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PURPOSE: The aim of this study was to examine whether there is a correlation between different types of ventricular septal defects (VSD) and chromosomal abnormalities in the low-risk setting of non-invasive prenatal testing (NIPT) and to evaluate the prognosis of fetuses with varying types of VSD. METHODS: Cases of pregnant women who underwent amniocentesis due to fetal VSD were collected by Tianjin Central Hospital of Obstetrics and Gynecology from May 2017 to May 2022. Exclusions were made for those without NIPT, with high-risk NIPT results, genetic disorders, and those lost to follow-up. Data collected included ultrasound classification of VSD, prenatal NIPT results, copy-number variations (CNVs) results, and neonatal outcomes. RESULTS: The prevalence of pathogenic CNVs was investigated in 74 cases of VSDs. Of these cases, 45 were isolated VSDs (9 muscular and 36 non-muscular) and 29 were non-isolated VSDs (10 with intracardiac and 19 with extra-cardiac structural anomalies). The results revealed that the incidence of pathogenic CNVs was lower in isolated VSDs compared to non-isolated VSDs in a low-risk NIPT condition (χ2 = 9.344, P = 0.002). There was no significant difference in the prevalence of pathogenic CNVs between VSDs with intracardiac and extra-cardiac structural anomalies (P = 0.541). Moreover, VSDs associated with intracardiac structural anomalies had the highest rate of surgical intervention. CONCLUSION: When NIPT is low-risk and VSD is isolated, the likelihood of fetal chromosomal defects is not increased. However, if there are intra- or extra-cardiac structural abnormalities present alongside VSD, the possibility of pathogenic CNV is considerably greater, necessitating invasive prenatal diagnosis. Isolated muscular VSDs usually do not require surgery, which can be used as a basis for prenatal counseling regarding fetal VSD.
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Atmospheric particulate matter (PM) exacerbates the risk factor for Alzheimer's and Parkinson's diseases (PD) by promoting the alpha-synuclein (α-syn) pathology in the brain. However, the molecular mechanisms of astrocytes involvement in α-syn pathology underlying the process remain unclear. This study investigated PM with particle size <200 nm (PM0.2) exposure-induced α-syn pathology in ICR mice and primary astrocytes, then assessed the effects of mammalian target of rapamycin inhibitor (PP242) in vitro studies. We observed the α-syn pathology in the brains of exposed mice. Meanwhile, PM0.2-exposed mice also exhibited the activation of glial cell and the inhibition of autophagy. In vitro study, PM0.2 (3, 10 and 30 µg/mL) induced inflammatory response and the disorders of α-syn degradation in primary astrocytes, and lysosomal-associated membrane protein 2 (LAMP2)-mediated autophagy underlies α-syn pathology. The abnormal function of autophagy-lysosome was specifically manifested as the expression of microtubule-associated protein light chain 3 (LC3II), cathepsin B (CTSB) and lysosomal abundance increased first and then decreased, which might both be a compensatory mechanism to toxic α-syn accumulation induced by PM0.2. Moreover, with the transcription factor EB (TFEB) subcellular localization and the increase in LC3II, LAMP2, CTSB, and cathepsin D proteins were identified, leading to the restoration of the degradation of α-syn after the intervention of PP242. Our results identified that PM0.2 exposure could promote the α-syn pathological dysregulation in astrocytes, providing mechanistic insights into how PM0.2 increases the risk of developing PD and highlighting TFEB/LAMP2 as a promising therapeutic target for antagonizing PM0.2 toxicity.
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Astrocitos , Autofagia , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice , Proteína 2 de la Membrana Asociada a los Lisosomas , Lisosomas , Ratones Endogámicos ICR , Material Particulado , alfa-Sinucleína , Animales , Astrocitos/efectos de los fármacos , alfa-Sinucleína/metabolismo , Autofagia/efectos de los fármacos , Ratones , Lisosomas/metabolismo , Lisosomas/efectos de los fármacos , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Proteína 2 de la Membrana Asociada a los Lisosomas/metabolismo , Material Particulado/toxicidad , Contaminantes Atmosféricos/toxicidadRESUMEN
Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by changes in the metabolism of short chain fatty acids (SCFAs), dysregulation of gut microbiota, and an imbalance of Treg/Th17. Herein, we explore the effects of the Ento-A (an alcohol extract of Periplaneta americana L.) on a mouse model of UC. First, a chronic and recurrent UC model was constructed in BALB/c mice by 2.2% DSS administration. UC mice were continuously treated for 14 days with Ento-A (50, 100, 200 mg/kg, i.g.) or a negative control. Ento-A alleviated many of the pathological changes observed in UC mice, such as body weight loss, disease activity index, changes in colon length, and colonic mucosal damage index. Ento-A also decreased levels of proinflammatory cytokines (IL-1ß, IL-6, IL-17A, and TNF-α), increased levels of anti-inflammatory cytokines (IL-10 and TGF-ß1) and repaired the intestinal mucosal barrier. Additionally, Ento-A regulated the proportions of Th17 cells, and Treg cells in mesenteric lymph nodes harvested from treated mice (as assessed by Flow cytometry), and the expression levels of IL-17A and Foxp3 in colon (as assessed by immunohistochemistry). 16 S rRNA gene sequencing revealed that Ento-A regulated gut microbiota. GC-MS analysis demonstrated that Ento-A also restored SCFAs content in the intestinal tract. Finally, transcriptomic analysis revealed that Ento-A regulated the IL-17 signaling pathway. In summary, Ento-A regulates the diversity and abundance of intestinal flora in UC mice, enhancing the secretion of SCFAs, subsequently regulating the IL-17 signaling pathway, and ultimately repairing the intestinal mucosal barrier.
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Colitis Ulcerosa , Colitis , Microbioma Gastrointestinal , Animales , Ratones , Interleucina-17 , Células Th17 , Transducción de Señal , Colitis/inducido químicamente , Colon , Citocinas , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Ratones Endogámicos C57BLRESUMEN
Telomere length (TL) shortening is a pivotal indicator of biological aging and is associated with many human diseases. The genetic determinates of human TL have been widely investigated, however, most existing studies were conducted based on adult tissues which are heavily influenced by lifetime exposure. Based on the analyses of terminal restriction fragment (TRF) length of telomere, individual genotypes, and gene expressions on 166 healthy placental tissues, we systematically interrogate TL-modulated genes and their potential functions. We discover that the TL in the placenta is comparatively longer than in other adult tissues, but exhibiting an intra-tissue homogeneity. Trans-ancestral TL genome-wide association studies (GWASs) on 644,553 individuals identify 20 newly discovered genetic associations and provide increased polygenic determination of human TL. Next, we integrate the powerful TL GWAS with placental expression quantitative trait locus (eQTL) mapping to prioritize 23 likely causal genes, among which 4 are functionally validated, including MMUT, RRM1, KIAA1429, and YWHAZ. Finally, modeling transcriptomic signatures and TRF-based TL improve the prediction performance of human TL. This study deepens our understanding of causal genes and transcriptomic determinants of human TL, promoting the mechanistic research on fine-grained TL regulation.
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Estudio de Asociación del Genoma Completo , Placenta , Adulto , Humanos , Femenino , Embarazo , Placenta/metabolismo , Acortamiento del Telómero , Telómero/genética , Perfilación de la Expresión GénicaRESUMEN
Yes-associated protein (YAP) is a pivotal regulator in cellular proliferation, survival, differentiation, and migration, with significant roles in embryonic development, tissue repair, and tumorigenesis. At the maternal-fetal interface, emerging evidence underscores the importance of precisely regulated YAP activity in ensuring successful pregnancy initiation and progression. However, despite the established association between YAP dysregulation and adverse pregnancy outcomes, insights into the impact of aberrant YAP levels in fetal-derived, particularly trophoblast cells, and the ensuing dysfunction at the maternal-fetal interface remain limited. This review comprehensively examines YAP expression and its regulatory mechanisms in trophoblast cells throughout pregnancy. We emphasize its integral role in placental development and maternal-fetal interactions and delve into the correlations between YAP dysregulation and pregnancy complications. A nuanced understanding of YAP's functions during pregnancy could illuminate intricate molecular mechanisms and pave the way for innovative prevention and treatment strategies for pregnancy complications. Video Abstract.
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Placenta , Complicaciones del Embarazo , Embarazo , Femenino , Humanos , Placenta/metabolismo , Trofoblastos/metabolismo , Factores de Transcripción/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Complicaciones del Embarazo/metabolismoRESUMEN
Background: As an important medicinal insect, Periplaneta americana (PA) has been applied for the treatment of wounds, burns, and ulcers with fewer side effects and a reduced recurrence rate, which provides great potential for developing new drugs based on its active constituents. Materials and methods: The main chromatographic peaks determined by high performance liquid chromatography (HPLC) in the PA concentrated ethanol-extract liquid (PACEL) were separated, purified, and identified by semi-preparative LC, mass spectrum, and 1H NMR spectroscopic analysis. The biological activities of the identified compounds were investigated by methylthiazolyldiphenyl-tetrazolium bromide (MTT) method based on in vitro human skin fibroblasts (HSF) and in vivo experiments based on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mouse model. Furthermore, RT-qPCR of six genes related to inflammation or intestinal epithelial cell proliferation was employed to investigate the molecular mechanism of the indole analogues recovering UC in mice. Results: Five indole analogues were purified and identified from PACEL, including tryptophan (Trp), tryptamine (pa01), 1,2,3,4-tetrahydrogen-ß-carboline-3-carboxylic acid (pa02), (1S, 3S)-1-methyl-1,2,3,4-tetrahydrogen-ß-carboline-3-carboxylic acid (pa03), and (1R, 3S)-1-methyl-1,2,3,4-tetrahydrogen-ß-carboline-3-carboxylic acid (pa04), among which the pa02 and pa04 were reported in PA for the first time. In vitro and in vivo experiments showed that PACEL, Trp, and pa02 had promoting HSF proliferation activity and intragastric administration of them could alleviate symptoms of weight loss and colon length shortening in the UC mice. Although recovery activity of the compound pa01 on the colon length was not as obvious as other compounds, it showed anti-inflammatory activity in histological analysis. In addition, The RT-qPCR results indicated that the three indole analogues could alleviate DSS-induced intestinal inflammation in mice by inhibiting pro-inflammatory cytokines (MMP7, IL1α) and down-regulating BMP8B expression. Conclusion: This study reported the isolation, purification, structure identification, and biological activity of the active indole analogues in PACEL. It was found for the first time that the PA extract contained many indole analogues and Trp, which exhibited good proliferation activity on HSF fibroblasts as well as anti-UC activity in mice. These indole analogues probably are important components related to the pharmacological activity in PA.
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BACKGROUND: Interleukin (IL)-6 is a pro-inflammatory cytokine that plays an important role in preterm birth (PTB), Several meta-analyses investigated the association between IL-6 and PTB, but definitive conclusion has not yet been achieved. This updated meta-analysis aimed to ascertain the association between IL-6 and PTB by examining IL-6 levels in both normal birth and PTB groups. MATERIAL AND METHODS: Prospective cohort studies were retrieved in PubMed, Embase, and the Cochrane library from their inception until 18 February 2020. The primary outcome was the association between IL-6 and PTB, and secondary outcomes were the association between IL-6 and spontaneous PTB. RESULTS: Nine studies involving 1904 patients were included. Overall, IL-6 from different sample types (maternal blood, amniotic fluid and cervicovaginal fluid) was associated with PTB (standard mean difference [SMD]: 0.86, 95% confidence interval [CI]: 0.32 to 1.39, p < 0.001). Furthermore, the association was significant for IL-6 only in amniotic fluid (SMD: 1.87, 95%CI: 0.82 to 2.93, p < 0.001) and cervicovaginal fluid (SMD: 0.46, 95%CI: 0.09 to 0.84, p = 0.022), but not significant in maternal blood (SMD: -0.11, 95%CI: -0.57 to 0.34, p = 0.623). In addition, IL-6 was also associated with spontaneous PTB (SMD: 1.57, 95% CI: 0.18 to 2.95, p < 0.001). CONCLUSIONS: Based on the available evidence, IL-6 in amniotic fluid and cervicovaginal fluid might be useful for predicting preterm birth.
KEY MESSAGESBased on the available evidenceIL-6 in amniotic fluid and cervicovaginal fluid might be useful for predicting preterm birth.
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Nacimiento Prematuro , Femenino , Humanos , Recién Nacido , Nacimiento Prematuro/epidemiología , Interleucina-6 , Estudios Prospectivos , Citocinas , Líquido Amniótico/químicaRESUMEN
Objectives: Ulcerative colitis (UC) remains an enduring, idiopathic inflammatory bowel disease marked by persistent mucosal inflammation initiating from the rectum and extending in a proximal direction. An ethanol extract of Periplaneta americana L., namely Kangfuxin (KFX), has a significant historical presence in Traditional Chinese Medicine and has been broadly utilized in clinical practice for the treatment of injury. Here, we aimed to determine the effect of KFX on 2,4,6-trinitro'benzene sulfonic acid (TNBS)-induced UC in Sprague-Dawley rats. Materials and Methods: We established the UC model by TNBS/ethanol method. Then, the rats were subject to KFX (50, 100, 200 mg/kg/day) for 2 weeks by intragastric gavage. The body weight, disease activity index (DAI), colonic mucosal injury index (CMDI), and histopathological score were evaluated. The colonic tissue interleukin (IL)-1ß, IL-6, tumor necrosis factor-α (TNF-α), IL-10, transforming growth factor-1 (TGF-ß1), and epidermal growth factor (EGF) were determined by Elisa. To study T-lymphocyte subsets, flow cytometry was performed. In addition, the expression level of NF-κB p65 was evaluated by immunohistochemistry and western blot analysis. Results: Compared with the TNBS-triggered colitis rats, the treatment of rats with KFX significantly increased the body weight, and decreased DAI, CMDI, and histopathological score. Also, KFX elicited a reduction in the secretion of colonic pro-inflammatory cytokines, namely IL-1ß, IL-6, and TNF-α, concomitant with up-regulation of IL-10, TGF-ß1, and EGF levels. Upon KFX treatment, the CD3+CD4+/CD3+CD8+ ratio in the spleen decreased, while the CD3+CD8+ subset and the CD3+CD4+CD25+/CD3+CD4+ ratio demonstrated an increase. In addition, the expression of NF-κB p65 in the colon was decreased. Conclusion: KFX effectively suppresses TNBS-induced colitis by inhibiting the activation of NF-κB p65 and regulating the ratio of CD4+/CD8+.
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BACKGROUND: Guizhi Shaoyao Zhimu decoction, a traditional Chinese medicine formula used empirically for the treatment of rheumatoid arthritis (RA), has been shown to alleviate bone destruction in rats with collagen-induced arthritis (CIA). PURPOSE: The aim of this study is to characterize the effects of Guizhi Shaoyao Zhimu granules (GSZGs) on bone destruction in RA and the underlying mechanism. STUDY DESIGN: A CIA arthritis model using DBA/1 mice. The animals were divided into a normal group; CIA model group; low, medium, and high-dose GSZG groups (3, 6, and 9 g/kg/day); and a methotrexate group (1.14 mg/kg/w). In vitro, a cytokine induced osteoclastogenesis model was established. METHODS: After 28 days of treatment, the paw volume was measured, bone destruction was examined by micro-CT, and the generation of osteoclasts in bone tissue was evaluated via tartrate-resistant acid phosphatase (TRAP) staining. Furthermore, the inhibitory effect and underlying mechanism of action of GSZG on RANKL-induced osteoclastogenesis were investigated in vitro. RESULTS: The in vivo analyses demonstrated that the paw volume and degree of bone erosion of mice in the medium- and high-dose GSZG groups were significantly decreased compared to the CIA model group. In addition, GSZG treatment suppressed the excessive generation of osteoclasts in the bone tissue of CIA mice. In vitro, GSZG inhibited RANKL-induced osteoclastogenesis and osteoclast-mediated bone resorption. Specifically, it only inhibited the generation of osteoclast precursors (OCPs); it had no significant effect on the fusion of OCPs or maturation of osteoclasts. Finally, we showed that the inhibitory effect of GSZG on osteoclastogenesis was related to the promotion of PTEN-induced kinase protein 1 (PINK1)/Parkin pathway-mediated mitophagy of osteoclast precursors, which was verified using a PINK1 knockdown small interfering RNA in OCPs. CONCLUSION: These findings indicate that GSZG is a candidate for the treatment of bone destruction in RA and provide a more detailed elucidation of the mechanism of GSZG anti-RA bone erosion, i.e., inhibition of the ROS/NF-κB axis through the PINK1/Parkin-mediated mitochondrial autophagic pathway to inhibit osteoclast precursor production, compared to the published literature.
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Artritis Experimental , Artritis Reumatoide , Resorción Ósea , Ratones , Ratas , Animales , Osteoclastos/metabolismo , Osteogénesis , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/metabolismo , Mitofagia , Ratones Endogámicos DBA , Artritis Reumatoide/tratamiento farmacológico , Resorción Ósea/tratamiento farmacológico , Resorción Ósea/metabolismo , Proteínas Quinasas/metabolismo , Ligando RANK/farmacología , Ligando RANK/metabolismoRESUMEN
Aberrant mitophagy has been identified as a driver for energy metabolism disorder in most cardiac pathological processes. However, finding effective targeted agents and uncovering their precise modulatory mechanisms remain unconquered. Fuzi, the lateral roots of Aconitum carmichaelii, shows unique efficacy in reviving Yang for resuscitation, which has been widely used in clinics. As a main cardiotonic component of Fuzi, mesaconine has been proven effective in various cardiomyopathy models. Here, we aimed to define a previously unrevealed cardioprotective mechanism of mesaconine-mediated restoration of obstructive mitophagy. The functional implications of mesaconine were evaluated in doxorubicin (DOX)-induced heart failure models. DOX-treated mice showed characteristic cardiac dysfunction, ectopic myocardial energy disorder, and impaired mitophagy in cardiomyocytes, which could be remarkably reversed by mesaconine. The cardioprotective effect of mesaconine was primarily attributed to its ability to promote the restoration of mitophagy in cardiomyocytes, as evidenced by elevated expression of PINK1, a key mediator of mitophagy induction. Silencing PINK1 or deactivating mitophagy could completely abolish the protective effects of mesaconine. Together, our findings suggest that the cardioprotective effects of mesaconine appear to be dependent on the activation of PINK1-induced mitophagy and that mesaconine may constitute a promising therapeutic agent for the treatment of heart failure.
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Studies have indicated that metal exposure is associated with an increased risk of metabolic syndrome (MetS). However, it is unclear whether overexposure to heavy metals occurs in miners and is associated with MetS risk remains unclear. In a cross-sectional study, analysis for metal exposure levels of 3428 participants from three types of workplaces was conducted. Relationships between metals in urine and MetS were characterized using a multivariate binary logistic regression model and restricted cubic spline analysis. The association between urinary metals and workplaces with respect to MetS was studied via mediation analysis and multiplicative interaction analysis. And a sensitivity analysis was performed to assess the robustness of the association between MetS and urinary metals in participants without obesity (n = 2811). Zn, Cu, Fe, Co, and Ni were found to be associated with MetS in the single-metal models, whereas only Zn and Cu showed considerable associations in the multimetal model. The odds ratios (95% CI) for MetS in the highest quartiles were 2.089 (1.611, 2.707) for urinary Zn and 1.394 (1.084, 1.794) for urinary Cu (both false discovery rate for both was < 0.05). Urinary Zn and Cu were positively associated with hypertriglyceridemia. In addition, higher Zn exposure was confirmed in underground workers than ground workers and office workers, and there was a significant association between urinary metal exposure and workplace, which together influenced the occurrence of MetS. These results provided scientific evidence for the relationship between Zn, Cu, workplaces, and MetS in coal workers and indicated that it is critical to reduce occupational metal exposure, especially in underground workers.
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Síndrome Metabólico , Metales Pesados , Exposición Profesional , Humanos , Síndrome Metabólico/epidemiología , Estudios Transversales , Metales Pesados/orina , Exposición Profesional/efectos adversos , ObesidadRESUMEN
Epidemiological studies have shown that ambient fine particulate matter (PM) can cause various neurodegenerative diseases, including Alzheimer's disease. Reactive astrocytes are strongly induced by ambient fine PM, although their role is poorly understood. Herein, we show that A1 reactive astrocytes (A1s) were induced by neuroinflammatory microglia activated by PM with an aerodynamic diameter ≤ 0.2 µm (PM0.2). The activated-microglia induced A1s by secreting interleukin-1α, tumor necrosis factor-α, and complement 1q, and these cytokines acting together were necessary and sufficient to induce A1s. PM0.2-induced A1s could promote synaptic damage in neurons by secreting complement 3 (C3). SB 290157, a highly selective C3aR nonpeptide antagonist, partially ameliorated glial conditioned medium-induced synaptic injury. In vitro synaptic damage was partially prevented when A1 formation was blocked by minocycline. Finally, this study showed that N-acetyl-L-cysteine ameliorated PM0.2-induced neural damage independent of A1 differentiation. Collectively, these findings explain why central nervous system neurons suffer synaptic damage and neuroinflammation after PM0.2 exposure and suggest that this exposure induces A1s to contribute to synaptic damage of neurons. This study indicates a potential approach for developing improved treatment of these diseases induced by particulate exposure. SYNOPSIS: PM0.2-activated neuroinflammatory microglia induced A1 reactive astrocytes (A1s) by secreting IL-1α, TNF-α, and C1q. PM0.2-induced A1s could promote synaptic damage of neuron by secreting complement 3.
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Enfermedad de Alzheimer , Material Particulado , Humanos , Material Particulado/toxicidad , Astrocitos , Complemento C3 , Sistema Nervioso Central/patología , Factor de Necrosis Tumoral alfaRESUMEN
Preeclampsia (PE) is the most common medical complication during pregnancy and the second leading cause of maternal death worldwide. However, a better predictive model of PE remains to be explored. A total of 15 severe preeclampsia (sPE) and 75 healthy control patients were included in this study. Patient data was obtained from September 2019 to September 2021. Nuchal translucency (NT) and crown-rump length (CRL) of the fetus were acquired by ultrasound. Maternal blood samples were collected at 11+0 to 13+6 weeks of gestation. Chemiluminescent immunoassays were used to detect serum testosterone (T) and estradiol (E2) levels. Time-resolved fluorescence analysis was used to examine the levels of serum pregnancy-associated plasma protein A (PAPPA) and ß-human chorionic gonadotrophin (ß-HCG) protein. The sPE group exhibited increased T levels, and decreased E2 levels and E2/T ratios from 11 to 14 weeks of gestation, compared with the control group. E2 and the E2/T ratio showed positive linear correlation with CRL in pregnant women. Body-mass-index (BMI), T, and E2 were determined to be the main factors that affected the occurrence of sPE at the 12-week gestation period time point. The receiver operating characteristic (ROC) curve revealed that the AUC of the E2/T ratio was .717. The imbalanced T and E2 levels in the patients had a specific intrinsic relevance with sPE, which suggests them as novel predictors of the sPE.
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Hipertensión , Preeclampsia , Embarazo , Humanos , Femenino , Primer Trimestre del Embarazo , Testosterona , Preeclampsia/diagnóstico , Estradiol , BiomarcadoresRESUMEN
The synanthropic pest and a model organism for entomological research, American cockroach, Periplaneta americana (Linnaeus), can survive in unfavorable environments for humans. To investigate the genetic mechanisms of success in environmental adaptation of P. americana, we de novo reassembled its whole genome based on next-generation sequencing and PacBio sequencing. The final genome reassembly consisted of approximately 3.34 Gb with scaffold N50 of 465.51 Kb. The completeness (95.4%) of the complete genome was evaluated with single-copy orthologous genes using BUSCO. We identified 18,618 protein-coding genes, 16,443 (88.32%) of which were well supported by public protein databases. We identified 482.04 Mb (approximately 14.45%) repeat elements, 1,385,093 perfect microsatellites simple sequence repeats in P. americana genome, which was higher than other four Blattaria insects. Comparative genomics analysis revealed obvious expansion in the gene families associated with chemoreception (olfactory receptors, gustatory receptors, ionotropic glutamate receptors, chemosensory protein, and sensory neuron membrane protein), which provided the necessary information for functional characterization of the chemosensory receptors of P. americana, with potential for new or refined applications of semiochemicals-based control of this pest insect. Similarly, gene families (cytochrome P450s, carboxyl/choline esterases, and UDP-glycosyl-transferases) encoding receptors for bitter or toxic substances and detoxification enzymes were obviously expanded in P. americana, enabling its ability to detect and detoxify many toxins. Enrichment analysis of positively selected genes in P. americana revealed items associated with metabolic process and catalytic activity, which possibly contributed to the pesticide resistance of P. americana. We also analyzed the homologs to antimicrobial peptide genes reported in the Drosophila genome, and identified two attacins and seven defensins in P. americana. Our data and findings will substantially facilitate molecular studies in P. americana, including elucidation of detoxification mechanisms of xenobiotic, as well as development of new pest management strategies for the control of pests like P. americana.
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Periplaneta , Receptores Odorantes , Animales , Alérgenos/metabolismo , Genoma , Secuenciación de Nucleótidos de Alto Rendimiento , Periplaneta/metabolismo , Receptores Odorantes/genética , Análisis de Secuencia de ADNRESUMEN
To explore the epigenetic mechanism of deoxyribonucleic acid (DNA) damage induced by vinyl chloride (VC), we studied the micronuclei of peripheral blood lymphocytes in 193 subjects (92 in a VC exposure group employed in a chlorine-alkali plant; 101 in a control group employed in a power plant) and selected three pairs from the subjects (exposed and control) for whole-genome bisulfite sequencing (WGBS). The results showed that the rate of micronucleus formation in the VC exposure group was higher than that of control group (6.05 ± 3.28 vs. 2.01 ± 1.79). A total of 9534 differentially methylated regions (DMRs) were identified by WGBS, of which 4816 were hypomethylated and 4718 were hypermethylated. The Kyoto encyclopedia of genes and genomes (KEGG) pathway and gene ontology (GO) analyses showed the top three KEGG pathways were cancer , neuroactive ligand-receptor interaction, and axon guidance, and the top three GO-BP pathways enriched were multicellular organismal process, developmental process, and anatomical structure development. In the most enriched DMR pathway (pathways in cancer), we found that BCL2, TJP2, TAOK1, PFKFB3, LIPI, and LIPH were hypermethylated, and the methylation levels of BNIP1 and GRPEL2 were decreased. The methylation of differentially methylated genes (DMGs) mentioned above were verified by methylation-specific PCR (MSP) and agarose gel electrophoresis (AGE) in 50 pairs of subjects, where the coincidence rate was 60-100%. In conclusion, the epigenetic perturbations of specific DMGs (BCL2, TJP2, TAOK1, PFKFB3, LIPI, LIPH, BNIP1, and GRPEL2) may be associated with DNA damage from vinyl chloride exposure.
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Neoplasias , Cloruro de Vinilo , ADN , Metilación de ADN , Humanos , Proteínas Proto-Oncogénicas c-bcl-2/genética , Cloruro de Vinilo/toxicidadRESUMEN
Preeclampsia (PE) is a common obstetric disease caused by placenta development abnormality, typically characterized as inadequate trophoblast invasion and spiral artery remodeling. In this study, we found that LMO2 level was decreased in both cytotrophoblast (CTB) and interstitial extravillous trophoblast (iEVT) in human PE placentas, and LMO2 selectively promoted cell migration in iEVT derived HTR-8/SVneo cells whereas increased proliferation in CTB derived JEG-3 cells. In mechanism, LMO2 interacted with NCKAP1, leading to destruction of WAVE regulatory complex and increased lamellipodia formation in HTR-8/SVneo cells, whereas interacted with ß-catenin and up-regulated a number of core Wnt/Hippo pathway target genes in JEG-3 cells. This study revealed the differentially functional patterns of LMO2 in different trophoblast subtypes, and suggested LMO2 as a novel target for PE prediction, prevention and treatment in clinical.
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Preeclampsia , Trofoblastos , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Línea Celular Tumoral , Movimiento Celular , Femenino , Humanos , Proteínas con Dominio LIM/genética , Proteínas con Dominio LIM/metabolismo , Placenta/metabolismo , Placentación , Preeclampsia/metabolismo , Embarazo , Proteínas Proto-Oncogénicas/metabolismo , Trofoblastos/metabolismoRESUMEN
Vinyl chloride (VC) is a common industrial organic chlorine and environmental pollutant. In recent years, the dietary structure of residents especially Chinese has gradually shifted to western dietary patterns. VC aggravates dietary fatty acid-induced hepatic steatosis, but its mechanism is still unclear. And if the risk factors for steatosis persist, more severe diseases such as fibrosis and cirrhosis will occur. Therefore, we studied the effects and mechanisms of VC (160 and 800 mg/m3 ) and its metabolite (chloroacetaldehyde, 2.25, 4.5, and 9 µM) on hepatic steatosis of high-fat diet (HFD)-fed mice and palmitic acid (PA, 100 µM) treated HepG2 cells. Liver and serum biochemical indicators and pathological staining of the liver showed that the hepatic steatosis of VC combined with HFD groups was more severe than that of single-exposure groups (HFD group, low-dose VC group, and high-dose VC group). Moreover, VC enhanced HFD-induced oxidative stress (OS) and endoplasmic reticulum stress (ERS) and further upregulated the expression of sterol regulatory element-binding protein 1 (SREBP-1) and FAS. Besides, antioxidants and ERS inhibitors reduced the steatosis of HepG2 cells induced by VC metabolites and PA. These results suggest that VC exposure can enhance the degree of hepatic steatosis in HFD-fed mice. VC combined with HFD led to OS and ERS and upregulated the expression of de novo lipogenesis-related proteins, which may be related to the occurrence of hepatic steatosis. And the increased expression of CYP2E1 induced by VC combined with HFD may be the cause of OS.
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Dieta Alta en Grasa/efectos adversos , Contaminantes Ambientales/toxicidad , Hígado Graso/patología , Cloruro de Vinilo/toxicidad , Animales , Hígado Graso/inducido químicamente , Hígado Graso/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Pruebas de Toxicidad SubcrónicaRESUMEN
Cancer-associated fibroblasts (CAFs) can promote the development and metastasis of prostate cancer partly by mediating tumor-associated inflammation. An increasing amount of studies have focused on the functional interactions between CAFs and immune cells in the tumor microenvironment (TME). We previously reported that G protein-coupled receptor 30 (GPR30) was highly expressed in prostate CAFs and plays a crucial role in prostate stromal cell activation. However, the effect and underlying mechanism of GPR30 expression in prostate CAFs affecting the interaction between CAFs and tumor-associated macrophages (TAMs) need further elucidation. Here, we found that, compared with CAF-shControl, CAF-shGPR30 inhibited macrophage migration through transwell migration assays, which should be attributed to the decreased expression of C-X-C motif chemokine ligand 12 (CXCL12). In addition, macrophages treated with a culture medium of CAF-shGPR30 exhibited attenuated M2 polarization with downregulated M2-like markers expression. Moreover, macrophages stimulated with a culture medium of CAF-shGPR30 were less efficient in promoting activation of fibroblast cells and invasion of PCa cells. Finally, cocultured CAF-shGPR30 and macrophages suppressed PCa cell invasion compared to cocultured CAF-shControl and macrophages by decreasing interleukin-6 (IL-6) secretion, and this effect could be abrogated with rescue expression of IL-6. Our results pinpoint the function of GPR30 in prostate CAFs on regulating the CAF-TAM interaction in the TME and provide new insights into PCa therapies via regulating TME.
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OBJECTIVE: Using network pharmacology research methods to explore the healing mechanism of American cockroach extract to accelerate wound healing after diabetic anal fistula surgery. METHOD: The main chemical constituents of extracts from Periplaneta americana were collected by literature retrieval. Chemical composition and targets related to diabetic anal fistula wound could be predicted based on PubChem, Swiss Target Prediction, OMIM, and GeneCards databases, and the putative targets of Periplaneta americana extraction (PAE) for diabetic anal fistula wound were obtained by Venn diagram. These common targets were predicted using the String database for protein-protein interaction (PPI) network and then screening key genes through Cytohubba. Meanwhile, the above targets were analyzed using the DAVID database for gene ontology (GO) enrichment analyses and the Kyoto Encyclopedia of Genes and Genomes (KEGG) path enrichment analyses. RESULTS: A total of 12 chemical components of PAE were obtained by literature retrieval, and 61 therapeutic targets that may accelerate the healing of diabetic anal fistula wounds were predicted by the database. According to PPI network analysis, PAE accelerates wound healing after diabetic anal fistula surgery which may be related to proteins such as AKT1, VEGFA, EGFR, CASP3, STAT3, MAPK1, TNF, JUN, ESR1, and MMP9. GO analysis results show that targets of PAE to promote wound healing were mainly involved in biological processes such as cell proliferation, macrophage differentiation, angiogenesis, and response to hypoxia. KEGG analysis showed that the target genes were mainly concentrated in the PI3K-Akt signaling pathway, HIF-1 signaling pathway, and estrogen signaling pathway. CONCLUSION: Periplaneta americana extract regulates multiple targets and multiple pathways to promote wound healing after diabetic anal fistula surgery. PI3K-Akt signaling pathway, HIF-1 signaling pathway, and sex hormone signaling pathway may be key pathways in the process of Periplaneta americana extract promoting wound healing.
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Treatment of patients with castration-resistant prostate cancer (CRPC) remains a major clinical challenge. We previously showed that estrogenic effects contribute to CRPC progression and are primarily caused by the increased endogenous estradiol produced via highly expressed aromatase. However, the mechanism of aromatase upregulation and its role in CRPC are poorly described. In this study, we report that HeyL is aberrantly upregulated in CRPC tissues, and its expression is positively correlated with aromatase levels. HeyL overexpression increased endogenous estradiol levels and estrogen receptor-α (ERα) transcriptional activity by upregulating CYP19A1 expression, which encodes aromatase, enhancing prostate cancer stem cell (PCSC) properties in PC3 cells. Mechanistically, HeyL bound to the CYP19A1 promoter and activated its transcription. HeyL overexpression significantly promoted bicalutamide resistance in LNCaP cells, which was reversed by the aromatase inhibitor letrozole. In PC3 cells, the HeyL-aromatase axis promoted the PCSC phenotype by upregulating autophagy-related genes, while the autophagy inhibitor chloroquine (CQ) suppressed the aromatase-induced PCSC phenotype. The activated HeyL-aromatase axis promoted PCSC autophagy via ERα-mediated estrogenic effects. Taken together, our results indicated that the HeyL-aromatase axis could increase endogenous estradiol levels and activate ERα to suppress PCSC apoptosis by promoting autophagy, which enhances the understanding of how endogenous estrogenic effects influence CRPC development.