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Gestational hypertension is a dangerous condition that is sometimes fatal to the mother and her unborn off-spring. The strong connection between hypertension and hypoxia is emphasized by the currently rampaging SARS-Cov-2, which can induce similar conditions, in which hemolysis and the subsequent oxidative damage may release hemoglobin and tissue factor into the serum. To detect these dangerous proteins normally absent from serum, we mimic the molecular pathology of hypoxia, resulting in a synthesizable molecular machine around which a new bioassay can be designed to simultaneously detect the two proteins in a one-step and reagentless fashion. The "open bridge"-like probe can split into two upon ATP-induced cross-linking of hemoglobin to the probe. The covalently captured hemoglobin can subsequently use its peroxidase-like activity to induce a second cross-coupling between the probe and the tissue factor. A fluorescent probe-target covalent complex is formed, enabling thorough rinsing to minimize nonspecific interference. Finally, using hemoglobin's peroxidase activity to improve sensitivity, the assay has been successfully applied in detecting the two proteins in the periphery serum of pregnant women. These results may promise a near future application of the proposed method for providing an early warning for gestational hypoxia and hypertension, particularly under the stress of SARS-Cov-2.
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The study aimed to investigate the therapeutic effects of the n-butanol extract of Pulsatilla Decoction(BEPD) on ulcerative colitis(UC) via the bone morphogenetic protein(BMP) signaling pathway. C57BL/6 mice were divided into six groups: control, model, mesalazine, and BEPD low-, medium-, and high-dose groups. Except for the control group, the rest groups were treated with 3% dextran sulfate sodium(DSS) freely for seven consecutive days to establish the UC mouse model, followed by treatment with different concentrations of BEPD and mesalazine by gavage. The murine body weight and disease activity index(DAI) were recorded. After the mice were sacrificed, their colon tissues were collected for histological analysis. Alcian blue/periodic acid-Schiff(AB/PAS) staining was used to detect the number and mucus secretion status of goblet cells; immunohistochemistry was performed to measure the expression of ki67, cleaved caspase-3, mucin 2(Muc2), and matrix metalloproteinase-9(MMP9) in colon tissues; and immunofluorescence was used to analyze the expression of tight junction proteins in colon tissues, and enzyme linked immunosorbent assay(ELISA) was employed to quantify the levels of tumor necrosis factor-α(TNF-α), interleukin(IL)-1ß, and IL-6. Western blot was conducted to evaluate the expression of BMP pathway-related proteins in mouse colon tissues. Quantitative real-time PCR(qRT-PCR) was performed to measure the expression of genes related to goblet cell differentiation in mouse colon tissues. In addition, this study also examined the protective effect and underlying mechanism of BEPD-containing serum on lipopolysaccharide(LPS)-induced barrier damages in LS174T goblet cells in vitro. The results showed that BEPD significantly alleviated UC symptoms in mice, restored goblet cell diffe-rentiation function, promoted Muc2 secretion and tight junction protein expression, and suppressed inflammatory factor secretion while activating the BMP signaling pathway. Therefore, BEPD may exert its therapeutic effects on UC by activating the BMP signaling pathway, providing a new strategy for drug intervention in UC.
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Colitis Ulcerosa , Medicamentos Herbarios Chinos , Ratones Endogámicos C57BL , Pulsatilla , Transducción de Señal , Animales , Transducción de Señal/efectos de los fármacos , Ratones , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/metabolismo , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/administración & dosificación , Masculino , Pulsatilla/química , Humanos , Proteínas Morfogenéticas Óseas/metabolismo , Proteínas Morfogenéticas Óseas/genéticaRESUMEN
As a novel drug delivery system, liposomes were used to improve pharmacokinetics/pharmacodynamics (PK/PD) characters, minimize toxicity, and enhance drug-target selectivity. However, heterogeneity of drug releasing process and liposome itself challenged traditional pharmaceutical analytical techniques, especially in vivo pharmacokinetic studies. In this study, a novel liposomal doxorubicin (L-DOX) pharmacokinetic analysis strategy was developed with capillary electrophoresis coupled with laser-induced fluorescence (CE-LIF) detector. The background electrolyte (BGE) system was composed of borate and sodium dodecyl sulfate (SDS), which was optimized to successfully achieve simultaneous online separation and quantitative analysis of free DOX and liposome-encapsulated DOX. The method was applied to the in vivo pharmacokinetic study of L-DOX in rats. The results showed that the concentration of total DOX (T-DOX) was gradually decreasing, while the concentration of L-DOX was relatively stable, with a concentration of 31.6 ± 4.8 µg/mL within 24 h. It was the first time to achieve liposomal drugs in vivo analysis with CE-LIF. CE-LIF was proved as potential rapidly real-time analytical methods for liposomal drugs in vivo occurrence monitoring.
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Doxorrubicina , Liposomas , Ratas , Animales , Doxorrubicina/análisis , Polietilenglicoles , Electroforesis Capilar/métodosRESUMEN
The nuclear receptor (NR) superfamily is one of the largest groups of transcription factors in living organisms. Oestrogen related receptor (ERR) is a class of nuclear receptors closely related to oestrogen receptors (ERs). In this study, the Nilaparvata lugens (N. lugens) ERR2 (NlERR2) was cloned, and the expression of NlERR2 was detected by qRT-PCR to explore the distribution of NlERR2 during development and in different tissues. Using RNAi and qRT-PCR, the interaction between NlERR2 and related genes of the 20-hydroxyecdysone (20E) and juvenile hormone (JH) signalling pathways was studied. The results showed that topical application of 20E and juvenile hormone III (JHIII) affected the expression of NlERR2, and NlERR2 could affect the expression of genes related to 20E and JH signalling pathways. Furthermore, NlERR2 and JH/20E hormone signalling-related genes affect moulting and ovarian development. NlERR2 and NlE93/NlKr-h1 affect the transcriptional expression of Vg-related genes. In summary, NlERR2 is related to hormone signalling pathways, which is also related to the expression of Vg and Vg related genes. Brown planthopper is one of the most important rice pests. This study provides an important basis for mining new targets for pest control.
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Hemípteros , Muda , Femenino , Animales , Muda/genética , Proteínas de Insectos/genética , Proteínas de Insectos/metabolismo , Ovario/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Hormonas/metabolismo , Hemípteros/fisiologíaRESUMEN
Chemical isotope labeling liquid chromatography mass spectrometry (LC-MS) is an emerging metabolomic strategy for the quantification and characterization of small molecular compounds in biological samples. However, its subsequent data analysis is not straightforward due to a large amount of data produced and interference of biological matrices. In order to improve the efficiency of searching and identification of target endogenous metabolites, a new software tool for nontargeted metabolomics data processing called MS-IDF was developed based on the principle of a narrow mass defect filter. The developed tool provided two function modules, including IsoFinder and MDFinder. The IsoFinder function module applied a conventional peak extraction method by using a fixed mass differences between the heavy and light labels and by the alignment of chromatographic retention time (RT). On the other hand, MDFinder was designed to incorporate the accurate mass defect differences between or among stable isotopes in the peak extraction process. By setting an appropriate filter interval, the target metabolites can be efficiently screened out while eliminating interference. Notably, the present results showed that the efficiency in compound identification using the new MDFinder module was nearly doubled as compared to the conventional IsoFinder method (an increase from 259 to 423 compounds). The Matlab codes of the developed MS-IDF software are available from github at https://github.com/jydong2018/MS_IDF. Based on the MS-IDF software tool, a novel and effective approach from nontargeted to targeted metabolomics research was developed and applied to the exploration of potential primary amine biomarkers in patients with schizophrenia. With this approach, potential biomarkers, including N,N-dimethylglycine, S-adenosine-l-methionine, dl-homocysteine, and spermidine, were discovered.
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Metabolómica , Programas Informáticos , Cromatografía Liquida/métodos , Humanos , Marcaje Isotópico/métodos , Espectrometría de Masas/métodos , Metabolómica/métodosRESUMEN
Drosophila E74 is an early gene located in the polytene chromosome 74EF puff position. E74 controls the production of late genes, indicating that it plays a crucial role in this cascade model. Nilaparvata lugens E74 is closely related to Diaphorina citri, Bemisia tabaci, and Laodelphax striatellus. After downregulating E74, molting, and nymphal mortality were increased, and ovarian development was delayed. Moreover, the expression of Vg was reduced at the transcriptional level, as measured by qRT-PCR, and the content of Vg protein was reduced, as detected by Western blotting. After downregulating E74, the expression of hormone-related genes, including Tai, ßFtz-F1, Met, Kr-h1, UspA, UspB, E93, and Br, was changed. The expression of E74 was significantly decreased after downregulating hormone-related genes. When the expression of E74 and ßFtz-F1 was downregulated together, nymph mortality and molting mortality were higher than those when E74 or ßFtz-F1 was downregulated alone. Thus, E74 probably interacts with ßFtz-F1 at the genetic level. In summary, this study showed that E74 plays a crucial role in the development, metamorphosis and reproduction of N. lugens, possibly via the interaction with ßFtz-F1 at the genetic level. This study provides a basis for the development of new target-based pesticides and new methods for the effective control of N. lugens.
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Proteínas de Drosophila , Hemípteros , Animales , Drosophila , Proteínas de Drosophila/genética , Hemípteros/fisiología , Hormonas/metabolismo , Metamorfosis Biológica/genética , Ninfa/genética , Ninfa/metabolismoRESUMEN
Juvenile hormone and ecdysone are key regulators in the metamorphosis and development. Grocho (Gro) is a highly conserved protein required for metamorphosis and development. Brown planthopper (Nilaparvata lugens) is a major pest affecting rice production in China and many Asian countries. Although the molecular function of Gro has been investigated in holometabolous insects such as Aedes aegypti and Drosophila melanogaster, their role in the hemimetabolous insect, brown planthopper, and the relationship between NlGro/NlGro1-L and JH/ecdysone signaling pathway, remained unknown. In this study, NlGroucho (NlGro) and NlGroucho1-like (NlGro1-L) were cloned. An analysis of the predicted protein sequence showed that NlGro has highly conserved Q domain and WD40 domain, and NlGro1-L has a highly conserved WD40 domain. The expression profiles of both genes were studied by quantitative real-time PCR (qRT-PCR). Their relative expressions were high in egg, head, wing, ovary, and testis. NlGro and NlGro1-L were found to interact genetically with juvenile hormone and ecdysone signaling by hormone treatment and RNAi of JH/ecdysone signaling-related genes. Moreover, when NlGro or NlGro1-L was down-regulated alone, the survival rate was decreased, the ovarian development was delayed, and the oviposition was also affected. All defects were aggravated when NlGro and NlGro1-L were down-regulated together. This study will help to develop new pesticides on the basis of the function of NlGro and NlGro1-L, and provide new possibilities for the control of Nilaparvata lugens.
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Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Hemípteros/crecimiento & desarrollo , Proteínas de Insectos/metabolismo , Hormonas Juveniles/farmacología , Metamorfosis Biológica , Ovario/crecimiento & desarrollo , Secuencia de Aminoácidos , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Femenino , Hemípteros/efectos de los fármacos , Hemípteros/genética , Hemípteros/metabolismo , Proteínas de Insectos/genética , Ovario/efectos de los fármacos , Ovario/metabolismo , Oviposición , Homología de Secuencia , Alas de Animales/efectos de los fármacos , Alas de Animales/crecimiento & desarrolloRESUMEN
Objective: To evaluate the comparative influence of NPT and standard surgical dressing administration on incidence risk for surgical site infections, complications, and hospital re-admission after hepatopancreatobiliary surgery. Methods: Five databases were systematically searched according to PRISMA guidelines. These databases included Web of Science, MEDLINE, CENTRAL, EMBASE, and Scopus for eligible studies published prior to March 2021. With eligible studies, we conducted a random-effects meta-analysis to evaluate comparative outcomes such as superficial surgical infection, deep surgical infection, seroma incidence, hematoma incidence, and hospital re-admission in patients receiving NPT or standard surgical dressings after hepatopancreatobiliary surgery. Results: The search strategy yielded 963 studies, with six studies meeting inclusion criteria. Odds of superficial surgical site infection (OR: 1.58), deep surgical site infection (1.43), seroma complication (1.64), hematoma complication (0.40) were insignificantly different between patients receiving NPT and standard surgical dressing. The odds of hospital re-admission rate (2.37), however, were elevated in patients receiving standard surgical dressing relative to those receiving NPT. Conclusion: This meta-analysis shows that NPT usage slightly reduces risk of hospital readmission as compared to standard surgical dressing. We did not observe any significant effect of NPT on superficial, deep surgical infections, seroma, and haematoma outcomes following hepatopancreatobiliary surgery. These findings may aid clinicians in stratifying risk and selecting treatment strategy in patients undergoing hepatopancreatobiliary surgery.
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High-throughput transcriptome sequencing was used to study the mechanism of Shenling Baizhu Powder(SLBZP) in the alleviation of the dextran sulfate sodium(DSS)-induced ulcerative colitis(UC) in mice. The mouse model of DDS-induced UC was treated with SLBZP by gavage. The changes in general state, disease activity index(DAI), and colon length were observed. The hematoxylin-eosin(HE) staining was used to observe the pathological changes in the colon tissues of mice. Enzyme-linked immunosorbent assay(ELISA) was used to determine the expression levels of tumor necrosis factor-α(TNF-α), interleukin(IL)-1ß, IL-6, IL-4, and IL-10 in the serum and tissues of mice. The differentially expressed genes in the control group, the model group, and the SLBZP group were analyzed by high-throughput transcriptome sequencing, and the Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analyses were conducted on the differentially expressed genes. The results showed that after intragastric administration of SLBZP, the symptoms of diarrhea and bloody stool were improved, and the disease active index(DAI) score was reduced. SLBZP effectively reduced the inflammatory cell infiltration and goblet cell loss in the colonic mucosal tissue, reduced the levels of TNF-α, IL-1ß, IL-6 in the serum and colon tissue, and increased the levels of IL-4 and IL-10 in the serum and colon tissue. There were 25 differential genes in SLBZP vs the model group, which were significantly enriched in immune response, immune system process, immunoglobulin production, and other biological processes. KEGG pathway analysis showed that the differential genes were enriched in signaling pathways such as neomycin, kanamycin, and gentamicin biosynthesis, cytokine-cytokine receptor interaction, primary immunodeficiency, and IgA synthesis of the intestinal immune network. This study shows that SLBZP may alleviate UC through immune regulation.
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Colitis Ulcerosa , Medicamentos Herbarios Chinos , Animales , Ratones , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/genética , Colon , Sulfato de Dextran/efectos adversos , Modelos Animales de Enfermedad , Interleucina-10/genética , Interleucina-4/genética , Interleucina-6/genética , Ratones Endogámicos C57BL , Polvos , Transcriptoma , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Medicamentos Herbarios Chinos/uso terapéuticoRESUMEN
INTRODUCTION: Ultrasound-guided thoracic paravertebral block (US-TPVB) is generally used for postoperative analgesia. We hypothesized that single-injection US-TPVB could be used as the principal anesthetic technique for a peritoneal dialysis catheter (PDC) procedure (implantation or removal). The anesthetic effect and venous ropivacaine level after a TPVB would be compared with that after local anesthetic infiltration (LAI). METHODS: Patients undergoing PDC procedures were randomized into Group LAI or TPVB. In Group LAI, 40 mL of 0.25% ropivacaine were used. In Group TPVB, single-injection of US-TPVB at T10-T11 level was performed with 20 mL of 0.25% ropivacaine. The quality of anesthesia, visual analogue scale of pain, and venous total plasma ropivacaine level were compared between the 2 groups. RESULTS: Seventy-four eligible patients were enrolled and 38 in Group TPVB. Thirty patients in Group TPVB and 26 patients in Group LAI underwent PDC procedures successfully. Higher satisfaction rates by nephrologists and patients (76.3 and 78.9%) were reported in Group TPVB (44.4 and 44.4% in Group LAI, respectively). The peak venous total plasma ropivacaine concentrations were below the reported toxic threshold in the 2 groups. CONCLUSIONS: A single-injection US-TPVB with 20 mL of 0.25% ropivacaine at T10-T11 could be the principal anesthetic technique for PDC procedures, which provided a comparable anesthetic effect to that of LAI with 40 mL ropivacaine. Higher satisfaction rates by nephrologists and patients were observed in Group TPVB. The 20 mL dose of 0.25% ropivacaine used for an US-TPVB was safe in end-stage renal diseases patients.
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Anestésicos Locales/uso terapéutico , Cateterismo/métodos , Bloqueo Nervioso/métodos , Diálisis Peritoneal/métodos , Ropivacaína/uso terapéutico , Adulto , Anestésicos Locales/administración & dosificación , Femenino , Humanos , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Ropivacaína/administración & dosificación , Resultado del Tratamiento , Ultrasonografía Intervencional/métodosRESUMEN
The fragmentation of two isomers of C3H4, propyne (CH3CCH) and allene (CH2CCH2), is investigated by 50 keV/u Ne8+ impact. Obvious isomer effects are observed by comparing the time-of-flight spectra generated from the two isomers. Six two-body fragmentation channels of C3H4 2+ dications are identified for each isomer. CH2 + + C2H2 + is found to be the most favored CC bond breaking channel for both isomers, indicating that CH3CCH2+ intends to rearrange to the structure containing the CH2 group before fragmentation. For CH bond breaking channels, it is found that the CH3CCH which contains a CH3 group is more efficient for H2 + and H3 + ejection. In addition, two-body dissociation channels of C3H4 3+ trications are identified. While the H+ + C3H3 2+ channel is observed in the fragmentation of both isomers, the H2 + + C3H2 2+ channel only occurs in the fragmentation of CH3CCH3+. For CH2CCH2 3+, the peak and shoulder structures in the kinetic energy release spectrum of the H+ + C3H3 2+ channel are attributed to different geometries of the C3H3 2+ product.
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BACKGROUND: Delayed gastric emptying and the resultant "full stomach" is the most important risk factor for perioperative pulmonary aspiration. Using point-of-care gastric sonography, we aimed to investigate the prevalence of full stomach and its risk factors in elective surgical patients with type 2 diabetes. METHODS: Type 2 diabetic and non-diabetic elective surgical patients were included from July 2017 to April 2018 in a 1:1 ratio. The study was retrospectively registered at July 2017, after enrollment of the first participant. Gastric ultrasound was performed 2 h after ingesting clear fluid or 6 h after a light meal. Full stomach was defined by the presence of gastric content in both semi-recumbent and right lateral decubitus positions. For patients with full or intermediate stomach, consecutive ultrasound scan was performed until empty stomach was detected. Logistic regression analyses were used to identify risk factors associated with full stomach. RESULTS: Fifty-two type 2 diabetic and fifty non-diabetic patients were analyzed. The prevalence of full stomach was 48.1% (25/52) in diabetic patients, with 44.0% for 2-h fast after clear fluid and 51.9% for 6-h fast after a light meal, significantly higher than 8% (4/50) in non-diabetic patients (P = 0.000). The average time to empty stomach in diabetic patients was 146.50 ± 40.91 mins for clear liquid and 426.50 ± 45.25 mins for light meal, respectively. Further analysis indicated that presence of diabetes-related eye disease was an independent risk factor of full stomach in diabetic patients (OR = 4.83, P = 0.010). CONCLUSIONS: Almost half of type 2 diabetic patients have a full stomach following the current preoperative fasting guideline. Preoperative ultrasound assessment of gastric content in type 2 diabetic patients is suggested, especially for those with diabetes -related eye disease. TRIAL REGISTRATION: The trial was registered at www.clinicaltrials.gov with registration number NCT03217630 . Retrospectively registered on 14th July 2017.
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Diabetes Mellitus Tipo 2/complicaciones , Vaciamiento Gástrico , Contenido Digestivo/diagnóstico por imagen , Ultrasonografía , Anciano , Estudios de Cohortes , Procedimientos Quirúrgicos Electivos , Oftalmopatías/epidemiología , Oftalmopatías/etiología , Femenino , Gastroparesia/diagnóstico por imagen , Gastroparesia/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Sistemas de Atención de Punto , Prevalencia , Estudios Prospectivos , Factores de Riesgo , Estómago/diagnóstico por imagen , Factores de TiempoRESUMEN
BACKGROUND: Telocytes (TCs), a recently discovered novel type of interstitial cells, were also found in a wide variety of human and mammalian reproductive organs/tissues, including uterus, oviduct and placenta. Previously, we demonstrated that TCs-conditioned media was capable of activating peritoneal macrophages (pMACs) through paracrine effects. This study investigates the hypothesis that direct interaction of TCs with pMACs will also play a significant role in immunoregulation of pMACs. METHODS: TCs and pMACs were derived from the uterus and intraperitoneal cavity of female BALB/c mice, respectively. TCs were identified by immunofluorescence and then co-cultured directly with pMACs for 24 h without added cytokines, to observe the in vitro biological behavior of pMACs. We used histochemical staining to study morphology and mitochondrial metabolism of pMACs, scanning electron microscopy to study heterocellular junctions, flow cytometry to investigate mitochondrial membrane potential (ΔΨm) and apoptosis, and transwell chambers to study invasion ability. Student-t test was used accordingly. RESULTS: Presently, TCs with typical structure and immunophenotype of double CD-34-positive/vimentin-positive were successfully isolated. pMACs co-cultured with TCs showed obviously morphological activation, with enhanced energy metabolism (P < 0.05). Meanwhile, direct physical cell-to-cell interaction promoted the development of heterocellular junctions between TCs and pMACs. Furthermore, TCs treatment markedly reduced the depletion of ΔΨm in co-cultured pMACs (all P < 0.05), and inhibited their apoptosis (P < 0.05). Functionally, pMACs co-cultured with TCs showed enhanced invasion ability (P < 0.05). CONCLUSIONS: Direct physical cell-to-cell interaction promoted the development of heterocellular junctions between TCs and pMACs, presumably responsible for the observed novel efficient way of pMACs activation via mitochondrial signaling pathway. TCs-educated pMACs might be a promising way to restore the defective immunosurveillance in endometriosis (EMs), led to the enhanced treatment efficacy of EMs in a simple and clinically feasible fashion.
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Apoptosis , Movimiento Celular , Forma de la Célula , Macrófagos Peritoneales/citología , Telocitos/citología , Animales , Separación Celular , Técnicas de Cocultivo , Metabolismo Energético , Femenino , Macrófagos Peritoneales/ultraestructura , Potencial de la Membrana Mitocondrial , Ratones Endogámicos BALB C , Telocitos/ultraestructuraRESUMEN
Maternal embryonic leucine zipper kinase (MELK), a serine/threonine protein kinase, has oncogenic properties and plays a key functional role in various cancer cells. Although MELK may not be a cancer addiction target, the development of specific MELK inhibitors would provide useful chemical tools for synthetic lethal investigation. Herein, we identified several hit compounds using a customized structure-based virtual screening, among which compounds 4 and 16 showed the most potent inhibition to MELK with IC50 values of 3.52 µM and 178.3 nM, respectively. In vitro cell-based assays revealed that 16 has no effect on the growth of various types of cancer cells, but has the potential to inhibit cancer cell migration and invasion. Western blotting analyses revealed that 16 suppresses the phosphorylation of focal adhesion kinase (FAK), a downstream molecule of MELK, which is a key kinase in regulating cancer cell migration and invasion.
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Antineoplásicos/química , Antineoplásicos/farmacología , Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Quinasa 1 de Adhesión Focal/metabolismo , Humanos , Invasividad Neoplásica , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: To determine the linear and non-linear interacting relationships between weather factors and hand, foot and mouth disease (HFMD) in children in Gansu, China, and gain further traction as an early warning signal based on weather variability for HFMD transmission. METHOD: Weekly HFMD cases aged less than 15 and meteorological information from 2010 to 2014 in Jiuquan, Lanzhou and Tianshu, Gansu, China were collected. Generalized linear regression models (GLM) with Poisson link and classification and regression trees (CART) were employed to determine the combined and interactive relationship of weather factors and HFMD in both linear and non-linear ways. RESULTS: GLM suggested an increase in weekly HFMD of 5.9% [95% confidence interval (CI): 5.4%, 6.5%] in Tianshui, 2.8% [2.5%, 3.1%] in Lanzhou and 1.8% [1.4%, 2.2%] in Jiuquan in association with a 1 °C increase in average temperature, respectively. And 1% increase of relative humidity could increase weekly HFMD of 2.47% [2.23%, 2.71%] in Lanzhou and 1.11% [0.72%, 1.51%] in Tianshui. CART revealed that average temperature and relative humidity were the first two important determinants, and their threshold values for average temperature deceased from 20 °C of Jiuquan to 16 °C in Tianshui; and for relative humidity, threshold values increased from 38% of Jiuquan to 65% of Tianshui. CONCLUSION: Average temperature was the primary weather factor in three areas, more sensitive in southeast Tianshui, compared with northwest Jiuquan; Relative humidity's effect on HFMD showed a non-linear interacting relationship with average temperature.
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Enfermedad de Boca, Mano y Pie/epidemiología , Niño , China/epidemiología , Clima , Enfermedad de Boca, Mano y Pie/etiología , Humanos , Incidencia , Modelos Lineales , Temperatura , Tiempo (Meteorología)RESUMEN
BACKGROUND: Catheter-related bladder discomfort (CRBD), secondary to catheterization of urinary bladder is distressing. The aim of this study was to assess the efficacy of preoperative education on CRBD with image illustration for alleviating CRBD. METHODS: Sixty adult male patients, undergoing elective colonal and rectal surgery, were randomized to receive tetracaine mucilage instilled into the urethra and applied to the catheter (tetracain group), or receive tetracaine mucilage in combination with image illustration on CRBD (image group) before urethral catheterization. The incidence and severity of CRBD were assessed at 0.5, 1, 2, and 6 h after patients' extubation. The severity of postoperative pain, incidence of postoperative agitation and other adverse events were also recorded. RESULTS: Patients in image group reported remarkably less CRBD than those in tetracaine group at 0.5,1, 2 and 6 h after extubation (20, 20, 6.7 and 6.7% v.s. 60, 73.3, 53.3 and 53.3%, respectively, P<0.01). Severe CRBD was not reported in either group. However, the incidence of moderate CRBD was significantly lower in image group, with 6.7% at 1 h and thereafter none occurred, compared to 6.7% at 0.5 h, and increasing to 20% at 1 h, 2 h and 6 h in tetracaine group, respectively. Moreover, patients in image group suffered less moderate to severe postoperative pain than that of tetracaine group (13.3% v.s. 40.0% at 1 h, P = 0.039, 33.3% v.s. 60% at 2 h and 6 h, P = 0.038). CONCLUSIONS: Preoperative education on uretheral catheterization via image illustrations could enhance the effect of tetracaine mucilage in reducing both the incidence and severity of CRBD. TRIAL REGISTRATION: The trial was registered at www,clinicaltrials.gov with registration number NCT03199105 (retrospectively registered). Date of trial registration which is "June 26, 2017".
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Anestésicos Locales/administración & dosificación , Dolor Postoperatorio/prevención & control , Tetracaína/administración & dosificación , Cateterismo Urinario/métodos , Adulto , Anciano , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Dolor Postoperatorio/epidemiología , Dolor Postoperatorio/etiología , Educación del Paciente como Asunto/métodos , Proyectos Piloto , Cuidados Preoperatorios , Estudios Prospectivos , Factores de Tiempo , Cateterismo Urinario/efectos adversos , Catéteres UrinariosRESUMEN
BACKGROUND: Overexpression of epidermal growth factor receptor (EGFR) occurs in approximately 90% of head and neck squamous cell carcinoma (HNSCC), and is correlated with poor prognosis. Thus, targeting EGFR is a promising strategy for treatment of HNSCC. Several small molecule EGFR inhibitors have been tested in clinical trials for treatment of HNSCC, but none of them are more effective than the current chemotherapeutic drugs. Thus, it is urgently needed to develop novel EGFR inhibitors for HNSCC treatment. METHODS: By screening an in-house focused library containing approximately 650 000 known kinase inhibitors and kinase inhibitor-like compounds containing common kinase inhibitor core scaffolds, we identified SKLB188 as a lead compound for inhibition of EGFR. The anticancer effects of SKLB188 on HNSCC cells were investigated by in vitro cell growth, cell cycle and apoptosis assays, as well as in vivo FaDu xenograft mouse model. Molecular docking, in vitro kinase profiling and western blotting were performed to characterise EGFR as the molecular target. RESULTS: SKLB188 inhibited HNSCC cell proliferation by inducing G1 cell cycle arrest, which was associated with downregulating the expression of Cdc25A, cyclins D1/A and cyclin-dependent kinases (CDK2/4), and upregulating the expression of cyclin-dependent kinase (CDK) inhibitors (p21Cip1 and p27Kip1), leading to decreased phosphorylation of Rb. SKLB188 also induced caspase-dependent apoptosis of HNSCC cells by downregulating the expression of Mcl-1 and survivin. Molecular docking revealed that SKLB188 could bind to the kinase domain of EGFR through hydrogen bonds and hydrophobic interactions. In vitro kinase assay showed that SKLB188 inhibited the activity of a recombinant human EGFR very potently (IC50=5 nM). Western blot analysis demonstrated that SKLB188 inhibited the phosphorylation of EGFR and its downstream targets, extracellular signal-regulated protein kinases 1 and 2 (Erk1/2) and Akt in the cells. In addition, SKLB188 dose-dependently inhibited FaDu xenograft growth in nude mice, and concurrently inhibited the phosphorylation of Erk1/2 and Akt in the tumours. CONCLUSIONS: SKLB188 potently inhibits the growth of HNSCC cells in vitro and in vivo by targeting EGFR signalling. The results provide a basis for further clinical investigation of SKLB188 as a targeted therapy for HNSCC. Our findings may open a new avenue for development of novel EGFR inhibitors for treatment of HNSCC and other cancers.
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Apoptosis/efectos de los fármacos , Carcinoma de Células Escamosas/metabolismo , Proliferación Celular/efectos de los fármacos , Receptores ErbB/antagonistas & inhibidores , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Neoplasias de Cabeza y Cuello/metabolismo , Purinas/farmacología , Animales , Western Blotting , Ciclina A/efectos de los fármacos , Ciclina A/metabolismo , Ciclina D1/efectos de los fármacos , Ciclina D1/metabolismo , Quinasa 2 Dependiente de la Ciclina/efectos de los fármacos , Quinasa 2 Dependiente de la Ciclina/metabolismo , Quinasa 4 Dependiente de la Ciclina/efectos de los fármacos , Quinasa 4 Dependiente de la Ciclina/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/efectos de los fármacos , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/efectos de los fármacos , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Regulación hacia Abajo , Receptores ErbB/metabolismo , Humanos , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Técnicas In Vitro , Ratones , Ratones Desnudos , Simulación del Acoplamiento Molecular , Transducción de Señal , Carcinoma de Células Escamosas de Cabeza y Cuello , Regulación hacia Arriba , Ensayos Antitumor por Modelo de Xenoinjerto , Fosfatasas cdc25/efectos de los fármacos , Fosfatasas cdc25/metabolismoRESUMEN
SIRT2, which is a NAD+ (nicotinamide adenine dinucleotide) dependent deacetylase, has been demonstrated to play an important role in the occurrence and development of a variety of diseases such as cancer, ischemia-reperfusion, and neurodegenerative diseases. Small molecule inhibitors of SIRT2 are thought to be potential interfering agents for relevant diseases. Discovery of SIRT2 inhibitors has attracted much attention recently. In this investigation, we adopted a consensus docking/scoring strategy to screen for novel SIRT2 inhibitors. Structural optimization and structure-activity relationship (SAR) analysis were then carried out on highly potent compounds with new scaffolds, which led to the discovery of 2-((5-benzyl-5H-[1,2,4]triazino[5,6-b]indol-3-yl)thio)-N-(naphthalen-1-yl)acetamide (SR86). This compound showed good activity against SIRT2 with an IC50 value of 1.3 µM. SR86 did not exhibit activity against SIRT1 and SIRT3, implying a good selectivity for SIRT2. In in vitro cellular assays, SR86 displayed very good antiviability activity against breast cancer cell line MCF-7. In Western blot assays, SR86 showed considerable activity in blocking the deacetylation of α-tubulin, which is a typical substrate of SIRT2. Collectively, because of the new scaffold structure and good selectivity of SR86, it could serve as a promising lead compound, hence deserving further studies.
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Diseño de Fármacos , Inhibidores de Histona Desacetilasas/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Simulación del Acoplamiento Molecular , Sirtuina 2/antagonistas & inhibidores , Sirtuina 2/metabolismo , Acetilación , Supervivencia Celular/efectos de los fármacos , Inhibidores de Histona Desacetilasas/química , Humanos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/química , Isoenzimas/metabolismo , Células MCF-7 , Conformación Proteica , Sirtuina 2/química , Relación Estructura-ActividadRESUMEN
The influence of socio-ecological factors on hand, foot and mouth disease (HFMD) were explored in this study using Bayesian spatial modeling and spatial patterns identified in dry regions of Gansu, China. Notified HFMD cases and socio-ecological data were obtained from the China Information System for Disease Control and Prevention, Gansu Yearbook and Gansu Meteorological Bureau. A Bayesian spatial conditional autoregressive model was used to quantify the effects of socio-ecological factors on the HFMD and explore spatial patterns, with the consideration of its socio-ecological effects. Our non-spatial model suggests temperature (relative risk (RR) 1.15, 95 % CI 1.01-1.31), GDP per capita (RR 1.19, 95 % CI 1.01-1.39) and population density (RR 1.98, 95 % CI 1.19-3.17) to have a significant effect on HFMD transmission. However, after controlling for spatial random effects, only temperature (RR 1.25, 95 % CI 1.04-1.53) showed significant association with HFMD. The spatial model demonstrates temperature to play a major role in the transmission of HFMD in dry regions. Estimated residual variation after taking into account the socio-ecological variables indicated that high incidences of HFMD were mainly clustered in the northwest of Gansu. And, spatial structure showed a unique distribution after taking account of socio-ecological effects.
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Enfermedad de Boca, Mano y Pie/epidemiología , Modelos Estadísticos , Teorema de Bayes , China/epidemiología , Clima , Femenino , Humanos , Incidencia , Masculino , Densidad de Población , Análisis Espacial , Tiempo (Meteorología)RESUMEN
Telocytes (TCs), a distinct interstitial cell population, have been identified in the uterus, oviduct and placenta, with multiple proposed potential biological functions. Their unique structure allows them to form intercellular junctions with various immunocytes, both in normal and diseased tissues, suggesting a potential functional relationship with the local immune response. It has been hypothesized that through direct heterocellular junctions or indirect paracrine effects, TCs influence the activity of local immunocytes that are involved in the inflammatory process and in immune-mediated reproductive abnormalities. However, no reliable cytological evidence for this hypothesis is currently available. In this study, we cultured primary murine uterine TCs and collected TC conditioned media (TCM). Mouse peritoneal macrophages (pMACs) were co-cultured for 48 hrs with TCM or with DMEM/F12 or lipopolysaccharide (LPS) as negative and positive controls, respectively. Normal uterine TCs with a typical structure and a CD-34-positive/vimentin-positive/c-kit-negative immunophenotype were observed during culture. Morphologically, TCM-treated pMACs displayed an obvious activation/immunoresponse, in contrast to over-stimulation and cell death after LPS treatment and no sign of activation in the presence of DMEM/F12. Accordingly, a cell counting kit 8 (CCK-8) assay indicated significant activation of pMACs by TCM and LPS compared to DMEM/F12, thus supporting the marked morphological differences among these groups of cells. Furthermore, within a panel of macrophage-derived cytokines/enzymes, interleukin-6 (IL-6) and inducible nitric oxide synthase were significantly elevated in TCM-treated pMACs; tumour necrosis factor α, IL1-R1, and IL-10 were slightly, but significantly, up-regulated; and no changes were observed for transforming growth factor-ß1, IL-1ß, IL-23α and IL-18. Our results indicate that TCs are not simply innocent bystanders but are rather functional players in the activation of pMACs; they trigger and maintain the immune response, likely through indirect paracrine effects. Thus, we provide preliminary in vitro evidence of immunoregulatory and immunosurveillance roles for TCs.