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BACKGROUND: Inflammatory bowel disease (IBD) represents a significant global health challenge, and there is an urgent need to explore novel therapeutic interventions. Natural products have demonstrated highly promising effectiveness in the treatment of IBD. PURPOSE: This study systematically reviews the latest research advancements in leveraging natural products for IBD treatment. METHODS: This manuscript strictly adheres to the PRISMA guidelines. Relevant literature on the effects of natural products on IBD was retrieved from the PubMed, Web of Science and Cochrane Library databases using the search terms "natural product," "inflammatory bowel disease," "colitis," "metagenomics", "target identification", "drug delivery systems", "polyphenols," "alkaloids," "terpenoids," and so on. The retrieved data were then systematically summarized and reviewed. RESULTS: This review assessed the different effects of various natural products, such as polyphenols, alkaloids, terpenoids, quinones, and others, in the treatment of IBD. While these natural products offer promising avenues for IBD management, they also face challenges in terms of clinical translation and drug discovery. The advent of metagenomics, single-cell sequencing, target identification techniques, drug delivery systems, and other cutting-edge technologies heralds a new era in overcoming these challenges. CONCLUSION: This paper provides an overview of current research progress in utilizing natural products for the treatment of IBD, exploring how contemporary technological innovations can aid in discovering and harnessing bioactive natural products for the treatment of IBD.
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Kidney Clear Cell Carcinoma (KIRC), the predominant form of kidney cancer, exhibits a diverse therapeutic response to Immune Checkpoint Inhibitors (ICIs), highlighting the need for predictive models of ICI efficacy. Our study has constructed a prognostic model based on 13 types of Programmed Cell Death (PCD), which are intertwined with tumor progression and the immune microenvironment. Validated by analyses of comprehensive datasets, this model identifies seven key PCD genes that delineate two subtypes with distinct immune profiles and sensitivities to anti-PD-1 therapy. The high-PCD group demonstrates a more immune-suppressive environment, while the low-PCD group shows better responses to PD-1 treatment. In particular, TOP2A emerged as crucial, with its inhibition markedly reducing KIRC cell growth and mobility. These findings underscore the relevance of PCDs in predicting KIRC outcomes and immunotherapy response, with implications for enhancing clinical decision-making.
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Ginsenosides, the primary pharmacologically active constituents of the Panax genus, have demonstrated a variety of medicinal properties, including anticardiovascular disease, cytotoxic, antiaging, and antidiabetes effects. However, the low concentration of ginsenosides in plants and the challenges associated with their extraction impede the advancement and application of ginsenosides. Heterologous biosynthesis represents a promising strategy for the targeted production of these natural active compounds. As representative triterpenoids, the biosynthetic pathway of the aglycone skeletons of ginsenosides has been successfully decoded. While the sugar moiety is vital for the structural diversity and pharmacological activity of ginsenosides, the mining of uridine diphosphate-dependent glycosyltransferases (UGTs) involved in ginsenoside biosynthesis has attracted a lot of attention and made great progress in recent years. In this paper, we summarize the identification and functional study of UGTs responsible for ginsenoside synthesis in both plants, such as Panax ginseng and Gynostemma pentaphyllum, and microorganisms including Bacillus subtilis and Saccharomyces cerevisiae. The UGT-related microbial cell factories for large-scale ginsenoside production are also mentioned. Additionally, we delve into strategies for UGT mining, particularly potential rapid screening or identification methods, providing insights and prospects. This review provides insights into the study of other unknown glycosyltransferases as candidate genetic elements for the heterologous biosynthesis of rare ginsenosides.
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Ginsenosídeos , Glicosiltransferases , Ginsenosídeos/biossíntese , Ginsenosídeos/química , Ginsenosídeos/metabolismo , Glicosiltransferases/metabolismo , Saccharomyces cerevisiae , Estrutura Molecular , Panax/química , Difosfato de Uridina/metabolismo , Bacillus subtilis/enzimologia , Vias BiossintéticasRESUMO
Idiopathic pulmonary fibrosis (IPF) is considered as a chronic, fibrosing interstitial pneumonia with unknown mechanism. The present work aimed to explore the function, biogenesis and regulatory mechanism of circELP2 in pulmonary fibrosis and evaluate the value of blocking circELP2-medicated signal pathway for IPF treatment. The results showed that heterogeneous nuclear ribonucleoprotein L initiated reverse splicing of circELP2 resulting in the increase of circELP2 generation. The biogenetic circELP2 activated the abnormal proliferation and migration of fibroblast and extracellular matrix deposition to promote pulmonary fibrogenesis. Mechanistic studies demonstrated that cytoplasmic circELP2 sponged miR-630 to increase transcriptional co-activators Yes-associated protein 1 (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ). Then, YAP1/TAZ bound to the promoter regions of their target genes, such as mTOR, Raptor and mLST8, which in turn activated or inhibited the genes expression in mitochondrial quality control pathway. Finally, the overexpressed circELP2 and miR-630 mimic were packaged into adenovirus vector for spraying into the mice lung to evaluate therapeutic effect of blocking circELP2-miR-630-YAP1/TAZ-mitochondrial quality control pathway in vivo. In conclusion, blocking circELP2-medicated pathway can alleviate pulmonary fibrosis, and circELP2 may be a potential target to treat lung fibrosis.
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Fibrose Pulmonar Idiopática , Peptídeos e Proteínas de Sinalização Intracelular , MicroRNAs , Animais , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/genética , Fibrose Pulmonar Idiopática/metabolismo , Pulmão/metabolismo , MicroRNAs/genética , Transdução de Sinais , Fatores de Transcrição/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismoRESUMO
The male reproductive toxicity of microplastics (MPs) and nanoplastics (NPs) has attracted great attention, but the latent mechanisms remain fragmented. This review performed the adverse outcome pathway (AOP) analysis and meta-analysis in 39 relevant studies, with the AOP analysis to reveal the cause-and-effect relationships of MPs/NPs-induced male reproductive toxicity and the meta-analysis to quantify the toxic effects. In the AOP framework, increased reactive oxygen species (ROS) is the molecular initiating event (MIE), which triggered several key events (KEs) at different levels. At the cellular level, the KEs included oxidative stress, mitochondrial dysfunction, sperm DNA damage, endoplasmic reticulum stress, apoptosis and autophagy of testicular cells, repressed expression of steroidogenic enzymes and steroidogenic acute regulatory protein, disrupted hypothalamic-pituitary-testicular (HPT) axis, and gut microbiota alteration. These KEs further induced the reduction of testosterone, impaired blood-testis barrier (BTB), testicular inflammation, and impaired spermatogenesis at tissue/organ levels. Ultimately, decreased sperm quality or quantity was noted and proved by meta-analysis, which demonstrated that MPs/NPs led to a decrease of 5.99 million/mL in sperm concentration, 14.62% in sperm motility, and 23.56% in sperm viability, while causing an increase of 10.65% in sperm abnormality rate. Overall, this is the first AOP for MPs/NPs-mediated male reproductive toxicity in mammals. The innovative integration of meta-analysis into the AOP analysis increases the rigorism of the results.
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Rotas de Resultados Adversos , Microplásticos , Animais , Masculino , Microplásticos/farmacologia , Plásticos , Motilidade dos Espermatozoides , Sêmen , Mamíferos , Poliestirenos/farmacologiaRESUMO
This study was performed to determine the effect of human umbilical cord mesenchymal stem cells (hucMSCs) treatment on pulmonary fibrosis and investigate the circFOXP1-mediated autophagic mechanism of hucMSCs treatment. Pulmonary fibrosis models were established by spraying bleomycin in mice and TGF-ß1 treatment of MRC-5 cells. Results showed that hucMSCs were retained in lung and hucMSCs treatment alleviated pulmonary fibrosis. Morphological staining indicated that hucMSCs-treated mice had thinner alveolar walls, effectively improved alveolar structure, significantly reduced alveolar inflammation, and decreased collagen deposition than control mice. Fibrotic proteins, including vimentin, α-SMA, collagens I and III, and the differentiation-related protein S100 calcium-binding protein A4 was reduced considerably in the hucMSCs-treated group. The mechanistic study revealed that the inhibition of hucMSCs treatment on pulmonary fibrogenesis depended on downregulating circFOXP1, in which hucMSCs treatment promoted circFOXP1-mediated autophagy process via blocking the nuclear human antigen R (HuR) translocation and promoting the HuR degradation, leading to a marked decrease in autophagy negative regulators EZH2, STAT1, and FOXK1. In conclusion, hucMSCs treatment significantly improved pulmonary fibrosis by downregulating the circFOXP1-HuR-EZH2/STAT1/FOXK1 autophagic axis. hucMSCs can act as an effective treatment for pulmonary fibrosis.
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Células-Tronco Mesenquimais , Fibrose Pulmonar , Camundongos , Humanos , Animais , Fibrose Pulmonar/terapia , Fibrose , Pulmão/metabolismo , Células-Tronco Mesenquimais/metabolismo , Autofagia , Cordão Umbilical , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Fator de Transcrição STAT1 , Fatores de Transcrição Forkhead/metabolismoRESUMO
Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial pneumonia of unknown cause. The most typical characteristic of IPF is gradual weakening of pulmonary elasticity and increase in hardness/rigidity with aging. This study aims to identify a novel treatment approach for IPF and explore mechanism of mechanical stiffness underlying human umbilical cord mesenchymal stem cells (hucMSCs) therapy. Target ability of hucMSCs was examined by labeling with cell membrane dye Dil. Anti-pulmonary fibrosis effect of hucMSCs therapy by reducing mechanical stiffness was evaluated by lung function analysis and MicroCT imaging system and atomic force microscope in vivo and in vitro. Results showed that stiff environment of fibrogenesis caused cells to establish a mechanical connection between cytoplasm and nucleus, initiating expression of related mechanical genes such as Myo1c and F-actin. HucMSCs treatment blocked force transmission and reduced mechanical force. For further exploration of mechanism, ATGGAG was mutated to CTTGCG (the binding site of miR-136-5p) in the full-length sequence of circANKRD42. Wildtype and mutant plasmids of circANKRD42 were packaged into adenovirus vectors and sprayed into lungs of mice. Mechanistic dissection revealed that hucMSCs treatment repressed circANKRD42 reverse splicing biogenesis by inhibiting hnRNP L, which in turn promoted miR-136-5p binds to 3'-Untranslated Region (3'-UTR) of YAP1 mRNA directly, thus inhibiting translation of YAP1 and reducing YAP1 protein entering nucleus. The condition repressed expression of related mechanical genes to block force transmission and reduce mechanical forces. The mechanosensing mechanism mediated directly by circANKRD42-YAP1 axis in hucMSCs treatment, which has potential general applicability in IPF treatment.
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Fibrose Pulmonar Idiopática , Células-Tronco Mesenquimais , MicroRNAs , Humanos , Camundongos , Animais , Fibrose Pulmonar Idiopática/metabolismo , Fibrose , Pulmão/patologia , MicroRNAs/metabolismo , Células-Tronco Mesenquimais/metabolismo , Miosina Tipo I/metabolismoRESUMO
Isoflavones, one of the most important secondary metabolites produced by soybeans (Glycine max (L.) Merr.), are important for a variety of biological processes, and are beneficial for human health. To identify genetic loci underlying soybean isoflavone content, a mapping population containing 119 F5:18 recombinant inbred lines, derived by crossing soybean cultivar "Zhongdou27" with "Dongong8004," was used. We identified 15 QTLs associated with isoflavone contents. A novel loci, qISO19-1, was mapped onto soybean chromosome 19 and was fine-mapped to a 62.8 kb region using a BC2F2 population. We considered GmMT1 as a candidate gene for the qISO19-1 locus due to the significant positive correlation recovered between its expression level and isoflavone content in the seeds of 43 soybean germplasms. Overexpression of GmMT1 in Arabidopsis and soybean cultivars increased isoflavone contents. Transgenic soybeans overexpressing GmMT1 also exhibited improved resistance to pathogenic infection, while transgenic Arabidopsis resisted salt and drought stress.
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Pulmonary fibrosis is a common pulmonary interstitial disease of pathogenesis without effective drugs for treatment. Therefore, discovering new and effective drugs is urgently needed. In the present study, we prepared a novel compound named acetyl oxygen benzoate engeletin ester (AOBEE), investigated its effect on experimental pulmonary fibrosis, and proposed a long non-coding RNA (lncRNA)-mediated mechanism of its action. Bleomycin-induced pulmonary fibrosis in mice exhibited that AOBEE improved forced vital capacity (FVC) and alveolar structure and inhibited α-SMA, vimentin, and collagen expression. TGFß1-stimulated fibroblast L929 cells showed that AOBEE reduced these fibrotic proteins expression and inhibited the activated-fibroblast proliferation and migration. Whole transcriptome sequencing was performed to screen out lncRNA-lnc865 and lnc556 with high expression under bleomycin treatment, but AOBEE caused a considerable decrease in lnc865 and lnc556. Mechanistic study elucidated that AOBEE alleviated pulmonary fibrosis through lnc865- and lnc556-mediated mechanism, in which both lnc865 and lnc556 sponged miR-29b-2-5p to target signal transducer and activator of transcription 3 (STAT3). Further signal pathway inhibitors and the Cignal Finder 45-pathway reporter array illustrated that the up- and downstream pathways were TGFß1-smad2/3 and p38MAPK, and Krüppel-like factor 4 (KLF4), respectively. In conclusion, AOBEE promoted KLF4 degradation leading to the attenuation of pulmonary fibrosis by inhibiting TGFß1-smad/p38MAPK-lnc865/lnc556-miR-29b-2-5p-STAT3 signal pathway. We hope this work will provide valuable information to design new drugs and therapeutic targets of lncRNAs for pulmonary fibrosis treatment.
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Flavonóis/farmacologia , Glicosídeos/farmacologia , Fatores de Transcrição Kruppel-Like/metabolismo , MicroRNAs/metabolismo , Fibrose Pulmonar/metabolismo , RNA Longo não Codificante/metabolismo , Fator de Transcrição STAT3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular , Flavonóis/química , Glicosídeos/química , Fator 4 Semelhante a Kruppel , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Modelos Biológicos , Proteólise/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismoRESUMO
The sucrose concentration in soybean seed significantly affects the flavor of soybean-derived products. In this study, an association panel of 178 elite accessions and 33,149 single-nucleotide polymorphisms (SNPs) was utilized to identify quantitative trait nucleotides (QTNs) of sucrose concentration in soybean seeds by genome-wide association study (GWAS). Five QTNs (rs2688589, rs29026218, rs5926884, rs6886889, and rs10299216) distributed across five genomic regions in five chromosomes were identified in two or more locations by GWAS. A total of 60 candidate genes near the 200-kb flanking region of these five identified loci were identified. Three of these genes (Glyma.04G032600, Glyma.04G034600, and Glyma.11G092100) have been reported to be involved in the process of sugar biosynthesis. Based on gene-based association and haplotype analyses, a total of 35 SNPs from 10 genes associated with sucrose concentration were identified. Of them, Glyma.04G032600 was the only gene that has been reported to be related to sucrose content; the other nine genes were novel and may be associated with sucrose content. These beneficial alleles and candidate genes may be of great value in improving sucrose content in soybean seeds.
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Estudo de Associação Genômica Ampla , Glycine max , Sequenciamento de Nucleotídeos em Larga Escala , Desequilíbrio de Ligação , Locos de Características Quantitativas , Sementes/genética , Glycine max/genética , SacaroseRESUMO
PURPOSE: Little attention has been put to parental self-efficacy (PSE) on the home care management and its impact on the health-related outcome in children with Hirschsprung disease (HD) after surgery. The purpose of this study was to investigate the association between PSE and post-operative outcome and quality of life (QoL) in children with HD. DESIGN AND METHODS: This study adopted a cross-sectional study design. Children diagnosed with HD who had surgery during 2015 and 2018, and their parents were included. Parental self-efficacy, children's post-operative fecal continence and QoL were evaluated with validated questionnaires; post-operative readmission and adverse events were extracted from electronic medical record system. RESULTS: Of the eligible families, 69.6% (96/138) responded to the follow-up. The median children's age at surgery and current age were 16 (interquartile range: 10-32) and 45 (interquartile range: 39.7-57) months, respectively. The mean PSE score is 8.78 points, with the lowest score in the bowel habit training dimension (7.88 ± 2.28), followed by getting social support dimension (8.07 ± 2.64). Multivariable linear regression showed that PSE was associated with fecal continence (ß = 0.043, 95% CI 0.013-0.072), pediatric QoL total score (ß = 0.210, 95% CI 0.011-0.409) and social score (ß = 0.273, 95% CI 0.022-0.525). No associations were observed between PSE and weight z-score, height z-score, readmission or adverse events. CONCLUSIONS: PSE is correlated with fecal continence and QoL of children with HD. PRACTICE IMPLICATIONS: PSE should be considered when designing a parental education program, with the focus on bowel habit training and getting social support.
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Doença de Hirschsprung , Qualidade de Vida , Criança , Pré-Escolar , Estudos Transversais , Doença de Hirschsprung/cirurgia , Humanos , Lactente , Pais , Autoeficácia , Inquéritos e QuestionáriosRESUMO
Hexaploid wheat (Triticum aestivum L.) is an important food crop but it is vulnerable to heat. The heat-responsive proteome of wheat remains to be fully elucidated because of previous technical and genomic limitations, and this has hindered our understanding of the mechanisms of wheat heat adaptation and advances in improving thermotolerance. Here, flag leaves of wheat during grain filling stage were subjected to high daytime temperature stress, and 258 heat-responsive proteins (HRPs) were identified with iTRAQ analysis. Enrichment analysis revealed that chlorophyll synthesis, carbon fixation, protein turnover, and redox regulation were the most remarkable heat-responsive processes. The HRPs involved in chlorophyll synthesis and carbon fixation were significantly decreased, together with severe membrane damage, demonstrating the specific effects of heat on photosynthesis of wheat leaves. In addition, the decrease in chlorophyll content may result from the decrease in HRPs involved in chlorophyll precursor synthesis. Further analysis showed that the accumulated effect of heat stress played a critical role in photosynthesis reduction, suggested that improvement in heat tolerance of photosynthesis, and extending heat tolerant period would be major research targets. The significantly accumulation of GSTs and Trxs in response to heat suggested their important roles in redox regulation, and they could be the promising candidates for improving wheat thermotolerance. In summary, our results provide new insight into wheat heat adaption and provide new perspectives on thermotolerance improvement.
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Despite progress, the combination therapy of a nanoscale delivery system and its loaded drug to increase the efficiency of anticancer treatment still remains a challenge. In this study, taking advantage of ascorbic acid with anticancer activity, complex nanovehicles were designed and constructed by co-assembly of the amphiphilic block polymers poly(ascorbyl acrylate)-block-poly(lactic acid) (PAA-b-PLA) and maleimide-decorating poly(ethylene glycol)-block-poly(lactic acid) (Mal-PEG-b-PLA) in aqueous solution. The combination of the nanoparticles' large surface and structural repeating characteristics of PAA led to an exponential increase in the ascorbyl content on the nanoparticle surface, which endowed the nanovehicles themselves with desired anticancer activity. In vitro cytotoxicity assays against normal cell line NIH3T3 and breast cancer cell line MCF-7 demonstrated that PAA-b-PLA/Mal-PEG-b-PLA complex nanoparticles exhibited benign biocompatibility against normal cells and prominent cancer inhibition ability. Paclitaxel (PTX)-loaded complex nanoparticles against MCF-7 were further investigated by MTS assay and flow cytometry. As a result, a synergistic effect of the complex nanoparticles and the loaded PTX in inducing cancer cell apoptosis was apparently noted. The newly developed PAA-b-PLA/Mal-PEG-b-PLA complex nanoparticles not only served as an effective and safe vector to deliver the therapeutic agents to the targeted site, but more importantly, they could also combine with the loaded therapeutic agents to achieve a synergistic effect for improving tumor inhibition efficiency.
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The class I terpenoid cyclase epi-isozizaene synthase (EIZS) utilizes the universal achiral isoprenoid substrate, farnesyl diphosphate, to generate epi-isozizaene as the predominant sesquiterpene cyclization product and at least five minor sesquiterpene products, making EIZS an ideal platform for the exploration of fidelity and promiscuity in a terpenoid cyclization reaction. The hydrophobic active site contour of EIZS serves as a template that enforces a single substrate conformation, and chaperones subsequently formed carbocation intermediates through a well-defined mechanistic sequence. Here, we have used the crystal structure of EIZS as a guide to systematically remold the hydrophobic active site contour in a library of 26 site-specific mutants. Remolded cyclization templates reprogram the reaction cascade not only by reproportioning products generated by the wild-type enzyme but also by generating completely new products of diverse structure. Specifically, we have tripled the overall number of characterized products generated by EIZS. Moreover, we have converted EIZS into six different sesquiterpene synthases: F96A EIZS is an (E)-ß-farnesene synthase, F96W EIZS is a zizaene synthase, F95H EIZS is a ß-curcumene synthase, F95M EIZS is a ß-acoradiene synthase, F198L EIZS is a ß-cedrene synthase, and F96V EIZS and W203F EIZS are (Z)-γ-bisabolene synthases. Active site aromatic residues appear to be hot spots for reprogramming the cyclization cascade by manipulating the stability and conformation of critical carbocation intermediates. A majority of mutant enzymes exhibit only relatively modest 2-100-fold losses of catalytic activity, suggesting that residues responsible for triggering substrate ionization readily tolerate mutations deeper in the active site cavity.
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Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Streptomyces coelicolor/enzimologia , Terpenos/química , Terpenos/metabolismo , Domínio Catalítico , Cristalografia por Raios X , Ciclização , Cinética , Modelos Moleculares , Estrutura Molecular , Mutagênese Sítio-DirigidaRESUMO
OBJECTIVE: To analyze the postoperative short-term and long-term outcomes in the management of type I esophageal atresia, and to explore the ideal operative strategy. METHODS: Clinical data of 22 patients with type I esophageal atresia treated from January 2005 to September 2012 were retrospectively reviewed. Of 22 patients, 6 patients gave up the treatment. Two underwent primary repair after birth. Of 14 patients undergoing cervical esophagostomy and gastrostomy, 8 patients received esophageal replacement. Postoperative short-term and long-term complications, nutritional state and neurodevelopment were studied on above 10 children with radical operations. RESULTS: Of 10 patients with radical operation, the short-term complications were hydrothorax in 1 case, anastomotic leakage in 4, dumping syndrome in 1, anastomotic stricture in 1. The long-term complications were esophageal stricture in 2 cases, and repeated respiratory infection in 3. These complications could be managed successfully. The postoperative follow-up duration ranged from 2 to 62 months. Two cases were lost during follow-up after 2 years. Weight-for-age was normal in 2 patients, mild malnutrition in 5 patients, and moderate malnutrition in 1 patients. Neurodevelopment is significantly delayed as compared to normal children. CONCLUSIONS: Operative strategy should be chosen according to the distance between proximal and distal esophagus in the treatment of type I esophageal atresia. The efficacy of radical operation is relative satisfactory in terms of short-term and long-term complications and the quality of life.
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Atresia Esofágica/cirurgia , Complicações Pós-Operatórias , Criança , Feminino , Seguimentos , Humanos , Masculino , Qualidade de Vida , Estudos RetrospectivosRESUMO
OBJECTIVE: To examine the long-term outcomes of total colonic aganglionosis (TCA) and to evaluate their nutritional status. METHODS: Eleven pediatric patients treated for TCA between January 1999 and December 2010 were included in the study and followed up. Physical measurements including height, weight and laboratory tests were assessed. Anorectal functions were evaluated with Kelly score and quality of life(QOL) using questionnaire. RESULTS: The length of follow-up ranged from 8 to 147 months. The children had satisfactory anorectal function (Kelly score, 5-6). One child had a Kelly score of 3. The children who were followed up less than 48 months had significant higher Kelly scores compared with those with more than 48 months follow-up(P<0.05). QOL was good in nine patients (QOL score, 9-10) and moderate (score, 7-8) in 2 patients. Weight-for-age was normal in 2 patients, mild malnutrition in 6 patients, and moderate malnutrition in 3 patients. Height-for-age was normal in 6 patients, mild malnutrition in 3 patients, and moderate malnutrition in 2 patients. The serum albumin was(49.0±2.7) g/L in children with well-educated parents, significantly higher than those with poorly-educated parents(44.3±1.9) g/L(P<0.05). CONCLUSIONS: Long-term outcomes of children with TCA are satisfactory with good anorectal function and quality of life. Low body weight is more common than low height. Children with well-educated parents have better nutrition status.
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Doença de Hirschsprung/cirurgia , Seguimentos , Humanos , Lactente , Masculino , Estado Nutricional , Resultado do TratamentoRESUMO
Potassium (K(+)) channels are essential to neuronal signaling and survival. Here we show that these proteins are targets of reactive oxygen species in mammalian brain and that their oxidation contributes to neuropathy. Thus, the KCNB1 (Kv2.1) channel, which is abundantly expressed in cortex and hippocampus, formed oligomers upon exposure to oxidizing agents. These oligomers were â¼10-fold more abundant in the brain of old than young mice. Oxidant-induced oligomerization of wild-type KCNB1 enhanced apoptosis in neuronal cells subject to oxidative insults. Consequently, a KCNB1 variant resistant to oxidation, obtained by mutating a conserved cysteine to alanine, (C73A), was neuroprotective. The fact that oxidation of KCNB1 is toxic, argues that this mechanism may contribute to neuropathy in conditions characterized by high levels of oxidative stress, such as Alzheimer's disease (AD). Accordingly, oxidation of KCNB1 channels was exacerbated in the brain of a triple transgenic mouse model of AD (3xTg-AD). The C73A variant protected neuronal cells from apoptosis induced by incubation with ß-amyloid peptide (Aß(1-42)). In an invertebrate model (Caenorhabditis elegans) that mimics aspects of AD, a C73A-KCNB1 homolog (C113S-KVS-1) protected specific neurons from apoptotic death induced by ectopic expression of human Aß(1-42). Together, these data underscore a novel mechanism of toxicity in neurodegenerative disease.
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Encéfalo/citologia , Neurônios/fisiologia , Estresse Oxidativo/fisiologia , Canais de Potássio Shab/fisiologia , 2,2'-Dipiridil/análogos & derivados , 2,2'-Dipiridil/toxicidade , Fatores Etários , Alanina/genética , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/toxicidade , Precursor de Proteína beta-Amiloide/genética , Análise de Variância , Animais , Animais Geneticamente Modificados , Apoptose/efeitos dos fármacos , Apoptose/genética , Apoptose/fisiologia , Caenorhabditis elegans , Células Cultivadas , Cricetinae , Cricetulus , Cisteína/genética , Modelos Animais de Doenças , Dissulfetos/toxicidade , Estimulação Elétrica , Embrião de Mamíferos , Feminino , Fluoresceínas/farmacologia , Humanos , Peróxido de Hidrogênio/farmacologia , Masculino , Espectrometria de Massas/métodos , Potenciais da Membrana/genética , Potenciais da Membrana/fisiologia , Camundongos , Neurônios/efeitos dos fármacos , Oxidantes/toxicidade , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Técnicas de Patch-Clamp , Fragmentos de Peptídeos/toxicidade , Presenilina-1/genética , Propanóis/farmacologia , Canais de Potássio Shab/genética , TransfecçãoRESUMO
Pyrogallol[4]arene macrocycles prepared from pyrogallol and n-dodecanal insert in phospholipid bilayers and form conducting pores that undergo reversible switching over a wide range of potentials.
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Calixarenos/química , Bicamadas Lipídicas/química , Fenilalanina/análogos & derivados , Fosfolipídeos/química , Pirogalol/análogos & derivados , Canais Iônicos , Potenciais da Membrana , Estrutura Molecular , Fenilalanina/química , Porosidade , Pirogalol/químicaRESUMO
A number of synthetic ion channels have been reported in recent years that incorporate unusual or sophisticated design elements. The present work demonstrates that extremely simple compounds can function as ion channels (insert in bilayers, exhibit open-close behavior) if they meet minimum criteria. A simple membrane spanning structure may function as a channel if 1) it possesses polar headgroups (is bolaamphiphilic), 2) possesses a "central relay," and 3) channel function (open-close behavior) must be detected after insertion of the amphiphile directly into the aqueous liposomal or cellular suspension. We show here compounds that are simple spans to which we have given the name "aplosspan" (from the Greek alpha pi lambda omicron sigma + span) that meet these criteria. They are similar to, but simpler than, structures reported in the literatures that incorporate more complex design features.
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Canais Iônicos/metabolismo , Lipossomos/química , Membranas/química , Canais Iônicos/química , Membranas/metabolismo , Estrutura MolecularRESUMO
We measured the Raman scattering of graphene deposited nanohole arrays. As the sample was azimuthally rotated, periodicities of 7.5 degrees and 5 degrees were revealed for the 2700 cm(-1) and 1600 cm(-1) Raman lines of graphene, respectively. This is contrary to the scattered laser line azimuthal symmetry of 30 degrees for the hole array alone. When a reference dye (stilbene) was deposited on the graphenated platforms, its Raman peak shifted as a function of incident (tilt) angle; this was contrary to the unshifted 1600 cm(-1) peak of graphene itself. The data suggest strong coupling between the molecular vibrations as portrayed by Raman spectra and surface plasmon polariton waves propagating along the graphene surface.