Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 182
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Bioorg Chem ; 93: 103315, 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31605927

RESUMO

Glutamic-oxaloacetic transaminase 1 (GOT1) regulates cellular metabolism through coordinating the utilization of carbohydrates and amino acids to meet nutrient requirements for sustained proliferation. As such, the GOT1 inhibitor may provide a new strategy for the treatment of various cancers. Adapalene has been approved by FDA for the treatment of acne, pimples and pustules, and it may also contribute to the adjunctive therapy for advanced stages of liver and colorectal cancers. In this work, we first examined the enzyme inhibition of over 500 compounds against GOT1 in vitro. As a result, Adapalene effectively inhibited GOT1 enzyme in a non-competitive manner. MST and DARTS assay further confirmed the high affinity between Adapalene and GOT1. Furthermore, the growth and migration of ovarian cancer ES-2 cells were obviously inhibited by the treatment of Adapalene. And it induced the apoptosis of ES-2 cells according to Western blot and Hoechst 33258 straining. In addition, molecular docking demonstrated that Adapalene coordinated in an allosteric site of GOT1 with low binding energy. Furthermore, knockdown of GOT1 in ES-2 cells decreased their anti-proliferative sensitivity to Adapalene. Together, our data strongly suggest Adapalene, as a GOT1 inhibitor, could be regarded as a potential drug candidate for ovarian cancer therapy.

2.
Anal Chem ; 91(21): 13803-13809, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31591882

RESUMO

Identification and quantitation of enantiomers is a critical and challenging step in the process of chiral capillary electrophoresis (CE) analysis, especially when the optically pure enantiomers are expensive or commercially unavailable. Herein, a method of CE in combination with circular dichroism (CD) spectroscopy for the identification of enantiomeric peak independent of single enantiomer standard was proposed. By comparing the theoretical CD spectrum of the single enantiomer calculated by time-dependent density functional theory (TDDFT) with the experimental CD spectrum of the enantiomeric mixture, the configuration of the dominant enantiomer in the nonracemic mixture was determined. Considering that the dominant enantiomer showed bigger peak area on the CE electrophoretogram, the enantiomeric peak was easily identified. Three kinds of enantiomers including seven chiral compounds (i.e., tryptophan, tyrosine, phenylalanine, Boc-valine, Boc-leucine, ibuprofen, and naproxen) were used to evaluate the reliability of the method. The concentration of the single enantiomer in the mixture can be further accurately quantified based on the total concentration of the mixture and the peak area ratio of a couple of enantiomers, and the accuracy was assessed by taking ibuprofen as an example. The developed CE-CD method provides an alternative tool for the analysis of nonracemic mixture with good ECD signals.

3.
Lasers Med Sci ; 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31485783

RESUMO

miR-548-3p is one of the members of miR-548 family, a large primate-specific miRNA gene family. The role of miR-548-3p in lung cancer was less studied. In this study, we found the expression of miR-548-3p was lower both in clinical tumor specimens and lung cancer cells compared with normal controls. In vitro, miR-548-3p inhibited lung cancer cell growth and promoted cell apoptosis at the S stage of cell cycle. The underlying mechanism of miR-548b-3p-induced cell proliferation inhibition and apoptosis may be associated with the inhibition of PI3K/AKT signaling pathway. In vivo, miR-548b-3p also suppressed tumor growth in xenografts model of lung cancer cells. Our results indicated that miR-548b-3p might be an anti-tumor target of lung cancer in the future.

4.
EMBO J ; : e101259, 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31538360

RESUMO

Psychiatric diseases are often accompanied by circadian disruptions, but the molecular underpinnings remain largely unclear. To address this, we screened genes that have been previously reported to be associated with psychiatric diseases and found that TRRAP, a gene associated with schizophrenia, is involved in circadian rhythm regulation. Knocking down Nipped-A, the Drosophila homolog of human TRRAP, leads to lengthened period of locomotor rhythms in flies. Molecular analysis demonstrates that NIPPED-A sets the pace of the clock by increasing the mRNA and protein levels of core clock genes timeless (tim) and Par domain protein 1ε (Pdp1ε). Furthermore, we found that NIPPED-A promotes the transcription of tim and Pdp1ε possibly by facilitating deubiquitination of histone H2B via the deubiquitination module of the transcription co-activator Spt-Ada-Gcn5 acetyltransferase complex. Taken together, these findings reveal a novel role for NIPPED-A in epigenetic regulation of the clock.

5.
J Org Chem ; 84(21): 13595-13603, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31549831

RESUMO

Five unusual dimers of ent-labdane diterpenoids (1-5) were isolated and identified from Andrographis paniculata, a famous medicinal plant. Bisandrographolide E (1) represents the first example of a labdane dimer possessing an unprecedent tricyclic system that comprised a spiroketal moiety fused with a ketal-γ-lactone unit in its skeleton. Its biosynthetically related intermediates, all four stereoisomers at C-12 and C-15', bisandrographolides F (2, a new compound) and A-C (3-5), were obtained at the same time. The steric configurations of the newly formed asymmetric carbons in 1-5 were first solved by single-crystal X-ray diffraction of the diacetone derivatives of 2-4 and ECD and NMR calculations of 1. More importantly, bisandrographolides 1-5, with different chemical structures or absolute configurations at C-12 and C-15', selectively activated different TRPV1-4 channels and protected cardiomyocytes from hypoxia-reoxygenation injury. Among them, 5 with 12R/15'S configuration activated TRPV1 most effectively and displayed the best cardiomyocyte protection.

6.
Spine (Phila Pa 1976) ; 44(20): 1441-1448, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31365514

RESUMO

STUDY DESIGN: A prospective study of cardiopulmonary function in patients with congenital scoliosis (CS). OBJECTIVE: To investigate the relationship of thoracic cage deformity and exercise tolerance in CS patients. SUMMARY OF BACKGROUND DATA: Congenital thoracic scoliosis and chest deformity lead to restrictive pulmonary dysfunction and in some severe cases cause cardiopulmonary failure. However, it is still unknown the relationship between thoracic deformity and exercise performance. METHODS: Patients with congenital thoracic spinal deformity were included and had radiological assessment of thoracic cage, pulmonary function testing, and cardiopulmonary exercise testing. Thoracic dimension including height, width, and depth were measured and geometry parameters were calculated. Two-tailed Pearson and Spearman correlation test and linear regression analysis were performed to investigate correlation of radiographic parameters, pulmonary function, and physical capacity. RESULTS: Sixty patients (41 females and 19 males) were included, with an average age of 18.9 years. Patients with smaller thoracic height (P < 0.001) and width (P < 0.01) and larger depth (P < 0.05) had significantly worse static pulmonary function. In exercise testing, these patients showed significant tendency of ventilation insufficiency, including lower minute ventilation (P < 0.05), faster breathing frequency (P < 0.05), and smaller tidal volume (P < 0.01). Thoracic depth was negatively correlated to exercise capacity, reflected by work rate (P < 0.001), peak oxygen intake (P < 0.001), and heart rate (P = 0.043). Patients with abnormal thoracic geometry, especially a lower ratio of height to depth and a lower ratio of width to depth, have significantly worse static pulmonary function and exercise capacity (all P < 0.05). CONCLUSION: Decreasing thoracic height and width results in restrictive pulmonary dysfunction. Distortion and asymmetry of the thoracic cage are associated with abnormal breathing pattern and reduction of exercise capacity. LEVEL OF EVIDENCE: 3.

7.
Bioorg Chem ; 92: 103186, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31465967

RESUMO

Kidney-type glutaminase (KGA), catalyzing the hydrolysis of glutamine to glutamate for energy supply, is over-expressed in many cancers and has been regarded as a new therapeutic target for cancers. Physapubescin I was isolated from the fruits of the edible herb Physalis pubescens L., commonly named as "husk tomato or hairy groundcherry", and was predicted to be a potential KGA inhibitor through structure-based virtual ligand screening. Enzyme inhibition assays, microscale thermophoresis (MST) and cellular thermal shift assay (CETSA) experiments have demonstrated the high efficiency and specificity of physapubescin I targeting KGA. EdU proliferation, Hoechst 33258 staining and cytotoxicity assays indicated that physapubescin I could inhibit cancer cell proliferation and promote apoptosis more effectively than the known KGA inhibitor, BPTES. Knockdown of KGA by siRNA reduced the inhibition of physapubescin I to SW1990 cells. Meanwhile, physapubescin I impaired glutamine metabolism in SW1990 cells with increasing intracellular level of glutamine, and correspondingly decreasing glutamate and its downstream metabolites, which may account for its inhibition of cancer cell proliferation and proapoptosis. Physapubescin I also showed significant tumor growth inhibition and low toxicity in a SW1990 xenograft mouse model. Collectively, physapubescin I may serve as a potential drug candidate or lead compound for cancer therapy by targeting KGA.

8.
BMC Infect Dis ; 19(1): 614, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31299917

RESUMO

BACKGROUND: To evaluate the efficacy and safety of telbivudine in chronic hepatitis B women during the second and third trimesters of pregnancy. METHODS: The week 12-34 of pregnant women were screened in this prospective non-intervention study, with HBV DNA > 106 IU/mL and alanine aminotransferase > 50 IU/L. The patients were received telbivudine treatment as a treatment group or without antiviral treatment as a control group. All infants were received recombinant hepatitis B vaccine 10 µg within 12 h of birth, at week 4 and week 24, immunoglobulin G within 12 h of birth and were detected HBV markers at the range from 7 to 12 months after delivery. RESULTS: A total of 241 patients were finally enrolled, 139 patients in telbivudine group and 102 patients in control group. HBsAg negative rate of infants was 99.3% (135/136) in telbivudine group and was 91.9% (91/99) in control group after 7 months (P = 0.005), respectively. The incidence of undetectable HBV DNA levels (47.5%) was significantly lower in telbivudine-treated mothers than that in the controls (0%), and 75.5% patients alanine aminotransferase returned to normal in telbivudine group, and 51% in control group at delivery (P < 0.001), respectively. CONCLUSIONS: Telbivudine can safely reduce mother-to-child transmission in chronic hepatitis B women after 12 weeks of gestation.


Assuntos
Antivirais/uso terapêutico , Vacinas contra Hepatite B/imunologia , Hepatite B Crônica/tratamento farmacológico , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Telbivudina/uso terapêutico , Adulto , Alanina Transaminase/sangue , Estudos de Casos e Controles , DNA Viral/sangue , Feminino , Idade Gestacional , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/genética , Vírus da Hepatite B/isolamento & purificação , Humanos , Imunoglobulina G/sangue , Lactente , Recém-Nascido , Gravidez , Estudos Prospectivos , Adulto Jovem
9.
Fitoterapia ; 137: 104265, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31302252

RESUMO

The aromatic plants of Vitex negundo var. heterophylla are not only herb medicine but also a functional food and an industrial crop. Its leaves can be used as a functional food for improving human's health, but the previous studies mainly focused on the volatile constituents, lignans, and iridoids. Our research led to the isolation of four new terpenoids (1-4), together with fifteen known compounds including seven flavonoids (9-15), two jasmonates (7-8) and six terpenoids (5-6, 16-19) from the leaves. Among all these compounds, 1, 2, 11, and 19 exhibited strong inhibitory activity against NO production in lipopolysaccharide (LPS)-induced RAW264.7 macrophage. The anti-inflammatory mechanism of the most active compound (2) is related to the inhibition of iNOS and COX-2, and the suppression of NF-κB pathway. Therefore, terpenoids and flavonoids from the leaves of Vitex negundo var. heterophylla might be used as potential anti-inflammatory candidates for developing medicine or value-added functional food.


Assuntos
Anti-Inflamatórios/farmacologia , Diterpenos/farmacologia , Norisoprenoides/farmacologia , Vitex/química , Animais , Anti-Inflamatórios/isolamento & purificação , China , Ciclo-Oxigenase 2/metabolismo , Diterpenos/isolamento & purificação , Interleucinas/metabolismo , Camundongos , Estrutura Molecular , Óxido Nítrico Sintase Tipo II/metabolismo , Norisoprenoides/isolamento & purificação , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Folhas de Planta/química , Células RAW 264.7
10.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(6): 528-533, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31208504

RESUMO

OBJECTIVE: To investigate the nutritional status of critically ill hospitalized children and to explore the value of nutritional risk screening tools in the nutritional risk assessment. METHODS: The clinical data of 211 critically ill children who were admitted to the pediatric intensive care unit from November 2017 to April 2018 were collected to evaluate their nutritional status on admission and at discharge. Two nutritional risk screening tools, STRONGkids and PYMS, were used for nutritional risk screening in the 211 children. RESULTS: Among the 211 patients, 68 (32.2%) were found to have malnutrition on admission, with 34 cases each of moderate and severe malnutrition. Moderate or high nutritional risk was found in 154 cases (73.0%) with STRONGkids and 165 cases (78.2%) with PYMS. Using weight-for-age Z-score as the gold standard to evaluate the efficacy of the two nutritional risk screening tools, the areas under the receiver operating characteristic curves of STRONGkids and PYMS were 0.822 and 0.759 respectively. Both tools had a significant clinical value in screening for malnutrition (P<0.05), but there was no significant difference in clinical efficacy between them (P>0.05). With the optimal cut-off value of 3 points, the sensitivities of STRONGkids and PYMS for screening of malnutrition were 92.1% and 76.2% respectively. The children with moderate or high nutritional risk on admission had a significantly poorer prognosis than those with low nutritional risk (P=0.014 and 0.001 respectively). The children with severe malnutrition had a significantly poorer prognosis than those with normal nutrition (P=0.0009). CONCLUSIONS: The detection rates of malnutrition and nutritional risk are high in critically ill children. Malnutrition/high nutritional risk is related to a poor prognosis. Both STRONGkids and PYMS have a clinical value for nutritional risk screening in critically ill children, and they have similar clinical efficacy; however, STRONGkids is more sensitive.


Assuntos
Desnutrição , Avaliação Nutricional , Criança , Estado Terminal , Humanos , Programas de Rastreamento , Estado Nutricional , Medição de Risco
11.
Emerg Microbes Infect ; 8(1): 823-826, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31164049

RESUMO

The spread of highly pathogenic avian influenza (HPAI) H5N1 virus is associated with wild fowl migration in East Asian-Australasian (EA) and Central Asian (CA) flyways. However, the spread of H5N1 virus between the two flyways is still unclear. Here, the movements of wild waterfowl were obtained from satellite tracking data covering seven bar-headed geese and three great black-headed gulls breeding in the Qinghai Lake area (along the EA flyway), and 20 whooper swans wintering in the Sanmenxia Reservoir area (at the CA flyway). From the 2688 samples that were screened from wild birds at Qinghai Lake after an outbreak of H5N1 in July 2015, four genomes of H5N1 virus were obtained from bar-headed geese. The results of phylogenetic analysis indicated that these H5N1 viruses belonged to clade 2.3.2.1c and their gene fragments were highly homologous with A/whooper swan/Henan/SMX1/2015 (H5N1) virus (ranging from 99.76% to 100.00%) isolated from a dead whooper swan from the Sanmenxia Reservoir area along the EA flyway in January 2015. Furthermore, the coincidental timing of the H5N1 outbreak with spring migration, together with phylogenetic evidence, provided new evidence of the east-to-west spread of HPAI H5N1 between the EA and CA migratory flyways of China.


Assuntos
Anseriformes/fisiologia , Virus da Influenza A Subtipo H5N1/fisiologia , Influenza Aviária/epidemiologia , Migração Animal , Animais , Animais Selvagens/fisiologia , Animais Selvagens/virologia , Anseriformes/virologia , Ásia/epidemiologia , Austrália/epidemiologia , China/epidemiologia , Virus da Influenza A Subtipo H5N1/classificação , Virus da Influenza A Subtipo H5N1/genética , Virus da Influenza A Subtipo H5N1/isolamento & purificação , Influenza Aviária/transmissão , Influenza Aviária/virologia , Filogenia , Estações do Ano
12.
J Bone Joint Surg Am ; 101(12): 1109-1118, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31220028

RESUMO

BACKGROUND: Patients with congenital scoliosis often have restrictive pulmonary dysfunction on static pulmonary function testing (PFT). Although frequently asymptomatic during daily activities, these patients are generally assumed to have reduced exercise capacity. The aim of this study was to use dynamic cardiopulmonary exercise testing (CPET) to investigate exercise capacity and its association with spinal deformity in patients with congenital scoliosis. METHODS: Sixty patients with congenital scoliosis who underwent preoperative spinal radiography, PFT, and CPET were included from January 2014 to November 2017. The impact of thoracic spinal deformity and rib anomalies on pulmonary function and physical capacity was investigated. RESULTS: A significant deterioration in pulmonary function with increases in the severity of the major thoracic curve was demonstrated by the forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and total lung capacity (all p < 0.001). The ratio of FEV1 to FVC was similar regardless of thoracic curve severity. A smaller tidal volume during exercise testing reflected restrictive dysfunction in the patients with the most severe curves. CPET also revealed a significant trend of faster breathing by patients with a severe thoracic curve (p < 0.001). Exercise capacity indicators such as work rate (p = 0.019), heart rate (p = 0.015), and oxygen saturation (p = 0.006) were significantly reduced only in patients with a thoracic curve of >100°. Pulmonary dysfunction was the major contributor to exercise intolerance. Compared with mild pulmonary dysfunction, moderate and severe dysfunction was associated with an abnormal breathing pattern and lower work rate (p = 0.032) and peak oxygen intake (p = 0.042), indicating worse exercise tolerance. CONCLUSIONS: Congenital scoliosis leads to restrictive pulmonary dysfunction, which reduces the tidal volume and forces patients to accelerate respiratory rates during exercise. Patients with a thoracic curve of >100° are unable to compensate and have significantly reduced exercise capacity. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

13.
Cell Prolif ; 52(4): e12634, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31094043

RESUMO

OBJECTIVES: Guillain-Barré syndrome (GBS) is a type of acute autoimmune disease, which occurs in peripheral nerves and their roots. There is extensive evidence that suggests many immune-associated genes have essential roles in GBS. However, the associations between immune genes and GBS have not been sufficiently examined as most previous studies have only focused on individual genes rather than their entire interaction networks. MATERIALS AND METHODS: In this study, multiple levels of data including immune-associated genes, GBS-associated genes, protein-protein interaction (PPI) networks and gene expression profiles were integrated, and an immune or GBS-directed neighbour co-expressed network (IOGDNC network) and a GBS-directed neighbour co-expressed network (GDNC network) were constructed. RESULTS: Our analysis shows the immune-associated genes are strongly related to GBS-associated genes whether at the interaction level or gene expression level. Five immune-associated modules were also identified which could distinguish between GBS and normal samples. In addition, functional analysis indicated that immune-associated genes are essential in GBS. CONCLUSIONS: Overall, these results highlight a strong relationship between immune-associated genes and GBS existed and provide a potential role for immune-associated genes as novel diagnostic and therapeutic biomarkers for GBS.


Assuntos
Síndrome de Guillain-Barré/genética , Transcriptoma/genética , Humanos , Mapas de Interação de Proteínas/genética
14.
Food Funct ; 10(6): 3386-3395, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31112178

RESUMO

3-Phosphoglycerate dehydrogenase (PHGDH) catalyzes the first rate-limiting step for the synthesis of glucose-derived serine by converting 3-phosphoglycerate (3-PG) to phosphohydroxypyruvate (p-Pyr), which has been reported to associate with tumorigenesis in many cancers. Iox A, a natural withanolide obtained from dietary tomatillo (Physalis ixocarpa), showed significant PHGDH inhibitory activity with an IC50 value of 1.66 ± 0.28 µM, and it was further confirmed to bind directly to PHGDH by the MST assay. Molecular docking demonstrated that Iox A coordinated at the allosteric site of PHGDH, which was consistent with the non-competitive kinetics. Meanwhile, Iox A selectively inhibited the proliferation of high PHGDH-expressing cancer cell lines (SW1990, MCF-7 and HeLa) and showed no obvious cytotoxicities on normal human cells (LO2, L929 and HPDE6-C7). In particular, Iox A showed a dose-dependent proapoptotic activity against SW1990 cells in a micromolar concentration as detected by flow cytometry and western blot analysis. DARTS and siRNA assays further demonstrated that Iox A directly targets at PHGDH to inhibit the proliferation of SW1990 cells. Furthermore, Iox A significantly inhibited the tumor growth in a SW1990 xenograft mouse model with low toxicities, suggesting its potential therapeutic application in pancreatic cancer treatment. Therefore, Iox A was identified as a novel natural PHGDH inhibitor with high targeting and low toxicities for the treatment of pancreatic cancers.

15.
J Agric Food Chem ; 67(18): 5147-5158, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-30995041

RESUMO

Ganoderma lucidum, as food, tea, dietary supplement, and medicine, is widely used in China and Eastern Asian countries. In order to discover its anti-inflammatory constituents and provide some references for the usage of G. lucidum and G. sinense, two official species in China, the fruiting bodies of G. lucidum were studied, leading to the isolation of six new triterpenoids (1-6) and 27 known analogues (7-33). Compound 4 exhibited the most potent inhibition on nitric oxide (NO) production induced by lipopolysaccharide (LPS) in RAW264.7 macrophage cells. The production of IL-6 and IL-1ß, as well as the expression of iNOS, COX-2, and NF-κB were dose-dependently reduced by 4. The phosphorylations of IκBα and IKKß in LPS-induced macrophage cells were blocked by 4. Therefore, 4 could be used as a potential anti-inflammatory candidate and the total triterpenoids might be developed as value-added functional food for the prevention of inflammation. In combination of previous studies, it should be cautious for the interchangeable usage of G. lucidum and G. sinense.


Assuntos
Anti-Inflamatórios/farmacologia , Reishi/química , Triterpenos/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , China , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Células RAW 264.7 , Triterpenos/química , Triterpenos/isolamento & purificação
16.
Biochem Biophys Res Commun ; 513(4): 898-903, 2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31003767

RESUMO

Current studies have shown that long-term exposure to fine particulate matter (PM2.5) can aggravate lung injury in asthmatic children. The HMGB1/RAGE pathway may play an important role, but few studies on the HMGB1/RAGE signaling pathway in PM2.5-induced asthma have been performed. Epigallocatechin-3-gallate (EGCG), which has antioxidant, anti-inflammatory and immunomodulatory effects, has not been examined in studies at home and abroad. In this study, we established an animal model of asthma and observed that the lung tissue was damaged, inflammatory cells infiltrated, bronchial wall thickness (WTt) and bronchial smooth muscle thickness (WTm) increased and the HMGB1 and RAGE mRNA and protein expression increased. The asthmatic rats exposed to PM2.5 showed significantly increased lung injury and inflammatory cell infiltration, WTt and WTm further increased, and HMGB1 and RAGE mRNA and protein levels were higher than those in the asthma group. The asthmatic rats exposed to PM2.5 were treated with EGCG, which alleviated the lung injury, reduced the number of inflammatory cells, decreased WTt and WTm, and reduced the expression of HMGB1 and RAGE mRNA and protein. The high-dose group showed more significant effects than the other groups. In conclusion, our results suggest that HMGB1 and RAGE are involved in the pathogenesis of asthma. PM2.5 exposure significantly aggravated airway inflammation injury in asthmatic rats. EGCG can reduce lung injury and airway remodeling in PM2.5-exposed asthmatic rats and has lung protective effects. The mechanism may be related to regulation of the HMGB1/RAGE signaling pathway. Our results may provide new ideas and methods for the prevention and treatment of PM2.5-induced asthma.

17.
PLoS One ; 14(4): e0214857, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30947317

RESUMO

Myasthenia gravis (MG) is an autoimmune disease. In recent years, considerable evidence has indicated that Gene Ontology (GO) functions, especially GO-biological processes, have important effects on the mechanisms and treatments of different diseases. However, the roles of GO functions in the pathogenesis and treatment of MG have not been well studied. This study aimed to uncover the potential important roles of risk-related GO functions and to screen significant candidate drugs related to GO functions for MG. Based on MG risk genes, 238 risk GO functions and 42 drugs were identified. Through constructing a GO function network, we discovered that positive regulation of NF-kappaB transcription factor activity (GO:0051092) may be one of the most important GO functions in the mechanism of MG. Furthermore, we built a drug-GO function network to help evaluate the latent relationship between drugs and GO functions. According to the drug-GO function network, 5 candidate drugs showing promise for treating MG were identified. Indeed, 2 out of 5 candidate drugs have been investigated to treat MG. Through functional enrichment analysis, we found that the mechanisms between 5 candidate drugs and associated GO functions may involve two vital pathways, specifically hsa05332 (graft-versus-host disease) and hsa04940 (type I diabetes mellitus). More interestingly, most of the processes in these two pathways were consistent. Our study will not only reveal a new perspective on the mechanisms and novel treatment strategies of MG, but also will provide strong support for research on GO functions.

18.
Pain Res Manag ; 2019: 9758273, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30944687

RESUMO

Study design: Retrospective characterization of nonspecific low back pain (NSLBP) in young adult female patients with and without lumbar scoliosis. Background: There is no consensus as to whether NSLBP in scoliosis patients is related to scoliosis per se or is just a normal symptom that could happen in anyone. Objectives: The aim of this study was to compare the differences in NSLBP between young adult female patients with and without lumbar scoliosis and to provide a theoretical basis for differential treatment of NSLBP in patients with and without lumbar scoliosis. Methods: Ninety female young adults with NSLBP were divided into scoliosis and nonscoliosis groups. Characteristics of pain, lumbar mobility, muscle strength, Cobb angle, axial trunk rotation (ATR) angle, and surface electromyography (SEMG) signal were compared between the two groups. Results: The pain location in scoliotic patients was more concentrated on the left side of the lumbar spine (P ≤ 0.001). The area affected by pain (P=0.028) and the numerical pain rating scale (NPRS) scores (P=0.014) of scoliotic patients were less than those of nonscoliotic patients. The difference between side-bending in scoliotic patients was greater than that in nonscoliotic patients (P=0.001). Scoliotic patients exhibited a significantly better ability for flexion (P=0.001) and extension (P=0.017) than nonscoliotic patients. The posterior muscles in scoliotic patients were stronger than those in nonscoliotic patients (P=0.014). The ratio of root-mean-square (RMS) on paraspinal muscles in scoliotic patients was greater than that in nonscoliotic patients (P ≤ 0.001). Scoliotic patients exhibited greater relaxation time during the flexion-relaxation phenomenon (FRP) than nonscoliotic patients (P=0.024). Conclusions: The characteristics of NSLBP experienced by patients with lumbar scoliosis were distinct from those of NSLBP experienced by nonscoliotic patients. The treatment of NSLBP in scoliotic patients should be different from that in nonscoliotic patients.


Assuntos
Dor Lombar/epidemiologia , Dor Lombar/etiologia , Escoliose/complicações , Escoliose/fisiopatologia , Feminino , Humanos , Dor Lombar/fisiopatologia , Vértebras Lombares , Amplitude de Movimento Articular , Estudos Retrospectivos , Adulto Jovem
19.
Eur J Med Chem ; 173: 282-293, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31009914

RESUMO

Two series of andrographolide derivatives with introduction of amide moiety into ring A by Beckmann rearrangement were synthesized. In series 1, the ring A was converted to caprolactam, and an amide moiety was linked to C-19 of ring A in series 2. Among them, compound 8h exhibited obvious inhibition on HK2 enzyme activity (IC50 = 9.36 ±â€¯0.08 µM) and LPS-induced NO production in RAW264.7 cells (IC50 = 22.38 ±â€¯3.57 µM), and potent binding affinity with HK2 (Kd = 5.12 ±â€¯0.82 µM). The preliminary structure-activity relationships (SARs) suggested that the formation of caprolactam of ring A and esterification of C-19-hydroxyl could improve the inhibitory effects on HK2 enzyme of andrographolide derivatives. Furthermore, compound 8h significantly reduced the levels of IL-1ß and IL-6, down-regulated the expressions of iNOS and COX-2. Its anti-inflammatory effect was related to the inhibition of both NF-κB pathway and glycolysis enzyme HK2. Since HK2 could be a novel and effective target for anti-inflammation, compound 8h might be a new anti-inflammatory agent targeting at HK2, or serve as a lead compound to design and synthesize more HK2 inhibitors with better inflammatory effects.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Diterpenos/farmacologia , Inibidores Enzimáticos/farmacologia , Hexoquinase/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Células Cultivadas , Diterpenos/síntese química , Diterpenos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Hexoquinase/metabolismo , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Células RAW 264.7 , Relação Estrutura-Atividade
20.
Bioorg Chem ; 87: 16-22, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30852233

RESUMO

Serine plays critically important roles in tumorigenesis. Homo sapiens 3-phosphoglycerate dehydrogenase (PHGDH) catalyzes the first committed step for the synthesis of glucose-derived serine via the phosphoserine pathway and has been associated with a wide variety of cancers, including breast cancer, melanoma, colon cancer, glioma, nasopharyngeal carcinoma, cervical adenocarcinoma, etc. Azacoccone E, an aza-epicoccone derivative from the culture of Aspergillus flavipes, exhibited effective inhibitory activity against PHGDH in vitro. The microscale thermophoresis (MST) method and the cellular thermal shift assay (CETSA) confirmed that azacoccone E directly bound to PHGDH. And the cell-based experiments showed that this compound was selectively toxic to PHGDH-dependent cancer cells and could cause apoptosis. Further biochemical assays revealed that it was a noncompetitive inhibitor with respect to the substrate of 3-PG and exhibited a time-dependent inhibition. Furthermore, molecular docking demonstrated that azacoccone E coordinated in an allosteric site of PHGDH with low binding energy. Therefore, azacoccone E can be considered as a possible drug candidate targeting at PHGDH for treatment of cancers.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA