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Acta Pharmacol Sin ; 2022 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-36476808


Normal sensory and cognitive function of the brain relies on its intricate and complex neural network. Synaptogenesis and synaptic plasticity are critical to neural circuit formation and maintenance, which are regulated by coordinated intracellular and extracellular signaling. Growth hormone (GH) is the most abundant anterior pituitary hormone. Its deficiencies could alter brain development and impair learning and memory, while GH replacement therapy in human patients and animal models has been shown to ameliorate cognitive deficits caused by GH deficiency. However, the underlying mechanism remains largely unknown. In this study, we investigated the neuromodulatory function of GH in young (pre-weaning) mice at two developmental time points and in two different brain regions. Neonatal mice were subcutaneously injected with recombinant human growth hormone (rhGH) on postnatal day (P) 14 or 21. Excitatory and inhibitory synaptic transmission was measured using whole-cell recordings in acute cortical slices 2 h after the injection. We showed that injection of rhGH (2 mg/kg) in P14 mice significantly increased the frequency of mEPSCs, but not that of mIPSCs, in both hippocampal CA1 pyramidal neurons and L2/3 pyramidal neurons of the barrel field of the primary somatosensory cortex (S1BF). Injection of rhGH (2 mg/kg) in P21 mice significantly increased the frequency of mEPSCs and mIPSCs in both brain regions. Perfusion of rhGH (1 µM) onto acute brain slices in P14 mice had similar effects. Consistent with the electrophysiological results, the dendritic spine density of CA1 pyramidal neurons and S1BF L2/3 pyramidal neurons increased following in vivo injection of rhGH. Furthermore, NMDA receptors and postsynaptic calcium-dependent signaling contributed to rhGH-dependent regulation of both excitatory and inhibitory synaptic transmission. Together, these results demonstrate that regulation of excitatory and inhibitory synaptic transmission by rhGH occurs in a developmentally dynamic manner, and have important implication for identifying GH treatment strategies without disturbing excitation/inhibition balance.

Chem Commun (Camb) ; 57(65): 8055-8058, 2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34291778


An efficient Pd-catalysed ß-C(sp3)-H arylation of diverse native amides with aryl iodides was developed. This protocol overcomes the necessity of the Thorpe-Ingold effect and features broad substrate scope and good functional group tolerance. The potential application of this protocol is collectively demonstrated by gram-scale synthesis and the synthesis of several bioactive molecules.

Chem Commun (Camb) ; 57(6): 765-768, 2021 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-33355557


Herein, we report a novel strategy to access CH2F-containing ketones through Pd-catalysed ß-selective methyl C(sp3)-H fluorination. The reaction features high regioselectivity and a broad substrate scope, constituting a modular method for the late-stage transformation of the native methyl (CH3) into the monofluoromethyl (CH2F) group.

Chem Commun (Camb) ; 55(49): 7049-7052, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31143893


A palladium catalyzed selective C(sp3)-H arylation and acetoxylation of alcohols using a practical bidentate auxiliary were developed. Masked alcohols were selectively arylated at the ß-position with diverse aryl iodides for the first time. Moreover, an efficient and site-selective acetoxylation of various primary methyl, methylene, and benzylic C(sp3)-H bonds was performed by using cheap K2S2O8 as the external oxidant.

Chem Commun (Camb) ; 55(14): 2019-2022, 2019 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-30564815


A novel palladium catalyzed highly para-selective C-H difluoromethylation of electron-deficient aromatic carbonyls was developed. Diverse substituted aromatic ketones and benzoates were selectively difluoromethylated at the remote para-site of carbonyl groups in moderate to good yields. Moreover, the difuoromethylation was also compatible with several complex bioactive molecules.

Neuron ; 94(6): 1155-1172.e8, 2017 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-28641114


The formation of functional synapses requires coordinated assembly of presynaptic transmitter release machinery and postsynaptic trafficking of functional receptors and scaffolds. Here, we demonstrate a critical role of presynaptic cadherin/catenin cell adhesion complexes in stabilizing functional synapses and spines in the developing neocortex. Importantly, presynaptic expression of stabilized ß-catenin in either layer (L) 4 excitatory neurons or L2/3 pyramidal neurons significantly upregulated excitatory synaptic transmission and dendritic spine density in L2/3 pyramidal neurons, while its sparse postsynaptic expression in L2/3 neurons had no such effects. In addition, presynaptic ß-catenin expression enhanced release probability of glutamatergic synapses. Newly identified ß-catenin-interacting protein p140Cap is required in the presynaptic locus for mediating these effects. Together, our results demonstrate that cadherin/catenin complexes stabilize functional synapses and spines through anterograde signaling in the neocortex and provide important molecular evidence for a driving role of presynaptic components in spinogenesis in the neocortex.

Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Caderinas/metabolismo , Adesão Celular , Espinhas Dendríticas/metabolismo , Neocórtex/metabolismo , Terminações Pré-Sinápticas/metabolismo , Células Piramidais/metabolismo , beta Catenina/metabolismo , Animais , Antígenos CD/metabolismo , Western Blotting , Proteínas de Transporte/metabolismo , Células HEK293 , Humanos , Imunoprecipitação , Camundongos , Camundongos Knockout , Neocórtex/embriologia , Proteínas do Tecido Nervoso/metabolismo , Ratos , Sinapses/metabolismo