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1.
Artículo en Inglés | MEDLINE | ID: mdl-32155673

RESUMEN

In this study, we investigated the lipid metabolism regulatory activity of a novel metformin derivative (MD568) and its potential mechanism of action in obese rats with type 2 diabetes (T2 DM). Previous gene chip analysis of 3T3-L1 cells have shown that MD568 regulates the transcription of genes involved in the peroxisome proliferator-activated receptor (PPAR) signalling pathway, fatty acid metabolism, and glycerolipid metabolism. In this study, obese T2 DM rats were treated with MD568 (200 mg/kg) for 8 weeks. Results showed that MD568 significantly reduced the body weight gain, plasma glucose, insulin, total cholesterol, triglyceride, and low density lipoprotein cholesterol levels. MD568 treatment also improved the insulin resistance of obese T2 DM model rats. In particular, in white adipose tissue, MD568 inhibited the excessive volume increment of adipose cells by down-regulating the protein levels of CCAAT/enhancer binding protein-α (C/EBP-α) and PPAR-γ, as well as the transcription of their target lipid metabolism-related genes. In the liver, MD568 inhibited hepatic fatty lesions and interfered with hepatic gluconeogenesis by regulating the expression of lipid metabolism-related genes and glycogen-related kinases. In conclusion, our results suggested that the newly synthesized MD568 affected the maintenance of lipid homeostasis in obese type 2 diabetic rats.

2.
Medicine (Baltimore) ; 99(9): e19294, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32118742

RESUMEN

The aim of the present study was to reveal the physical symptom changes and their correlations with mental health status in deep underground miners.A total of 286 deep underground miners completed a cross-sectional questionnaire study at China Pingmei Shenma mine complex. The questionnaire included sociodemographics, self-reported physical symptoms, underground adverse environmental factors, and the Symptom Checklist-90-Revised (SCL-90-R). Five environmental parameters of 1 deep mine were also measured.Data from 266 valid questionnaires were analyzed. The 3 most frequent complaints about underground adverse conditions were moisture [62.03% (165/266)], dim light [45.86% (122/266)], and high temperature [42.11% (112/266)]. Fatigue [40.22% (107/266)], hearing loss [34.96% (93/266)], and tinnitus [31.58% (84/266)] were reported to be the three most common physical symptoms. Insomnia was reported in 204 participants (76.69%) mainly due to the difficulty of falling asleep [42.35% (84/204)] and dreams [39.70% (81/204)]. Mean scores of SCL-90-R subscales including somatization, anxiety, phobic anxiety, psychoticism, and paranoid ideation were elevated compared to Chinese norms, while there was diminished interpersonal sensitivity. Univariate analyses indicated that the 3 most common physical symptoms were associated with poorer SCL-90-R scores. With increasing depth below ground, air pressure, relative humidity, CO2 concentration and temperature rose, while total gamma radiation dose-rate decreased.The physical and mental health status of deep underground miners was poorer than the general Chinese male population. Some adverse environmental factors were identified that may have influenced health status. Measures are suggested to improve the deep underground working environment.


Asunto(s)
Salud Mental/normas , Síndrome , Lugar de Trabajo/psicología , Adulto , China , Correlación de Datos , Estudios Transversales , Humanos , Masculino , Salud Mental/estadística & datos numéricos , Persona de Mediana Edad , Mineros , Psicometría/instrumentación , Psicometría/métodos , Encuestas y Cuestionarios , Factores de Tiempo , Lugar de Trabajo/normas
3.
Biomed Pharmacother ; 126: 109734, 2020 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-32114355

RESUMEN

Numerous researches supported that non-alcoholic fatty liver disease (NAFLD) was an emerging problem associated with increased visceral adiposity (obesity), diabetes and related metabolic disorders. Huang-Qi San (HQS) is composed of three traditional Chinese medicines (Astragali Radix, Pueraria Radix and Cortex Mori Radicis) with a weight ratio of 1:2:1. HQS has been reported to be effective in improving glucose-lipid metabolism, but its underlying mechanism on NAFLD has not been fully understood. The purpose of the present study was to assess the protective effects of HQS on obesity-induced hepatic steatosis in rats fed with high fat diet (HFD). Our data revealed that administration of HQS (1.2 and 2.4 g/kg body weight) resulted in significant reduction in body weight (BW) and organs coefficients of visceral fat. The full-Body CT scan demonstrated that HQS reduced liver fat ratio, visceral and subcutaneous fat mass in a dose-dependent manner. Additionally, HQS decreased plasma TC, TG, FFA and FABP4 levels, normalized glucose and insulin levels, and improved the glucose tolerance. Pathological examination showed that HQS alleviated hepatic steatosis and reduced the cell size of epididymal visceral adipose tissue. Hepatic lipid accumulation was also reduced by HQS treatment compared with HFD fed rats. RNA-Seq analysis combining with qPCR demonstrated that the mRNA expression of some important glucose and lipid metabolism-related genes including Acat2, Apoc4, Bhmt, Cyp3a62, Cyp51, Egln3 (Phd3), Fads1, Fads2, Gnmt, Hmgcs1 and Pemt, were significantly changed by HQS treatment. Taken together, these results suggested that HQS had beneficial effects on glucose-lipid metabolism and hepatic steatosis, and its mechanism might be related to the functions of the genes in regulating glucose and lipid metabolism.

4.
Artículo en Inglés | MEDLINE | ID: mdl-32189490

RESUMEN

Interactions among anti-wear additives (AWs), friction modifiers (FMs), and dispersant in a lubricating oil are critical for tribological performance. This study investigates compatibilities of three oil-soluble ionic liquids (ILs, candidate AWs) with a FM, molybdenum dithiocarbamate (MoDTC), and a dispersant, polyisobutene succinimide (PIBSI), under boundary lubrication. Either synergistic or antagonistic effects were observed depending on the IL's chemistry. Adding an aprotic phosphonium-alkylphosphate or phosphonium-alkylphosphinate IL into the oil containing MoDTC and PIBSI showed detrimental impact on the friction and wear behavior. PIBSI was found to preferably interact/react with the aprotic IL to lose its ability to suspend MoDTC and to partially consume or even deplete the IL. In contrast, a protic ammonium-alkylphosphate IL seemed to be able to co-exist with PIBSI and work synergistically with MoDTC, yielding a sustainable, ultra-low boundary friction. A three-stage tribochemical process is proposed to explain how this IL+MoDTC pair interacts with the contact surface to form a chemically-reacted, wear-protective tribofilm supporting a physically-adsorbed, friction-reducing film on top. This study provides fundamental insights of the compatibilities among three common lubricant components, anti-wear, friction modifier, and dispersant, which can be used to guide future lubricant development.

6.
Eur J Med Chem ; 191: 112151, 2020 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-32109778

RESUMEN

Activity-based protein profiling (ABPP) has become an emerging chemical proteomic approach to illustrate the interaction mechanisms between compounds and proteins. This approach has combined organic synthesis, biochemistry, cell biology, biophysics and bioinformatics to accelerate the process of drug discovery in target identification and validation, as well as in the stage of lead discovery and optimization. This review will summarize new developments and applications of ABPP in medicinal chemistry. Here, we mainly described the design principles of activity-base probes (ABPs) and general workflows of ABPP approach. Moreover, we discussed various basic and advanced ABPP strategies and their applications in medicinal chemistry, including competitive and comparative ABPP, two-step ABPP, fluorescence polarization ABPP (FluoPol-ABPP) and ABPs for visualization. In conclusion, this review will give a general overview of the applications of ABPP as a powerful and efficient technique in medicinal chemistry.

7.
BMC Cancer ; 20(1): 150, 2020 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-32093621

RESUMEN

BACKGROUND: To investigate clinicopathological variables influencing overall survival, overall recurrence, and post-recurrence survival (PRS) in patients who experienced curative-intent surgical resection of stage I non-small-cell lung cancer (NSCLC). METHODS: We investigated a series of 1387 patients with stage I NSCLC who underwent surgical resection from 2008 to 2015. The effect clinicopathological factors on death, recurrence, and PRS were evaluated by Kaplan-Meier estimates and cox regression analysis. RESULTS: Among the 1387 stage I patients, 301 (21.7%) experienced recurrence. The 5-year cumulative incidence of recurrence (CIR) for all patients was 20.2% and median PRS was 25.5 months. The older age (P = 0.036), p-stage IB (P = 0.001), sublobar resection(P<0.001), histology subtype (P<0.001), and lymphovascular invasion (LVI) (P = 0.042) were significantly associated with worse overall survival. Among 301 recurrent patients, univariable analysis indicated that p-stage IB (versus IA) (P<0.001), LVI (P<0.001) and visceral pleural invasion (VPI) (P<0.001) were remarkably correlated with the higher incidence of recurrence. Taking the effect of clinicopathological variables on PRS into consideration, smoking history (P = 0.043), non-adenocarcinoma (P = 0.013), high architectural grade of LUAD (P = 0.019), EGFR wild status (P = 0.002), bone metastasis (P =0.040) and brain metastasis (P = 0.042) were substantially related with poorer PRS. Multivariate analysis demonstrated that high architectural grade of LUAD (P = 0.008), brain metastasis (P = 0.010) and bone metastasis (P = 0.043) were independently associated with PRS. CONCLUSION: In patients with resected stage I NSCLC, the older age, p-stage IB (versus IA), sublobar resection, histology subtype, and LVI were significantly associated with worse overall survival. P-stage IB (versus IA), LVI, and VPI were significantly correlated with the higher incidence of recurrence. High architectural grade of LUAD, brain metastasis and bone metastasis were independent risk factors with PRS.

8.
Artículo en Inglés | MEDLINE | ID: mdl-32085900

RESUMEN

Microtubules are made up of tubulin protein and play a very important part in numerous cellular events of eukaryotic cells, which is why they are seen as attractive targets for tumor chemotherapy. BNC105, a known vascular targeting agent, has entered in phase II clinical trials. It has previously been confirmed that BNC105 is an effective microtubule targeting agent for various cancers. BNC105 exhibits selectivity for tumor cells, elicits vascular disrupting effects, and inhibits tumor growth. However, the molecular mechanism of BNC105 is still elusive. Herein, the crystal structure of BNC105 in complex with tubulin protein is revealed, demonstrating the its interaction with the colchicine binding site. In order to thoroughly evaluate its molecular mechanism from a structural-activity-relationship standpoint, the binding mode of tubulin to BNC-105 is compared with colchicine, CA-4 and other BNC-105 derivatives. Our study not only confirms the detailed interactions of the BNC105-tubulin complex, but also offer substantial structural foundation for the design and development of novel benzo[b]furan derivatives as microtubule targeting agents.

9.
Medicine (Baltimore) ; 99(5): e18977, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32000429

RESUMEN

To address the remaining medical misconducts after the zero-makeup drug policy (ZMDP), e.g., over-examinations, China has given the priority to government supervision on medical institutions. This study evaluated the effect of government supervision on medical costs among inpatients with chronic obstructive pulmonary disease (COPD) in Sichuan province, the first province in China where the medical supervision was conducted.A linear interrupted time series (ITS) model was employed to analyze data about 72,113 inpatients from 32 hospitals. Monthly average medicine costs, diagnostic costs, and medical services costs, nursing costs from January 2015 to June 2018 were analyzed, respectively.The average hospitalization costs fell with a monthly trend of 42.90Yuan before the implementation of supervision (P < .001), and the declining trend remained with the more dramatic rate (-158.70Yuan, P < .001) after the government audit carried out. For western medicine costs, the monthly decreasing trend remained after the implementation of supervision (-66.44Yuan, P < .001); meanwhile, the monthly upward trend was changed into a downtrend trend for traditional Chinese medicine costs (-11.80Yuan, P = .009). Additionally, the increasing monthly trend in average diagnostics costs disappeared after government supervision, and was inversed to an insignificant decreasing trend at the rate of 26.18Yuan per month. Moreover, the previous upward trends were changed into downward trends for both medical service costs and nursing costs (P = .056, -44.71Yuan; P = .007, -11.17Yuan, respectively) after the supervision carried out.Our findings reveal that government supervision in Sichuan province was applicable to curb the growth of medical costs for inpatients with COPD, which may reflect its role in restraining physicians' compensating behaviors after the ZMDP. The government medical supervision holds promise to dismiss medical misconducts in Sichuan province, the experience of which may offer implications for other regions of China as well as other low- and middle-income countries.


Asunto(s)
Regulación Gubernamental , Hospitalización/economía , Pacientes Internos/estadística & datos numéricos , Enfermedad Pulmonar Obstructiva Crónica/economía , Garantía de la Calidad de Atención de Salud , Anciano , China , Femenino , Humanos , Masculino , Persona de Mediana Edad
10.
11.
Sci Transl Med ; 12(524)2020 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-31894106

RESUMEN

Circulating tumor DNA (ctDNA) has emerged as a useful diagnostic and prognostic biomarker in many cancers. Here, we conducted a study to investigate the potential use of ctDNA methylation markers for the diagnosis and prognostication of colorectal cancer (CRC) and used a prospective cohort to validate their effectiveness in screening patients at high risk of CRC. We first identified CRC-specific methylation signatures by comparing CRC tissues to normal blood leukocytes. Then, we applied a machine learning algorithm to develop a predictive diagnostic and a prognostic model using cell-free DNA (cfDNA) samples from a cohort of 801 patients with CRC and 1021 normal controls. The obtained diagnostic prediction model discriminated patients with CRC from normal controls with high accuracy (area under curve = 0.96). The prognostic prediction model also effectively predicted the prognosis and survival of patients with CRC (P < 0.001). In addition, we generated a ctDNA-based molecular classification of CRC using an unsupervised clustering method and obtained two subgroups of patients with CRC with significantly different overall survival (P = 0.011 in validation cohort). Last, we found that a single ctDNA methylation marker, cg10673833, could yield high sensitivity (89.7%) and specificity (86.8%) for detection of CRC and precancerous lesions in a high-risk population of 1493 participants in a prospective cohort study. Together, our findings showed the value of ctDNA methylation markers in the diagnosis, surveillance, and prognosis of CRC.

12.
J Integr Plant Biol ; 2020 Jan 07.
Artículo en Inglés | MEDLINE | ID: mdl-31912615

RESUMEN

Endophytic fungi can be beneficial to plant growth. However, the molecular mechanisms underlying colonization of Acremonium spp. remain unclear. In this study, a novel endophytic Acremonium strain was isolated from the buds of Panax notoginseng and named Acremonium sp. D212. The Acremonium sp. D212 could colonize the roots of P. notoginseng, enhance the resistance of P. notoginseng to root rot disease, and promote root growth and saponin biosynthesis in P. notoginseng. Acremonium sp. D212 could secrete indole-3-acetic acid (IAA) and jasmonic acid (JA), and inoculation with the fungus increased the endogenous levels of IAA and JA in P. notoginseng. Colonization of the Acremonium sp. D212 in the roots of the rice line Nipponbare was dependent on the concentration of methyl jasmonate (MeJA) (2-15 µmol/L) and 1-naphthalenacetic acid (NAA) (10-20 µmol/L). Moreover, the roots of the JA signaling-defective coi1-18 mutant were colonized by Acremonium sp. D212 to a lesser degree than those of the wild-type Nipponbare and miR393b-overexpressing lines, and the colonization was rescued by MeJA but not by NAA. It suggests that the cross-talk between JA signaling and the auxin biosynthetic pathway plays a crucial role in the colonization of Acremonium sp. D212 in host plants.

13.
J Cell Physiol ; 235(5): 4913-4927, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-31693178

RESUMEN

BACKGROUND: Lung cancer is the leading cause of cancer-related deaths worldwide and the prognosis remains poor. The recent introduction of the immune checkpoint inhibitor (ICI), or plus chemotherapy, both resulted in the survival benefit for patients with advanced non-small-cell lung cancer (NSCLC), but it remains unanswered which is superior. The current study aimed to estimate the comparative efficacy and safety of ICI-chemotherapy versus ICI-monotherapy in advanced NSCLC. METHODS: Studies were identified by searching PubMed, Embase, and Cochrane library. The randomized controlled trials (RCTs) that ICI monotherapy or ICI plus chemotherapy compared with chemotherapy in NSCLC were included with available primary endpoints of progression-free survival (PFS), overall survival (OS), objective response rate, or treatment-related adverse events. A fixed-effect or random-effects model was adopted depending on between-study heterogeneity. RESULTS: A total of 20 RCTs involving 12,025 patients with NSCLC were included. Both ICI-monotherapy and ICI-chemotherapy resulted in significantly prolonged survival compared to chemotherapy and the former led to significantly longer PFS. The magnitude of survival benefits appeared to be greatest among those treated with pembrolizumab plus platinum-based chemotherapy (OS, 0.56; PFS, 0.54). Additionally, OS and PFS advantages of ICI therapies were observed in patients with NSCLC with low or high programmed cell death 1 ligand 1 (PD-L1) expression level, but not in intermediate PD-L1 TPS. CONCLUSIONS: Pembrolizumab plus platinum-based chemotherapy was recommended as the optimal first-line therapy for advanced patients with NSCLC. Additionally, PD-L1 alone is not recommended as an adequate molecular biomarker to identify eligible patients for routine clinical practice in immunotherapy.

14.
Environ Pollut ; 257: 113548, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31733961

RESUMEN

Existing studies have typically investigated only the association between single pollutants and health outcomes. However, in the real world, people are exposed to multiple air pollutants simultaneously. The effect of air pollutants on emergency department (ED) visits has not been previously studied in the Sichuan Basin, which is one of the most polluted areas. We collected nonaccidental, respiratory and cardiovascular daily ED visits and daily concentrations of PM2.5, PMc, CO, SO2, NO2 and O3 in Chengdu, China, from 2014 to 2016. A weighted variable for the combination of multiple air pollutants was constructed to assess the joint adverse health effects. Each air pollutant was assigned a health-related weight, which indicated the pollutant's relative contribution to the joint effect. The effects on specific subpopulations (males and females; 15-65 years old and >65 years old) were also examined. With an increase of 10 µg/m3 of the combined multiple air pollutants, the daily ED visits for nonaccidental, respiratory and cardiovascular causes increased by 0.96% (95% CI: 0.51%-1.39%), 1.19% (95% CI: 0.53%, 1.85%) and 4.36% (95% CI: 1.06%, 7.76%) at lag 1, respectively. Males presented more pronounced effects, except for cardiovascular disease, than females. Elderly individuals were found to be more sensitive than young individuals. For nonaccidental and respiratory diseases, the contributions of particulate matter (PM) were dominant among the air pollutants, whereas cardiovascular disease was mainly affected by gaseous air pollutants. The combination of multiple air pollutants was significantly associated with ED visits in the Sichuan Basin, China. The joint effect of the combination of multiple air pollutants was highest for cardiovascular disease at lag 1. The relative contributions of individual pollutants varied by disease and subpopulation. These findings suggest that under different pollution scenarios, preventive strategies should target those with different diseases and different subpopulations.

15.
Int J Cancer ; 146(1): 208-222, 2020 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-31251822

RESUMEN

The role of Fyn-related kinase (FRK) in malignant tumors remains controversial. Our study investigated the function of FRK in lung cancer. Immunohistochemistry staining and generating a knockout of FRK by CRISPR/Cas9 in H1299 (FRK-KO-H1299) cells were strategies used to explore the role of FRK. Immunohistochemistry staining indicated that FRK expression was elevated in 223 lung cancer tissues compared to 26 distant normal lung tissues. FRK contributed to poor survival status in lung cancer patients and acted as a predictor for poor prognosis of lung cancer. Knockout of FRK by CRISPR/Cas9 markedly inhibited proliferation, invasion, colony formation and epithelial-mesenchymal transition (EMT) process in the lung cancer cell line H1299. Further exploration indicated that FRK-KO damaged the stemness phenotype of H1299 by inhibiting CD44 and CD133 expression. Seahorse detection and a U-13 C flux assay revealed that FRK-KO induced metabolism reprogramming by inhibiting the Warburg effect and changing the energy type in H1299 cells. Epidermal growth factor stimulation recovered the expression of FRK and biological functions, metabolic reprogramming and stemness phenotype of H1299 cells. FRK plays an oncogenic role in lung cancer cells via a novel regulation mechanism of enhancing the stemness of H1299 cells by inducing metabolism reprogramming, which finally promotes EMT and metastasis. Our study also indicates that FRK could be used as a potential therapeutic target for drug development.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Proteínas de Neoplasias/fisiología , Células Madre Neoplásicas/patología , Oncogenes , Proteínas Tirosina Quinasas/fisiología , Sistemas CRISPR-Cas , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Transición Epitelial-Mesenquimal/genética , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Pronóstico , Proteínas Tirosina Quinasas/genética
16.
Toxicol Lett ; 318: 57-64, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31585160

RESUMEN

3-Bromopyruvate (3-BrPA) is a promising agent that has been widely studied in the treatment of cancer and pulmonary hypertension. Rotenone is a pesticide commonly used on farms and was shown to have anti-cancer activity and delay fibrosis progression in chronic kidney disease in a recent study. However, there are few studies showing the toxicity of rotenone and 3-BrPA in the myocardium. To support further medical exploration, it is necessary to clarify the side effects of these compounds on the heart. This study was designed to examine the cardiotoxicity of 3-BrPA and rotenone by investigating electrical and structural cardiac remodeling in rats. Forty male rats were divided into 4 groups (n = 10 in each group) and injected intraperitoneally with 3-BrPA, rotenone or a combination of 3-BrPA and rotenone. The ventricular effective refractory period (VERP), corrected QT interval (QTc), and ventricular tachycardia/ventricular fibrillation (VT/VF) inducibility were measured. The expression of Cx43, Kir2.1, Kir6.2, DHPRα1, KCNH2, caspase3, caspase9, Bax, Bcl2, and P53 was detected. Masson's trichrome, TUNEL, HE, and PAS staining and transmission electron microscopy were used to detect pathological and ultrastructural changes. Our results showed that rotenone alone and rotenone combined with 3-BrPA significantly increased the risk of ventricular arrhythmias. Rotenone combined with 3-BrPA caused myocardial apoptosis, and rotenone alone and rotenone combined with 3-BrPA caused electrical and structural cardiac remodeling in rats.


Asunto(s)
Antineoplásicos/toxicidad , Ventrículos Cardíacos/efectos de los fármacos , Insecticidas/toxicidad , Piruvatos/toxicidad , Rotenona/toxicidad , Taquicardia Ventricular/inducido químicamente , Fibrilación Ventricular/inducido químicamente , Remodelación Ventricular/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/metabolismo , Cardiotoxicidad , Conexina 43/genética , Conexina 43/metabolismo , Frecuencia Cardíaca/efectos de los fármacos , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/fisiopatología , Ventrículos Cardíacos/ultraestructura , Masculino , Canales de Potasio de Rectificación Interna/genética , Canales de Potasio de Rectificación Interna/metabolismo , Ratas Wistar , Periodo Refractario Electrofisiológico/efectos de los fármacos , Medición de Riesgo , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/patología , Taquicardia Ventricular/fisiopatología , Fibrilación Ventricular/metabolismo , Fibrilación Ventricular/patología , Fibrilación Ventricular/fisiopatología
17.
J Med Chem ; 63(2): 827-846, 2020 Jan 23.
Artículo en Inglés | MEDLINE | ID: mdl-31860298

RESUMEN

We recently reported the crystal structure of tubulin in complex with a colchicine binding site inhibitor (CBSI), ABI-231, having 2-aryl-4-benzoyl-imidazole (ABI). Based on this and additional crystal structures, here we report the structure-activity relationship study of a novel series of pyridine analogues of ABI-231, with compound 4v being the most potent one (average IC50 ∼ 1.8 nM) against a panel of cancer cell lines. We determined the crystal structures of another potent CBSI ABI-274 and 4v in complex with tubulin and confirmed their direct binding at the colchicine site. 4v inhibited tubulin polymerization, strongly suppressed A375 melanoma tumor growth, induced tumor necrosis, disrupted tumor angiogenesis, and led to tumor cell apoptosis in vivo. Collectively, these studies suggest that 4v represents a promising new generation of tubulin inhibitors.

18.
Cell Rep ; 29(6): 1660-1674.e7, 2019 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-31693903

RESUMEN

The incidence of human papilloma virus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) is increasing and implicated in more than 60% of all oropharyngeal carcinomas (OPSCCs). Although whole-genome, transcriptome, and proteome analyses have identified altered signaling pathways in HPV-induced HNSCCs, additional tools are needed to investigate the unique pathobiology of OPSCC. Herein, bioinformatics analyses of human HPV(+) HNSCCs revealed that all tumors express full-length E6 and identified molecular subtypes based on relative E6 and E7 expression levels. To recapitulate the levels, stoichiometric ratios, and anatomic location of E6/E7 expression, we generated a genetically engineered mouse model whereby balanced expression of E6/E7 is directed to the oropharyngeal epithelium. The addition of a mutant PIK3CAE545K allele leads to the rapid development of pre-malignant lesions marked by immune cell accumulation, and a subset of these lesions progress to OPSCC. This mouse provides a faithful immunocompetent model for testing treatments and investigating mechanisms of immunosuppression.

19.
BMC Plant Biol ; 19(1): 473, 2019 Nov 06.
Artículo en Inglés | MEDLINE | ID: mdl-31694537

RESUMEN

BACKGROUND: Soil salinization and alkalization are among the major agricultural threats that affect crop productivity worldwide, which are increasing day by day with an alarming rate. In recent years, several halophytes have been investigated for their utilization in soil remediation and to decipher the mechanism of salt-tolerance in these high salt tolerant genetic repositories. Suaeda salsa is an annual halophytic herb in the family Amaranthaceae, displaying high salt and alkali-resistance and having nutritive value. However, the fundamental biological characteristics of this valuable plant remain to be elucidated until today. RESULTS: In this study, we observed the morphology and development of Suaeda salsa, including seed morphology, seed germination, plant morphology, and flower development. Using microscopy, we observed the male and female gametophyte developments of Suaeda salsa. Also, chromosome behaviour during the meiosis of male gametophyte was studied. Eventually, the genome size of Suaeda salsa was estimated through flow cytometry using Arabidopsis as reference. CONCLUSIONS: Our findings suggest that the male and female gametophyte developments of Suaeda salsa are similar to those of the model plant Arabidopsis, and the diploid Suaeda salsa contains nine pairs of chromosomes. The findings also indicate that the haploid genome of Suaeda salsa is approximately 437.5 MB. The observations and results discussed in this study will provide an insight into future research on Suaeda salsa.


Asunto(s)
Amaranthaceae/genética , Cromosomas de las Plantas , Genoma de Planta , Plantas Tolerantes a la Sal/genética , Amaranthaceae/anatomía & histología , Flores/anatomía & histología , Tamaño del Genoma , Células Germinativas de las Plantas/crecimiento & desarrollo , Tolerancia a la Sal/genética , Plantas Tolerantes a la Sal/anatomía & histología
20.
Int Heart J ; 60(6): 1387-1397, 2019 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-31666452

RESUMEN

Coronary heart disease (CHD) is a prevalent and chronic life-threatening disease. However, there is no reliable way for early diagnosis and prevention of CHD so far. The precise molecular pathological mechanism of CHD remains obscure. Therefore, developing novel biomarkers is urgently needed.In order to evaluate the potential of untargeted plasma metabolomics in biomarker discovery for characterizing CHD, plasma metabolites from patients newly diagnosed with CHD and controls were profiled using liquid chromatography quadrupole time-of-flight mass spectrometry. Differential metabolites were identified using both univariate and multivariate statistical analyses. Metabolites with significant changes were subjected to binary logistic regression analysis, and a CHD prediction model was established. A total of 28 differential plasma metabolites were identified, of which the concentrations of 11 increased significantly and those of 17 decreased significantly in patients with CHD compared with controls. The altered metabolic pathways included reduced phospholipid metabolism, increased monoglyceride metabolism, and abnormal fatty acid metabolism. Furthermore, binary logistic regression showed that nine metabolites could be used as potential plasma biomarkers for the diagnosis of CHD. The prediction model based on these nine metabolites was then tested with an independent cohort of samples (area under the curve = 0.929).Our plasma metabolomics study not only yielded fundamental insights into dysregulated metabolism in CHD but also presented a combinatorial biomarker that might support the clinical diagnosis of CHD.


Asunto(s)
Biomarcadores/sangre , Enfermedad Coronaria/sangre , Enfermedad Coronaria/diagnóstico , Metabolómica , Anciano , Estudios de Casos y Controles , Cromatografía Liquida , Angiografía Coronaria , Femenino , Humanos , Modelos Logísticos , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Valor Predictivo de las Pruebas
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