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BACKGROUND: Osteoporosis in pre-dialysis chronic kidney disease (CKD) patients has been overlooked, and the risk factors of osteoporosis in these patients have not been adequately studied. OBJECTIVE: To identify risk factors for osteoporosis in pre-dialysis CKD patients and develop predictive models to estimate the likelihood of osteoporosis. METHODS: Dual-energy X-ray absorptiometry was used to measure bone mineral density, and clinical examination results were collected from 326 pre-dialysis CKD patients. Binary logistic regression was employed to explore the risk factors associated with osteoporosis and develop predictive models. RESULTS: In this cohort, 53.4% (n = 174) were male, 46.6% (n = 152) were female, and 21.8% (n = 71) were diagnosed with osteoporosis. Among those diagnosed with osteoporosis, 67.6% (n = 48) were female and 32.4% (n = 23) were male. Older age and low 25-(OH)-Vitamin D levels were identified as risk factors for osteoporosis in males. For females, older age, being underweight, higher bone alkaline phosphatase (NBAP), and advanced CKD (G5) were significant risk factors, while higher iPTH was protective. Older age, being underweight, and higher NBAP were risk factors for osteoporosis in the G1-4 subgroup. In the G5 subgroup, older age and higher NBAP increased the risk, while high 25-(OH)-Vitamin D or iPTH had protective effects. Nomogram models were developed to assess osteoporosis risk in pre-dialysis patients based on gender and renal function stage. CONCLUSION: Risk factors for osteoporosis vary by gender and renal function stages. The nomogram clinical prediction models we constructed may aid in the rapid screening of patients at high risk of osteoporosis.
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Absorciometría de Fotón , Densidad Ósea , Osteoporosis , Insuficiencia Renal Crónica , Humanos , Femenino , Masculino , Osteoporosis/etiología , Osteoporosis/epidemiología , Osteoporosis/diagnóstico , Persona de Mediana Edad , Factores de Riesgo , Insuficiencia Renal Crónica/complicaciones , Anciano , Adulto , Vitamina D/sangre , Vitamina D/análogos & derivados , Fosfatasa Alcalina/sangre , Modelos Logísticos , Nomogramas , Diálisis RenalRESUMEN
BACKGROUND: Diabetic kidney disease (DKD) is among the most important causes for chronic kidney disease. Anthocyanins (ANT) are polyphenolic compounds present in various food and play an important role in ameliorating hyperglycemia and insulin sensitivity. However, the effects of ANT in DKD are still poorly understood. This study aimed to investigate the effect of ANT (cyanidin-3-O-glucoside [C3G]) on the renal function of DKD, and whether the anti-DKD effect of ANT is related to metabolic pathways. METHODS: To explore the role of ANT in DKD, we performed the examination of blood glucose, renal function, and histopathology. As for the mechanism, we designed the label-free quantification proteomics and nontargeted metabolomics analysis for kidney and serum. Subsequently, we revealed the anti-DKD effect of ANT through the bioinformatic analysis. RESULTS: We showed that the fasting blood glucose level (- 6.1 mmol/L, P = 0.037), perimeter of glomerular lesions (- 24.1 µm, P = 0.030), fibrosis score of glomerular (- 8.8%, P = 0.002), and kidney function (Cystatin C: - 701.4 pg/mL, P = 0.043; urine creatinine: - 701.4 mmol/L, P = 0.032) were significantly alleviated in DKD mice after ANT treatment compared to untreated in the 20th week. Further, proteins and metabolites in the kidneys of DKD mice were observed to be dramatically altered due to changes in amino acid metabolism with ANT treatment; mainly, taurine and hypotaurine metabolism pathway was upregulated (P = 0.0001, t value = 5.97). Furthermore, upregulated tryptophan metabolism (P < 0.0001, t value = 5.94) and tyrosine metabolism (P = 0.0037, t value = 2.91) pathways had effects on serum of DKD mice as responsed ANT regulating. CONCLUSIONS: Our results suggested that prevention of the progression of DKD by ANT could be related to the regulation of amino acid metabolism. The use of dietary ANT may be one of the dietary strategies to prevent and treat DKD.
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Diabetes Mellitus , Nefropatías Diabéticas , Ratones , Animales , Nefropatías Diabéticas/metabolismo , Antocianinas/farmacología , Antocianinas/uso terapéutico , Glucemia , Riñón/patología , Aminoácidos , Diabetes Mellitus/patologíaRESUMEN
BACKGROUND: Arteriovenous fistula (AVF) is considered to be the best choice of vascular access, but the maturation rate and patency rate of AVF are not satisfactory. Many studies have explored the influencing factors of AVF failure but do not involve the direct relationship between monocyte count and AVF failure. This study aims to explore the relationship between monocyte count and AVF dysfunction related to stenosis. METHODS: From September 2017 to September 2018, basic clinical data and laboratory parameters of patients were collected. All included patients were followed up to September 2019. The stenosis-related AVF failure events that occurred after the patient included in the study and the time of their occurrence were recorded. All patients were divided into 3 groups based on the tertile of monocyte count. Kaplan-Meier method was used to compare the patency rate of AVF in each group. The effects of variables on AVF failure were analyzed. A multivariate Cox regression model with p < 0.05 was included in the univariate Cox regression analysis. RESULTS: A total of 120 patients were included in this study. According to the recorded baseline monocyte count levels, they were divided into 3 groups according to their tertiles, 34 cases in the T1 group (T1 < 0.32 × 109/L), 44 cases in the T2 group (0.32 ≤ T2 < 0.51 × 109/L), and 42 cases in T3 group (T3 ≥0.51 × 109/L). After a median follow-up of 20 months, a total of 31 AVF failure events occurred. Kaplan-Meier survival curves showed that patients with a baseline monocyte count ≥0.51 × 109/L had the lowest patency rate of AVF (log-rank test χ2 = 7.525, p = 0.023). After adjusting to basic clinical data and biochemical indicators, there were statistically significant differences in patency rates of the 3 groups (hazard ratio = 2.774, 95% CI = 1.092-7.043). CONCLUSION: Monocyte count ≥0.51 × 109/L is an independent risk factor for AVF failure, and AVF failure caused by monocytes may be driven by inflammation.
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Fístula Arteriovenosa , Derivación Arteriovenosa Quirúrgica , Fístula Arteriovenosa/etiología , Derivación Arteriovenosa Quirúrgica/efectos adversos , Constricción Patológica/etiología , Humanos , Monocitos , Diálisis Renal/efectos adversos , Diálisis Renal/métodos , Estudios Retrospectivos , Factores de RiesgoRESUMEN
How p53 participates in acute kidney injury (AKI) progress and what are the underlying mechanisms remain illusive. For this issue, it is important to probe into the role of p53 in cisplatin-induced AKI. We find that p53 was upregulated in cisplatin-induced AKI, yet, pifithrin-α inhibites the p53 expression to attenuated renal injury and cell apoptosis both in vivo cisplatin-induced AKI mice and in vitro HK-2 human renal tubular epithelial cells. To knock down p53 by siRNA significantly decreased the miRNA, miR-199a-3p, expression in HK-2 cells. Blockade of miR-199a-3p significantly reduced cisplatin-induced cell apoptosis and inhibited caspase-3 activity. Mechanistically, we identified that miR-199a-3p directly bound to mechanistic target of rapamycin (mTOR) 3'-untranslated region and overexpressed miR-199a-3p reduce the expression and phosphorylation of mTOR. Furthermore, we demonstrated that p53 inhibited mTOR activation through activating miR-199a-3p. In conclusion, our findings reveal that p53, upregulating the expression of miR-199a-3p affects the progress of cisplatin-induced AKI, which might provide a promising therapeutic target of AKI.
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Lesión Renal Aguda/genética , MicroARNs/genética , Neoplasias/genética , Proteína p53 Supresora de Tumor/genética , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/patología , Animales , Apoptosis/efectos de los fármacos , Benzotiazoles/farmacología , Proliferación Celular/efectos de los fármacos , Cisplatino/efectos adversos , Cisplatino/farmacología , Resistencia a Antineoplásicos/genética , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Túbulos Renales/efectos de los fármacos , Túbulos Renales/patología , Ratones , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Serina-Treonina Quinasas TOR/genética , Tolueno/análogos & derivados , Tolueno/farmacología , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Flavin-containing monooxygenase 5 (FMO5) is a phase I enzyme that plays an important role in xenobiotic metabolism. Here, we aimed to characterize diurnal rhythms of Fmo5 expression and activity in mouse liver and to investigate the potential roles of clock genes (Bmal1, Rev-erbα, and E4bp4) in the generation of diurnal rhythms. Fmo5 mRNA and protein showed robust diurnal rhythms, with peak values at zeitgeber time (ZT) 10/14 and trough values at ZT2/22 in mouse liver. Consistently, a diurnal rhythm was observed for in vitro microsomal Baeyer-Villiger oxidation of pentoxifylline (PTX), a specific reaction catalyzed by Fmo5. Pharmacokinetic studies revealed a more extensive Baeyer-Villiger oxidation of PTX at dosing time of ZT14 than at ZT2, consistent with the diurnal pattern of Fmo5 protein. Fmo5 expression was downregulated and its rhythm was blunted in Bmal1 -/- and Rev-erbα -/- mice. Positive regulation of Fmo5 by Bmal1 and Rev-erbα was confirmed in primary mouse hepatocytes and/or Hepa1-6 cells. Furthermore, Fmo5 expression was upregulated and its rhythm was attenuated in E4bp4 -/- mice. Negative regulation of Fmo5 by E4bp4 was validated using primary mouse hepatocytes. Combined luciferase reporter and chromatin immunoprecipitation assays demonstrated that Bmal1 (a known Rev-erbα activator) activated Fmo5 transcription via direct binding to an E-box (-1822/-1816 bp) in the promoter, whereas E4bp4 (a known Rev-erbα target gene) inhibited Fmo5 transcription by binding to two D-boxes (-1726/-1718 and -804/-796 bp). In conclusion, circadian clock genes control diurnal expression of Fmo5 through transcriptional actions on E-box and D-box cis-elements. SIGNIFICANCE STATEMENT: Hepatic Fmo5 displayed diurnal rhythmicities in expression and activity in mice. We uncovered the molecular mechanism by which the rhythmic Fmo5 expression was generated. Fmo5 promoter presents E-box and D-box binding elements for transcriptional actions from circadian clock proteins such as Bmal1, E4bp4, and Dbp. These findings have implications for understanding clock-controlled drug metabolism and for facilitating the practice of chronotherapeutics.
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Ritmo Circadiano/fisiología , Regulación Enzimológica de la Expresión Génica , Hígado/enzimología , Oxigenasas/genética , Animales , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares/fisiología , Oxigenasas/metabolismo , Regiones Promotoras Genéticas , Transcripción GenéticaRESUMEN
Cervical cancer is considered as the second most common female malignant disease. There is an urgent need to illustrate risk factors which can trigger the motility of cervical cancer cells. Our present study revealed that nanomolar concentration of bisphenol A (BPA) significantly promoted the in vitro migration and invasion of cervical cancer HeLa, SiHa, and C-33A cells. Further, BPA treatment increased the expression of metalloproteinase-9 (MMP-9) and fibronectin (FN) in both HeLa and SiHa cells, while did not obviously change the expression of MMP-2, vimentin (Vim) or N-Cadherin (N-Cad). BAY 11-7082, the inhibitor of NF-κB, significantly abolished BPA induced up regulation of FN and MMP-9 in cervical cancer cells. While the inhibitors of PKA (H89), ERK1/2 (PD 98059), EGFR (AG1478), or PI3K/Akt (LY294002) had no effect on the expression of either FN or MMP-9. BPA treatment rapidly increased the phosphorylation of both IκBα and p65, stimulated nuclear translocation, and up regulated the promoter activities of NF-κB. The BPA induced up regulation of MMP-9 and FN and activation of NF-κB were mediated by phosphorylation of IKKß via PKC signals. Collectively, our study found for the first time that BPA stimulated the cervical cancer migration via IKK-ß/NF-κB signals.
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Compuestos de Bencidrilo/toxicidad , Disruptores Endocrinos/toxicidad , Quinasa I-kappa B/metabolismo , FN-kappa B/metabolismo , Fenoles/toxicidad , Neoplasias del Cuello Uterino/patología , Línea Celular Tumoral , Movimiento Celular , Femenino , Fibronectinas/metabolismo , Humanos , Metaloproteinasa 9 de la Matriz/metabolismo , Invasividad Neoplásica , Fosforilación , Proteína Quinasa C/metabolismo , Transducción de SeñalRESUMEN
Estrogen-related receptor alpha (ERRα) plays an important role in the development of hormone-dependent cancers, but its roles in lung cancer remain elusive. The present study was aimed to investigate the effects of ERRα on the proliferation and metastasis of lung cancer A549 cells. The mRNA and protein levels of ERRα were detected in lung cancer A549 and MCF-7 cells and bronchial epithelial BEAS-2B cells by qRT-PCR and Western blotting, respectively. ERRα plasmid transfection and XCT-790 (an inverse agonist of ERRα) were used to up-regulate or down-regulate ERRα expression in A549 cells, respectively. The viability of A549 cells was measured by cell counting kit-8 (CCK-8) and the motility of A549 cells by wound healing assay and Transwell migration/invasion assay. The epithelial markers E-cadherin (E-Cad) and zona occludin-1 (ZO-1), the mesenchymal markers fibronectin (FN) and vimentin (Vim) and the transcription factors (Snail, Zeb1 Twist and Slug) were further detected at mRNA and protein levels by qRT-PCR and Western blotting, respectively. The results showed that ERRα promoted the growth of lung cancer A549 cells in vitro. XCT-790 significantly inhibited the migration and invasion of A549 cells. Over-expression of ERRα promoted the epithelial-to-mesenchymal transition (EMT) of A549 cells, down-regulated the epithelial makers E-Cad and ZO-1, and up-regulated the mesenchymal makers FN and Vim. Silencing of Slug, but not other transcription factors, significantly abolished the ERRα-induced EMT of A549 cells. It was suggested that ERRα promoted the migration and invasion of A549 cells by inducing EMT, and Slug was involved in the process. Targeting ERRα might be an efficient approach for lung cancer treatment.
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Proliferación Celular , Transición Epitelial-Mesenquimal , Regulación de la Expresión Génica , Neoplasias Pulmonares/metabolismo , Proteínas de Neoplasias/biosíntesis , Receptores de Estrógenos/biosíntesis , Línea Celular Tumoral , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/prevención & control , Metástasis de la Neoplasia , Proteínas de Neoplasias/genética , Receptores de Estrógenos/genética , Receptor Relacionado con Estrógeno ERRalfaRESUMEN
Early diagnosis and treatment are crucial for managing kidney disease, yet there remains a need to further explore pathological mechanisms and develop minimally invasive diagnostic methods. In this study, we employed single-cell RNA sequencing (scRNA-seq) to assess the cellular heterogeneity of kidney diseases. We analyzed gene expression profiles from renal tissue, peripheral blood mononuclear cells (PBMCs), and urine of four patients with nephritis. Our findings identified 12 distinct cell subsets in renal tissues and leukocytes. These subsets encompassed fibroblast cells, mesangial cells, epithelial cells, proximal tubule cells (PTCs), and six immune cell types: CD8+ T cells, macrophages, natural killer cells, dendritic cells, B cells, and neutrophils. Interestingly, PTCs were present in both PBMCs and urine samples but absent in healthy blood samples. Furthermore, several populations of fibroblast cells, mesangial cells, and PTCs exhibited pro-inflammatory or pro-apoptotic behaviors. Our gene expression analysis highlighted the critical role of inflammatory PTCs and fibroblasts in nephritis development and progression. These cells showed high expression of pro-inflammatory genes, which could have chemotactic and activating effect on neutrophils. This was substantiated by the widespread in these cells. Notably, the gene expression profiles of inflammatory PTCs in PBMCs, urine, and kidney tissues had high similarity. This suggests that PTCs in urine and PBMCs hold significant potential as alternative markers to invasive kidney biopsies.
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Enfermedades Renales , Nefritis , Humanos , Leucocitos Mononucleares , Enfermedades Renales/diagnóstico , Biopsia , BiomarcadoresRESUMEN
PURPOSE: Diabetic kidney disease (DKD) is the most common complication of type 2 diabetes mellitus (T2DM), and its pathogenesis is not yet fully understood and lacks noninvasive and effective diagnostic biomarkers. In this study, we performed urine metabolomics to identify biomarkers for DKD and to clarify the potential mechanisms associated with disease progression. METHODS: We applied a liquid chromatography-mass spectrometry-based metabolomics method combined with bioinformatics analysis to investigate the urine metabolism characteristics of 79 participants, including healthy subjects (n = 20), T2DM patients (n = 20), 39 DKD patients that included 19 DKD with microalbuminuria (DKD + micro) and 20 DKD with macroalbuminuria (DKD + macro). RESULTS: Seventeen metabolites were identified between T2DM and DKD that were involved in amino acid, purine, nucleotide and primarily bile acid metabolism. Ultimately, a combined model consisting of 2 metabolites (tyramine and phenylalanylproline) was established, which had optimal diagnostic performance (area under the curve (AUC) = 0.94). We also identified 19 metabolites that were co-expressed within the DKD groups and 41 metabolites specifically expressed in the DKD + macro group. Ingenuity pathway analysis revealed three interaction networks of these 60 metabolites, involving the sirtuin signaling pathway and ferroptosis signaling pathway, as well as the downregulation of organic anion transporter 1, which may be important mechanisms that mediate the progression of DKD. CONCLUSIONS: This work reveals the metabolic alterations in T2DM and DKD, constructs a combined model to distinguish them and delivers a novel strategy for studying the underlying mechanism and treatment of DKD.
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Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Humanos , Nefropatías Diabéticas/diagnóstico , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/metabolismo , Metabolómica/métodos , Biomarcadores , Albuminuria/complicacionesRESUMEN
Background: CKD-MBD is a mineral and bone metabolism syndrome caused by chronic kidney disease. FGF23 is an important factor regulating phosphorus and is the main influencer in the CKD-MBD process. In this study, we observed the correlation among serum FGF23 and calcium, phosphorus and parathyroid hormone, and the correlation between FGF23 levels and cardiac structural changes in MHD patients. Methods: We examined serum FGF23 concentrations in 107 cases of MHD patients using the ELISA method, recorded demographic information and biochemical data, and analyzed the correlation between serum FGF23 levels and blood calcium and blood phosphorus and PTH levels. All patients were evaluated by cardiac color ultrasound, and we finally analyzed the association between the FGF23 level and cardiac structural changes. Results: In 107 cases of MHD patients, serum FGF23 levels were linearly associated with serum calcium (r = 0.27 P < 0.01) and parathyroid hormone levels (r = 0.25, P < 0.05). FGF 23 was negatively correlated with age (r = -0.44, P < 0.01).Serum FGF23 levels were correlated with right atrial hypertrophy in HD patients (P < 0.05). No correlation was found among FGF23, left ventricular hypertrophy/enlargement, and valve calcification stenosis (P > 0.05). Conclusion: Serum FGF23 showed a positive correlation among blood calcium levels and PTH levels in hemodialysis patients, and FGF23 levels can affect the incidence of right atrial hypertrophy in MHD patients.
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Acute kidney injury (AKI) is a susceptible factor for chronic kidney disease (CKD). There is still a lack of effective prevention methods in clinical practice. This study investigated the protective effect of the urinary exosomes from premature infants on cisplatin-induced acute kidney injury. Here we isolated exosomes from the fresh urine of premature infants. A C57BL/6 mice model of cisplatin-induced acute kidney injury was given 100 ug urinary exosomes 24 hours after model establishment. The kidneys were collected for pathological examination and the evaluation of renal tubular damage and apoptosis. In the in vitro experiment, human renal cortex/proximal tubular cells (HK-2) were induced by cisplatin to assess the effect of the urine exosomes from premature infants. Exosome microRNA (miRNA) sequencing technology was applied to investigate the miRNAs enriched in exosomes and the dual-luciferase gene reporter system to examine the targeting relationship of the miRNA with target genes. The results indicated that the urinary exosomes could decrease the serum creatinine level and the apoptosis of renal tubular cells, and reduce mice mortality. In addition, miR-30a-5p was the most abundant miRNA in the exosomes. It protected HK-2 cells from cisplatin-induced apoptosis by targeting and down-regulating the mitogen-activated protein kinase 8 (MAPK8). Together, our findings identified that the urinary exosomes derived from premature infants alleviated cisplatin-induced acute kidney injury and inhibited the apoptosis of HK-2 via miR-30a-5p, which could target MAPK8. These findings implied that urinary exosomes from premature infants riched in miR-30a-5p might become a potential treatment for AKI.
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Enfermedad Hepática Inducida por Sustancias y Drogas/terapia , Cisplatino/efectos adversos , Exosomas/trasplante , Recien Nacido Prematuro/orina , Proteína Quinasa 8 Activada por Mitógenos/genética , Animales , Línea Celular , Enfermedad Hepática Inducida por Sustancias y Drogas/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Creatinina/sangre , Modelos Animales de Enfermedad , Regulación hacia Abajo , Exosomas/genética , Femenino , Células HEK293 , Humanos , Recién Nacido , Ratones , Ratones Endogámicos C57BL , MicroARNs/genéticaRESUMEN
BACKGROUND: Previous studies have reported that serum magnesium (Mg) deficiency is involved in the development of heart failure, particularly in patients with end-stage kidney disease. The association between serum Mg levels and mortality risk in patients receiving hemodialysis is controversial. We aimed to estimate the prognostic value of serum Mg concentration on all-cause mortality and cardiovascular mortality in patients receiving hemodialysis. METHODS: We did a systematic literature search in PubMed, EMBASE, Cochrane Library, and Web of Science to identify eligible studies that reported the prognostic value of serum Mg levels in mortality risk among patients on hemodialysis. We performed a meta-analysis by pooling and analyzing hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: We identified 13 observational studies with an overall sample of 42,967 hemodialysis patients. Higher all-cause mortality (adjusted HR 1.58 [95% CI: 1.31-1.91]) and higher cardiovascular mortality (adjusted HR 3.08 [95% CI: 1.27-7.50]) were found in patients with lower serum Mg levels after multivariable adjustment. There was marked heterogeneity (I2 = 79.6%, p < 0.001) that was partly explained by differences in age stratification and study area. In addition, subgroup analysis showed that a serum Mg concentration of ≤1.1 mmol/L might be the vigilant cutoff value. CONCLUSION: A lower serum Mg level was associated with higher all-cause mortality and cardiovascular mortality in patients receiving hemodialysis.
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Aptamers are a class of targeting ligands that bind exclusively to biomarkers of interest. Aptamers have been identified as candidates for the construction of various smart systems for therapy, diagnosis, bioimaging, and drug delivery due to their high target affinity and specificity. Aptamers are accounted as chemical antibodies that can be readily linked to drugs, sensors, signal enhancers, or nanocarriers for functionalization. Use of aptamer-guided medications, especially nanomedicines, has resulted in encouraging outcomes compared to those use of aptamer-free counterparts. This article reviews recent advances in the use of aptamers as targeting ligands for various biomedical and pharmaceutical purposes. Special interests focus on aptamer-based theranostics, biosensing, bioimaging, drug potentiation, and targeted drug delivery.
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Aptámeros de Nucleótidos/farmacología , Técnicas Biosensibles/métodos , Sistemas de Liberación de Medicamentos/métodos , Nanomedicina Teranóstica/métodos , Animales , Aptámeros de Nucleótidos/química , Aptámeros de Nucleótidos/uso terapéutico , Biomarcadores , Humanos , Ligandos , Nanomedicina/métodosRESUMEN
Clear cell renal cell carcinoma (ccRCC) is the most prevalent type of RCC; however, prognostic prediction tools for ccRCC are scant. Developing mRNA or long non-coding RNA (lncRNA)-based risk assessment tools may improve the prognosis in patients with ccRCC. RNA-sequencing and prognostic data from patients with ccRCC were downloaded from The Cancer Genome Atlas and the European Bioinformatics Institute Array database at the National Center for Biotechnology Information. Differentially expressed (DE) RNAs (DERs) and prognostic DERs were screened between less favorable and favorable prognoses using the limma package in R 3.4.1, and analyzed using univariate and multivariate Cox regression analyses, respectively. Risk score models were constructed using optimal combinations of DEmRNAs and DElncRNAs identified using the Least Absolute Shrinkage And Selection Operator Cox regression model of the penalized package. Associations between risk score models and overall survival time were evaluated. Independent prognostic clinical factors were screened using univariate and multivariate Cox regression analyses, and nomogram models were constructed. Gene Ontology biological processes and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were conducted using the clusterProfiler package in R3.4.1. A total of 451 DERs were identified, including 404 mRNAs and 47 lncRNAs, between less favorable and favorable prognoses, and 269 DERs, including 233 mRNAs and 36 lncRNAs, were identified as independent prognostic factors. Optimal combinations including 10 DEmRNAs or 10 DElncRNAs were screened using four risk score models based on the status or expression levels of the 10 DEmRNAs or 10 DElncRNAs. The model based on the expression levels of the 10 DEmRNAs had the highest prognostic power. These prognostic DEmRNAs may be involved in biological processes associated with the inflammatory response, complement and coagulation cascades and neuroactive ligand-receptor interaction pathways. The present validated risk assessment tool based on the expression levels of these 10 DEmRNAs may help to identify patients with ccRCC at a high risk of mortality. These 10 DEmRNAs in optimal combinations may serve as prognostic biomarkers and help to elucidate the pathogenesis of ccRCC.
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INTRODUCTION: The 6-phosphogluconate dehydrogenase (6PGD) was upregulated in many solid cancers and plays an important role in tumorigenesis. In the present study, we want to discover an old drug as an inhibitor of 6PGD for suppressing tumor growth. METHODS: We determined the expression of 6PGD in cancer tissues using Gene Expression Omnibus (GEO) profiles and explored the importance of 6PGD expression in cancer progression by using Kaplan-Meier Plotter. We identified Ebselen as a 6PGD inhibitor by using 6PGD in vitro enzyme activity assay. Cell viability, cell proliferation, tumor growth and cell metabolism assay were used to explore the role of 6PGD and its inhibitor in cancer cells. RESULTS: We found that the expression of 6PGD was upregulated in different cancer tissues and it can promote tumorigenesis. Here, we analyzed our 6PGD inhibitor screening data again and found an old drug Ebselen, which blocks cancer cell proliferation and tumor growth by inhibiting 6PGD enzyme activity, while knocking down 6PGD would partially abolish the inhibition of Ebselen on cell proliferation and cell metabolism. CONCLUSION: Our results suggested that the conventional drug Ebselen could serve as a novel inhibitor of 6PGD for suppressing cancer growth by inhibiting 6PGD enzyme activity.
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The present techniques of clinical and histopathological diagnosis hardly distinguish chromophobe renal cell carcinoma (ChRCC) from renal oncocytoma (RO). To identify differentially expressed genes (DEGs) as effective biomarkers for diagnosis and prognosis of ChRCC and RO, three mRNA microarray datasets (GSE12090, GSE19982, and GSE8271) were downloaded from the GEO database. Functional enrichment analysis of DEGs was performed by DAVID. STRING and Cytoscape were applied to construct the protein-protein interaction (PPI) network and key modules of DEGs. Visualized plots were conducted by the R language. We downloaded clinical data from the TCGA database and the influence of key genes on the overall survival of ChRCC was performed by Kaplan-Meier and Cox analyses. Gene set enrichment analysis (GSEA) was utilized in exploring the function of key genes. A total of 79 DEGs were identified. Enrichment analyses revealed that the DEGs are closely related to tissue invasion and metastasis of cancer. Subsequently, 14 hub genes including ESRP1, AP1M2, CLDN4, and CLDN7 were detected. Kaplan-Meier analysis indicated that the low expression of CLDN7 and GNAS was related to the worse overall survival in patients with ChRCC. Univariate Cox analysis showed that CLDN7 might be a helpful biomarker for ChRCC prognosis. Subgroup analysis revealed that the expression of CLDN7 showed a downtrend with the development of the clinical stage, topography, and distant metastasis of ChRCC. GSEA analysis identified that cell adhesion molecules cams, B cell receptor signaling pathway, T cell receptor signaling pathway, RIG-I like receptor signaling pathway, Toll-like receptor signaling pathway, and apoptosis pathway were associated with the expression of CLDN7. In conclusion, ESRP1, AP1M2, CLDN4, PRSS8, and CLDN7 were found to distinguish ChRCC from RO. Besides, the low expression of CLDN7 was closely related to ChRCC progression and could serve as an independent risk factor for the overall survival in patients with ChRCC.
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Adenoma Oxifílico , Carcinoma de Células Renales , Biología Computacional , Bases de Datos de Ácidos Nucleicos , Regulación Neoplásica de la Expresión Génica , Genes Relacionados con las Neoplasias , Neoplasias Renales , Adenoma Oxifílico/genética , Adenoma Oxifílico/metabolismo , Adenoma Oxifílico/mortalidad , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/mortalidad , Supervivencia sin Enfermedad , Femenino , Humanos , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Neoplasias Renales/mortalidad , Masculino , Tasa de SupervivenciaRESUMEN
Selenium as a biologically active element lends much support to health maintenance and disease prevention. It is now presenting pleiotropic effects on therapy and drug delivery. In this study, a profiling on the physiological functions, therapeutic significances, clinical/preclinical performances, and biomedical and drug delivery applications of selenium in different modalities was carried out. Major interests focused on selenium-based nanomedicines in confronting various diseases pertaining to selenium or not, especially in antitumor and antidiabetes. Furthermore, the article exclusively discusses selenium nanoparticles featured by ameliorative functions with emphasis on their applications in medical practice and drug delivery. The state-of-the-art in medical discovery as well as research and development on selenium and nano-selenium is discussed in this review.
Asunto(s)
Sistemas de Liberación de Medicamentos , Selenio/administración & dosificación , Animales , Tecnología Biomédica , Humanos , Nanomedicina , Nanopartículas/administración & dosificación , Preparaciones Farmacéuticas/administración & dosificaciónRESUMEN
The present study aimed to identify new key genes as potential biomarkers for the diagnosis, prognosis or targeted therapy of clear cell renal cell carcinoma (ccRCC). Three expression profiles (GSE36895, GSE46699 and GSE71963) were collected from Gene Expression Omnibus. GEO2R was used to identify differentially expressed genes (DEGs) in ccRCC tissues and normal samples. The Database for Annotation, Visualization and Integrated Discovery was utilized for functional and pathway enrichment analysis. STRING v10.5 and Molecular Complex Detection were used for protein-protein interaction (PPI) network construction and module analysis, respectively. Regulation network analyses were performed with the WebGestal tool. UALCAN web-portal was used for expression validation and survival analysis of hub genes in ccRCC patients from The Cancer Genome Atlas (TCGA). A total of 65 up- and 164 downregulated genes were identified as DEGs. DEGs were enriched with functional terms and pathways compactly related to ccRCC pathogenesis. Seventeen hub genes and one significant module were filtered out and selected from the PPI network. The differential expression of hub genes was verified in TCGA patients. Kaplan-Meier plot showed that high mRNA expression of enolase 2 (ENO2) was associated with short overall survival in ccRCC patients (P=0.023). High mRNA expression of cyclin D1 (CCND1) (P<0.001), fms related tyrosine kinase 1 (FLT1) (P=0.004), plasminogen (PLG) (P<0.001) and von Willebrand factor (VWF) (P=0.008) appeared to serve as favorable factors in survival. These findings indicate that the DEGs may be key genes in ccRCC pathogenesis and five genes, including ENO2, CCND1, PLT1, PLG and VWF, may serve as potential prognostic biomarkers in ccRCC.
RESUMEN
Renal cell carcinoma (RCC) is the third most frequent malignancy within urological oncology. However, the mechanisms responsible for RCC metastasis are still needed further illustration. Our present study revealed that a seven-transmembrane receptor G-protein coupled estrogen receptor (GPER) was highly detected in various RCC cell lines such as ACHN, OS-RC-2 and SW839. The activation of GPER by its specific agonist G-1 significantly promoted the in vitro migration and invasion of ACHN and OS-RC-2 cells. G-1 also up regulated the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9. The inhibitor of MMP-9 (Cat-444278), but not MMP-2 (Sc-204092), abolished G-1 induced cell migration, which suggested that MMP-9 is the key molecule mediating G-1 induced RCC progression. Further, G-1 treatment resulted in phosphorylation of AKT and ERK in RCC cells. PI3K/AKT inhibitor (LY294002), while not ERK inhibitor (PD98059), significantly abolished G-1 induced up regulation of MMP-9 in both AHCN and OS-RC-2 cells. Generally, our data revealed that activation of GPER by its specific agonist G-1 promoted the metastasis of RCC cells through PI3K/AKT/MMP-9 signals, which might be a promising new target for drug discovery of RCC patients.