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Brain-derived neurotrophic factor (BDNF) is a predominant neurotrophic factor in the brain, indispensable for neuronal growth, synaptic development, neuronal repair, and hippocampal neuroplasticity. Among its genetic variants, the BDNF Val66Met polymorphism is widespread in the population and has been associated with the onset and aggravation of diverse pathologies, including metabolic conditions like obesity and diabetes, cardiovascular ailments, cancer, and an array of psychiatric disorders. Psychiatric disorders constitute a broad category of mental health issues that influence mood, cognition, and behavior. Despite advances in research and treatment, challenges persist that hinder our understanding and effective intervention of these multifaceted conditions. Achieving and maintaining stable body weight is pivotal for overall health and well-being, and the relationship between psychiatric conditions and body weight is notably intricate and reciprocal. Both weight gain and loss have been linked to varying mental health challenges, making the disentanglement of this relationship critical for crafting holistic treatment strategies. The BDNF Val66Met polymorphism's connection to weight fluctuation in psychiatric patients has garnered attention. This review investigated the effects and underlying mechanisms by which the BDNF Val66Met polymorphism moderates body weight among individuals with psychiatric disorders. It posits the polymorphism as a potential biomarker, offering prospects for improved monitoring and therapeutic approaches for mental illnesses.
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Esophageal squamous cell carcinoma (ESCC) is a malignant epithelial tumor, characterized by squamous cell differentiation, it is the sixth leading cause of cancer-related deaths globally. The increased mortality rate of ESCC patients is predominantly due to the advanced stage of the disease when discovered, coupled with higher risk of metastasis, which is an exceedingly malignant characteristic of cancer, frequently leading to a high mortality rate. Unfortunately, there is currently no specific and effective marker to predict and treat metastasis in ESCC. MicroRNAs (miRNAs) are a class of small non-coding RNA molecules, approximately 22 nucleotides in length. miRNAs are vital in modulating gene expression and serve pivotal regulatory roles in the occurrence, progression, and prognosis of cancer. Here, we have examined the literature to highlight the intimate correlations between miRNAs and ESCC metastasis, and show that ESCC metastasis is predominantly regulated or regulated by genetic and epigenetic factors. This review proposes a potential role for miRNAs as diagnostic and therapeutic biomarkers for metastasis in ESCC metastasis, with the ultimate aim of reducing the mortality rate among patients with ESCC.
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Carcinoma , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , MicroARNs , Humanos , MicroARNs/genética , Carcinoma de Células Escamosas de Esófago/genética , Neoplasias Esofágicas/genética , EpigenómicaRESUMEN
Cisplatin (CDDP) is the first-line drug in the clinical treatment of esophageal squamous cell carcinoma (ESCC), which has severe nephrotoxicity. Diosmetin (DIOS) can protect kidney from oxidative damage, however, its function in ESCC is unknown. This study aims to explore the effect and mechanism of DIOS on ESCC and its combined effect with CDDP. Herein, we found that DIOS significantly inhibited the progression of ESCC in vitro and in vivo. Furthermore, the anti-tumor effect of DIOS was not statistically different from that of CDDP. Mechanically, transcriptomics revealed that DIOS inhibited the E2F2/RRM2 signaling pathway. The transcriptional regulation of RRM2 by E2F2 was verified by luciferase assay. Moreover, docking model, CETSA, pull-down assay and CDK2 inhibitor assay confirmed that DIOS directly targeted CDK2, leading to significant suppression of ESCC. Additionally, the patient-derived xenografts (PDX) model showed that the combination of DIOS and CDDP significantly inhibited the growth of ESCC. Importantly, the combined treatment with DIOS and CDDP significantly reduced the mRNA expression levels of kidney injury biomarkers KIM-1 and NGAL in renal tissue, as well as the levels of blood urea nitrogen, serum creatinine and blood uric acid compared to the single treatment with CDDP. In conclusion, DIOS could be an effective drug and a potential chemotherapeutic adjuvant for ESCC treatment. Furthermore, DIOS could reduce the nephrotoxicity of CDDP to some extent.
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Antineoplásicos , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Cisplatino/farmacología , Cisplatino/uso terapéutico , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/genética , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Línea Celular Tumoral , Quinasa 2 Dependiente de la Ciclina/genética , Factor de Transcripción E2F2RESUMEN
PURPOSE: Esophageal squamous carcinoma (ESCC) with a high incidence in China, lacks effective therapeutic targets. Phosphoglycerate dehydrogenase (PHGDH) is a key enzyme in serine biosynthesis. However, the biological role of PHGDH in ESCC has not been revealed. METHODS: The expression of PHGDH in ESCC was investigated by UALCAN. The relationship between PHGDH expression and its prognostic value was analyzed by Kaplan-Meier and univariate Cox regression. Further, the potential functions of PHGDH involved in ESCC were explored through DAVID database and GSEA software. In addition, the expression of PHGDH was verified in ESCC. Then, the effects of PHGDH knockdown on ESCC were evaluated in vitro and in vivo by cell proliferation, clone formation, cell cycle, apoptosis, tube formation assays and ESCC cells derived xenograft model. In addition, western blotting and immunohistochemistry were used to detect the expression of Wnt/ß-catenin pathway which was associated with PHGDH. RESULTS: Bioinformatics analysis found that PHGDH was highly expressed in ESCC, and meaningfully, patients with high PHGDH expression had a poor prognosis. Moreover, the overexpression of PHGDH was verified in ESCC. Afterwards, PHGDH knockdown inhibited the cell proliferation, induced cell cycle arrest and apoptosis in ESCC cells, and inhibited the angiogenesis of HUVECs induced by ESCC conditioned medium, as well as inhibited the growth of xenograft tumor. Mechanistically, PHGDH knockdown inhibited Wnt/ß-catenin signaling pathway in ESCC. CONCLUSION: High expression of PHGDH predicts a poor prognosis for ESCC. PHGDH knockdown inhibits ESCC progression by suppressing Wnt/ß-catenin signaling pathway, indicating that PHGDH might be a potential target for ESCC therapy.
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Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas/patología , Fosfoglicerato-Deshidrogenasa/genética , Fosfoglicerato-Deshidrogenasa/metabolismo , Neoplasias Esofágicas/metabolismo , Vía de Señalización Wnt , beta Catenina/metabolismo , Proliferación Celular , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Movimiento CelularRESUMEN
MicroRNA (miRNA), a noncoding singlestranded RNA molecule with a length of 2125 nucleotides transcripts, has been identified to play important roles in tumorigenesis and shows great potential applications in cancer diagnosis, prognosis and therapy. Brain derived neurotrophic factor (BDNF) is a member of the nerve growth factor family and usually serves as a biomarker in neurological and neuropsychiatric diseases for diagnosis and treatment by regulating its highaffinity receptor TrkB (Tyrosine Kinase Receptor B). Abnormal expression of BDNF is also closely related to the development of cancer, cancerrelated pain and depression. However, little significant progress has been made in the application of BDNF in cancers. Recent studies have shown that the expression of BDNF is directly regulated by a cluster of miRNAs. This review concluded and discussed the role and mechanism of miRNAs targeting BDNF in cancers, and provided novel insights into the diagnosis and therapy of cancer in the future.
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Factor Neurotrófico Derivado del Encéfalo , MicroARNs , Neoplasias , Humanos , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/terapia , Pronóstico , Receptor trkB/genética , Receptor trkB/metabolismoRESUMEN
Background: Perineural invasion (PNI) is a malignant metastatic mode of tumors and has been reported in many tumors including esophageal cancer (EC). However, the role of PNI in EC has been reported differently. This systematic review and meta-analysis aims to focus on the role of PNI in EC. Methods: Eight databases of CNKI, VIP, Wanfang, Scopus, Wiley, ISI, PubMed, and EBSCO are used for literature search. The association of PNI with gender, pathological stages of T and N (pT and pN), lymphovascular invasion (LVI), lymph node metastasis, 5-year overall survival (OS), and 5-year disease-free survival (DFS) was examined in the meta-analysis by Revman5.0 Software. The pooled OR/HR and 95% CI were used to assess the risk and prognostic value. Results: Sixty-nine published studies were screened for analysis of PNI in EC. The incidence of PNI in esophageal squamous carcinoma (ESCC) and esophageal adenocarcinoma (EAC) was different, but not statistically significant (p > 0.05). The PNI-positive patients had a significantly higher risk of pT stage (OR = 3.85, 95% CI = 2.45-6.05, p < 0.00001), pN stage (OR = 1.86, 95% CI = 1.52-2.28, p < 0.00001), LVI (OR = 2.44, 95% CI = 1.55-3.85, p = 0.0001), and lymph node metastasis (OR = 2.87, 95% CI = 1.56-5.29, p = 0.0007). Furthermore, the cumulative analysis revealed a significant correlation between PNI and poor OS (HR = 1.37, 95% CI = 1.24-1.51, p < 0.0001), as well as poor DFS (HR = 1.55, 95% CI = 1.38-1.74, p < 0.0001). Conclusion: PNI occurrence is significantly related to tumor stage, LVI, lymph node metastasis, OS, and DFS. These results indicate that PNI can serve as an indicator of high malignant degree and poor prognosis in EC.
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As a novel lactate-derived post-translational modification (PTM), lysine lactylation (Kla) is involved in diverse biological processes, and participates in human tumorigenesis. Identification of Kla substrates with their exact sites is crucial for revealing the molecular mechanisms of lactylation. In contrast with labor-intensive and time-consuming experimental approaches, computational prediction of Kla could provide convenience and increased speed, but is still lacking. In this work, although current identified Kla sites are limited, we constructed the first Kla benchmark dataset and developed a few-shot learning-based architecture approach to leverage the power of small datasets and reduce the impact of imbalance and overfitting. A maximum 11.7% (0.745 versus 0.667) increase of area under the curve (AUC) value was achieved in contrast to conventional machine learning methods. We conducted a comprehensive survey of the performance by combining 8 sequence-based features and 3 structure-based features and tailored a multi-feature hybrid system for synergistic combination. This system achieved >16.2% improvement of the AUC value (0.889 versus 0.765) compared with single feature-based models for the prediction of Kla sites in silico. Taken few-shot learning and hybrid system together, we present our newly designed predictor named FSL-Kla, which is not only a cutting-edge tool for Kla site profile but also could generate candidates for further experimental approaches. The webserver of FSL-Kla is freely accessible for academic research at http://kla.zbiolab.cn/.
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Dihydroartemisinin (DHA) is an active metabolite of artemisinin and its derivatives (ARTs), and it is an effective clinical drug widely used to treat malaria. Recently, the anticancer activity of DHA has attracted increasing attention. Nevertheless, there is no systematic summary on the anticancer effects of DHA. Notably, studies have shown that DHA exerts anticancer effects through various molecular mechanisms, such as inhibiting proliferation, inducing apoptosis, inhibiting tumor metastasis and angiogenesis, promoting immune function, inducing autophagy and endoplasmic reticulum (ER) stress. In this review, we comprehensively summarized the latest progress regarding the anticancer activities of DHA in cancer. Importantly, the underlying anticancer molecular mechanisms and pharmacological effects of DHA in vitro and in vivo are the focus of our attention. Interestingly, new methods to improve the solubility and bioavailability of DHA are discussed, which greatly enhance its anticancer efficacy. Remarkably, DHA has synergistic anti-tumor effects with a variety of clinical drugs, and preclinical and clinical studies provide stronger evidence of its anticancer potential. Moreover, this article also gives suggestions for further research on the anticancer effects of DHA. Thus, we hope to provide a strong theoretical support for DHA as an anticancer drug.
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Antineoplásicos Fitogénicos/farmacología , Artemisininas/farmacología , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos Fitogénicos/uso terapéutico , Artemisia , Artemisininas/uso terapéutico , Sistemas de Liberación de Medicamentos , Humanos , FitoterapiaRESUMEN
Excessive accumulation of reducing agents in the ER leads to a constitutively high UPR. And the co-function of GSH, Cys and HOCl in biological processes is not well understood. To address this, a TP probe, NPCC, was developed for monitoring reductive stress in the ER. It can also distinguish cancer cells from normal cells.
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Cumarinas/química , Estrés del Retículo Endoplásmico/fisiología , Retículo Endoplásmico/metabolismo , Colorantes Fluorescentes/química , Pirazoles/química , Animales , Cumarinas/síntesis química , Cisteína/química , Cisteína/metabolismo , Colorantes Fluorescentes/síntesis química , Glutatión/química , Glutatión/metabolismo , Cabras , Células HeLa , Humanos , Ácido Hipocloroso/química , Ácido Hipocloroso/metabolismo , Ratones , Microscopía Confocal/métodos , Microscopía Fluorescente/métodos , Oxidación-Reducción , Pirazoles/síntesis química , Pez CebraRESUMEN
Gold nanoclusters have become promising radiosensitizers due to their ultrasmall size and robust ability to adsorb, scatter, and re-emit radiation. However, most of the previously reported gold nanocluster radiosensitizers do not have a precise atomic structure, causing difficulties in understanding the structure-activity relationship. In this study, a structurally defined gold-levonorgestrel nanocluster consisting of Au8(C21H27O2)8 (Au8NC) with bright luminescence (58.7% quantum yield) and satisfactory biocompatibility was demonstrated as a nanoradiosensitizer. When the Au8NCs were irradiated with X-rays, they produced reactive oxygen species (ROS), resulting in irreversible cell apoptosis. As indicated by in vivo tumor formation experiments, tumorigenicity was significantly suppressed after one radiotherapy treatment with the Au8NCs. In addition, compared with tumors treated with X-rays (4 Gy) alone, tumors treated with the nanosensitizer exhibited an inhibition rate of 74.2%. This study contributes to the development of atomically precise gold nanoclusters as efficient radiosensitizers.
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Neoplasias Esofágicas/radioterapia , Carcinoma de Células Escamosas de Esófago/radioterapia , Oro/farmacología , Levonorgestrel/farmacología , Nanopartículas/uso terapéutico , Compuestos Orgánicos de Oro/farmacología , Fármacos Sensibilizantes a Radiaciones/farmacología , Animales , Muerte Celular/efectos de los fármacos , Neoplasias Esofágicas/diagnóstico por imagen , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas de Esófago/metabolismo , Carcinoma de Células Escamosas de Esófago/patología , Femenino , Oro/química , Humanos , Levonorgestrel/química , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/química , Neoplasias Experimentales/diagnóstico por imagen , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/radioterapia , Imagen Óptica , Compuestos Orgánicos de Oro/síntesis química , Compuestos Orgánicos de Oro/química , Tamaño de la Partícula , Fármacos Sensibilizantes a Radiaciones/síntesis química , Fármacos Sensibilizantes a Radiaciones/química , Organismos Libres de Patógenos Específicos , Propiedades de Superficie , Células Tumorales Cultivadas , Cicatrización de Heridas/efectos de los fármacosRESUMEN
Recent reports showed that regulator of Cullins-1 (ROC1) play an important role in tumor progression in a tumor-specific manner. However, the role and mechanism of ROC1 in esophageal cancer remains elusive. Here we demonstrated that ROC1 was overexpressed in esophageal squamous cell carcinomas, which was positive associated with poor prognosis of esophageal cancer patients. ROC1 knockdown significantly inhibited the growth of esophageal cancer cells in vitro and in vivo. Mechanistically, ROC1 silencing induced G2 cell cycle arrest and triggered apoptosis by accumulating the pro-apoptotic protein NOXA. Consistently, the downregulation of NOXA expression via siRNA substantially attenuated apoptosis induced by ROC1 silencing. These findings suggest that ROC1 is an appealing drug target for esophageal cancer.
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Apoptosis , Carcinoma de Células Escamosas/patología , Proteínas Portadoras/metabolismo , Neoplasias Esofágicas/patología , Puntos de Control de la Fase G2 del Ciclo Celular , Animales , Carcinoma de Células Escamosas/mortalidad , Proteínas Portadoras/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Proliferación Celular , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Progresión de la Enfermedad , Neoplasias Esofágicas/mortalidad , Carcinoma de Células Escamosas de Esófago , Esófago/patología , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Masculino , Ratones , Persona de Mediana Edad , Proteínas Nucleares/metabolismo , Pronóstico , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Tasa de Supervivencia , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Esophageal squamous cell carcinoma (ESCC) is the most common cancer in China, and multidrug resistance (MDR) remains one of the biggest problems in ESCC chemotherapy. In this study, we aimed to investigate the mechanism of Caveolin-1, an integral membrane protein, on regulating ESCC MDR. First, immunohistochemistry was used to check the protein expression of Caveolin-1, MDR-related protein of P-glycoprotein (P-gp), and multidrug resistance protein 1 (MRP1) in 84 pathologically characterized ESCC tissues, matched adjacent tumor, and adjacent normal-looking tissues. The results showed that Caveolin-1 expression level was elevated in ESCC tissues than that of matched adjacent tumor and adjacent normal-looking tissues (P < 0.05), and the expression of Caveolin-1 has close correlation with P-gp and MRP1 during tumor genesis of ESCC (P = 0.034, P = 0.009, respectively). Then, Caveolin-1 overexpression and knockdown were used to investigate its effect on expressions of P-gp and MRP1 in ESCC cell line Ec9706. The messenger RNA (mRNA) and protein expression levels of P-gp and MRP1 were checked by real-time quantitative reverse transcription-PCR (qRT-PCR) and Western blot (WB). The results showed that Caveolin-1 overexpression significantly promotes the mRNA and protein expression of MRP1 (P < 0.05), while almost has no effect on the mRNA and protein expression of P-gp (P > 0.05); Cavoelin-1 knockdown inhibits the mRNA and protein expressions of both P-gp and MRP1 (P < 0.05). The similar result was found in another ESCC cell line Eca109. So, it is concluded that Caveolin-1 affects ESCC MDR by regulating the expressions of P-gp and MRP1; therefore, it can be taken as a significant marker and target in tumor therapy.
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Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Carcinoma de Células Escamosas/genética , Caveolina 1/genética , Resistencia a Antineoplásicos/genética , Neoplasias Esofágicas/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Línea Celular Tumoral , Carcinoma de Células Escamosas de Esófago , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Masculino , Persona de Mediana Edad , ARN Mensajero/genéticaRESUMEN
CD133 was recently reported to be a cancer stem cell and prognostic marker. Quercetin is considered as a potential chemopreventive agent due to its involvement in suppression of oxidative stress, proliferation and metastasis. In this study, the expression of CD133/CD44 in esophageal carcinomas and Eca109/9706 cells was explored. In immunoflurorescence the locations of CD133+ and multidrug resistance 1 (MDR 1)+ in the same E-cancer cells were coincident, mainly in cytomembranes. In esophageal squamous cell carcinomas detected by double/single immunocytochemistry, small CD133+ cells were located in the basal layer of stratified squamous epithelium, determined as CSLC (cancer stem like cells); CD44+ surrounding the cells appeared in diffuse pattern, and the larger CD44+ (hi) cells were mainly located in the prickle cell layer of the epithelium, as progenitor cells. In E-cancer cells exposed to nanoliposomal quercetin (nLQ with cytomembrane permeability), down-regulation of NF-κBp65, histone deacetylase 1 (HDAC1) and cyclin D1 and up-regulation of caspase-3 were shown by immunoblotting, and attenuated HDAC1 with nuclear translocation and promoted E-cadherin expression were demonstrated by immunocytochemistry. In particular, enhanced E-cadherin expression reflected the reversed epithelial mesenchymal transition (EMT) capacity of nLQ, acting as cancer attenuator/preventive agent. nLQ acting as an HDAC inhibitor induced apoptotic cells detected by TUNEL assay mediated via HDAC-NF-κB signaling. Apoptotic effects of liposomal quercetin (LQ, with cytomembrane-philia) combined with CD133 antiserum were also detected by CD133 immunocytochemistry combined with TUNEL assay. The combination could induce greater apoptotic effects than nLQ induced alone, suggesting a novel anti-CSC treatment strategy.
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Antígenos CD/inmunología , Apoptosis/efectos de los fármacos , Apoptosis/inmunología , Carcinoma de Células Escamosas/terapia , Neoplasias Esofágicas/terapia , Glicoproteínas/inmunología , Sueros Inmunes/administración & dosificación , Péptidos/inmunología , Quercetina/administración & dosificación , Antígeno AC133 , Antioxidantes/administración & dosificación , Cadherinas/metabolismo , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Caspasa 3/metabolismo , Proliferación Celular/efectos de los fármacos , Ciclina D1/efectos de los fármacos , Ciclina D1/genética , Regulación hacia Abajo/efectos de los fármacos , Portadores de Fármacos/administración & dosificación , Neoplasias Esofágicas/inmunología , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago , Histona Desacetilasa 1/efectos de los fármacos , Histona Desacetilasa 1/metabolismo , Humanos , Liposomas/administración & dosificación , FN-kappa B/efectos de los fármacos , FN-kappa B/metabolismo , Nanopartículas/administración & dosificación , Células Madre Neoplásicas/metabolismo , Sensibilidad y Especificidad , Células Tumorales CultivadasRESUMEN
Zebrafish (Danio rerio) Z-OTU, containing OTU and TUDOR domains, was predicted to be a member of OTU-related protease, a family of the deubiquitylating enzymes (DUBs). A previous report from our laboratory clearly describes the expression patterns of z-otu mRNA. Here, we characterized the Z-OTU protein during zebrafish oogenesis and early embryogenesis. After prokaryotic expression, the recombinant protein of the OTU domain and GST was purified and injected into rabbits to obtain the polyclonal antibody-anti-Z-OTU, which was used for immunohistochemistry in zebrafish ovaries and embryos. Interestingly, obvious differences existed between the expression patterns of z-otu mRNA and its protein during oogenesis and early embryogenesis. In stage I oocytes, z-otu mRNA was detected in cytoplasm while its protein existed in the germinal vesicle. In addition, its protein was distributed during entire oogenesis, while mRNA was not detected in oocytes at stage IV or mature oocytes. The z-otu mRNA disappeared after midblastula transition (MBT) and its protein gradually decreased after this stage. We inferred that Z-OTU protein, like other OTU-related protease with DUB activity, was required for germinal vesicle breakdown of oocytes during meiosis, germinal vesicle migration, and embryo cleavage maintenance.
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Cisteína Endopeptidasas/metabolismo , Desarrollo Embrionario , Oocitos/metabolismo , Oogénesis , Proteínas de Pez Cebra/metabolismo , Pez Cebra/embriología , Pez Cebra/metabolismo , Secuencia de Aminoácidos , Animales , Cisteína Endopeptidasas/química , Cisteína Endopeptidasas/genética , Femenino , Masculino , Datos de Secuencia Molecular , Oocitos/citología , Transporte de Proteínas , Conejos , Alineación de Secuencia , Pez Cebra/genética , Proteínas de Pez Cebra/química , Proteínas de Pez Cebra/genéticaRESUMEN
Caveolin-1 (Cav-1) isoforms, including Cav-1α and Cav-1ß, were identified as integral membrane proteins and the major components of caveolae. Cav-1 proteins are highly conserved during evolution from {itCaenorhabditis elegans} to human and are capable of interacting with many signaling molecules through their caveolin scaffolding domains to regulate the activities of multiple signaling pathways. Thus, Cav-1 plays crucial roles in the regulation of cellular proliferation, differentiation and apoptosis in a cell-specific and contextual manner. In addition, Cav-1 is essential for embryonic development of vertebrates owing to its regulation of BMP, Wnt, TGF-ß and other key signaling molecules. Moreover, Cav-1 is mainly expressed in terminally differentiated cells and its abnormal expression is often associated with human diseases, such as tumor progression, cardiovascular diseases, fibrosis, lung regeneration, and diseases related to virus. In this review, we will further discuss the potential of Cav-1 as a target for disease therapy and multiple drug resistance.
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Caveolin-1 (Cav-1) is the principal component of plasma membrane caveolae that negatively regulates a number of cellular signaling events including canonical Wnt signaling. Activation of the Wnt/beta-catenin pathway is essential for dorsal organizer formation and specification in early vertebrate embryos, but it remains not well understood what controls dorsal activity of maternal beta-catenin and how Cav-1 functions in zebrafish embryogenesis. Here, we report that Cav-1 is required for proper dorsoventral patterning in zebrafish. Both Wnt and BMP signals act coordinately to negatively control transcriptional expression of cav-1 during embryonic development. Ectopic expression of Cav-1alpha or -1beta resulted in formation of typical ventralized embryos, whereas Cav-1 knockdown led to abnormal embryos with expanded expression of dorsal genes. Cav-1 overexpression disrupts the nuclear translocation of beta-catenin through the interaction of its scaffolding domain with Cav-1 binding motif of beta-catenin. This reciprocal interaction is necessary for the ventralizing activity of Cav-1. We have further demonstrated that human Cav-1 proteins have conserved ventralizing activity in zebrafish embryogenesis. Thus, maternally expressed zebrafish Cav-1 regulates dorsoventral patterning by limiting nuclear translocation of active beta-catenin.
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Caveolina 1/metabolismo , Regulación del Desarrollo de la Expresión Génica , beta Catenina/metabolismo , Transporte Activo de Núcleo Celular , Secuencias de Aminoácidos , Animales , Tipificación del Cuerpo , Biología Evolutiva/métodos , Femenino , Humanos , Ratones , Plásmidos/metabolismo , Estructura Terciaria de Proteína , Transducción de Señal , Pez CebraRESUMEN
Using the digital differential display program of the National Center for Biotechnology Information, we identified a contig of expression sequence tags (ESTs) (Accession No. BM316936), which came from zebrafish ovary and testis libraries. The full-length cDNA of this transcript was cloned and further confirmed by polymerase chain reaction and sequencing. The full-length cDNA of the novel gene is 807bp and encodes a novel protein of 187 amino acids, which shares no significant homology with any other known proteins. Characterization of genomic sequences of the gene revealed that it spans 6kb on the linkage group 3 and is composed of five exons and four introns. RT-PCR analysis showed that it was expressed in mature oocytes and one-cell stage, and persisted until 24h of development. RT-PCR also revealed that it is expressed in gonad and kidney, with the highest level of expression in the testis. The expression sites of the novel gene in adult gonad were further localized by in situ hybridization to oogonia and growing oocytes in ovary and to spermatogonia, spermatocytes but not to spermatids in testis. Based on its abundance in testis and the germline stem cell-spermatogonia and oogonia, we hypothesize that it may function as a testicular development and gametogenesis related gene that plays important roles in spermatogenesis, and named it Zsrg (zebrafish testis spermatogenesis related gene, Zsrg).
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Células Germinativas/metabolismo , Células Madre/metabolismo , Proteínas de Pez Cebra/química , Proteínas de Pez Cebra/metabolismo , Pez Cebra/embriología , Pez Cebra/metabolismo , Secuencia de Aminoácidos , Animales , Células Cultivadas , Clonación Molecular , Regulación del Desarrollo de la Expresión Génica/fisiología , Datos de Secuencia Molecular , Especificidad de Órganos , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Homología de Secuencia de Aminoácido , Distribución Tisular , Pez Cebra/genética , Proteínas de Pez Cebra/genéticaRESUMEN
In this study,the full-length cDNAs of GH (Growth Hormone) gene was isolated from six important economic fishes, Siniperca kneri, Epinephelus coioides, Monopterus albus, Silurus asotus, Misgurnus anguillicaudatus and Carassius auratus gibelio Bloch. It is the first time to clone these GH sequences except E. coioides GH. The lengths of the above cDNAs are as follows: 953 bp, 1 023 bp, 825 bp, 1 082 bp, 1 154 bp and 1 180 bp. Each sequence includes an ORF of about 600 bp which encodes a protein of about 200 amino acid: S. kneri, E. coioides and M. albus GHs of 204 amino acid, S. asotus GH of 200 amino acid, M. anguillicaudatus and C. auratus gibelio GHs of 210 amino acid. Then detailed sequence analysis of the six GHs with many other fish sequences was performed. The six sequences all showed high homology to other sequences, especially to sequences within the same order, and many conserved residues were identified, most localized in five domains. The phylogenetic trees (MP and NJ) of many fish GH ORF sequences (including the new six) with Amia calva as outgroup were generally resolved and largely congruent with the morphology-based tree though some incongruities were observed, suggesting GH ORF should be paid more attention to in teleostean phylogeny.
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ADN Complementario/análisis , Peces/genética , Hormona del Crecimiento/genética , Homología de Secuencia de Aminoácido , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Bagres/genética , Clonación Molecular , Cipriniformes/genética , Carpa Dorada/genética , Datos de Secuencia Molecular , Sistemas de Lectura Abierta/genética , Perciformes/genética , Filogenia , Alineación de Secuencia , Análisis de Secuencia de ADNRESUMEN
Several studies have suggested that Otu domain had de-ubiquitinating activity and Tudor domain was important for the formation of germ cells. Here, we reported a novel zebrafish ovary-specific gene containing Otu and Tudor domain, z-otu, which was expressed at stages I-III oocytes and embryonic stages from zygotes to early blastula during embryonic cells maintained their totipotency. Therefore, z-otu might link the ubiquitin signaling pathway to early oogenesis and maintaining the totipotency of embryonic cell.
Asunto(s)
Cisteína Endopeptidasas/genética , Desarrollo Embrionario/genética , Regulación del Desarrollo de la Expresión Génica , Oogénesis/genética , Proteínas de Pez Cebra/genética , Pez Cebra/embriología , Pez Cebra/genética , Secuencia de Aminoácidos , Animales , Cisteína Endopeptidasas/química , Embrión no Mamífero/citología , Exones/genética , Femenino , Perfilación de la Expresión Génica , Intrones/genética , Datos de Secuencia Molecular , Ovario/citología , Estructura Terciaria de Proteína , ARN Mensajero/genética , ARN Mensajero/metabolismo , Alineación de Secuencia , Proteínas de Pez Cebra/químicaRESUMEN
High length and nucleotide polymorphisms in intron2 of GH I gene were detected in 162 individuals,which were from seven wild crucian carp colonies, two goldfish colonies and one Fangzheng crucian carp colony. Using denaturating polyareylamide gel electrophoresis (DPAGE) and single-strand conformation polymorphism (SSCP), seven length variants and 15 haplotypes were identified in these fishes. The length types and haplotypes diversity was 4.32% and 9.26%, respectively. Sequence analysis of the 15 haplotypes indicated the following results: (1) The size of intron2 varied from 243 to 263 bp. In the 15 haplotypes,the average percentages of the four bases (A,T,G and C) were 34.13%, 37.36%, 15.13% and 13.38%, respectively; the frequency of G + C(28.51%) was much lower than that of A + T (71.49%). The GT/AG domain was found in exon-intron junctions,which was the 5' and 3' splice donor and acceptor sites in higher eukaryotic gene introns. The similarity sequence of GTAAGTA was located on the junction between exon2 and intron2. And there existed a richer pyrimidine region (TTTGCCTTTTGTTATC) near the 3' end of intron2. (2) The seven length variants (A, B, C, D, E, F and G) were determined to be 189, 196, 204, 205, 206, 207 and 209 bp, respectively. The polymorphism resulted from the variable repeat number of T (N = 0, 8, 9, 10, 11 and 13) and the difference in one or two motifs deletions of TGAAAAC, TT and GAGTG. (3) Compared the sequences of the 15 haplotypes, 17 substitution sites were observed, of which two were of transversion sites and 15 were of transition sites. Obviously, the transition mutations (88.24%) were more frequent than transversion mutations (11.76%). Analysis of the distributions of the length types, haplotypes and composite genotypes suggested that genetic diversity was varied in different colonies. In the goldfish colonies, only one length type (A), two haplotypes (A1 and A2) and one composite genotype (A1A2) were observed. Two length types (C and D), four haplotypes (C1, C2, D2 and D5) and one composite genotype (C1C2D2D5) presented in the Fangzheng crucian carp colonies. The highest level of genetic diversity was exhibited in the seven wild crucian carp colonies: seven length types (A, B, C, D, E, F and G), 14 haplotypes (A1, A2, A3, B, C1, C2, D1, D2, D3, D4, E1, E2, F and G) and 14 composite genotypes (A1A2A3, A1A2A3B, A1C1C2D1D2D3, A1C1C2D2, A1C1C2D2D3, A1C1C2D3E2, BC1C2D2, BC1C2D3D4, C1C2D2, C1C2D2D3, C1C2D3D4, C1C2D3D4F, C1C2D4, D2E1G) were shared by the seven wild colonies. The numbers of observed length types, haplotypes and genotypes within the wild colonies ranged from 3 to 6, 6 to 10 and 2 to 6, respectively. Whether the length and nucleotide polymorphisms in the intron2 of crucian carp GH I gene were associated with gene expression and gene regulation remained unsolved and required further investigations.