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Myocardial ischemia-reperfusion injury (MIRI) most frequently happens in acute myocardial infarction (AMI) when rapid reperfusion is utilized to save the ischemia myocardium. MIRI is the main contributing of poor healing in AMI and is related to high mortality and disability rates around the worldwide. Currently, there is no effective precautionary measure for MIRI. Ferroptosis is a novel regulated cell death characterized by iron overload and reactive oxygen species (ROS) accumulation, which lead to death membrane lipid peroxidation. An increasing amount of studies indicates that ferroptosis plays a vital role in the occurrence and progression of MIRI. Given the crucial role of ferroptosis in MIRI, it is critical to understand the cardiomyocyte iron metabolism and investigate the molecular mechanisms of ferroptosis. In this review, we systematically summarize the molecular and metabolic pathways of ferroptosis in context of MIRI, which could provide novel understandings for the pathophysiological machine and new ideas for treatment.
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Premature ovarian insufficiency (POI) is defined as onset of menopause characterized by amenorrhea, hypergonadotropism, and hypoestrogenism, before the age of 40 years. The POI is increasing, which seriously affects the quality of patients' life. Due to its diversity of pathogenic factors, complex pathogenesis and limited treatment methods, the search for finding effective treatment of POI has become a hotspot. Stem cells are characterized by the ability of self-renewal and differentiation and play an important role in the regeneration of injured tissues, which is therapy is expected to be used in the treatment of POI. The aim of this review is to summarize the pathogenic mechanisms and the research progress of POI treatment with stem cells from different sources.
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Infertilidad Femenina , Insuficiencia Ovárica Primaria , Células Madre , Humanos , Femenino , Insuficiencia Ovárica Primaria/terapia , Infertilidad Femenina/terapia , Ovario , Envejecimiento , Trasplante de Células Madre/métodos , AnimalesRESUMEN
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders related to adrenal steroid biosynthesis, and mainly caused by mutations in the CYP21A2 gene encoding 21-hydroxylase. Adrenal tumors are common in CAH, but functional adrenal tumors are rare. Here, we report a 17-year-old female with virilized external genitalia and primary amenorrhea, accompanied by a right adrenal tumor. Her 17-OHP level was normal, cortisol and androgen levels were significantly elevated, and the tumor pathology showed adrenal cortical adenoma. Gene testing for CYP21A2 showed c.518T > A in exon 4 and c.29313C > G in intron 2. The possibility of untreated classic CAH with 21-OH deficiency causing functional adrenal cortical adenoma should be considered. When clinical diagnosis highly considers CAH and cannot rule out the influence of functional adrenal tumors' secretion function on 17-OHP, gene mutation analysis should be performed.
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Neoplasias de la Corteza Suprarrenal , Hiperplasia Suprarrenal Congénita , Adenoma Corticosuprarrenal , Esteroide 21-Hidroxilasa , Humanos , Hiperplasia Suprarrenal Congénita/genética , Hiperplasia Suprarrenal Congénita/diagnóstico , Hiperplasia Suprarrenal Congénita/complicaciones , Femenino , Adolescente , Neoplasias de la Corteza Suprarrenal/genética , Neoplasias de la Corteza Suprarrenal/diagnóstico , Adenoma Corticosuprarrenal/genética , Adenoma Corticosuprarrenal/diagnóstico , Adenoma Corticosuprarrenal/complicaciones , Esteroide 21-Hidroxilasa/genética , Esteroide 21-Hidroxilasa/metabolismoRESUMEN
BACKGROUND: Congenital myasthenic syndrome is a heterogeneous group of inherited neuromuscular transmission disorders. Variants in RAPSN are a common cause of CMS, accounting for approximately 14%-27% of all CMS cases. Whether preimplantation genetic testing for monogenic disease (PGT-M) could be used to prevent the potential birth of CMS-affected children is unclear. METHODS: Application of WES (whole-exome sequencing) for carrier testing and guidance for the PGT-M in the absence of a genetically characterized index patient as well as assisted reproductive technology were employed to prevent the occurrence of birth defects in subsequent pregnancy. The clinical phenotypes of stillborn fetuses were also assessed. RESULTS: The family carried two likely pathogenic variants in RAPSN(NM_005055.5): c.133G>A (p.V45M) and c.280G>A (p.E94K). And the potential birth of CMS-affected child was successfully prevented, allowing the family to have offspring devoid of disease-associated variants and exhibiting a normal phenotype. CONCLUSION: This report constitutes the first documented case of achieving a CMS-free offspring through PGT-M in a CMS-affected family. By broadening the known variant spectrum of RAPSN in the Chinese population, our findings underscore the feasibility and effectiveness of PGT-M for preventing CMS, offering valuable insights for similarly affected families.
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Síndromes Miasténicos Congénitos , Niño , Femenino , Embarazo , Humanos , Síndromes Miasténicos Congénitos/diagnóstico , Síndromes Miasténicos Congénitos/genética , Pruebas Genéticas , FenotipoRESUMEN
BACKGROUND: Inflammatory response of central nervous system is an important component mechanism in the bladder pain of interstitial cystitis/bladder pain syndrome (IC/BPS). Exosomes transfer with microRNAs (miRNA) from mesenchymal stem cell (MSCs) might inhibit inflammatory injury of the central nervous system. Herein, the purpose of our study was to explore the therapeutic effects by which extracellular vesicles ï¼EVsï¼ derived from miR-9-edreched MSCs in IC/BPS and further investigate the potential mechanism to attenuate neuroinflammation. METHODS: On the basis of IC/BPS model, we used various techniques including bioinformatics, cell and molecular biology, and experimental zoology, to elucidate the role and molecular mechanism of TLR4 in regulating the activation of NLRP3 inflammasome in bladder pain of IC/BPS, and investigate the mechanism and feasibility of MSC-EVs enriched with miR-9 in the treatment of bladder pain of IC/BPS. RESULTS: The inflammatory responses in systemic and central derived by TLR4 activation were closely related to the cystitis-induced pelvic/bladder nociception in IC/BPS model. Intrathecal injection of miR-9-enreched MSCs derived exosomes were effective in the treatment of cystitis-induced pelvic/bladder nociception by inhibiting TLR4/NF-κb/NLRP3 signal pathway in central nervous system of IC/BPS mice. CONCLUSIONS: This study demonstrated that miR-9-enreched MSCs derived exosomes alleviate neuroinflammaiton and cystitis-induced bladder pain by inhibiting TLR4/NF-κb/NLRP3 signal pathway in interstitial cystitis mice, which is a promising strategy against cystitis-induced bladder pain.
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Cistitis Intersticial , Cistitis , Exosomas , Células Madre Mesenquimatosas , MicroARNs , Animales , Ratones , Cistitis Intersticial/terapia , Receptor Toll-Like 4/genética , Proteína con Dominio Pirina 3 de la Familia NLR/genética , FN-kappa B , Vejiga Urinaria , MicroARNs/genética , DolorRESUMEN
Background: According to a recent report by the WHO, approximately 17.5\% (about one-sixth) of the global adult population is affected by infertility. Consequently, researchers worldwide have proposed various machine learning models to improve the prediction of clinical pregnancy outcomes during IVF cycles. The objective of this study is to develop a machine learning(ML) model that predicts the outcomes of pregnancies following in vitro fertilization (IVF) and assists in clinical treatment. Methods: This study conducted a retrospective analysis on provincial reproductive centers in China from March 2020 to March 2021, utilizing 13 selected features. The algorithms used included XGBoost, LightGBM, KNN, Naïve Bayes, Random Forest, and Decision Tree. The results were evaluated using performance metrics such as precision, recall, F1-score, accuracy and AUC, employing five-fold cross-validation repeated five times. Results: Among the models, LightGBM achieved the best performance, with an accuracy of 92.31%, recall of 87.80%, F1-score of 90.00\%, and an AUC of 90.41%. The model identified the estrogen concentration at the HCG injection(etwo), endometrium thickness (mm) on HCG day(EM TNK), years of infertility(Years), and body mass index(BMI) as the most important features. Conclusion: This study successfully demonstrates the LightGBM model has the best predictive effect on pregnancy outcomes during IVF cycles. Additionally, etwo was found to be the most significant predictor for successful IVF compared to other variables. This machine learning approach has the potential to assist fertility specialists in providing counseling and adjusting treatment strategies for patients.
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Infertilidad , Resultado del Embarazo , Embarazo , Adulto , Femenino , Humanos , Estudios Retrospectivos , Teorema de Bayes , Fertilización In Vitro/métodos , Infertilidad/terapia , Aprendizaje AutomáticoRESUMEN
BACKGROUND: Rapidly progressive glomerulonephritis (RPGN) is clinically manifestations as a rapidly progressive renal failure and pathologically as crescentic and necrotizing lesions with infiltration of inflammatory cells in the glomeruli. Uremic encephalopathy (UE) usually develops in patients who are suffering from acute or chronic renal failure. OBJECTIVE: The purpose of this article is to provide reference for clinical diagnosis and treatment of renal disease complicated with seizures. Patients Two cases of anti-glomerular basement membrane type rapidly progressive glomerulonephritis complicated with seizures were reported. MATERIALS & METHODS: In case 1, a 40-year-old woman was hospitalized for the treatment of nausea, anorexia, and fever. On admission, she presented with elevated serum inflammatory indicators, moderate anemia, and advanced acute kidney injury requiring hemodialysis. Her anti-glomerular basement membrane (GBM) antibody in serum and renal tissues was found to be extremely high. She was finally diagnosed with anti-GBM disease. She was treated with a combination of corticosteroid pulse therapy, oral cyclophosphamide and prednisolone, and plasma exchange, while continued to require maintenance hemodialysis for end-stage kidney disease. During treatment, she suddenly suffered blindness, seizure, and consciousness disturbance. She was diagnosed as posterior reversible leukoencephalopathy syndrome by magnetic resonance imaging (MRI). The posterior reversible leukoencephalopathy syndrome subsided quickly after control of her hypertension and reinforcement of immunosuppressive treatment. In case 2, the patient also developed epileptic symptoms on the basis of GBM disease, and was given treatment similar to that of Case 1, so that the epileptic symptoms were controlled. RESULT: Reversible posterior leukoencephalopathy syndrome, especially when accompanied by cerebral hemorrhage, may lead to irreversible and lethal neurological abnormalities, and nephrologists should, therefore, be aware of the potential risk of reversible posterior leukoencephalopathy syndrome in patients with anti-GBM disease. We can discuss the current two cases in the light of the previous literature.
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Enfermedad por Anticuerpos Antimembrana Basal Glomerular , Glomerulonefritis , Síndrome de Leucoencefalopatía Posterior , Humanos , Femenino , Adulto , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/complicaciones , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/diagnóstico , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/terapia , Síndrome de Leucoencefalopatía Posterior/complicaciones , Síndrome de Leucoencefalopatía Posterior/diagnóstico , Glomerulonefritis/complicaciones , Glomerulonefritis/diagnóstico , Glomerulonefritis/terapia , Convulsiones/complicacionesRESUMEN
Background: Unilateral twin ectopic pregnancy is extremely rare in natural pregnancy, with an incidence rate of only 1 in 200,000-2,500,000, represents a major health risk for reproductive-aged women, leading to even life-threatening complications. There is a lack of data on the prevalence of this rare disease after in-vitro fertilization-embryo transfer (IVF-ET) cycles. Case Report: We present a case of a 51-year-old woman with rare unilateral twin ectopic pregnancy after frozen embryo transfer treated with bilateral salpingectomy, followed by a review of the literature. Conclusion: Twin ectopic pregnancy is a very rare type of pregnancy that requires a high index of suspicion to diagnose and treat early to prevent complications and maternal death.
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INTRODUCTION: Approximately 50% of cases with recurrent spontaneous abortion (RSA) have unexplained etiology. Aberrant expression of transmembrane and ubiquitin-like domain containing 1 (TMUB1) is closely related to a series of diseases, including RSA. However, the function and underlying mechanism of TMUB1 in the occurrence of RSA has not been described. METHODS: TMUB1 expression was detected in the placental villous tissues of 30 women with normal miscarriages and 12 women with RSA. The pregnant mice were injected intraperitoneally with lipopolysaccharide (LPS) to induce abortion. Human chorionic trophoblast cells were treated with LPS. Pathological analysis of placental tissues was performed by hematoxylin and eosin staining. RESULTS: TMUB1 was highly expressed in the placental villous tissues of RSA patients compared to the patients who underwent induced abortions. After LPS administration, the mice exhibited high embryo absorption and pathological alterations, as well as presented an increase in inflammation and apoptosis (the etiology of RSA induction) in placental tissues. Moreover, the upregulated expression of TMUB1 was also found in placental tissues of LPS-induced mice, and further investigation showed that TMUB1 deficiency blocked embryo loss as well as inhibited apoptotic rate and inflammation after LPS activation. Furthermore, we found that the loss of TMUB1 suppressed the phosphorylation of IkappaB kinase (IKK) α/ß and attenuated cytoplasmic-nuclear translocation of nuclear factor-κB (NF-κB) p65 in LPS-induced cells. CONCLUSION: Our results indicate that TMUB1 may involve in the modulation of apoptosis and NF-κB pathway-mediated inflammation in RSA. Therefore, TMUB1 may develop as a potential biomarker for RSA treatment.
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Aborto Espontáneo , FN-kappa B , Humanos , Femenino , Ratones , Embarazo , Animales , FN-kappa B/metabolismo , Lipopolisacáridos/toxicidad , Placenta , Inflamación/metabolismo , Quinasa I-kappa B/metabolismo , ApoptosisRESUMEN
BACKGROUND: MTHFD2 is a folate-coupled metabolic enzyme, which has been proved to participant in the metabolic reprogramming and tumor cell-sustaining proliferative capacity. However, the function of MTHFD2 in the development of ovarian cancer and its potential molecular mechanisms is still unclear. MATERIALS AND METHODS: The expression, various mutations, prognosis, and related network signaling pathways of MTHFD2 were analyzed using bioinformatics-related websites, including Oncomine, GEPIA, UCSC, cBioPortal, KM Plotter, TISIDB and TIMER. The prognostic value of MTHFD2 expression was validated by our own ovarian cancer samples using RT-qPCR. The migration ad invasion of ovarian cancer cells were further analyzed by CCK-8 and transwell assay. The Western-blot assay was performed to explore the protein levels of MTHFD2 and MOB1A. RESULTS: We obtained the following important results. (1) MTHFD2 expression was markedly up-regulated in ovarian cancer than normal samples. (2) Among patients with ovarian cancer, those with higher MTHFD2 expression was associated with lower survival rate. (3) The major mutation type of MTHFD2 in ovarian cancer samples was missense mutation. (4) MTHFD2 knockdown inhibited proliferation, migration, invasion, as well as the expression of MOB1A in vitro. CONCLUSION: MTHFD2, as a NAD + -dependent enzyme, accelerated tumor progression by up-regulating MBO1A, suggesting that this protein may be an independent prognostic factor and a potential therapeutic target for future ovarian cancer treatments.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Aminohidrolasas/genética , Aminohidrolasas/metabolismo , Metilenotetrahidrofolato Deshidrogenasa (NADP)/genética , Metilenotetrahidrofolato Deshidrogenasa (NADP)/metabolismo , Enzimas Multifuncionales/genética , Enzimas Multifuncionales/metabolismo , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Adulto , Anciano , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Biología Computacional , Bases de Datos Genéticas , Femenino , Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Linfocitos Infiltrantes de Tumor/patología , Persona de Mediana Edad , Mutación Missense , Invasividad Neoplásica , Neoplasias Ováricas/patología , Pronóstico , Transducción de Señal , Tasa de Supervivencia , Regulación hacia Arriba , Adulto JovenRESUMEN
BACKGROUND: Cyclin-dependent kinase 13 plays a critical role in the regulation of gene transcription. Recent evidence suggests that heterozygous variants in CDK13 are associated with a syndromic form of mental deficiency and developmental delay, which is inherited in an autosomal dominant manner. METHODS: A mentally retarded mother (33-year-old) and son (10-year-old boy) in our hospital with CDK13 variant (c.2149 (exon 4) G>A. p.Gly717Arg) were detected by whole-exome sequencing (WES). All published CDK13 variant syndrome cases as of November 11, 2021, were searched, and their clinical information was recorded and summarized. RESULTS: We studied two patients in a Chinese family with a heterozygous constitutional CDK13 variant (c.2149 (exon 4) G>A. p.Gly717Arg), exhibiting the classical characteristics of dysmorphic facial features and intellectual developmental disorder (CHDFIDD, OMIM # 617360), without congenital heart defects. This is the first reported case of an adult patient with a CDK13 variant that gave birth to the next generation with the same variant. Preimplantation genetic testing for monogenic disease (PGT-M) was performed for the proband and her husband with full informed consent and successfully blocked the inheritance of the disease. CONCLUSION: Our study is of great significance for molecular diagnosis and genetic counseling of patients with CDHFIDD and extends the variant spectrum of CDK13.
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Cardiopatías Congénitas , Discapacidad Intelectual , Diagnóstico Preimplantación , Adulto , Niño , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/genética , Femenino , Cardiopatías Congénitas/genética , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Masculino , Fenotipo , EmbarazoRESUMEN
BACKGROUND: Karyopherin α-2 (KPNA2) is a member of karyopherin family, which is proved to be responsible for the import or export of cargo proteins. Studies have determined that KPNA2 is associated with the development and prognosis of various cancers, yet the role of KPNA2 in ovarian carcinoma and its potential molecular mechanisms remains unclear. MATERIALS AND METHODS: The expression and prognosis of KPNA2 in ovarian cancer was investigated using GEPIA and Oncomine analyses. Mutations of KPNA2 in ovarian cancer were analyzed by cBioPortal database. The prognostic value of KPNA2 expression was evaluated by our own ovarian carcinoma samples using RT-qPCR. Subsequently, the cell growth, migration and invasion of ovarian cancer cells were investigated by CCK-8 and transwell assay, respectively. The protein levels of KPNA2 and KIF4A were determined by western blot. RESULTS: We obtained the following important results. (1) KPNA2 and KIF4A wereoverexpressed in ovairan cancer tissues and cells. (2) Among patients with ovarian cancer, overexpressed KPNA2 was associated with lower survival rate. (3) Mutations (R197* and S140F) in KPNA2 will have some influences on protein structure, and then may cause protein function abnormal. (4) KPNA2 konckdown inhibited proliferation, migration, invasion, as well as the expression of KIF4A. CONCLUSION: KPNA2, as a tumorigenic gene in ovarian cancer, accelerated tumor progression by up-regulating KIF4A, suggesting that KPNA2 might be a hopeful indicator of treatment and poor prognosis.
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Cinesinas/biosíntesis , Neoplasias Ováricas/metabolismo , alfa Carioferinas/metabolismo , Carcinogénesis , Femenino , Humanos , Cinesinas/genética , Cinesinas/metabolismo , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Pronóstico , Transducción de SeñalRESUMEN
Myocardial infarction (MI) is one of most common cardiovascular diseases, and ischemia/reperfusion (I/R) injury is one of the risk factors for severe myocardial injury and dysfunction, even leading to high mortality of myocardial infarction. Liraglutide, a novel glucagon-like peptide 1 (GLP-1) analogue, has been reported to reduce cardiac rupture and infarct size and improve cardiac function in normal and diabetic rodents, however, the mechanisms of liraglutide on cardiomyocytes is not clear. The current research was designed to investigate the hypothesis that liraglutide would protect cardiomyocytes through regulating homer1 expression under hypoxia/reoxygenation (H/R) condition. The results of the present study indicated liraglutide reduced hypoxia-reoxygenation induced cell death and attenuated intracellular calcium overload in H9C2 cardiomyocytes under H/R condition. Moreover, liraglutide significantly increased the Homer1 protein expression, and this protection might be related to Homer1-dependent regulation of endoplasmic reticulum (ER) calcium homeostasis. Taken together, liraglutide protects H9C2 cell against H/R induced cell injury, and this protective effect may inhibit intracellular calcium overload to some extent, through Homer1-dependent regulation of ER calcium homeostasis.
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Proteínas de Andamiaje Homer/metabolismo , Precondicionamiento Isquémico Miocárdico , Liraglutida/farmacología , Daño por Reperfusión Miocárdica/prevención & control , Calcio/metabolismo , Células Cultivadas , Homeostasis , Proteínas de Andamiaje Homer/genética , Humanos , Infarto del Miocardio/prevención & control , Miocitos Cardíacos/efectos de los fármacos , ARN Mensajero/metabolismoRESUMEN
Polycystic ovary syndrome (PCOS) is one of the most common endocrine metabolic disorders characterized by hyperandrogenism, polycystic ovaries and ovulatory dysfunction. Several studies have suggested that the aberrant expression of microRNAs (miRNAs/miRs) plays an important role in the pathogenesis of PCOS; however, the role and underlying mechanisms of miR132 in the development of PCOS remain unclear. In the present study, the expression of miR132 in granulosa cells (GCs) derived from 26 patients with PCOS and 30 healthy controls was detected by reverse transcriptionquantitative PCR (RTqPCR). The apoptosis of GCs was examined using a TUNEL assay. The human ovarian granulosalike tumor cell line, KGN, was cultured for Cell Counting Kit8 assays following the overexpression or knockdown of miR132. TargetScan was applied to identify the potential targets of miR132, which was further verified by a luciferase assay, RTqPCR and western blotting. The expression of miR132 was decreased in GCs from patients with PCOS. Moreover, the GCs of patients with PCOS exhibited significantly increased apoptotic nuclei. Furthermore, the overexpression of miR132 inhibited the viability of KGN cells. In addition, the results verified that miR132 directly targeted forkhead box protein A1 (Foxa1), the knockdown of which suppressed KGN cell viability. On the whole, the findings of the present study demonstrated that miR132 inhibited cell viability and induced apoptosis by directly interacting with Foxa1. Thus, miR132 may be a potential target for the treatment of patients with PCOS.
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Células de la Granulosa/metabolismo , MicroARNs/genética , Síndrome del Ovario Poliquístico/genética , Regiones no Traducidas 3'/genética , Apoptosis/genética , Línea Celular Tumoral , Proliferación Celular/genética , Supervivencia Celular/genética , Femenino , Células de la Granulosa/fisiología , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Factor Nuclear 3-alfa del Hepatocito/fisiología , Humanos , MicroARNs/metabolismo , Activación Transcripcional/genéticaRESUMEN
Congenital bilateral absence of the vas deferens (CBAVD) is predominantly caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CBAVD accounts for 26% of male infertility cases and up to 25% of cases of obstructive azoospermia. With the use of preimplantation genetic diagnosis, testicular or epididymal sperm aspiration, intracytoplasmic sperm injection and in vitro fertilization, patients affected by CBAVD are able to have children who do not carry CFTR gene mutations, thereby preventing disease. Therefore, genetic counseling should be provided to couples receiving assisted reproductive techniques to discuss the impact of CFTR gene mutations on reproductive health. In the present article, the current literature concerning the CFTR gene and its association with CBAVD is reviewed.
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Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Asesoramiento Genético , Enfermedades Urogenitales Masculinas/genética , Mutación , Reproducción/genética , Técnicas Reproductivas Asistidas , Conducto Deferente/anomalías , Azoospermia/genética , Femenino , Humanos , Infertilidad Masculina/genética , MasculinoRESUMEN
BACKGROUND: Karyopherin alpha 2 (KPNA2) is a nuclear import factor that plays a crucial role in nucleocytoplasmic transport, as well as cell proliferation, migration, and invasion in several cancers. However, the roles of KPNA2 in breast cancer as well as the underlying molecular mechanisms have not been elucidated. MATERIALS AND METHODS: To evaluate gene expression alterations during breast carcinogenesis, KPNA2 expression was analyzed using the Gene Expression Profiling Interactive Analysis and Oncomine analyses. The correlation between methylation and expression was analyzed using the MEXPRESS tool, UALCAN cancer database, and cBioPortal browser. Then, the expression and prognostic value of KPNA2 were investigated by our own breast cancer samples using RT-PCR. KPNA2 methylation level was detected by methylation-specific PCR. RESULTS: We obtained the following important results. (1) KPNA2 expression was significantly higher in breast cancer than normal samples and regulated by aberrant DNA hypomethylation of promoter region. (2) Among patients with breast cancer, those with higher KPNA2 expression had a lower survival rate. (3) The major mutation type of KPNA2 in breast cancer samples was missense mutation. (4) Homer1 was able to promote breast cancer progression may be through upregulating TPX2 expression. CONCLUSION: Our findings suggest that aberrant DNA hypomethylation of promoter regions contributes to the aberrant expression of KPNA2 in breast cancer, which might be a potential indicator of poor prognosis.
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BACKGROUND: Homer scaffolding protein 1 (Homer1) is a postsynaptic scaffold protein that regulates the structure and function of excitatory synaptic as well as its intracellular signal transduction. However, the role of Homer1 in colorectal cancer as well as the underlying molecular mechanisms has not been elucidated. MATERIALS AND METHODS: To evaluate the alternations of gene expression during colorectal cancer, Homer1 expression was analyzed using the gene expression profiling interactive analysis and Oncomine analyses. The prognostic value of Homer1 expression was validated by our own colorectal cancer specimens using RT-PCR. Then, the cell viability, migration and invasion of colorectal cancer cell lines were detected by CCK-8 and transwell assay. RESULTS: We obtained the following important results. (1) Homer1 expression was significantly higher in colorectal cancer than normal samples. (2) Among patients with colorectal cancer, those with higher Homer1 expression had a lower survival rate. (3) The major mutation type of Homer1 in colorectal cancer samples was missense mutation. (4) Homer1 was able to promote colorectal cancer cell proliferation, migration, and invasion through up-regulating G3BP1 in vitro. CONCLUSION: Our findings suggest that Homer1 may play a role in malignancy of colorectal cancer mainly through the G3BP1 signaling pathway, which might be a potential indicator of poor prognosis.
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Forkhead box protein A1 (FOXA1) is a pioneer factor of estrogen receptor α (ER)-chromatin binding and function, yet the role of FOXA1 in breast cancer and the underlying molecular mechanisms have not yet been elucidated. To evaluate gene expression alterations during breast carcinogenesis, FOXA1 expression was analyzed using the Serial Analysis of Gene Expression Genie suite, a gene expression profiling interactive analysis, and Oncomine analyses. The correlation between methylation and expression was analyzed using the MEXPRESS tool and UCSC Xena browser. Then, the expression and prognostic value of FOXA1 was validated by our own breast cancer samples using RT-PCR. We obtained the following important results. (1) The expression level of FOXA1 was significantly higher in breast cancer than normal tissues. (2) ER, PR, HEGR-2, and nodal status were positively correlated with FOXA1 expression. (3) Among patients with ER+ tumors, those with higher FOXA1 expression levels had better survival probabilities. (4) The major mutation type in FOXA1 in breast cancer samples was missense mutations. (5) FOXA1 expression was significantly higher in ER+ breast tumors than in ER- tumors or normal tissues. Our findings suggest that the aberrant DNA hypomethylation of promoter regions is one mechanism underlying the aberrant expression of FOXA1 in ER+ breast cancer, which might be a potential indicator of favorable prognosis.
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Neoplasias de la Mama/metabolismo , Epigénesis Genética , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Regulación hacia Abajo , Femenino , Regulación Neoplásica de la Expresión Génica , Factor Nuclear 3-alfa del Hepatocito/genética , Humanos , Persona de Mediana Edad , Pronóstico , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptor ErbB-2/genética , Receptores de Estrógenos/genética , Receptores de Progesterona/genética , Transcriptoma , Regulación hacia ArribaRESUMEN
Altered Toll-like receptor (TLR)4 activation has been identified in several chronic pain conditions but has not been well studied in interstitial cystitis/bladder pain syndrome (IC/BPS). Our previously published human studies indicated that patients with IC/BPS present altered systemic TLR4-mediated inflammatory responses, which were significantly correlated with reported pain severity. In the present study, we sought to determine whether altered TLR4 activation plays a role in pelvic/bladder pain seen in patients with IC/BPS using our validated IC/BPS-like transgenic autoimmune cystitis model (URO-OVA). URO-OVA mice developed responses consistent with pelvic and bladder pain after cystitis induction, which was associated with increased splenocyte production of TLR4-mediated proinflammatory cytokines IL-1ß, IL-6, and TNF-α. Increased spinal expression of mRNAs for proinflammatory cytokines IL-6 and TNF-α, glial activation markers CD11b and glial fibrillary acidic protein, and endogenous TLR4 ligand high mobility group box 1 was also observed after cystitis induction. Compared with URO-OVA mice, TLR4-deficient URO-OVA mice developed significantly reduced nociceptive responses, although similar bladder inflammation and voiding dysfunction, after cystitis induction. Intravenous administration of TAK-242 (a TLR4-selective antagonist) significantly attenuated nociceptive responses in cystitis-induced URO-OVA mice, which was associated with reduced splenocyte production of TLR4-mediated IL-1ß, IL-6, and TNF-α as well as reduced spinal expression of mRNAs for IL-6, TNF-α, CD11b, glial fibrillary acidic protein, and high mobility group box 1. Our results indicate that altered TLR4 activation plays a critical role in bladder nociception independent of inflammation and voiding dysfunction in the URO-OVA model, providing a potential mechanistic insight and therapeutic target for IC/BPS pain.
Asunto(s)
Enfermedades Autoinmunes/metabolismo , Cistitis Intersticial/metabolismo , Dolor Nociceptivo/metabolismo , Umbral del Dolor , Receptor Toll-Like 4/metabolismo , Vejiga Urinaria/metabolismo , Analgésicos/farmacología , Animales , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/fisiopatología , Células Cultivadas , Cistitis Intersticial/genética , Cistitis Intersticial/inmunología , Cistitis Intersticial/fisiopatología , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Mediadores de Inflamación/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Dolor Nociceptivo/genética , Dolor Nociceptivo/inmunología , Dolor Nociceptivo/fisiopatología , Ovalbúmina/genética , Ovalbúmina/inmunología , Ovalbúmina/metabolismo , Umbral del Dolor/efectos de los fármacos , Transducción de Señal , Columna Vertebral/inmunología , Columna Vertebral/metabolismo , Bazo/inmunología , Bazo/metabolismo , Sulfonamidas/farmacología , Receptor Toll-Like 4/antagonistas & inhibidores , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/inmunología , Vejiga Urinaria/efectos de los fármacos , Vejiga Urinaria/inmunología , Vejiga Urinaria/fisiopatología , UrodinámicaRESUMEN
Mesenchymal stem cells (MSCs) hold great promise as potential therapies for tumors through the delivery of various anticancer agents. However, exogenous tissuederived MSCs, such as those of bone marrow, have exhibited a tendency for malignant transformation in the tumor microenvironment. This issue remains controversial and is poorly understood. In the present study, the role of interleukin 22 (IL22)/IL22 receptor subunit α 1 (IL22RA1) and signal transducer and activator of transcription 3 (STAT3) signaling in the malignant transformation of MSCs was investigated. Following isolation of rat MSCs and their indirect coculture with C6 glioma cells, the transformed MSCs exhibited tumor cell characteristics. The Cancer Genome AtlasGlioblastoma Multiforme analysis revealed that primary and recurrent glioblastomas have increased IL22RA1 expression, compared with normal tissues, whereas the expression of IL22 was low in glioblastoma and normal tissues. mRNA and protein expression levels of IL22RA1 were significantly increased in the MSCs cocultured with C6 glioma cells. Furthermore, MSCs incubated with IL22 exhibited increased proliferation, migration and invasion. STAT3 demonstrated activation and nuclear translocation in the presence of IL22. Additionally, STAT3 small interfering RNA significantly inhibited the migration and invasion ability of MSCs, and the expression of the STAT3 downstream targets cyclin D1 and Bcell lymphomaextra large under IL22 stimulation, indicating that IL22 also promoted MSC migration and invasion through STAT3 signaling. These data indicated that IL22 serves a critical role in the malignant transformation of rat MSCs, which is associated with an enhancement of the IL22RA1/STAT3 signaling pathway in the tumor microenvironment.