RESUMO
It is an effective scheme to the phase retrieval for axial intensity derivative computing. In this paper, we demonstrate a method for estimating the axial intensity derivative and improving the calculation accuracy in the transport of intensity equation (TIE) from multiple intensity measurements. The method takes both the higher-order intensity derivatives and the noise into account, and minimizes the impact of detecting noise. The simulation results demonstrate that the proposed method can effectively reduce the error of intensity derivative computing.
Assuntos
Algoritmos , Artefatos , Modelos Teóricos , Fotometria/métodos , Simulação por Computador , Razão Sinal-RuídoRESUMO
Natural product-derived bengamides possess potent antiproliferative activity and target human methionine aminopeptidases for their cellular effects. Using bengamides as a template, several derivatives were designed and synthesized as inhibitors of methionine aminopeptidases of Mycobacterium tuberculosis, and initial antitubercular activity were observed. Here, we present three new X-ray structures of the tubercular enzyme MtMetAP1c in complex with the inhibitors in the Mn(II) form and in the Ni(II) form. All amide moieties of the bengamide derivatives bind to the unique shallow cavity and interact with a flat surface created by His-212 of MtMetAP1c in the Mn(II) form. However, the active site metal has significant influence on the binding mode, because the amide takes a different conformation in the Ni(II) form. The interactions of these inhibitors at the active site provide the structural basis for further modification of these bengamide inhibitors for improved potency and selectivity.
Assuntos
Aminopeptidases/antagonistas & inibidores , Azepinas/química , Azepinas/farmacologia , Mycobacterium tuberculosis/enzimologia , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Aminopeptidases/química , Aminopeptidases/metabolismo , Azepinas/metabolismo , Produtos Biológicos/química , Domínio Catalítico , Desenho de Fármacos , Humanos , Manganês/metabolismo , Metionil Aminopeptidases , Modelos Moleculares , Níquel/metabolismo , Inibidores de Proteases/metabolismoRESUMO
Methionine aminopeptidase (MetAP) carries out an essential function of protein N-terminal processing in many bacteria and is a promising target for the development of novel antitubercular agents. Natural bengamides potently inhibit the proliferation of mammalian cells by targeting MetAP enzymes, and the X-ray crystal structure of human typeâ 2 MetAP in complex with a bengamide derivative reveals the key interactions at the active site. By preserving the interactions with the conserved residues inside the binding pocket while exploring the differences between bacterial and human MetAPs around the binding pocket, seven bengamide derivatives were synthesized and evaluated for inhibition of MtMetAP1a and MtMetAP1c in different metalloforms, inhibition of M.â tuberculosis growth in replicating and non-replicating states, and inhibition of human K562 cell growth. Potent inhibition of MtMetAP1a and MtMetAP1c and modest growth inhibition of M.â tuberculosis were observed for some of these derivatives. Crystal structures of MtMetAP1c in complex with two of the derivatives provided valuable structural information for improvement of these inhibitors for potency and selectivity.
Assuntos
Aminopeptidases/antagonistas & inibidores , Antituberculosos/química , Antituberculosos/farmacologia , Azepinas/química , Azepinas/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Aminopeptidases/química , Aminopeptidases/metabolismo , Linhagem Celular , Sobrevivência Celular , Cristalografia por Raios X , Humanos , Metionil Aminopeptidases , Modelos Moleculares , Mycobacterium tuberculosis/química , Tuberculose/tratamento farmacológicoRESUMO
PURPOSE: The purpose of this study was to explore and discuss the effects of 660-nm gallium-aluminum-arsenide low-energy laser (GaAlAs LEL) irradiation on neural regeneration after acellular nerve allograft repair of the sciatic nerve gap in rats. METHODS: Eight male and female Sprague-Dawley rats were used as nerve donors, and 32 healthy Wistar rats were randomly divided into four groups: normal control group, acellular rat sciatic nerve (ARSN) group, laser group, and autograft group. Twelve weeks after surgery, nerve conduction velocity, restoration rate of tibialis anterior wet muscle weight, myelinated nerve number, and calcitonin gene-related peptide (CGRP) protein and mRNA expression of the spinal cord and muscle at the injury site were quantified and statistically analyzed. RESULTS: Compared with the ARSN group, laser therapy significantly increased nerve conduction velocity, restoration rate of tibialis anterior wet muscle weight, myelinated nerve number, and CGRP protein and mRNA expression of the L(4) spinal cord at the injury site. CONCLUSIONS: These findings demonstrate that 660-nm GaAlAs LEL therapy upregulates CGRP protein and mRNA expression of the L(4) spinal cord at the injury site and increases the rate of regeneration and target reinnervation after acellular nerve allograft repair of the sciatic nerve gap in rats. Low-energy laser irradiation may be a useful, noninvasive adjunct for promoting nerve regeneration in surgically induced defects repaired with ARSN.
