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Background: We describe a rare case of giant adrenal calcification as the main cause of sudden onset epigastric pain in a 57-year-old female patient. Case description: Computed tomography (CT) of the whole abdomen in this patient showed calcified foci measuring approximately 7.8 × 5.4 × 7.1 cm in the hepatorenal recess, and no enhancement effect was seen. Secondary causes of adrenal calcification in this patient were ruled out, and a rare diagnosis of a primary giant adrenal calcification was made. Subsequently, the right adrenal gland and calcified mass were completely resected. The calcification did not recur during 6 months of follow up. Conclusions: Although other cases of adrenal calcification of unknown origin have been reported, cases of giant idiopathic adrenal calcification are rare. In this case, huge calcification of the right adrenal gland caused abdominal pain, which disappeared after the mass was excised. The etiology, pathogenesis, clinical symptoms, and prognosis of idiopathic adrenal calcification are still unclear. Additional case reports are needed to gain a better understanding of the diagnosis and treatment of this condition.
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Single-cell sequencing is an emerging technology that can effectively identify cell types in tumors. In the tumor microenvironment of bladder cancer, macrophages play a crucial role in invasion and immune escape. This study aimed to assess the expression of macrophage-related genes (MRGs) in the tumor microenvironment of bladder cancer patients and construct a prognostic model based on MRGs using bioinformatics methods. METHODS: Single-cell sequencing data from bladder cancer patients was downloaded from the GEO. After quality control and cell type identification, macrophages in the samples were extracted for re-clustering. Feature genes were then identified, and MRGs were assessed. Genetic data from TCGA database bladder cancer patients was also downloaded and organized. The intersection of MRGs and the TCGA gene set was determined. Clinical information was connected with this intersection, and the data was divided into training and validation sets. The training set was used for model construction and the validation set for model verification. A prognostic model based on MRGs was built using the LASSO algorithm and Cox regression. Patients were divided into high-risk and low-risk groups based on their prognostic features, and survival information in the training and validation sets was observed. The predictive ability of the model was assessed using a ROC curve, followed by a calibration plot to predict 1-, 3-, and 5-year survival rates. RESULTS: Four cell types were identified, and after extracting macrophages, three cell subgroups were clustered, resulting in 1,078 feature genes. The top 100 feature genes from each macrophage subgroup were extracted and intersected with TCGA expressed genes to construct the model. A risk prediction model composed of CD74, METRN, PTPRR, and CDC42EP5 was obtained. The survival and ROC curves showed that this model had good predictive ability. A calibration curve also demonstrated good prognostic ability for patients. CONCLUSION: This study, based on single-cell data, TCGA data, and clinical information, constructed an MRG-based prognostic model for bladder cancer using multi-omics methods. This model has good accuracy and reliability in predicting the survival and prognosis of patients with bladder cancer, providing a reference for understanding the interaction between MRGs and bladder cancer.
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Type 1 insulin-like growth factor receptor (IGF1R) plays an important role in cancer, however, posttranscriptional regulation such as N6-methyladenosine (m6A) of IGF1R remains unclear. Here, we reveal a role for a lncRNA Downregulated RNA in Cancer (DRAIC) suppress tumor growth and metastasis in clear cell Renal Carcinoma (ccRCC). Mechanistically, DRAIC physically interacts with heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) and enhances its protein stability by blocking E3 ligase F-box protein 11 (FBXO11)-mediated ubiquitination and proteasome-dependent degradation. Subsequently, hnRNPA2B1 destabilizes m6A modified-IGF1R, leading to inhibition of ccRCC progression. Moreover, four m6A modification sites are identified to be responsible for the mRNA degradation of IGF1R. Collectively, our findings reveal that DRAIC/hnRNPA2B1 axis regulates IGF1R mRNA stability in an m6A-dependent manner and highlights an important mechanism of IGF1R fate. These findings shed light on DRAIC/hnRNPA2B1/FBXO11/IGF1R axis as potential therapeutic targets in ccRCC and build a link of molecular fate between m6A-modified RNA and ubiquitin-modified protein.
Assuntos
Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B , Neoplasias Renais , Receptor IGF Tipo 1 , Humanos , Receptor IGF Tipo 1/metabolismo , Receptor IGF Tipo 1/genética , Camundongos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Neoplasias Renais/metabolismo , Animais , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/genética , Progressão da Doença , Estabilidade de RNA/genética , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Estabilidade Proteica , Adenosina/análogos & derivados , Adenosina/metabolismo , Ubiquitinação , Proliferação de Células/genética , Camundongos NusRESUMO
Hypoxia is a common hallmark of cancer and plays a crucial role in promoting epithelial-mesenchymal transition (EMT). Hormonally Upregulated Neu-associated Kinase (HUNK) regulates EMT through its kinase activity. However, whether hypoxia is involved in HUNK-mediated EMT is incompletely understood. This study unveils an association between HUNK kinase activity and hypoxia in colorectal cancer (CRC). Importantly, hypoxia does not alter the expression levels of HUNK, but directly affects the phosphorylation levels of downstream proteins with indication of HUNK activity. Functionally, the upregulation of migration, invasion, and expression of EMT markers in CRC cells under hypoxic conditions can be attributed, in part, to the downregulation of HUNK-mediated phosphorylation of downstream proteins. These findings highlight the intricate relationship between HUNK, hypoxia and the molecular mechanisms of cancer EMT. Understanding these mechanisms may provide valuable insights into therapeutic targets for inhibiting cancer metastasis.
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Neoplasias Colorretais , Neoplasias , Humanos , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Transição Epitelial-Mesenquimal , Hipóxia , Linhagem Celular Tumoral , Movimento Celular , Regulação Neoplásica da Expressão Gênica , Neoplasias Colorretais/patologiaRESUMO
BACKGROUND: The transcription factor YY1 is an important regulator for metabolic homeostasis. Activating mutations in YY1 lead to tumorigenesis of pancreatic ß-cells, however, the physiological functions of YY1 in ß-cells are still unknown. Here, we investigated the effects of YY1 ablation on insulin secretion and glucose metabolism. METHODS: We established two models of ß-cell-specific YY1 knockout mice. The glucose metabolic phenotypes, ß-cell mass and ß-cell functions were analyzed in the mouse models. Transmission electron microscopy was used to detect the ultrastructure of ß-cells. The flow cytometry analysis, measurement of OCR and ROS were performed to investigate the mitochondrial function. Histological analysis, quantitative PCR and ChIP were performed to analyze the target genes of YY1 in ß-cells. RESULTS: Our results showed that loss of YY1 resulted in reduction of insulin production, ß-cell mass and glucose tolerance in mice. Ablation of YY1 led to defective ATP production and mitochondrial ROS accumulation in pancreatic ß-cells. The inactivation of YY1 impaired the activity of mitochondrial oxidative phosphorylation, induced mitochondrial dysfunction and diabetes in mouse models. CONCLUSION: Our findings demonstrate that the transcriptional activity of YY1 is essential for the maintenance of mitochondrial functions and insulin secretion in ß-cells.
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Diabetes Mellitus/metabolismo , Resistência à Insulina/genética , Secreção de Insulina/genética , Células Secretoras de Insulina/metabolismo , Mitocôndrias/metabolismo , Fator de Transcrição YY1/genética , Animais , Diabetes Mellitus/genética , Modelos Animais de Doenças , Glucose/metabolismo , Camundongos , Camundongos Knockout , Mitocôndrias/genética , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Prostate cancer (PCa) is the most common malignant tumor for men. But the mechanism is unclear. EIF3C was shown to be overexpressed in PCa tissues and cell lines. EIF3C overexpression was correlated to age and tumor stage in PCa patients and indicated poor survival. The proliferation, migration, and invasiveness of PC3 cells were all inhibited after EIF3C knockdown. Additionally, the phosphorylation level of PI3K and Akt was downregulated while total NF-κB and Myc decreased after EIF3C knockdown. But the expression of IκB increased reversely. Therefore, EIF3C at least partially regulates the activity of PI3K/Akt/NF-κB signaling pathway in PC3 cells.
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Carcinogênese/genética , Fator de Iniciação 3 em Eucariotos/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata/genética , Animais , Carcinogênese/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação para Baixo , Fator de Iniciação 3 em Eucariotos/genética , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/genética , Prognóstico , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proto-Oncogenes , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/genética , Taxa de Sobrevida , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Cholesterol increases the risk of aggressive prostate cancer and has emerged as a potential therapeutic target for prostate cancer. The functional roles of cholesterol in prostate cancer metastasis are not fully understood. Here, we found that cholesterol induces the epithelial-to-mesenchymal transition (EMT) through extracellular-regulated protein kinases 1/2 pathway activation, which is mediated by EGFR and adipocyte plasma membrane-associated protein (APMAP) accumulation in cholesterol-induced lipid rafts. Mechanistically, APMAP increases the interaction with EGFR substrate 15-related protein (EPS15R) to inhibit the endocytosis of EGFR by cholesterol, thus promoting cholesterol-induced EMT. Both the mRNA and protein levels of APMAP are upregulated in clinical prostate cancer samples. Together, these findings shed light onto an APMAP/EPS15R/EGFR axis that mediates cholesterol-induced EMT of prostate cancer cells. SIGNIFICANCE: This study delineates the molecular mechanisms by which cholesterol increases prostate cancer progression and demonstrates that the binding of cholesterol-induced APMAP with EPS15R inhibits EGFR internalization and activates ERK1/2 to promote EMT. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/12/3063/F1.large.jpg.
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Colesterol/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glicoproteínas de Membrana/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Proteólise/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Apoptose , Estudos de Casos e Controles , Proliferação de Células , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Masculino , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Prognóstico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
According to the X-ray crystal structures of CYP17A1 (including its complexes with inhibitors), it is shown that a hydrogen bond exists between CYP17A1 and its inhibitors (such as abiraterone and TOK-001). Previous short MD simulations (50 ns) suggested that the binding of abiraterone to CYP17A1 is stronger than that of TOK-001. In this work, by carrying out long atomistic MD simulations (200 ns) of CYP17A1 and its complexes with abiraterone and TOK-001, we observed a binding mode between CYP17A1 and abiraterone, which is different from the binding mode between CYP17A1 and TOK-001. In the case of abiraterone binding, the unfilled volume in the active site cavity increases the freedom of movement of abiraterone within CYP17A1, leading to the collective motions of the helices G and B' as well as the breaking of hydrogen bond existing between the 3ß-OH group of abiraterone and N202 of CYP17A1. However, the unfilled volume in the active site cavity can be occupied by the benzimidazole ring of TOK-001, restraining the motion of TOK-001. By pulling the two inhibitors (abiraterone and TOK-001) out of the binding pocket in CYP17A1, we discovered that abiraterone and TOK-001 were moved from their binding sites to the surface of protein similarly through the channels formed by the helices G and B'. In addition, based on the free energy calculations, one can see that it is energetically favorable for the two inhibitors (abiraterone and TOK-001) to enter into the binding pocket in CYP17A1.
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Androstadienos/química , Androstenos/química , Antineoplásicos/química , Benzimidazóis/química , Citocromo P-450 CYP1A1/antagonistas & inibidores , Citocromo P-450 CYP1A1/química , Neoplasias da Próstata/tratamento farmacológico , Androstadienos/farmacologia , Androstenos/farmacologia , Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Sítios de Ligação , Domínio Catalítico , Heme/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Ferro/química , Masculino , Simulação de Acoplamento Molecular , Conformação Proteica em alfa-HéliceRESUMO
BACKGROUND: Effective targeting therapies for common chronic liver disease nonalcoholic steatohepatitis (NASH) are in urgent need. MicroRNA-targeted therapeutics would be potentially an effective treatment strategy of hepatic diseases. Here we investigated the functional role of miR-221/222 and the therapeutic effects of antimiRs-221/222 in NASH mouse models. METHODS: We generated the miR-221/222flox/flox mice on a C57BL/6â¯J background and the hepatic miR-221/222 knockout (miR-221/222-LKO) mice. The mice were challenged with the methionine and choline deficient diet (MCDD) or chronic carbon tetrachloride (CCl4) treatment to generate experimental steatohepatitis models. Adenovirus-mediated re-expression of miR-221/222 was performed on the MCDD-fed miR-221/222-LKO mice. The MCDD and control diet-fed mice were treated with locked nucleic acid (LNA)-based antimiRs of miR-221/222 to evaluate the therapeutic effects. Histological analysis, RNA-seq, quantitative PCR and Western blot of liver tissues were carried out to study the hepatic lipid accumulation, inflammation and collagen deposition in mouse models. FINDINGS: Hepatic deletion of miR-221/222 resulted in significant reduction of liver fibrosis, lipid deposition and inflammatory infiltration in the MCDD-fed and CCl4-treated mouse models. The hepatic steatosis and fibrosis were dramatically aggravated by miR-221/222 re-expression in MCDD-fed miR-221/222-LKO mice. AntimiRs of miR-221/222 could effectively reduce the MCDD-mediated hepatic steatosis and fibrosis. Systematically mechanistic study revealed that hepatic miR-221/222 controlled the expression of target gene Timp3 and promoted the progression of NASH. INTERPRETATION: Our findings demonstrate that miR-221/222 are crucial for the regulation of lipid metabolism, inflammation and fibrosis in the liver. LNA-antimiRs targeted miR-221/222 could reduce steatohepatitis with prominent antifibrotic effect in NASH mice. FUND: This work is supported by the Natural Science Foundation of China (81530020, 81390352 to Dr. Ning and 81522032 to Dr. Cao and 81670793 to Dr. Jiang); National Key Research and Development Program (No. 2016YFC0905001 and 2017YFC0909703 to Dr. Cao); the Shanghai Rising-Star Program (15QA1402900 to Dr. Cao); Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant (20171905 to Dr. Jiang).
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Adenoviridae , Marcação de Genes , Vetores Genéticos , MicroRNAs , Hepatopatia Gordurosa não Alcoólica , Animais , Linhagem Celular , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Knockout , MicroRNAs/genética , MicroRNAs/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/terapiaRESUMO
Prostate cancer (PCa) is the most common malignancy and the leading cause of cancer deaths in males. Recent studies demonstrate that long non-coding RNAs (lncRNAs) are involved in many aspects of PCa. However, their biological roles in PCa remain imperfectly understood. Here,wecharacterized anlncRNA, PCaspecific expression and EZH2-associatedtranscript (PCSEAT, annotated as PRCAT38), which is specifically overexpressedin PCa. We further demonstrated that knockdown of PCSEAT results in the reduction of PCa cell growth and motility, and overexpression of PCSEAT reverses these phenotypes. Furthermore, bioactive PCSEAT is incorporated into exosomes and transmitted to adjacent cells, thus promoting cell proliferation and motility. Mechanistically, we found that PCSEAT promotes cell proliferation, at least in part by affecting miR-143-3p- and miR-24-2-5p-mediated regulation of EZH2, suggesting that PCSEAT and EZH2 competitively 'sponge' miR-143-3p and miR-24-2-5p.Overall, ourresultsrevealthat PCSEAT is specifically overexpressed in PCa patients and a potential oncogene in PCa cells via mediating EZH2 activity, indicating that PCSEAT may be a potential therapeutic target in PCa.
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Proteína Potenciadora do Homólogo 2 de Zeste/genética , Neoplasias da Próstata/genética , RNA Longo não Codificante/genética , Ligação Competitiva , Carcinogênese/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Técnicas de Silenciamento de Genes , Humanos , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Oncogenes , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Regulação para CimaRESUMO
Emerging evidence has indicated that transforming growth factor-beta 1 (TGF-ß1) induces the epithelial-mesenchymal transition (EMT) in cancer cells, thus promoting their motility and invasiveness. Quercetin, a member of the polyphenolic flavonoid family, has been reported to display anticancer activity against a broad range of cancer cell types. Indeed, numerous studies have shown the cancer preventive effects and molecular mechanisms of quercetin in vitro using diverse cell model systems. However, the potential effect of quercetin on EMT remains unclear. In this study, we identified a unique function of quercetin in inhibiting the EMT process induced by TGF-ß1. In particular, quercetin rescued the morphological changes and EMT-like phenotypes in TGF-ß1-activated SW480â¯cells, and this inhibition of TGF-ß1-induced EMT was mediated via the suppression of Twist1 expression. In addition, quercetin strongly suppressed TGF-ß1-induced invasion of SW480â¯cells. Thus, quercetin may be considered a novel therapeutic agent for the treatment of patients with refractory cancer and for the prevention of the metastatic cascade initiated by EMT.
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Caderinas/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Proteínas Nucleares/metabolismo , Quercetina/farmacologia , Fator de Crescimento Transformador beta1/efeitos adversos , Proteína 1 Relacionada a Twist/metabolismo , Antígenos CD , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Metástase Neoplásica , Proteínas Nucleares/genética , Regiões Promotoras Genéticas/genética , Proteína 1 Relacionada a Twist/genéticaRESUMO
BACKGROUND: MicroRNAs are often abnormally expressed in human non-small cell lung cancer (NSCLC) and are thought to play a critical role in the emergence or maintenance of NSCLC by binding to its target messenger RNA. We assessed the effects of miR-155 on cell proliferation and invasion to elucidate the role played by miR-155/PDCD4 in NSCLC. METHODS: Quantitative reverse transcription-PCR, Western blotting, and cell counting kit-8, luciferase, and transwell invasion assays were conducted on a normal human bronchial epithelial cell line (BEAS-2B) and three NSCLC cell lines (SPC-A-1, A549, and H2170). RESULTS: We confirmed that miR-155 was upregulated, while PDCD4 messenger RNA and protein levels were downregulated in NSCLC cell lines. miR-155 negatively regulated PDCD4 at both transcriptional and post-transcriptional levels. Moreover, PDCD4 was forecast as an assumed target of miR-155 using bioinformatic methods and we demonstrated that PDCD4 was a direct target of miR-155 using luciferase reporter assays. Furthermore, PDCD4 overexpression could restrain NSCLC proliferation and invasion induced by miR-155. CONCLUSION: Our results collectively demonstrate that miR-155 exerts an oncogenic role in NSCLC by directly targeting PDCD4.
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Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , MicroRNAs/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Regiões 3' não Traduzidas , Células A549 , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos , Invasividade Neoplásica , Transplante de Neoplasias , Regulação para CimaRESUMO
OBJECTIVE: Thymic neuroendocrine tumor is the second-most prevalent cause of ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS), which is a rare disease characterized by ectopic ACTH oversecretion from nonpituitary tumors. However, the genetic abnormalities of thymic neuroendocrine tumors with EAS remain largely unknown. We aim to elucidate the genetic abnormalities and identify the somatic mutations of potential tumor-related genes of thymic neuroendocrine tumors with EAS by whole exome sequencing. DESIGN AND METHODS: Nine patients with thymic neuroendocrine tumors with EAS who were diagnosed at Shanghai Clinical Center for Endocrine and Metabolic Diseases in Ruijin Hospital between 2002 and 2014 were enrolled. We performed whole exome sequencing on the DNA obtained from thymic neuroendocrine tumors and matched peripheral blood using the Hiseq2000 platform. RESULTS: We identified a total of 137 somatic mutations (median of 15.2 per tumor; range, 1-24) with 129 single-nucleotide mutations (SNVs). The predominant substitution in these mutations was C:G > T:A transition. Approximately 80% of detected mutations resulted in amino acid changes. However, we failed to discover any recurrent mutations in these nine patients. By functional predictions, HRAS, PAK1 and MEN1, previously reported in neuroendocrine tumors, were identified as candidate tumor-related genes associated with thymic neuroendocrine tumors. CONCLUSIONS: Using whole exome sequencing, we identified genetic abnormalities in thymic neuroendocrine tumors with EAS. Thereby, this study acts as a further supplement of the genetic features of neuroendocrine tumors. Somatic mutations of three potential tumor-related genes (HRAS, PAK1 and MEN1) might contribute to the tumorigenesis of thymic neuroendocrine tumors with EAS.
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Síndrome de ACTH Ectópico/genética , Exoma/genética , Tumores Neuroendócrinos/genética , Neoplasias do Timo/genética , Síndrome de ACTH Ectópico/sangue , Hormônio Adrenocorticotrópico/sangue , Adulto , Biologia Computacional , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/sangue , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias do Timo/sangue , Quinases Ativadas por p21/genéticaRESUMO
The mechanism underlying the increased susceptibility of type 2 diabetes in offspring of maternal malnutrition is poorly determined. Here we tested the hypothesis that functional microRNAs (miRNAs) mediated the maternal low-protein (LP) isocaloric diet induced pancreatic ß-cell impairment. We performed miRNA profiling in the islets from offspring of LP and control diet mothers to explore the potential functional miRNAs responsible for ß-cell dysfunction. We found that LP offspring exhibited impaired glucose tolerance due to decreased ß-cell mass and insulin secretion. Reduction in the ß-cell proliferation rate and cell size contributed to the decreased ß-cell mass. MiR-15b was up-regulated in the islets of LP offspring. The up-regulated miR-15b inhibited pancreatic ß-cell proliferation via targeting cyclin D1 and cyclin D2. Inhibition of miR-15b in LP islet cells restored ß-cell proliferation and insulin secretion. Our findings demonstrate that miR-15b is critical for the regulation of pancreatic ß-cells in offspring of maternal protein restriction, which may provide a further insight for ß-cell exhaustion originated from intrauterine growth restriction.
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Proliferação de Células/fisiologia , Dieta com Restrição de Proteínas , Células Secretoras de Insulina/metabolismo , Fenômenos Fisiológicos da Nutrição Materna/fisiologia , MicroRNAs/metabolismo , Pâncreas/metabolismo , Animais , Linhagem Celular Tumoral , Ciclina D1/metabolismo , Ciclina D2/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Teste de Tolerância a Glucose , Insulina/sangue , Células Secretoras de Insulina/citologia , Camundongos , MicroRNAs/genética , Pâncreas/citologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismoRESUMO
Germ cell apoptosis may be associated with the male infertility. The pathogenesis is to be further understood. Viral infection is one of the causative factors of apoptosis of the body cells. This study aims to investigate the role of activation of Toll like receptor (TLR)3 in the induction of germ cell apoptosis. In this study, spermatogonial stem cells (SSC) were isolated from C57BL/6 mouse testes. The expression of TLR3 on SSC was by RT-qPCR and Western blotting. polyinosinic-polycytidylic acid (Poly I:C) was employed to activate TLR3 on SSCs. The results showed that re-activation by PolyI:C induced SSC apoptosis. Exposure to PolyI:C induced interferon regulatory factor 3 (IRF3) phosphorylation in SSCs. TLR3 and IRF3 formed a complex in the SSCs. The complex of TLR3/IRF3 bound to the promoter of Fas ligand and promoted Fas ligand expression in SSC, and thus induced SSC apoptosis. In conclusion, the results of the present study indicate that activation of TLR3 by PolyI:C induces the SSC apoptosis, which implies that viral infection may interfere with the male germ cell development.
Assuntos
Células-Tronco Adultas/metabolismo , Apoptose/efeitos dos fármacos , Poli I-C/farmacologia , Receptor 3 Toll-Like/metabolismo , Células-Tronco Adultas/efeitos dos fármacos , Animais , Células Cultivadas , Proteína Ligante Fas/metabolismo , Fator Regulador 3 de Interferon/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Fosforilação , Testículo/citologiaRESUMO
VSIG4 has been recently described as a B7 family-related protein. The immunotherapeutic potential of dendritic cells (DCs) transfected with VSIG4 recombinant adenovirus has not been characterized. In the present study, DCs were transfected with human VSIG4 (hVSIG4) recombinant adenovirus, a novel costimulatory molecule known to be a potent inhibitor of T cell activation. Transfected DCs were cocultured with allogeneic T cells and proliferation, cytokine production and T cell activation marker expression were assessed. The results showed that T cell proliferation potential, cytokine production and activation marker expression were suppressed after coculture with hVSIG4 recombinant adenovirus-transfected DCs. These findings suggest that DCs transfected with hVSIG4 recombinant adenovirus are capable of inducing allogeneic T cell suppression, which represents an ideal strategy for manipulating the immune response to transplanation or autoimmune diseases.