ABSTRACT
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.
Subject(s)
Adrenal Cortex Neoplasms , Adrenal Hyperplasia, Congenital , Adrenocortical Adenoma , Steroid 21-Hydroxylase , Humans , Adrenal Hyperplasia, Congenital/genetics , Adrenal Hyperplasia, Congenital/diagnosis , Adrenal Hyperplasia, Congenital/complications , Female , Adolescent , Adrenal Cortex Neoplasms/genetics , Adrenal Cortex Neoplasms/diagnosis , Adrenocortical Adenoma/genetics , Adrenocortical Adenoma/diagnosis , Adrenocortical Adenoma/complications , Steroid 21-Hydroxylase/genetics , Steroid 21-Hydroxylase/metabolismABSTRACT
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.
Subject(s)
Autoimmune Diseases/metabolism , Cystitis, Interstitial/metabolism , Nociceptive Pain/metabolism , Pain Threshold , Toll-Like Receptor 4/metabolism , Urinary Bladder/metabolism , Analgesics/pharmacology , Animals , Autoimmune Diseases/genetics , Autoimmune Diseases/immunology , Autoimmune Diseases/physiopathology , Cells, Cultured , Cystitis, Interstitial/genetics , Cystitis, Interstitial/immunology , Cystitis, Interstitial/physiopathology , Cytokines/genetics , Cytokines/metabolism , Disease Models, Animal , Inflammation Mediators/metabolism , Mice, Inbred C57BL , Mice, Knockout , Nociceptive Pain/genetics , Nociceptive Pain/immunology , Nociceptive Pain/physiopathology , Ovalbumin/genetics , Ovalbumin/immunology , Ovalbumin/metabolism , Pain Threshold/drug effects , Signal Transduction , Spine/immunology , Spine/metabolism , Spleen/immunology , Spleen/metabolism , Sulfonamides/pharmacology , Toll-Like Receptor 4/antagonists & inhibitors , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/immunology , Urinary Bladder/drug effects , Urinary Bladder/immunology , Urinary Bladder/physiopathology , UrodynamicsABSTRACT
BACKGROUND/AIMS: CD24 is a highly glycosylated mucin-like antigen on the cell surface, which has recently emerged as a novel oncogene and metastasis promoter. We performed bioinformatics analysis to investigate whether CD24 can serve as a prognostic indicator in breast cancer. METHODS: CD24 expression was assessed using SAGE Genie tools and Oncomine analysis. The PrognoScan database, Kaplan-Meier Plotter, and bc-GenExMiner were used to identify the prognostic roles of CD24 in breast cancer. RESULTS: We found that CD24 was more frequently overexpressed in breast cancer than in normal breast tissue and correlated with worse prognosis. Meanwhile, high CD24 expression was associated with increased risk of HER2, basal-like, triple-negative breast cancer, and higher Scarff-Bloom-Richardson grade. Data mining in multiple big databases confirmed a positive correlation between CD24 mRNA expression and SDC1 mRNA expression in breast cancer tissue. CONCLUSIONS: Our findings suggest that CD24 overexpression is more common in breast cancer than in corresponding normal tissue. In addition, CD24 and SDC1 can serve as prognostic indicators for breast cancer. However, large-scale and comprehensive research is needed to further confirm these results.
Subject(s)
Biomarkers, Tumor/metabolism , Breast Neoplasms/diagnosis , CD24 Antigen/metabolism , Biomarkers, Tumor/genetics , Breast/metabolism , Breast/pathology , Breast Neoplasms/metabolism , Breast Neoplasms/mortality , CD24 Antigen/genetics , Databases, Factual , Disease-Free Survival , Female , Humans , Kaplan-Meier Estimate , Middle Aged , Prognosis , Proportional Hazards Models , RNA, Messenger/metabolism , Risk Factors , Syndecan-1/genetics , Syndecan-1/metabolism , Triple Negative Breast Neoplasms/diagnosis , Triple Negative Breast Neoplasms/metabolismABSTRACT
BACKGROUND/AIMS: Maternally expressed gene 3 (MEG3) is an imprinted gene with maternal expression, which may function as a tumor suppressor by inhibiting angiogenesis. To identify the prognostic value of MEG3 in breast cancer, systematic analysis was performed in this study. METHODS: To evaluate gene alteration during breast carcinogenesis, we explored MEG3 expression using the Serial Analysis of Gene Expression Genie suite and Oncomine analysis. The prognostic roles of MEG3 in breast cancer were investigated using the PrognoScan database. The heat map and methylation status of MEG3 were determined using the UCSC Genome Browser. RESULTS: We found that MEG3 was more frequently downregulated in breast cancer than in normal tissues and this correlated with prognosis. However, estrogen receptor and progesterone receptor status were found to be positively correlated with MEG3 expression. Conversely, basal-like status, triple-negative breast cancer status, and Scarff Bloom & Richardson grade criterion were negatively correlated with MEG3 expression. Following data mining in multiple big data databases, we confirmed a positive correlation between MEG3 and heparan sulfate proteoglycan 2 (HSPG2) expression in breast cancer tissues. CONCLUSION: MEG3 could be adopted as a marker to predict the prognosis of breast cancer with HSPG2. However, large-scale and comprehensive research is needed to clarify our results.
Subject(s)
Biomarkers, Tumor/metabolism , Breast Neoplasms/pathology , Computational Biology/methods , RNA, Long Noncoding/metabolism , Adult , Biomarkers, Tumor/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/mortality , DNA Methylation , Databases, Factual , Female , Gene Expression Regulation, Neoplastic , Heparan Sulfate Proteoglycans/genetics , Heparan Sulfate Proteoglycans/metabolism , Humans , Middle Aged , Prognosis , RNA, Long Noncoding/genetics , RNA, Messenger/metabolism , Survival Analysis , Triple Negative Breast Neoplasms/diagnosis , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/pathologyABSTRACT
BACKGROUND: Statins can reduce reproductive damage induced by obesity or high-fat diet (HFD), but the specific regulatory mechanisms are largely unknown. Since mTOR/p70s6k sinaling promotes spermatogonia proliferation and spermatogenesis, we hypothesized that this pathway will be involved in the protective effects of statin in HFD-induced reproductive dysfunction. METHODS: Male Sprague Dawley rats (3 weeks old) were randomly divided into a control group (standard diet), HFD group, and a fluvastatin group (HFD + fluvastatin at 6mg/kg, once daily by oral gavage). After 8 weeks, body weight was obtain and rats were sacrificed. Weights of the testes, gross morphology, sperm parameters, circulating levels of sex hormones, lipid levels, and tissue mTOR, p-P70s6k were measured. Another set of male rats were treated with rapamycin or vehicle. Flow cytometry was used to detect the spermatogonia marker c-kit and cell cycle. p-P70s6k expression was analyzed by Western blot. RESULTS: HFD not only results in rat obesity but also leads to spermatogenetic damage and fluvastatin was able to partially block the effects of HFD. Fluvastatin also partially reversed the suppression of mTOR and p-p70s6k expresson. CONCLUSION: Our data suggest that fluvastatin has protective effects on reproductive function in obese male rats most probably through enhanced signaling of mTOR.
Subject(s)
Diet, High-Fat , Fatty Acids, Monounsaturated/pharmacology , Indoles/pharmacology , Protective Agents/pharmacology , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/metabolism , Animals , Body Weight/drug effects , Cells, Cultured , Estradiol/analysis , Fluvastatin , Lipids/blood , Luteinizing Hormone/analysis , Male , Obesity/metabolism , Obesity/pathology , Obesity/veterinary , Proto-Oncogene Proteins c-kit/metabolism , Rats , Rats, Sprague-Dawley , Ribosomal Protein S6 Kinases, 70-kDa/genetics , Ribosomal Protein S6 Kinases, 70-kDa/metabolism , Spermatogenesis/drug effects , Spermatogonia/cytology , Spermatogonia/drug effects , Spermatogonia/metabolism , TOR Serine-Threonine Kinases/genetics , Testis/metabolism , Testis/pathology , Testosterone/analysisABSTRACT
Mesenchymal stem cells (MSCs) have the potential to be the source for cell-based therapies. However, MSCs can undergo malignant transformation in a tumor microenvironment where a high level of interleukin (IL)-6 is present. In this study, we investigated the role of IL-6 and signal transducer and activator of transcription 3 (STAT3) signaling in malignant transformation of MSCs. Rat MSCs were isolated and indirectly cocultured with C6 glioma cells. Coculture of MSCs with astrocytes was used as a control. After 7 days of culture, the cells were assessed for malignant transformation using MTT assay and immunofluorescence staining. The levels of hepatocyte growth factor, IL-6, and basic fibroblast growth factor, and the expression of STAT3 and soluble IL-6 receptor in the cultured cells and conditioned media were measured using RT-PCR, ELISA, and Western blot analysis. The expression levels of STAT3 downstream targets, CyclinD1 and Bcl-xl, were determined as well. Our data showed that almost all of the MSCs became phenotypically malignant after indirect coculture with glioma cells, which was confirmed by tumor formation assays when these cells were injected into nude mice. The expression of IL-6 was significantly increased in MSCs cocultured with glioma cells, which was associated with significantly increased expressions of soluble IL-6 receptor, transmembrane glycoprotein GP130, STAT3, phosphorylated STAT3, CyclinD1, and Bcl-xl. Similar results were obtained when the MSCs were treated with IL-6. Treatment of the cocultured MSCs and glioma cells with STA-21, to block the constitutive STAT3 signaling, reduced the risk of MSC tumor-like transformation in the tumor microenvironment. These data suggest that IL-6 plays a critical role in malignant transformation of rat MSCs, which is associated with an enhancement of the STAT3 signaling pathway in the tumor microenvironment.
Subject(s)
Cell Transformation, Neoplastic/metabolism , Interleukin-6/metabolism , Mesenchymal Stem Cells/metabolism , Mesenchymal Stem Cells/pathology , STAT3 Transcription Factor/metabolism , Animals , Astrocytes/cytology , Cell Line, Tumor , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/pathology , Coculture Techniques , Culture Media, Conditioned , Fibroblast Growth Factors , Glioma/genetics , Glioma/metabolism , Glioma/pathology , Interleukin-6/genetics , Janus Kinases/metabolism , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Rats , Rats, Wistar , STAT3 Transcription Factor/genetics , Signal Transduction , Tumor MicroenvironmentABSTRACT
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.
Subject(s)
Infertility, Female , Primary Ovarian Insufficiency , Stem Cells , Humans , Female , Primary Ovarian Insufficiency/therapy , Infertility, Female/therapy , Ovary , Aging , Stem Cell Transplantation/methods , AnimalsABSTRACT
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.
Subject(s)
Cystitis, Interstitial , Cystitis , Exosomes , Mesenchymal Stem Cells , MicroRNAs , Animals , Mice , Cystitis, Interstitial/therapy , Toll-Like Receptor 4/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NF-kappa B , Urinary Bladder , MicroRNAs/genetics , PainABSTRACT
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.
Subject(s)
Myasthenic Syndromes, Congenital , Child , Female , Pregnancy , Humans , Myasthenic Syndromes, Congenital/diagnosis , Myasthenic Syndromes, Congenital/genetics , Genetic Testing , PhenotypeABSTRACT
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.
ABSTRACT
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.
Subject(s)
Infertility , Pregnancy Outcome , Pregnancy , Adult , Female , Humans , Retrospective Studies , Bayes Theorem , Fertilization in Vitro/methods , Infertility/therapy , Machine LearningABSTRACT
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.
Subject(s)
Anti-Glomerular Basement Membrane Disease , Glomerulonephritis , Posterior Leukoencephalopathy Syndrome , Humans , Female , Adult , Anti-Glomerular Basement Membrane Disease/complications , Anti-Glomerular Basement Membrane Disease/diagnosis , Anti-Glomerular Basement Membrane Disease/therapy , Posterior Leukoencephalopathy Syndrome/complications , Posterior Leukoencephalopathy Syndrome/diagnosis , Glomerulonephritis/complications , Glomerulonephritis/diagnosis , Glomerulonephritis/therapy , Seizures/complicationsABSTRACT
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.
Subject(s)
Abortion, Spontaneous , NF-kappa B , Humans , Female , Mice , Pregnancy , Animals , NF-kappa B/metabolism , Lipopolysaccharides/toxicity , Placenta , Inflammation/metabolism , I-kappa B Kinase/metabolism , ApoptosisABSTRACT
Mesenchymal stem cells (MSCs) have potential applications in regenerative medicine and tissue engineering as well as being potential carriers for tumour therapy. However, the safety of using MSCs in tumours is unknown. Herein, we analyse malignant transformation of MSCs in the tumour microenvironment. Rat bone marrow MSCs were cultured with malignant rat glioma C6 cells without direct cell-cell contact. After 7 days, the cells were assessed for transformation using flow cytometry, real-time quantitative PCR, immunofluorescence and chromosomal analysis. In addition, wild-type (WT) p53, mutant p53 and mdm2 was determined using Western blotting. Almost all MSCs became phenotypically malignant cells, with significantly decreased WT p53 expression and increased expression of mutant p53 and mdm2, along with an aneuploid karyotype. To evaluate tumorigenesis in vivo, the MSCs indirect co-cultured with C6 cells for 7 days were transplanted subcutaneously into immuno-deficient mice. The cells developed into a large tumour at the injection site within 8 weeks, with systemic symptoms including cachexia and scoliosis. Pathological and cytological analysis revealed poorly differentiated pleomorphic cells with a dense vascular network and aggressive invasion into the adjacent muscle. These data demonstrate that MSCs became malignant cancer cells when exposed to the tumour microenvironment and suggest that factors released from the cancer cells have a critical role in the malignant transformation of MSCs.
Subject(s)
Bone Marrow Cells/metabolism , Cell Transformation, Neoplastic/metabolism , Mesenchymal Stem Cells/metabolism , Tumor Microenvironment , Animals , Antigens, CD/metabolism , Blotting, Western , Cell Line, Tumor , Cells, Cultured , Coculture Techniques , Endoglin , Flow Cytometry , Intracellular Signaling Peptides and Proteins/metabolism , Karyotype , Mesenchymal Stem Cell Transplantation , Mice , Microscopy, Fluorescence , Mutation , Neoplasm Invasiveness , Neoplasms, Experimental/genetics , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Proto-Oncogene Proteins c-mdm2/genetics , Proto-Oncogene Proteins c-mdm2/metabolism , Rats , Receptors, Transferrin/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Transplantation, Heterologous , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolismABSTRACT
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.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Aminohydrolases/genetics , Aminohydrolases/metabolism , Methylenetetrahydrofolate Dehydrogenase (NADP)/genetics , Methylenetetrahydrofolate Dehydrogenase (NADP)/metabolism , Multifunctional Enzymes/genetics , Multifunctional Enzymes/metabolism , Ovarian Neoplasms/genetics , Ovarian Neoplasms/metabolism , Adaptor Proteins, Signal Transducing/genetics , Adult , Aged , Cell Line, Tumor , Cell Movement , Cell Proliferation , Computational Biology , Databases, Genetic , Female , Gene Expression , Gene Knockdown Techniques , Humans , Lymphocytes, Tumor-Infiltrating/pathology , Middle Aged , Mutation, Missense , Neoplasm Invasiveness , Ovarian Neoplasms/pathology , Prognosis , Signal Transduction , Survival Rate , Up-Regulation , Young AdultABSTRACT
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.
Subject(s)
Heart Defects, Congenital , Intellectual Disability , Preimplantation Diagnosis , Adult , Child , Developmental Disabilities/diagnosis , Developmental Disabilities/genetics , Female , Heart Defects, Congenital/genetics , Humans , Intellectual Disability/diagnosis , Intellectual Disability/genetics , Male , Phenotype , PregnancyABSTRACT
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.
Subject(s)
Homer Scaffolding Proteins/metabolism , Ischemic Preconditioning, Myocardial , Liraglutide/pharmacology , Myocardial Reperfusion Injury/prevention & control , Calcium/metabolism , Cells, Cultured , Homeostasis , Homer Scaffolding Proteins/genetics , Humans , Myocardial Infarction/prevention & control , Myocytes, Cardiac/drug effects , RNA, Messenger/metabolismABSTRACT
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.
Subject(s)
Kinesins/biosynthesis , Ovarian Neoplasms/metabolism , alpha Karyopherins/metabolism , Carcinogenesis , Female , Humans , Kinesins/genetics , Kinesins/metabolism , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Prognosis , Signal TransductionABSTRACT
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.
Subject(s)
Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Genetic Counseling , Male Urogenital Diseases/genetics , Mutation , Reproduction/genetics , Reproductive Techniques, Assisted , Vas Deferens/abnormalities , Azoospermia/genetics , Female , Humans , Infertility, Male/genetics , MaleABSTRACT
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.