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1.
J Neurooncol ; 168(2): 239-247, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38700610

RESUMO

PURPOSE: There is lack of comprehensive analysis evaluating the impact of clinical, molecular, imaging, and surgical data on survival of patients with gliomatosis cerebri (GC). This study aimed to investigate prognostic factors of GC in adult-type diffuse glioma patients. METHODS: Retrospective chart and imaging review was performed in 99 GC patients from adult-type diffuse glioma (among 1,211 patients; 6 oligodendroglioma, 16 IDH-mutant astrocytoma, and 77 IDH-wildtype glioblastoma) from a single institution between 2005 and 2021. Predictors of overall survival (OS) of entire patients and IDH-wildtype glioblastoma patients were determined. RESULTS: The median OS was 16.7 months (95% confidence interval [CI] 14.2-22.2) in entire patients and 14.3 months (95% CI 12.2-61.9) in IDH-wildtype glioblastoma patients. In entire patients, KPS (hazard ratio [HR] = 0.98, P = 0.004), no 1p/19q codeletion (HR = 10.75, P = 0.019), MGMTp methylation (HR = 0.54, P = 0.028), and hemorrhage (HR = 3.45, P = 0.001) were independent prognostic factors on multivariable analysis. In IDH-wildtype glioblastoma patients, KPS (HR = 2.24, P = 0.075) was the only independent prognostic factor on multivariable analysis. In subgroup of IDH-wildtype glioblastoma with CE tumors, total resection of CE tumor did not remain as a significant prognostic factor (HR = 1.13, P = 0.685). CONCLUSIONS: The prognosis of GC patients is determined by its underlying molecular type and patient performance status. Compared with diffuse glioma without GC, aggressive surgery of CE tumor in GC patients does not improve survival.


Assuntos
Neoplasias Encefálicas , Isocitrato Desidrogenase , Neoplasias Neuroepiteliomatosas , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Prognóstico , Neoplasias Neuroepiteliomatosas/patologia , Neoplasias Neuroepiteliomatosas/mortalidade , Neoplasias Neuroepiteliomatosas/genética , Estudos Retrospectivos , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/cirurgia , Neoplasias Encefálicas/diagnóstico , Adulto , Idoso , Isocitrato Desidrogenase/genética , Glioma/patologia , Glioma/mortalidade , Glioma/genética , Glioma/cirurgia , Glioma/diagnóstico , Adulto Jovem , Taxa de Sobrevida , Mutação , Seguimentos
2.
BMC Pediatr ; 23(1): 36, 2023 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-36681822

RESUMO

BACKGROUND: Early extubation success (ES) in preterm infants may reduce various mechanical ventilation-associated complications; however, extubation failure (EF) can cause adverse short- and long-term outcomes. Therefore, the present study aimed to identify differences in risk factors and clinical outcomes between ES and EF in very early preterm infants. METHODS: This retrospective study was conducted between January 2017 and December 2021. Premature infants born at 32 weeks' gestational age in whom extubation had failed at least once were assigned to the EF group. Successfully extubated patients with a similar gestational age and birth weight as those in the EF group were assigned to the ES group. EF was defined as the need for re-intubation within 120 h of extubation. Various variables were compared between groups. RESULTS: The EF rate in this study was 18.6% (24/129), and approximately 80% of patients with EF required re-intubation within 90.17 h. In the ES group, there was less use of inotropes within 7 days of life (12 [63.2%] vs. 22 [91.7%], p = 0.022), a lower respiratory severity score (RSS) at 1 and 4 weeks (1.72 vs. 2.5, p = 0.026; 1.73 vs. 2.92, p = 0.010), and a faster time to reach full feeding (18.7 vs. 29.7, p = 0.020). There was a higher severity of bronchopulmonary dysplasia BPD (3 [15.8%] vs. 14 [58.3%], p = 0.018), longer duration of oxygen supply (66.5 vs. 92.9, p = 0.042), and higher corrected age at discharge (39.6 vs. 42.5, p = 0.043) in the EF group. The cutoff value, sensitivity, and specificity of the respiratory severity score (RSS) at 1 week were 1.98, 0.71, and 0.42, respectively, and the cutoff value, sensitivity, and specificity of RSS at 4 weeks were 2.22, 0.67, and 0.47, respectively. CONCLUSIONS: EF caused adverse short-term outcomes such as a higher BPD severity and longer hospital stay. Therefore, extubation in very early preterm infants should be carefully evaluated. Using inotropes, feeding, and RSS at 1 week of age can help predict extubation success.


Assuntos
Displasia Broncopulmonar , Doenças do Prematuro , Lactente , Recém-Nascido , Humanos , Recém-Nascido Prematuro , Estudos de Coortes , Estudos Retrospectivos , Extubação , Fatores de Risco , Displasia Broncopulmonar/terapia , Respiração Artificial
3.
BMC Pediatr ; 23(1): 525, 2023 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-37872515

RESUMO

BACKGROUND: Respiratory support is crucial for newborns with underdeveloped lung. The clinical outcomes of patients depend on the clinician's ability to recognize the status underlying the presented symptoms and signs. With the increasing number of high-risk infants, artificial intelligence (AI) should be considered as a tool for personalized neonatal care. Continuous monitoring of vital signs is essential in cardiorespiratory care. In this study, we developed deep learning (DL) prediction models for rapid and accurate detection of mechanical ventilation requirements in neonates using electronic health records (EHR). METHODS: We utilized data from the neonatal intensive care unit in a single center, collected between March 3, 2012, and March 4, 2022, including 1,394 patient records used for model development, consisting of 505 and 889 patients with and without invasive mechanical ventilation (IMV) support, respectively. The proposed model architecture includes feature embedding using feature-wise fully connected (FC) layers, followed by three bidirectional long short-term memory (LSTM) layers. RESULTS: A mean gestational age (GA) was 36.61 ± 3.25 weeks, and the mean birth weight was 2,734.01 ± 784.98 g. The IMV group had lower GA, birth weight, and longer hospitalization duration than the non-IMV group (P < 0.05). Our proposed model, tested on a dataset from March 4, 2019, to March 4, 2022. The mean AUROC of our proposed model for IMV support prediction performance demonstrated 0.861 (95%CI, 0.853-0.869). It is superior to conventional approaches, such as newborn early warning score systems (NEWS), Random Forest, and eXtreme gradient boosting (XGBoost) with 0.611 (95%CI, 0.600-0.622), 0.837 (95%CI, 0.828-0.845), and 0.0.831 (95%CI, 0.821-0.845), respectively. The highest AUPRC value is shown in the proposed model at 0.327 (95%CI, 0.308-0.347). The proposed model performed more accurate predictions as gestational age decreased. Additionally, the model exhibited the lowest alarm rate while maintaining the same sensitivity level. CONCLUSION: Deep learning approaches can help accurately standardize the prediction of invasive mechanical ventilation for neonatal patients and facilitate advanced neonatal care. The results of predictive, recall, and alarm performances of the proposed model outperformed the other models.


Assuntos
Unidades de Terapia Intensiva Neonatal , Respiração Artificial , Lactente , Humanos , Recém-Nascido , Respiração Artificial/métodos , Peso ao Nascer , Inteligência Artificial , Registros Eletrônicos de Saúde
4.
Molecules ; 27(22)2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36432017

RESUMO

Fermented bean products are used worldwide; most of the products are made using only a few kinds of beans. However, the metabolite changes and contents in the beans generally used during fermentation are unrevealed. Therefore, we selected four different beans (soybean, Glycine max, GM; wild soybean, Glycine soja, GS; common bean, Phaseolus vulgaris, PV; and hyacinth bean, Lablab purpureus, LP) that are the most widely consumed and fermented with Aspergillus oryzae. Then, metabolome and multivariate statistical analysis were performed to figure out metabolite changes during fermentation. In the four beans, carbohydrates were decreased, but amino acids and fatty acids were increased in the four beans as they fermented. The relative amounts of amino acids were relatively abundant in fermented PV and LP as compared to other beans. In contrast, isoflavone aglycones (e.g., daidzein, glycitein, and genistein) and DDMP-conjugated soyasaponins (e.g., soyasaponins ßa and γg) were increased in GM and GS during fermentation. Notably, these metabolite changes were more significant in GS than GM. In addition, the increase of antioxidant activity in fermented GS was significant compared to other beans. We expect our research provides a basis to extend choice for bean fermentation for consumers and food producers.


Assuntos
Aspergillus oryzae , Phaseolus , Aspergillus oryzae/metabolismo , Glycine max/química , Fermentação , Phaseolus/metabolismo , Aminoácidos/metabolismo
5.
BMC Pediatr ; 21(1): 415, 2021 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-34544386

RESUMO

BACKGROUND: Only 10 cases of cecal epidermoid cyst (CEC) have been reported in the literature. Furthermore, its pathogenesis remains unclear. We report a rare case of congenital CEC in neonate, and discuss its clinicopathological findings. CASE PRESENTATION: A cystic lesion was incidentally identified in the retroperitoneal area of the abdominal right lower quadrant during a routine prenatal ultrasonography (US), prompting an ileocolectomy 3 days after birth. This congenital cyst was composed of mucosal lining cells and submucosal connective tissues, and the inner lining mucosa was composed of stratified squamous epithelium and focally mucin-producing ciliated epithelium. Based on the macroscopic and microscopic findings, the cystic lesion was diagnosed as a congenital cecal epidermoid cyst. CONCLUSIONS: The management of a fetal abdominal mass should be tailored individually, considering that epidermoid cysts can occur in the cecum during the perinatal period. We report the clinicopathological findings in this case, including its possible pathogenesis.


Assuntos
Cisto Epidérmico , Ceco , Cisto Epidérmico/diagnóstico por imagem , Epitélio , Humanos
6.
Molecules ; 26(9)2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33926033

RESUMO

A series of PROTACs (PROteolysis-TArgeting Chimeras) consisting of bicalutamide analogs and thalidomides were designed, synthesized, and biologically evaluated as novel androgen receptor (AR) degraders. In particular, we found that PROTAC compound 13b could successfully demonstrate a targeted degradation of AR in AR-positive cancer cells and might be a useful chemical probe for the investigation of AR-dependent cancer cells, as well as a potential therapeutic candidate for prostate cancers.


Assuntos
Antagonistas de Androgênios/química , Anilidas/química , Nitrilas/química , Receptores Androgênicos/química , Talidomida/química , Compostos de Tosil/química , Antagonistas de Androgênios/síntese química , Antagonistas de Androgênios/farmacologia , Anilidas/farmacologia , Sítios de Ligação , Linhagem Celular , Técnicas de Química Sintética , Humanos , Modelos Biológicos , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Nitrilas/farmacologia , Ligação Proteica , Proteólise/efeitos dos fármacos , Receptores Androgênicos/metabolismo , Relação Estrutura-Atividade , Talidomida/farmacologia , Compostos de Tosil/farmacologia
7.
BMC Pediatr ; 20(1): 336, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32635904

RESUMO

BACKGROUND: Choroid plexus papillomas (CPPs) are rare, usually benign, neoplasms originating in the central nervous system. In this study, we present the first case of a giant airway-obstructing CPP in the pharynx of a newborn. CASE PRESENTATION: A cystic mass located in the pharynx was noted in a fetus at the 29th week of gestation. Elective cesarean section was performed at the 38th week of gestation with successful intubation and ex utero intrapartum treatment. On computed tomography, there was a huge airway-obstructing cystic mass in the choana and pharynx. Elective surgery with total excision was performed, and histological examination confirmed the diagnosis of CPP. CONCLUSION: We report the first case of an extracerebral airway-obstructing CPP in the pharynx of a newborn. Radiologic examinations are not enough for the diagnosis of CPPs, and complete excision of the tumor with histological confirmation is indispensable for accurate diagnosis and treatment.


Assuntos
Obstrução das Vias Respiratórias , Papiloma do Plexo Corióideo , Obstrução das Vias Respiratórias/diagnóstico por imagem , Obstrução das Vias Respiratórias/etiologia , Obstrução das Vias Respiratórias/cirurgia , Cesárea , Feminino , Humanos , Recém-Nascido , Imageamento por Ressonância Magnética , Papiloma do Plexo Corióideo/diagnóstico , Papiloma do Plexo Corióideo/diagnóstico por imagem , Faringe , Gravidez , Tomografia Computadorizada por Raios X
8.
Fetal Pediatr Pathol ; 38(1): 72-79, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30523708

RESUMO

INTRODUCTION: Bart's syndrome, a hereditary mechanobullous disorder characterized by aplasia cutis congenita (ACC) with epidermolysis bullosa (EB), has not been genotyped frequently. CASE REPORT: A full-term female neonate had well-demarcated absence of skin on both legs at birth, with blisters and erosive patches developing immediately after birth. Electron microscopy showed blister formation under the lamina densa layer. Genetic studies revealed two heterogenous frameshift mutations in exons 31 and 109 of COL7A1. A diagnosis of Bart's syndrome, recessive dystrophic EB with ACC, was made. There was no pyloric atresia or ureteral stenosis, but congenital hypothyroidism was diagnosed 42 days after birth. CONCLUSION: The novel frameshift mutations in COL7A1 may result in Bart's syndrome and suggest the importance of genetic testing in diagnosis of this disease.


Assuntos
Colágeno Tipo VII/genética , Displasia Ectodérmica/genética , Epidermólise Bolhosa Distrófica/genética , Feminino , Mutação da Fase de Leitura , Humanos , Recém-Nascido , Síndrome
9.
Cell Immunol ; 332: 94-100, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30100205

RESUMO

Retinoic acid-inducible gene I (RIG-I) detects viral RNAs and induces antiviral responses. During viral RNA recognition by RIG-I, tripartite motif protein 25 (TRIM25) plays a critical regulatory role by inducing K63-linked RIG-I polyubiquitination. Previous proteomics analysis revealed several phosphorylation sites on TRIM25, including tyrosine 278 (Y278), yet the roles of these modifications remain elusive. Here, we demonstrated that TRIM25 interacted with c-Src and underwent tyrosine phosphorylation by c-Src kinase upon viral infection and the phosphorylation is required for the complete activation of RIG-I signaling. Analysis using a c-Src inhibitor and TRIM25 mutant, in which tyrosine 278 is substituted by phenylalanine (Y278F), suggested that the phosphorylation positively regulates K63-linked polyubiquitination of RIG-I and subsequent antiviral signaling. The TRIM25 Y278F mutant displayed decreased E3-ubiquitin ligase activity in vitro, suggesting that this phosphorylation event affects the E3-ligase activity of TRIM25. Thus, we provide a molecular mechanism of c-Src-mediated positive regulation of RIG-I signaling.


Assuntos
Antivirais/metabolismo , Proteína DEAD-box 58/metabolismo , Fosforilação/fisiologia , Transdução de Sinais/fisiologia , Fatores de Transcrição/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação/fisiologia , Quinases da Família src/metabolismo , Sequência de Aminoácidos , Animais , Proteína Tirosina Quinase CSK , Linhagem Celular , Células HEK293 , Humanos , Camundongos , Camundongos Knockout , Fenilalanina/metabolismo , Receptores Imunológicos , Tirosina/metabolismo
10.
Curr Genomics ; 19(8): 712-722, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30532650

RESUMO

In nature, microbes do not exist in isolation but co-exist in a variety of ecological and biological environments and on various host organisms. Due to their close proximity, these microbes interact among themselves, and also with the hosts in both positive and negative manners. Moreover, these interactions may modulate dynamically upon external stimulus as well as internal community changes. This demands systematic techniques such as mathematical modeling to understand the intrinsic community behavior. Here, we reviewed various approaches for metabolic modeling of microbial communities. If detailed species-specific information is available, segregated models of individual organisms can be constructed and connected via metabolite exchanges; otherwise, the community may be represented as a lumped network of metabolic reactions. The constructed models can then be simulated to help fill knowledge gaps, and generate testable hypotheses for designing new experiments. More importantly, such community models have been developed to study microbial interactions in various niches such as host microbiome, biogeochemical and bioremediation, waste water treatment and synthetic consortia. As such, the metabolic modeling efforts have allowed us to gain new insights into the natural and synthetic microbial communities, and design interventions to achieve specific goals. Finally, potential directions for future development in metabolic modeling of microbial communities were also discussed.

11.
Fetal Pediatr Pathol ; 37(5): 363-371, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30252581

RESUMO

BACKGROUND: Thanatophoric dysplasia (TD) results from sporadic de novo mutations in the FGFR3 gene. Upon confirming intrauterine diagnosis of this perinatal disease, pregnancy termination is recommended. There is limited information on the natural history of longer-term survivors with type 1 TD. CASE REPORT: A full-term neonate was confirmed via postnatal genetic testing to have type 1 TD. At 28 days, chylous ascites developed. Medium-chain triglyceride use improved the ascites. Cerebral ventriculomegaly worsened throughout life. Death due to respiratory failure occurred at age 5 months. CONCLUSION: The chylous ascites in this child with type 1 TD and survival past the neonatal stage suggests that type 1 TD may be accompanied by abnormalities of the lymphatic channels. Moreover, ventriculomegaly can be progressive.


Assuntos
Ascite Quilosa/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/deficiência , Displasia Tanatofórica/complicações , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Displasia Tanatofórica/genética
12.
Mol Pharmacol ; 92(3): 347-357, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28696213

RESUMO

Calcium-dependent inactivation of high voltage-activated Ca2+ channels plays a crucial role in limiting rises in intracellular calcium (Ca2+i). A key mediator of these effects is calmodulin, which has been found to bind the C-terminus of the pore-forming α subunit. In contrast, little is known about how Ca2+i can regulate low voltage-activated T-type Ca2+ channels. Using whole cell patch clamp, we examined the biophysical properties of Ca2+ current through the three T-type Ca2+ channel isoforms, Cav3.1, Cav3.2, or Cav3.3, comparing internal solutions containing 27 nM and l µM free Ca2+ Both activation and inactivation kinetics of Cav3.3 current in l µM Ca2+i solution were more rapid than those in 27 nM Ca2+i solution. In addition, both activation and steady-state inactivation curves of Cav3.3 were negatively shifted in the higher Ca2+i solution. In contrast, the biophysical properties of Cav3.1 and Cav3.2 isoforms were not significantly different between the two internal solutions. Overexpression of CaM1234 (a calmodulin mutant that doesn't bind Ca2+) occluded the effects of l µM Ca2+i on Cav3.3, implying that CaM is involved in the Ca2+i regulation effects on Cav3.3. Yeast two-hybrid screening and co-immunoprecipitation experiments revealed a direct interaction of CaM with the carboxyl terminus of Cav3.3. Taken together, our results suggest that Cav3.3 T-type channel is potently regulated by Ca2+i via interaction of Ca2+/CaM with the carboxyl terminus of Cav3.3.


Assuntos
Canais de Cálcio Tipo T/fisiologia , Cálcio/fisiologia , Calmodulina/fisiologia , Animais , Canais de Cálcio Tipo T/química , Células HEK293 , Humanos , Imunoprecipitação , Ratos
13.
J Biol Chem ; 291(45): 23645-23653, 2016 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-27655917

RESUMO

Microglia are the immune effector cells that are activated in response to pathological changes in the central nervous system. Microglial activation is accompanied by the alteration of integrin expression on the microglia surface. However, changes of integrin expression upon chemoattractant (ADP) stimulation still remain unknown. In this study, we investigated whether ADP induces the alteration of integrin species on the cell surface, leading to changes in chemotactic ability on different extracellular matrix proteins. Flow cytometry scans and on-cell Western assays showed that ADP stimulation induced a significant increase of α6 integrin-GFP, but not α5, on the surface of microglia cells. Microglia also showed a greater motility increase on laminin than fibronectin after ADP stimulation. Time lapse microscopy and integrin endocytosis assay revealed the essential role of calcium-independent phospholipase A2 activity for the recycling of α6 integrin-GFP from the endosomal recycling complex to the plasma membrane. Lack of calcium-independent phospholipase A2 activity caused a reduced rate of focal adhesion formation on laminin at the leading edge. Our results suggest that the alteration of integrin-mediated adhesion may regulate the extent of microglial infiltration into the site of damage by controlling their chemotactic ability.


Assuntos
Difosfato de Adenosina/metabolismo , Quimiotaxia , Integrina alfa6/metabolismo , Laminina/metabolismo , Microglia/citologia , Fosfolipases A2 Independentes de Cálcio/metabolismo , Animais , Linhagem Celular , Movimento Celular , Humanos , Integrina alfa6/genética , Camundongos , Microglia/metabolismo , Fosfolipases A2 Independentes de Cálcio/genética , Transporte Proteico , Interferência de RNA , RNA Interferente Pequeno/genética
14.
Artigo em Inglês | MEDLINE | ID: mdl-28559272

RESUMO

Despite recent advances in therapeutic strategies against hepatitis B virus (HBV) infection, chronic hepatitis B remains a major global health burden. Recent studies have shown that targeting host factors instead of viral factors can be an effective antiviral strategy with low risk of the development of resistance. Efforts to identify host factors affecting viral replication have identified p38 mitogen-activated protein kinase (MAPK) as a possible target for antiviral strategies against various viruses, including HBV. Here, a series of biphenyl amides were synthesized as novel p38 MAPK selective inhibitors and assessed for their anti-HBV activities. The suppression of HBV surface antigen (HBsAg) production by these compounds was positively correlated with p38 MAPK-inhibitory activity. The selected compound NJK14047 displayed significant anti-HBV activity, as determined by HBsAg production, HBeAg secretion, and HBV production. NJK14047 efficiently suppressed the secretion of HBV antigens and HBV particles from HBV genome-transfected cells and HBV-infected sodium taurocholate cotransporting polypeptide-expressing human hepatoma cells. Furthermore, NJK14047 treatment resulted in a significant decrease of pregenomic RNA and covalently closed circular DNA (cccDNA) of HBV in HBV-harboring cells, indicating its ability to inhibit HBV replication. Considering that suppression of HBsAg secretion and elimination of cccDNA of HBV are the major aims of anti-HBV therapeutic strategies, the results suggested the potential use of these compounds as a novel class of anti-HBV agents targeting host factors critical for viral infection.


Assuntos
Antivirais/farmacologia , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Amidas/química , Amidas/farmacologia , Antivirais/química , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Sobrevivência Celular , DNA Circular/análise , Antígenos de Superfície da Hepatite B/efeitos dos fármacos , Antígenos E da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/fisiologia , Hepatite B Crônica/virologia , Humanos , Inibidores de Proteínas Quinases/química , Replicação Viral/efeitos dos fármacos
15.
Biochem Biophys Res Commun ; 477(3): 311-6, 2016 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-27346133

RESUMO

Respiratory syncytial virus (RSV) and influenza A virus are leading causes of acute lower respiratory infectious disease. Respiratory diseases caused by RSV and influenza A virus result in serious economic burden and life-threatening disease for immunocompromised people. With the revelation that p38 mitogen-activated protein kinase (MAPK) activity in host cells is crucial for infection and replication of RSV and influenza A virus, inhibition of p38 MAPK activity has been suggested as a potential antiviral therapeutic strategy. However, the low selectivity and high toxicity of the p38 MAPK inhibitors necessitate the development of better inhibitors. Herein, we report the synthesis of a novel p38 MAPK inhibitor, NJK14047, with high kinase selectivity. In this work, it was demonstrated that NJK14047 inhibits RSV- and influenza A-mediated p38 MAPK activation in epithelial cells. Subsequently, NJK14047 treatment resulted in decreased viral replication and viral mRNA synthesis. In addition, secretion of interleukin-6 from infected cells was greatly diminished by NJK14047, suggesting that it can ameliorate immunopathological responses to RSV and influenza A. Collectively, the results suggest that NJK14047 has therapeutic potential to treat respiratory viral infection through the suppression of p38 MAPK activation, which is suggested to be an essential step for respiratory virus infection.


Assuntos
Antivirais/farmacologia , Vírus da Influenza A/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Linhagem Celular , Ativação Enzimática , Vírus da Influenza A/crescimento & desenvolvimento , Vírus da Influenza A/fisiologia , Camundongos , RNA Viral/antagonistas & inibidores , RNA Viral/biossíntese , Vírus Sinciciais Respiratórios/crescimento & desenvolvimento , Vírus Sinciciais Respiratórios/fisiologia , Ensaio de Placa Viral , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
16.
Bioorg Med Chem Lett ; 26(7): 1844-8, 2016 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-26905830

RESUMO

In this study, a series of bis(4-hydroxy)benzophenone oxime ether derivatives such as 12c, 12e and 12h were identified as novel estrogen receptor (ER) agonists that have additional and complementary anti-proliferative activities via ER-independent mechanism in cancer cells. These compounds are expected to overcome the therapeutic limitation of existing ER agonists such as estradiol and tamoxifen, which have been known to induce the proliferation of cancer cells.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Estrogênios/química , Estrogênios/farmacologia , Oximas/química , Oximas/farmacologia , Benzofenonas/química , Benzofenonas/farmacologia , Linhagem Celular Tumoral , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor alfa de Estrogênio/metabolismo , Humanos , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo
17.
Proc Natl Acad Sci U S A ; 110(37): E3526-34, 2013 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-23980168

RESUMO

An arthropod-specific peptidergic system, the neuropeptide designated here as natalisin and its receptor, was identified and investigated in three holometabolous insect species: Drosophila melanogaster, Tribolium castaneum, and Bombyx mori. In all three species, natalisin expression was observed in 3-4 pairs of the brain neurons: the anterior dorso-lateral interneurons, inferior contralateral interneurons, and small pars intercerebralis neurons. In B. mori, natalisin also was expressed in two additional pairs of contralateral interneurons in the subesophageal ganglion. Natalisin-RNAi and the activation or silencing of the neural activities in the natalisin-specific cells in D. melanogaster induced significant defects in the mating behaviors of both males and females. Knockdown of natalisin expression in T. castaneum resulted in significant reduction in the fecundity. The similarity of the natalisin C-terminal motifs to those of vertebrate tachykinins and of tachykinin-related peptides in arthropods led us to identify the natalisin receptor. A G protein-coupled receptor, previously known as tachykinin receptor 86C (also known as the neurokinin K receptor of D. melanogaster), now has been recognized as a bona fide natalisin receptor. Taken together, the taxonomic distribution pattern of the natalisin gene and the phylogeny of the receptor suggest that natalisin is an ancestral sibling of tachykinin that evolved only in the arthropod lineage.


Assuntos
Proteínas de Drosophila/fisiologia , Fertilidade/fisiologia , Proteínas de Insetos/fisiologia , Insetos/fisiologia , Neuropeptídeos/fisiologia , Comportamento Sexual Animal/fisiologia , Taquicininas/fisiologia , Sequência de Aminoácidos , Animais , Bombyx/genética , Bombyx/fisiologia , Encéfalo/citologia , Encéfalo/metabolismo , Sequência Conservada , Proteínas de Drosophila/antagonistas & inibidores , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/fisiologia , Feminino , Fertilidade/genética , Proteínas de Insetos/antagonistas & inibidores , Proteínas de Insetos/genética , Insetos/genética , Interneurônios/metabolismo , Masculino , Dados de Sequência Molecular , Neuropeptídeos/antagonistas & inibidores , Neuropeptídeos/genética , Filogenia , Interferência de RNA , Receptores de Taquicininas/genética , Receptores de Taquicininas/fisiologia , Transdução de Sinais , Taquicininas/antagonistas & inibidores , Taquicininas/genética , Tribolium/genética , Tribolium/fisiologia
18.
Biochem Biophys Res Commun ; 451(2): 282-7, 2014 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-25088993

RESUMO

Extracts of Prunella vulgaris have been shown to exert antiestrogenic effects. To identify the compounds responsible for these actions, we isolated the constituents of P. vulgaris and tested their individual antiestrogenic effects. Rosmarinic acid, caffeic acid, ursolic acid (UA), oleanolic acid, hyperoside, rutin and betulinic acid (BA) were isolated from the flower stalks of P. vulgaris var. lilacina Nakai (Labiatae). Among these constituents, UA and BA showed significant antiestrogenic effects, measured as a decrease in the mRNA level of GREB1, an estrogen-responsive protein; the effects of BA were stronger than those of UA. UA and BA were capable of suppressing estrogen response element (ERE)-dependent luciferase activity and expression of estrogen-responsive genes in response to exposure to estradiol, further supporting the suppressive role of these compounds in estrogen-induced signaling. However, neither UA nor BA was capable of suppressing estrogen signaling in cells ectopically overexpressing estrogen receptor α (ERα). Furthermore, both mRNA and protein levels of ERα were reduced by treatment with UA or BA, suggesting that UA and BA inhibit estrogen signaling by suppressing the expression of ERα. Interestingly, both compounds enhanced prostate-specific antigen promoter activity. Collectively, these findings demonstrate that UA and BA are responsible for the antiestrogenic effects of P. vulgaris and suggest their potential use as therapeutic agents against estrogen-dependent tumors.


Assuntos
Moduladores de Receptor Estrogênico/farmacologia , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor alfa de Estrogênio/metabolismo , Estrogênios/metabolismo , Triterpenos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Moduladores de Receptor Estrogênico/isolamento & purificação , Receptor alfa de Estrogênio/genética , Feminino , Humanos , Células MCF-7 , Masculino , Proteínas de Neoplasias/genética , Triterpenos Pentacíclicos , Fitoterapia , Plantas Medicinais/química , Regiões Promotoras Genéticas , Antígeno Prostático Específico/genética , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Prunella/química , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Triterpenos/isolamento & purificação , Ácido Betulínico , Ácido Ursólico
19.
Microb Cell Fact ; 13: 61, 2014 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-24774833

RESUMO

BACKGROUND: Thermus thermophilus, an extremely thermophilic bacterium, has been widely recognized as a model organism for studying how microbes can survive and adapt under high temperature environment. However, the thermotolerant mechanisms and cellular metabolism still remains mostly unravelled. Thus, it is highly required to consider systems biological approaches where T. thermophilus metabolic network model can be employed together with high throughput experimental data for elucidating its physiological characteristics under such harsh conditions. RESULTS: We reconstructed a genome-scale metabolic model of T. thermophilus, iTT548, the first ever large-scale network of a thermophilic bacterium, accounting for 548 unique genes, 796 reactions and 635 unique metabolites. Our initial comparative analysis of the model with Escherichia coli has revealed several distinctive metabolic reactions, mainly in amino acid metabolism and carotenoid biosynthesis, producing relevant compounds to retain the cellular membrane for withstanding high temperature. Constraints-based flux analysis was, then, applied to simulate the metabolic state in glucose minimal and amino acid rich media. Remarkably, resulting growth predictions were highly consistent with the experimental observations. The subsequent comparative flux analysis under different environmental conditions highlighted that the cells consumed branched chain amino acids preferably and utilized them directly in the relevant anabolic pathways for the fatty acid synthesis. Finally, gene essentiality study was also conducted via single gene deletion analysis, to identify the conditional essential genes in glucose minimal and complex media. CONCLUSIONS: The reconstructed genome-scale metabolic model elucidates the phenotypes of T. thermophilus, thus allowing us to gain valuable insights into its cellular metabolism through in silico simulations. The information obtained from such analysis would not only shed light on the understanding of physiology of thermophiles but also helps us to devise metabolic engineering strategies to develop T. thermophilus as a thermostable microbial cell factory.


Assuntos
Genoma Bacteriano , Thermus thermophilus/genética , Thermus thermophilus/metabolismo , Aminoácidos/metabolismo , Técnicas de Cultura Celular por Lotes , Biomassa , Redes e Vias Metabólicas/genética
20.
Pediatr Neonatol ; 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38972804

RESUMO

BACKGROUND: We aimed to describe the clinical and microbiological characteristics of enterococcal bacteremia, as well as the effect of Enterococcus resistance against vancomycin on clinical outcomes in Korean children. METHODS: We retrospectively reviewed the medical records of children diagnosed with enterococci isolated from blood cultures at Pusan National University Children's Hospital between December 2009 and November 2021. RESULTS: In total, 64 patients were enrolled in the study. The median age was 0 years (range 0-15), and 43 (67.2%) patients were male. Enterococcus faecalis (50%) was the most commonly identified bacterial strain. Significant underlying diseases were present in 60 patients (93.8%), and the source of bacteremia was identified in 36 patients (56.3%). Among these, intravascular device was the most common identifiable source. Fifty-six (87.5%) patients had previously received broad-spectrum antibiotics and 54 (84.4%) patients were nosocomial in origin. Twenty-nine (45.3%) strains were resistant to ampicillin, and 16 (25%) strains were resistant to vancomycin. All patients with vancomycin-resistant enterococci (VRE) had underlying disease (P = 0.199), and focus of bacteremia was significantly more frequent in VRE patients (P = 0.014). Of all the patients, after appropriate antibiotic treatment, five (7.8%) patients had recurrent enterococcal bacteremia, and seven (10.9%) patients were diagnosed with bacteremia, defined as other pathogens from blood culture. The 30-day mortality rate was 7.8%. CONCLUSION: Enterococcal bacteremia in children is usually nosocomial and occurs in children with serious underlying diseases. Because the number of enrolled patients and mortality were small in our study, it is difficult to identify whether the factor that determines prognosis in patients with enterococcal bacteremia is VRE or an underlying disease. Further studies with a large number of patients in a specific group are needed.

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