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Related studies have pointed out that Killer immunoglobulin-like receptor 2DL4 (KIR2DL4) was associated with vascular remodeling in early pregnancy, and it might play an important role in immunity. In this study, recurrent implantation failure (RIF)-related GSE58144 dataset was extracted from the Gene Expression Omnibus (GEO) database. Firstly, the immune micro-environment analyses were conducted to analyze the pathogenesis of KIR2DL4 in RIF. Then, the gene set enrichment analysis (GSEA) was performed to investigate the function of KIR2DL4. Moreover, the TF-mRNA-miRNA and the co-expression networks were constructed to reveal the potential regulation of KIR2DL4. Furthermore, the genes that were associated with KIR2DL4 and differentially expressed in RIF were obtained and defined as key genes, and the functions of these genes were further explored. KIR2DL4 could be used for clinical diagnosis of RIF, and it was correlated with the changes in the immune micro-environment in RIF. From the perspective of function, KIR2DL4 was associated with complement and coagulation cascades, natural killer cell-mediated cytotoxicity, etc. Moreover, the TF-mRNA-miRNA regulatory network was constructed with KIR2DL4, 9 TFs, and 29 miRNAs. Furthermore, KIR2DL4, ACSM1, IL2RB, and PTPN11 were screened as key genes, which were associated with immune-related functions. This study deeply analyzed the function of KIR2DL4 and its role in RIF, and we found that STAT1 might up-regulate KIR2DL4 by INF-γ/JAK2/STAT1 signaling pathway. Besides, over-expressed KIR2DL4 in the mid-luteal endometrium might influence embryo implantation by affecting the embryo implantation microenvironment, which might help deepen the understanding of the molecular mechanism of RIF.
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OBJECTIVES: To investigate cases of five Campylobacter jejuni outbreaks and describe laboratory characteristics of these infections. METHODS: Whole-genome sequencing and conventional methods were combined to thoroughly investigate the outbreaks, and data of contemporaneous sporadic cases was included for comparison. RESULTS: Seven sequence types (STs) of C. jejuni caused 83 cases, including ST9079 which recurred across 2 years. Trace-back investigation could not identify any food items of infection but detected identical campylobacters from food contacts. Phylogenetic analysis unveiled genetic closeness between outbreak strains and some concurrent sporadic strains, indicating local campylobacteriosis may not be wholly sporadic but rather a series of linked cases. Virulence genes disclosed species/case-specific signatures to differentiate outbreaks from truly non-outbreak strains. Resistance to fluoroquinolones and/or macrolides was prevalent (90.8%, 108/119), with a noteworthy portion exhibiting multidrug resistance (31.1%, 37/119). Five types of plasmids were harbored among outbreak isolates, of which one plasmid harboring anti-stress and resistant genes was rarely found in C. jejuni. CONCLUSIONS: This is the first reported sequential outbreak of C. jejuni in China. Our observations help to define the genomic landscape and antimicrobial resistance patterns of Campylobacter, emphasizing the need for a broader 'One Health' perspective to combat the threats posed by campylobacteriosis.
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Antibacterianos , Infecciones por Campylobacter , Campylobacter jejuni , Brotes de Enfermedades , Filogenia , Secuenciación Completa del Genoma , Campylobacter jejuni/genética , Campylobacter jejuni/efectos de los fármacos , Campylobacter jejuni/aislamiento & purificación , Campylobacter jejuni/clasificación , Humanos , China/epidemiología , Infecciones por Campylobacter/epidemiología , Infecciones por Campylobacter/microbiología , Adulto , Niño , Masculino , Femenino , Antibacterianos/farmacología , Adolescente , Persona de Mediana Edad , Farmacorresistencia Bacteriana Múltiple/genética , Adulto Joven , Preescolar , Pruebas de Sensibilidad Microbiana , Plásmidos/genética , Genoma BacterianoRESUMEN
BACKGROUND: Polycystic ovary syndrome (PCOS), a prevalent endocrine disorder among women of reproductive age, is characterized by disturbances in hormone levels and ovarian dysfunction. Ferroptosis, a unique form of regulated cell death characterized by iron-dependent lipid peroxidation. Emerging evidence indicates that ferroptosis may have a significant role in the pathogenesis of PCOS, highlighting the importance of studying this mechanism to better understand the disorder and potentially develop novel therapeutic interventions. METHODS: To create an in vivo PCOS model, mice were injected with dehydroepiandrosterone (DHEA) and the success of the model was confirmed through further assessments. Ferroptosis levels were evaluated through detecting ferroptosis-related indicators. Ferroptosis-related genes were found through bioinformatic analysis and identified by experiments. An in vitro PCOS model was also established using DHEA treated KGN cells. The molecular binding relationship was confirmed using a chromatin immunoprecipitation (ChIP) assay. RESULTS: In PCOS model, various ferroptosis-related indicators such as MDA, Fe2+, and lipid ROS showed an increase, while GSH, GPX4, and TFR1 exhibited a decrease. These findings indicate an elevated level of ferroptosis in the PCOS model. The ferroptosis-related gene FADS2 was identified and validated. FADS2 and PPAR-α were shown to be highly expressed in ovarian tissue and primary granulosa cells (GCs) of PCOS mice. Furthermore, the overexpression of both FADS2 and PPAR-α in KGN cells effectively suppressed the DHEA-induced increase in ferroptosis-related indicators (MDA, Fe2+, and lipid ROS) and the decrease in GSH, GPX4, and TFR1 levels. The ferroptosis agonist erastin reversed the suppressive effect, suggesting the involvement of ferroptosis in this process. Additionally, the FADS2 inhibitor SC26196 was found to inhibit the effect of PPAR-α on ferroptosis. Moreover, the binding of PPAR-α to the FADS2 promoter region was predicted and confirmed. This indicates the regulatory relationship between PPAR-α and FADS2 in the context of ferroptosis. CONCLUSIONS: Our study indicates that PPAR-α may have an inhibitory effect on DHEA-induced ferroptosis in GCs by enhancing the expression of FADS2. This discovery provides valuable insights into the pathophysiology and potential therapeutic targets for PCOS.
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Ácido Graso Desaturasas , Ferroptosis , Células de la Granulosa , PPAR alfa , Síndrome del Ovario Poliquístico , Regulación hacia Arriba , Animales , Femenino , Ratones , Deshidroepiandrosterona/farmacología , Modelos Animales de Enfermedad , Ferroptosis/efectos de los fármacos , Células de la Granulosa/metabolismo , Células de la Granulosa/efectos de los fármacos , Ratones Endogámicos C57BL , Síndrome del Ovario Poliquístico/metabolismo , Síndrome del Ovario Poliquístico/patología , Síndrome del Ovario Poliquístico/genética , PPAR alfa/metabolismo , PPAR alfa/genética , Regulación hacia Arriba/efectos de los fármacos , Ácido Graso Desaturasas/genética , Ácido Graso Desaturasas/metabolismoRESUMEN
OBJECTIVE: Thyroid cancer (TC) is one of the fastest-growing malignant tumors. This study sought to explore the mechanism of immune escape mediated by receptor tyrosine kinase (KIT) in TC. METHODS: The expression microarray of TC was acquired through the GEO database, and the difference analysis and Kyoto encyclopedia of genes and genomes pathway enrichment analysis were carried out. KIT levels in TC cell lines (K1/SW579/BCPAP) and human normal thyroid cells were detected using reverse transcription quantitative polymerase chain reaction and western blot analysis. TC cells were transfected with overexpressed (oe)-KIT and CD8+ T cells were cocultured with SW579 cells. Subsequently, cell proliferation, migration, and invasion abilities, CD8+ T cell proliferation, cytokine levels (interferon-γ [IFN-γ]/tumor necrosis factor-α [TNF-α]) were determined using colony formation assay, Transwell assays, flow cytometry, and enzyme-linked immunosorbent assay. The phosphorylation of MAPK pathway-related protein (ERK) was measured by western blot analysis. After transfection with oe-KIT, cells were treated with anisomycin (an activator of the MAPK pathway), and the protein levels of p-ERK/ERK and programmed death-ligand 1 (PD-L1) were detected. RESULTS: Differentially expressed genes (N = 2472) were obtained from the GEO database. KIT was reduced in TC samples and lower in tumor cells than those in normal cells. Overexpression of KIT inhibited immune escape of TC cells. Specifically, the proliferation, migration, and invasion abilities of TC cells were lowered, the proliferation level of CD8+ T cells was elevated, and IFN-γ and TNF-α levels were increased. KIT inhibited the activation of the MAPK pathway in TC cells and downregulated PD-L1. CONCLUSION: KIT suppressed immune escape of TC by blocking the activation of the MAPK pathway and downregulating PD-L1.
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Antígeno B7-H1 , Neoplasias de la Tiroides , Humanos , Proliferación Celular/genética , Proteínas Tirosina Quinasas , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Factor de Necrosis Tumoral alfaRESUMEN
AIMS: Cronobacter spp. are emerging food-borne pathogens capable of causing life-threatening illness via several distinct routes. Although endeavors to reduce the incidence of Cronobacter infections are implemented, potential risk of these microorganisms on food safety remains poorly understood. Here, we evaluated the genomic features of clinical Cronobacter and the possible food reservoirs of these infections. METHODS AND RESULTS: Whole-genome sequencing (WGS) data of all human clinical cases (n = 15) during 2008-2021 in Zhejiang were used and compared to sequenced Cronobacter genomes (n = 76) representing various food products. Cronobacter strains exhibited a high degree of genetic diversity by WGS-based subtyping. A variety of serotypes (n = 12) and sequence types (n = 36) were identified, including six novel STs (ST762-ST765, ST798, and ST803) first-time described in this study. Nine clinical clusters representing 12/15 (80%) patients match a potential food source. Genomic insights into virulence genes revealed species/hosts specificity signatures associated with autochthonous populations. Resistance to streptomycin, azithromycin, sulfanilamide isoxazole, cefoxitin, amoxicillin, ampicillin, and chloramphenicol, as well as multidrug resistance, was noted. WGS data can be used to predict resistance phenotypes in amoxicillin, ampicillin, and chloramphenicol, which were extensively used in clinical treatment. CONCLUSIONS: The wide dissemination of pathogenic potential and antibiotic-resistant strains in multiple food sources emphasized the importance of rigorous food safety policies to reduce Cronobacter contamination in China.
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Cronobacter , Humanos , Cronobacter/genética , Microbiología de Alimentos , Cloranfenicol , Genómica , Ampicilina , AmoxicilinaRESUMEN
Increasing human salmonellosis caused by Salmonella enterica serovar Kentucky and London has raised serious concerns. To better understand possible health risks, insights were provided into specific genetic traits and antimicrobial resistance of 88 representative isolates from human and food sources in Zhejiang Province, China, during 2016-2021. Phylogenomic analysis revealed consistent clustering of isolates into the respective serovar or sequence types, and identified plausible interhost transmission via distinct routes. Each serovar exhibited remarkable diversity in host range and disease-causing potential by cgMLST analyses, and approximately half (48.6%, 17/35) of the food isolates were phylogenetically indistinguishable to those of clinical isolates in the same region. S. London and S. Kentucky harbored serovar-specific virulence genes contributing to their functions in pathogenesis. The overall resistance genotypes correlated with 97.7% sensitivity and 60.2% specificity to the identified phenotypes. Resistance to ciprofloxacin, cefazolin, tetracycline, ampicillin, azithromycin, chloramphenicol, as well as multidrug resistance, was common. High-level dual resistance to ciprofloxacin and cephalosporins in S. Kentucky ST198 isolates highlights evolving threats of antibiotic resistance. These findings underscored the necessity for the development of effective strategies to mitigate the risk of food contamination by Salmonella host-restricted serovars.
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BACKGROUND: Bulbus Fritillariae Cirrhosae (BFC) is an endangered high-altitude medicine and food homology plant with anti-tumor, anti-asthmatic, and antitussive activities as it contains a variety of active ingredients, especially steroidal alkaloids. Bulbus Fritillariae Thunbergia (BFT) is another species of Fritillaria that grows at lower altitude areas. Production of plant-derived active ingredients through a synthetic biology strategy is one of the current hot topics in biological research, which requires a complete understanding of the related molecular pathways. Our knowledge of the steroidal alkaloid biosynthesis in Fritillaria species is still very limited. RESULTS: To promote our understanding of these pathways, we performed non-target metabolomics and transcriptome analysis of BFC and BFT. Metabolomics analysis identified 1288 metabolites in BFC and BFT in total. Steroidal alkaloids, including the proposed active ingredients of Fritillaria species peimine, peimisine, peiminine, etc., were the most abundant alkaloids detected. Our metabolomics data also showed that the contents of the majority of the steroidal alkaloids in BFC were higher than in BFT. Further, our comparative transcriptome analyses between BFC and BFT identified differentially expressed gene sets among these species, which are potentially involved in the alkaloids biosynthesis of BFC. CONCLUSION: These findings promote our understanding of the mechanism of steroidal alkaloids biosynthesis in Fritillaria species.
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Alcaloides , Fritillaria , Fritillaria/genética , Perfilación de la Expresión Génica , Metaboloma , Raíces de PlantasRESUMEN
Fritillaria cirrhosa, the most valuable source of the precious Chinese medicinal material Fritillariae Cirrhosae Bulbus, suffers from various stresses during growth which influence the yield and quality of the medicinal part. This study aims to explore the genes related to stress resistance in this medicinal species. To be specific, based on the transcriptome data of F. cirrhosa, a gene encoding the late embryogenesis abundant(LEA) protein was obtained, which was named as FcLEA-D29. The gene sequence and protein structure were analyzed with bioinformatics methods and qRT-PCR was used to detect the expression of the gene in different tissues and in response to temperature stress. The low-temperature tolerance of FcLEA-D29 was verified by the prokaryotic expression system. The results showed that FcLEA-D29 contained an open reading frame of 777 bp, encoding 258 amino acids. Multiple sequence alignment revealed that FcLEA-D29 protein belonged to LEA-D29 subfamily of LEA3 family. qRT-PCR results showed that FcLEA-D29 was specifically expressed in bulbs and responded to low temperature. The strain with the recombinant plasmid demonstrated better growth status than the control strain in the instance of low temperature stress, suggesting that FcLEA-D29 may play a role in bulb development and low temperature response of F. cirrhosa. This study laid a basis for further research on the role of FcLEA-D29 in the accumulation of secondary metabolites in F. cirrhosa, especially alkaloids, under low temperature and provided evidence for the low-temperature adaptation of F. cirrhosa.
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Alcaloides , Fritillaria , Fritillaria/química , Reacción en Cadena de la Polimerasa , Clonación MolecularRESUMEN
Hyperglycemia-mediated endothelial inflammation participates in the pathogenesis of cardiovascular complications in subjects with diabetes. Previous studies reported that phosphatase and tensin homolog deleted on chromosome ten (PTEN) and SET8 participate in high glucose-mediated endothelial inflammation. In this study, we hypothesize that SET8 regulates PTEN expression, thus contributing to high glucose-mediated vascular endothelial inflammation. Our data indicated that plasma soluble intercellular adhesion molecule-1 (sICAM-1) and endothelial selectin (e-selectin) were increased in patients with diabetes and diabetic rats. PTEN expression was augmented in the peripheral blood mononuclear cells of patients with diabetes and in the aortic tissues of diabetic rats. Our in vitro study indicated that high glucose increased monocyte/endothelial adhesion, endothelial adhesion molecule expression and p65 phosphorylation in human umbilical vein endothelial cells (HUVECs). Moreover, high glucose led to endothelial inflammation via upregulation of PTEN. Furthermore, high glucose inhibited SET8 expression and histone H4 lysine 20 methylation (H4K20me1), a downstream target of SET8. SET8 overexpression reversed the effects of high-glucose treatment. shSET8-mediated endothelial inflammation was counteracted by siPTEN. Furthermore, SET8 was found to interact with FOXO1. siFOXO1 attenuated high glucose-mediated endothelial inflammation. FOXO1 overexpression-mediated endothelial inflammation was counteracted by siPTEN. H4K20me1 and FOXO1 were enriched in the PTEN promoter region. shSET8 increased PTEN promoter activity and augmented the positive effect of FOXO1 overexpression on PTEN promoter activity. Our in vivo study indicated that SET8 was downregulated and FOXO1 was upregulated in the peripheral blood mononuclear cells of patients with diabetes and the aortic tissues of diabetic rats. In conclusion, SET8 interacted with FOXO1 to modulate PTEN expression in vascular endothelial cells, thus contributing to hyperglycemia-mediated endothelial inflammation.
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Endotelio Vascular/metabolismo , Glucosa/metabolismo , N-Metiltransferasa de Histona-Lisina/metabolismo , Fosfohidrolasa PTEN/genética , Adulto , Anciano , Animales , Biomarcadores , Glucemia , Células Cultivadas , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Proteína Forkhead Box O1 , Expresión Génica , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Fosfohidrolasa PTEN/metabolismo , Ratas , Vasculitis/etiología , Vasculitis/metabolismo , Vasculitis/patologíaRESUMEN
OBJECTIVES: Hypoxia leads to endothelial cell inflammation, apoptosis, and damage, which plays an important role in the complications associated with ischemic cardiovascular disease. As an oxidoreductase, p66Shc plays an important role in the regulation of reactive oxygen species (ROS) production and apoptosis. Ketamine is widely used in clinics. This study was designed to assess the potential protective effect of ketamine against hypoxia-induced injury in human umbilical vein endothelial cells (HUVECs). Moreover, we explored the potential mechanism by which ketamine protected against hypoxia-induced endothelial injury. METHODS: The protective effects of ketamine against hypoxia-induced injury was assessed using cell viability and adhesion assays, quantitative polymerase chain reaction, and western blotting. RESULTS: Our data showed that hypoxia reduced HUVEC viability, increased the adhesion between HUVECs and monocytes, and upregulated the expression of endothelial adhesion molecules at the protein and mRNA levels. Moreover, hypoxia increased ROS accumulation and upregulated p66Shc expression. Furthermore, hypoxia downregulated sirt1 expression in HUVECs. Alternatively, ketamine was shown to reverse the hypoxia-mediated reduction of cell viability and increase in the adhesion between HUVECs and monocytes, ameliorate hypoxia-induced ROS accumulation, and suppress p66Shc expression. Moreover, EX527, a sirt1 inhibitor, reversed the protective effects of ketamine against the hypoxia-mediated reduction of cell viability and increase in adhesion between HUVECs and monocytes. CONCLUSION: Ketamine reduces hypoxia-induced p66Shc expression and attenuates ROS accumulation via upregulating sirt1 in HUVECs, thus attenuating hypoxia-induced endothelial cell inflammation and apoptosis.
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Apoptosis/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Hipoxia , Ketamina/farmacología , Especies Reactivas de Oxígeno/metabolismo , Supervivencia Celular , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Estrés Oxidativo , Proteína Transformadora 1 que Contiene Dominios de Homología 2 de Src , Venas UmbilicalesRESUMEN
Campylobacter is a zoonotic pathogen that causes foodborne diarrheal illness globally. To better understand health risks in Southeastern China, Campylobacter spp. were surveyed in humans and representative poultry products over 3 years. One hundred and ninety-five representative isolates (n = 148, Campylobacter jejuni; n = 45, Campylobacter coli; n = 2 Campylobacter hyointestinalis) were examined for genetic relatedness and antimicrobial susceptibility. Nearly all Campylobacter isolates (99.0%, 193/195) were resistant to at least one class of antimicrobials, and 45.6% (89/195) of the isolates exhibited multidrug resistance. Genotypic analysis revealed high diversity among tested strains. Multilocus sequence typing (MLST) displayed 120 sequence types (STs) including 42 novel STs being added to the PubMLST international database. Sixty-two STs belonged to 16 previously characterized clonal complexes (CCs), of which CC-21, CC-45, CC-464, CC-574, CC-353, and CC-828 were most frequently identified. In addition, pulsed-field gel electrophoresis (PFGE) fingerprinting resulted in 66 PFGE SmaI patterns among the 125 isolates, with eight patterns shared between human and poultry sources. Subtyping data did not correlate with antimicrobial resistance phenotypes. Taken together, this large-scale surveillance study highlights high antimicrobial resistance and molecular features of Campylobacter isolates in Southeastern China.
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Pathogenic Cronobacter species are responsible for life-threatening illness in neonates. A ten-year comprehensive survey was conducted to examine the population structure and antimicrobial resistant patterns of Cronobacter isolates from food (n = 78) and clinical (n = 12) sources in Wenzhou, China. A total of 90 (4.4%) isolates were recovered from 2051 collected samples. The occurrence of Cronobacter spp. was highest in spices with a rate of 22% (26/119), whereas the lowest contamination rate of 1% was found in powered infant and toddler formula (7/494), special medical infant formula (1/95) and human stool samples (12/1024). Cronobacter strains revealed a high degree of genetic diversity among the isolates tested. Pulsed-field gel electrophoresis (PFGE) distinguished 75 clonal groups, and the biggest cluster consisted of four strains. Multilocus sequence typing (MLST) method displayed 43 sequence types (STs), of which ST1, ST4, ST8, ST64, ST148 and ST201 were most frequently identified. Meanwhile, two new sequence types were discovered and added to the PubMLST international database. Resistance to ceftriaxone, cefotaxiv, amoxicillin, ampicillin, cefoxitin, tetracycline, streptomycin, azithromycin, chloramphenicol, as well as multidrug resistance, was noted. Taken together, this large-scale surveillance study highlights the wide dissemination and diverse molecular features of Cronobacter spp. in Wenzhou China.
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Cronobacter/genética , Heces/microbiología , Contaminación de Alimentos/análisis , Fórmulas Infantiles/microbiología , Especias/microbiología , China , Cronobacter/aislamiento & purificación , Farmacorresistencia Microbiana , Humanos , Lactante , Pruebas de Sensibilidad Microbiana , PrevalenciaRESUMEN
RESEARCH QUESTION: Maximizing the number of oocytes and embryos obtained in the shortest possible time is of considerable potential clinical significance for women with poor prognosis. The aim of this study was to develop a clinically applicable strategy to obtain more oocytes and viable embryos in one menstrual cycle for poor-prognosis women. DESIGN: Prospective cohort study of 146 women with poor prognosis who received rescue in-vitro maturation (IVM) (nâ¯=â¯50) or double ovarian stimulation (DuoStim) (nâ¯=â¯96) between December 2015 and February 2018. Outcomes, number of oocytes retrieved and matured, and embryo developmental potential were compared between the two groups. RESULTS: The rates of mature oocytes, available embryos and top-quality embryos from luteal phase stimulation (LPS) of DuoStim were all significantly higher than those derived from the immature oocytes of rescue IVM (P < 0.05). The relative contributions of LPS in the DuoStim group for proportion of mature oocytes, available embryos and top-quality embryos were all significantly higher than IVM in the rescue IVM group (P < 0.001). The overall cancellation rate of no oocyte or available embryo significantly decreased from 30.21% to 9.38% (P < 0.001) when DuoStim was carried out, which decreased from 24.00% to 12.00% with no significant difference in the rescue IVM group when immature sibling oocytes were matured in vitro. CONCLUSION: Rescue IVM and DuoStim can contribute more competent oocytes and viable embryos in the shortest possible time for poor-prognosis women, of which DuoStim may be more efficient.
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Fertilización In Vitro/métodos , Técnicas de Maduración In Vitro de los Oocitos , Recuperación del Oocito , Inducción de la Ovulación/métodos , Adulto , Femenino , Humanos , Pronóstico , Estudios ProspectivosRESUMEN
OBJECTIVE: To explore whether cumulative serum urate (cumSU) is correlated with diabetes type II mellitus incidence. METHODS: In this study, we recruited individuals participating in all Kailuan health examinations from 2006 to 2013 without stroke, cancer, gestation, myocardial infarction, and diabetes type II diagnosis in the first three examinations. CumSU was calculated by multiplying the average serum urate concentration and the time between the two examinations (umol/L × year). CumSU levels were categorized into five groups: Q1-Q5. The effect of cumSU on diabetes type II incidence was estimated by logistic regression. RESULTS: A total of 36,277 individuals (27,077 men and 9200 women) participated in the final analysis. The multivariate logistic regression model showed the odds ratios (95% confidence intervals) of diabetes type II from Q1 to Q5 were 1.00 (reference), 1.25 (1.00 to 1.56), 1.43 (1.15 to 1.79), 1.49 (1.18 to 1.87), and 1.80 (1.40 to 2.32), respectively. Multivariable odds ratios per 1-standard deviation increase in cumSU were 1.26 (1.17 to 1.37) in all populations, 1.20 (1.10 to 1.32) for men, and 1.52 (1.27 to 1.81) for women, respectively. CONCLUSIONS: CumSU is a significant risk factor for diabetes type II. Individuals with higher cumSU, especially women, are at a higher risk of diabetes type II independent of other known risk factors.Key Points⢠Cumulative exposure to serum urate is a significant risk factor for diabetes type II.⢠Individuals with higher cumSU, especially women, are at a higher risk of diabetes type II.
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Diabetes Mellitus Tipo 2/sangre , Ácido Úrico/sangre , Adulto , China/epidemiología , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
OBJECTIVES: Hypoxia leads to endothelial cell inflammation, apoptosis, and damage, which plays an important role in the complications associated with ischemic cardiovascular disease. As an oxidoreductase, p66Shc plays an important role in the regulation of reactive oxygen species (ROS) production and apoptosis. Ketamine is widely used in clinics. This study was designed to assess the potential protective effect of ketamine against hypoxia-induced injury in human umbilical vein endothelial cells (HUVECs). Moreover, we explored the potential mechanism by which ketamine protected against hypoxia-induced endothelial injury. METHODS: The protective effects of ketamine against hypoxia-induced injury was assessed using cell viability and adhesion assays, quantitative polymerase chain reaction, and western blotting. RESULTS: Our data showed that hypoxia reduced HUVEC viability, increased the adhesion between HUVECs and monocytes, and upregulated the expression of endothelial adhesion molecules at the protein and mRNA levels. Moreover, hypoxia increased ROS accumulation and upregulated p66Shc expression. Furthermore, hypoxia downregulated sirt1 expression in HUVECs. Alternatively, ketamine was shown to reverse the hypoxia-mediated reduction of cell viability and increase in the adhesion between HUVECs and monocytes, ameliorate hypoxia-induced ROS accumulation, and suppress p66Shc expression. Moreover, EX527, a sirt1 inhibitor, reversed the protective effects of ketamine against the hypoxia-mediated reduction of cell viability and increase in adhesion between HUVECs and monocytes. CONCLUSION: Ketamine reduces hypoxia-induced p66Shc expression and attenuates ROS accumulation via upregulating sirt1 in HUVECs, thus attenuating hypoxia-induced endothelial cell inflammation and apoptosis.
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Humanos , Especies Reactivas de Oxígeno/metabolismo , Apoptosis/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Ketamina/farmacología , Hipoxia , Venas Umbilicales , Supervivencia Celular , Estrés Oxidativo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Proteína Transformadora 1 que Contiene Dominios de Homología 2 de SrcRESUMEN
To determine the correlation between QKI and pancreatic cancer tissues, the QKI expression of pancreatic cancer cells and fibroblasts in the tumor-surrounding microenvironment were detected. Then, QKI overexpression and interference with QKI short hairpin RNA in LX-2 (a fibroblast cell line) were established in vitro. Meanwhile, to observe the cell proliferation, invasion, migration, and other changes, QKI, and related epithelial-mesenchymal transition (EMT) molecules were detected by a polymerase chain reaction and Western blot analysis. In addition, an in vivo tumorigenicity test in node mice was performed to confirm whether QKI expression can promote the proliferation, invasion, and metastasis of pancreatic cancer ductal epithelial cells. Finally, the autophagy levels of fibroblasts with QKI overexpression were observed by electron microscopy to further explore the QKI pathogenic mechanism. It was found that cell proliferation, invasion, migration, and EMT-related markers were increased in QKI-overexpressed fibroblasts LX-2. Furthermore, in vivo, liver and peritoneal metastasis decreased overall survival rate and increasing autophagy levels in QKI-overexpressing nude mice were observed. Meanwhile, knock down QKI with small interfering RNA can reverse all the above effects. QKI can promote the proliferation, metastasis, and invasion of pancreatic cancer through activating fibroblasts surrounding pancreatic cancer and accelerating EMT and increasing the autophagy in pancreatic cancer. QKI may become a potential target for the treatment of pancreatic cancer.
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OBJECTIVES: To screen and identify the probe markers specifically binding to human cervical cancer, a phage-displayed 12-mer peptide library was used for biopanning of SiHa cells. RESULTS: After four rounds of whole-cell subtraction biopanning, the phage recovery was 21-fold higher (from 3.9 × 10-5 to 8.3 × 10-4) than that of the first round, and specific phage clones were significantly enriched. 57 randomly selected phage clones were tested by ELISA, and 36 phage clones were identified as positive clones. After sequencing of positive clones, six different peptide sequences were obtained and CSP3 showed best affinity and specificity to SiHa cells via immunofluorescence assay. CONCLUSIONS: Peptide, CSP3, bound to SiHa cells specifically and sensitively. It may be a potential candidate for molecular imaging detection and targeting therapy of cervical cancer.
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Péptidos/metabolismo , Análisis de Secuencia de Proteína/métodos , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/metabolismo , Células CACO-2 , Línea Celular Tumoral , Detección Precoz del Cáncer , Femenino , Humanos , Células MCF-7 , Imagen Molecular , Terapia Molecular Dirigida , Biblioteca de Péptidos , Péptidos/química , Neoplasias del Cuello Uterino/tratamiento farmacológicoRESUMEN
Polychlorinated biphenyls (PCBs) are ubiquitous legacy persistent pollutants and epidemiological data showed that PCB burdens were associated with failed implantation in human. However, the mechanism how PCB exposure affects the embryo implantation is not clear. Using an in vitro model for human embryo implantation employing the human choriocarcinoma cell line JAR and the human endometrial cell line Ishikawa, we have shown that PCB mixture Aroclor 1254 at environmental-relevant concentrations (2.5, 12.5, and 62.5µM) dose-dependently impaired the endometrial receptivity by reducing the adhesion of JAR spheroid attachment and increasing the spheroid outgrowth. The receptive-up-regulated micro-RNA, mir-30d was also down-regulated in endometrial cells by the exposure. Following transient transfection of mir-30d mimic, the disrupted attachment and outgrowth of JAR spheroids was partially restored in the model. By measurement of cadherin switch and vimentin expression, the PCB exposure also activated epithelial mesenchymal transition (EMT) in endometrial cells. In accordance, mir-30d mimic suppressed the EMT markers induced by PCBs. Luciferase reporter assay confirmed that the EMT regulator Snai1 was targeted by mir-30d, and the expression of Snai1 was dose-dependently up-regulated by PCB exposure. Taken together, our study revealed that PCBs may affect the receptivity of endometrial cells by impairing the interaction between receptivity-up-regulated microRNA and EMT process.
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Endometrio/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , MicroARNs/metabolismo , Bifenilos Policlorados/toxicidad , Cadherinas/genética , Cadherinas/metabolismo , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo , Implantación del Embrión/efectos de los fármacos , Endometrio/citología , Endometrio/metabolismo , Femenino , Humanos , MicroARNs/genética , Factores de Transcripción de la Familia Snail/genética , Factores de Transcripción de la Familia Snail/metabolismo , Regulación hacia Arriba , Vimentina/genética , Vimentina/metabolismoRESUMEN
Human umbilical cord-derived mesenchymal stem cells (hUCMSCs) are considered to be an ideal cell source for cell therapy of many diseases. The aim of this study was to investigate the contribution of the microenvironment to the hepatic differentiation potential of hUCMSCs in vitro and in vivo and to explore their therapeutic use in acute liver injury in rats. We established a new model to simulate the liver tissue microenvironment in vivo using liver homogenate supernatant (LHS) in vitro. This induced environment could drive hUCMSCs to differentiate into hepatocyte-like cells within 7 days. The differentiated cells expressed hepatocyte-specific markers and demonstrated hepatocellular functions. We also injected hUCMSCs into rats with CCl4-induced acute hepatic injury. The hUCMSCs were detected in the livers of recipient rats and expressed the human hepatocyte-specific markers, suggesting that hUCMSCs could differentiate into hepatocyte-like cells in vivo in the liver tissue microenvironment. Levels of biochemistry markers improved significantly after transplantation of hUCMSCs compared with the nontransplantation group (P < 0.05). In conclusion, this study demonstrated that the liver tissue microenvironment may contribute to the differentiation of hUCMSCs into hepatocytes both in vitro and in vivo.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/terapia , Trasplante de Células Madre de Sangre del Cordón Umbilical , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/citología , Cordón Umbilical/citología , Animales , Biomarcadores/metabolismo , Tetracloruro de Carbono/toxicidad , Diferenciación Celular/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Hepatocitos/citología , Humanos , Hígado/patología , RatasRESUMEN
BRCA1-interacting protein 1 (BRIP1), a DNA-dependent ATPase and a DNA helicase, is critical for BRCA-associated DNA damage repair functions and may be associated with the tumourigenesis and aggressiveness of various cancers. Here, we constructed a BRIP1 recombinant plasmid, overexpressed it in a cervical cancer cell line (HeLa) and found that ectopic expression of BRIP1 could remarkably enhance the antitumor activity of cisplatin, as demonstrated by decreased cell viability, colony formation and tumour xenografts' weight. Moreover, BRIP1 promoted cisplatin-mediated cell apoptosis and suppressed tumour angiogenesis. We also found that the synergistic inhibition effect of BRIP1 might be partially attributed to attenuation of Rac1 GTPase activation and that Rac1 GTPase re-activation could reverse the sensitizing effect induced by BRIP1. Our study suggested that up-regulation of BRIP1 could enhance chemosensitivity of HeLa cells to cisplatin through inhibiting Rac1 GTPase activation, and it provides a new insight into the essential role of BRIP1 in cervical cancer chemotherapy.