concentration were significantly increased in the PPH group and increased more significantly in the agonist group, but were significantly reduced in the antagonist group (P<0.05). CONCLUSIONS: CaSR plays an important role in the development of PPH in neonatal mice, possibly by increasing eNOS expression and NO concentration.


Assuntos
Hipertensão Pulmonar , Animais , Animais Recém-Nascidos , Cálcio , Hipóxia , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico , Óxido Nítrico Sintase Tipo III , Receptores de Detecção de Cálcio
17.
Turk J Med Sci ; 49(1): 412-421, 2019 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-30761838

RESUMO

Background/aim: Sphingosine 1-phosphate receptor 2 (S1PR2), a member of the seven-transmembrane receptor family, can be activated by its natural ligand sphingosine 1-phosphate (S1P) to initiate signal transduction and is involved in a wide range of biological effects such as immune cell migration and vascular permeability. Its relationship with neuropathic pain (NP) has not been reported. In this study, the effects of S1PR2 on the development of NP were studied. Materials and methods: We generated a model of NP by partial sciatic nerve ligation (pSNL). The 50% paw withdrawal threshold of the wild-type (WT) group and the S1PR2 deficiency group were measured at several time points after surgery. The inflammatory factor levels of the two groups were measured by real-time quantitative polymerase chain reaction (RT-PCR). Neutrophil infiltration and glial cell activation were detected by immunofluorescence. Matrix metalloproteinase 9 (MMP9) and its substrate myelin basic protein (MBP) were measured by RT-PCR, western blotting, and immunofluorescence. Result: The S1PR2 deficiency group showed a reduction in 50% paw withdrawal threshold compared with WT mice (P < 0.05) at 3 days after the operation. In the ligated sciatic nerve of the S1PR2 deficiency group, the mRNA expression of IL-1ß was increased; the numbers of infiltrating neutrophils and activated astrocytes were also increased. The expression of MMP9 was elevated while MBP was decreased. Conclusion: S1PR2 deficiency could increase the pain sensitivity of a NP mouse model and promote the development of NP


Assuntos
Neuralgia/metabolismo , Receptores de Lisoesfingolipídeo/deficiência , Receptores de Lisoesfingolipídeo/genética , Nervo Isquiático/lesões , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Metaloproteinases da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infiltração de Neutrófilos/genética , Receptores de Lisoesfingolipídeo/metabolismo , Medula Espinal/química
18.
Chem Biodivers ; 16(3): e1800510, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30447139

RESUMO

Seventeen novel 2,5-disubstituted benzimidazole derivatives were designed, synthesized and evaluated for their antibacterial activities. The tested compounds B1-B4 and C2-C6 exhibited not only good antifungal activity but also favorable broad-spectrum antibacterial activity. Also, the lowest MIC of antibacterial and antifungal activity was 2 µg/mL and 4 µg/mL, respectively. It suggested that the structure of compound including the different substituent and its sites directly affected the efficacy of the synthesized compounds.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Bactérias/efeitos dos fármacos , Benzimidazóis/farmacologia , Desenho de Drogas , Fungos/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Benzimidazóis/síntese química , Benzimidazóis/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Micro-Ondas , Estrutura Molecular , Relação Estrutura-Atividade
19.
J Am Chem Soc ; 141(2): 1074-1083, 2019 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-30562464

RESUMO

An asymmetric intermolecular, three-component radical-initiated dicarbofunctionalization of 1,1-diarylalkenes with diverse carbon-centered radical precursors and electron-rich heteroaromatics by a copper(I) and chiral phosphoric acid cooperative catalysis strategy has been developed, providing straightforward access to chiral triarylmethanes bearing quaternary all-carbon stereocenters with high efficiency as well as excellent chemo- and enantioselectivity. The key to success is not only the introduction of a sterically demanding chiral phosphoric acid to favor radical difunctionalization over the otherwise remarkable side reactions but also the in situ generation of carbocation intermediates from benzylic radical to realize asymmetric induction with the aid of a removable hydroxy directing group via cooperative interactions with chiral phosphate. Density functional theory calculations elucidated the critical chiral environment created by the hydrogen-bonding and ion-pair interactions between the chiral phosphoric acid catalyst and substrates, which leads to the enantioselective C-C bond formation.

20.
Curr Neurovasc Res ; 15(4): 336-344, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30468126

RESUMO

INTRODUCTION: Parkinson's Disease (PD) is a debilitating, age-related disorder characterized by selective degeneration of dopaminergic neurons in the midbrain substantia nigra (SNc). Dopaminergic neurons originating in the midbrain project to the striatum (Caudate-putamen-CPU). Although studies have suggested that the extracellular signal-regulated kinase ½ (ERK ½) in the brain is activated after 1-Methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP) exposure, to our knowledge no study has yet been done to demonstrate whether such activation occurs in neurons or in glia. MATERIAL AND METHODS: In the current study, we utilized both an acute and a repeat dose mouse model of PD using the neurotoxicant MPTP as the causative agent. Immunohistochemical studies using phospho ERK ½ antibody suggested that ERK ½ activation takes place in the striatum (CPU) and SNc of both animal models. Moreover, double immunolabeling studies using phospho ERK ½ and the microglial marker, CD11b or the astrocyte marker, Glial Fibrillary Acidic Protein (GFAP) suggested that the phospho ERK ½ was present exclusively in the microglia and not in the astrocytes. RESULTS: Western Blot results suggested that there were no alterations in ERK in either MPTPtreated animals or in control animals; however, phospho ERK ½ was found to be significantly increased in the striatum and SNc in both acute chronic mouse PD models. Tyrosine Hydroxylase (TH) immunolabeling revealed significant decreases in dopaminergic neurons in the SNc in both animal models' concomitant with activation of microglia and ERK activation. CONCLUSION: These observations suggest that ERK activation takes place following MPTP treatment and that activation of ERK occurs primarily in the microglia. The data provided also suggest that ERK activation may be involved in transcriptional activation of microglia following neurotoxicant insults.


Assuntos
Corpo Estriado/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Intoxicação por MPTP/patologia , Microglia/metabolismo , Substância Negra/metabolismo , Animais , Antígeno CD11b/metabolismo , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Tirosina 3-Mono-Oxigenase
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