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BACKGROUND AND AIMS: The role of serum uric acid (SUA) in the prognosis of chronic kidney disease (CKD) is inconclusive. To explore the association of SUA level with all-cause and cardiovascular disease (CVD) mortality in patients with CKD. METHODS AND RESULTS: Leveraging data from the National Health and Nutritional Examination Survey (NHANES) and linked national death records up to December 31 2019, we explored the association of SUA with all-cause and CVD mortality using weighted cox proportional hazards regression models and restricted cubic spline (RCS) models in patients with CKD stages 3-5. The study finally included 2644 patients with CKD stages 3-5, with a median SUA level of 6.5 mg/dL. After a median follow-up of 55 months, a total of 763 deaths were recorded, with 279 of them attributed to CVD. In the fully adjusted model, per 1 mg/dL increment in SUA concentration was found to be associated with increased HRs (95% CIs) of 1.07 (1.00, 1.14) for all-cause mortality and 1.11 (1.00, 1.24) for CVD mortality. Compared to Q2 (reference), those in Q4 had adjusted HRs of 1.72 (1.36, 2.17) for all-cause mortality and 2.17 (1.38, 3.41) for CVD mortality, while those in Q1 had adjusted HRs of 1.49 (1.19, 1.85) for all-cause mortality and 1.93 (1.26, 2.98) for CVD mortality. CONCLUSIONS: Both higher and lower SUA levels were associated with increased risks of all-cause and CVD mortality in patients with CKD stages 3-5.
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Biomarcadores , Enfermedades Cardiovasculares , Causas de Muerte , Hiperuricemia , Encuestas Nutricionales , Insuficiencia Renal Crónica , Ácido Úrico , Humanos , Ácido Úrico/sangre , Masculino , Femenino , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/diagnóstico , Insuficiencia Renal Crónica/mortalidad , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/diagnóstico , Persona de Mediana Edad , Medición de Riesgo , Biomarcadores/sangre , Anciano , Hiperuricemia/sangre , Hiperuricemia/mortalidad , Hiperuricemia/diagnóstico , Factores de Tiempo , Pronóstico , Estados Unidos/epidemiología , Factores de Riesgo , Adulto , Factores de Riesgo de Enfermedad CardiacaRESUMEN
Elderly patients infected with severe acute respiratory syndrome coronavirus 2 are at higher risk of severe clinical manifestation, extended hospitalization, and increased mortality. Those patients are more likely to experience persistent symptoms and exacerbate the condition of basic diseases with long COVID-19 syndrome. However, the molecular mechanisms underlying severe COVID-19 in the elderly patients remain unclear. Our study aims to investigate the function of the interaction between disease-characteristic genes and immune cell infiltration in patients with severe COVID-19 infection. COVID-19 datasets (GSE164805 and GSE180594) and aging dataset (GSE69832) were obtained from the Gene Expression Omnibus database. The combined different expression genes (DEGs) were subjected to Gene Ontology (GO) functional enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Diseases Ontology functional enrichment analysis, Gene Set Enrichment Analysis, machine learning, and immune cell infiltration analysis. GO and KEGG enrichment analyses revealed that the eight DEGs (IL23A, PTGER4, PLCB1, IL1B, CXCR1, C1QB, MX2, ALOX12) were mainly involved in inflammatory mediator regulation of TRP channels, coronavirus disease-COVID-19, and cytokine activity signaling pathways. Three-degree algorithm (LASSO, SVM-RFE, KNN) and correlation analysis showed that the five DEGs up-regulated the immune cells of macrophages M0/M1, memory B cells, gamma delta T cell, dendritic cell resting, and master cell resisting. Our study identified five hallmark genes that can serve as disease-characteristic genes and target immune cells infiltrated in severe COVID-19 patients among the elderly population, which may contribute to the study of pathogenesis and the evaluation of diagnosis and prognosis in aging patients infected with severe COVID-19.
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Organ fibrosis can occur in virtually all major organs with relentlessly progressive and irreversible progress, ultimately resulting in organ dysfunction and potentially death. Unfortunately, current clinical treatments cannot halt or reverse the progression of fibrosis to end-stage organ failure, and thus, advanced antifibrotic therapeutics are urgently needed. In recent years, a growing body of research has revealed that circular RNAs (circRNAs) play pivotal roles in the development and progression of organ fibrosis through highly diverse mechanisms of action. Thus, manipulating circRNAs has emerged as a promising strategy to mitigate fibrosis across different organ types. In this review, we systemically summarize the current state of knowledge about circRNA biological properties and the regulatory mechanisms of circRNAs. A comprehensive overview of major fibrotic signaling pathways and representative circRNAs that are known to modulate fibrotic signals are outlined. Then, we focus on the research progress of the versatile functional roles and underlying molecular mechanisms of circRNAs in various fibrotic diseases in different organs, including the heart, liver, lung, kidney and skin. Finally, we offer a glimpse into the prospects of circRNA-based interference and therapy, as well as their utilization as biomarkers in the diagnosis and prognosis of fibrotic diseases. Video abstract.
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ARN Circular , ARN , Humanos , ARN Circular/genética , ARN/genética , ARN/metabolismo , Fibrosis , Piel/metabolismo , Transducción de Señal/genéticaRESUMEN
The abnormal lipid and glucose metabolisms are linked to the metabolic disorders, tumorigenesis, and fibrotic diseases, which attracts the increasing attention to find out the key molecules involved in the lipid and glucose metabolism as the possible therapeutic targets on these diseases. A transcriptional factor Twist1 has been associated with not only the embryonic development, cancer, and fibrotic diseases, but also the regulation of lipid and glucose metabolism. In this review, we will discuss the roles and mechanisms of Twist1 in the obesity-associated white adipose tissue inflammation and insulin resistance, brown adipose tissue metabolism, fatty acid oxidation, and glucose metabolism in skeletal muscle to provide a rational perspective to consider Twist1 as a potential treatment target in clinic. Video Abstract.
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Resistencia a la Insulina , Músculo Esquelético , Humanos , Músculo Esquelético/metabolismo , Metabolismo de los Lípidos , Inflamación/metabolismo , Glucosa/metabolismo , LípidosRESUMEN
BACKGROUND: Delirium is a common complication clinically and is associated with the poor outcomes, yet it is frequently unrecognised and readily disregarded. Although the 3-minute diagnostic interview for confusion assessment method-defined delirium (3D-CAM) has been used in a variety of care settings, a comprehensive evaluation of its accuracy in all available care settings has not been performed. OBJECTIVE: This study aimed to evaluate the diagnostic test accuracy of the 3D-CAM in delirium detection through a systematic review and meta-analysis. METHODS: We systematically searched PubMed, EMBASE, the Cochrane Library, Web of Science, CINAHL (EBSCO) and ClinicalTrials.gov published from inception to 10 July 2022. The quality assessment of the diagnostic accuracy studies-2 tool was applied to evaluate methodological quality. A bivariate random effects model was used to pool sensitivity and specificity. RESULTS: Seven studies with 1,350 participants and 2,499 assessments were included, which were carried out in general medical wards, intensive care units, internal medical wards, surgical wards, recovery rooms and post-anaesthesia care units. The prevalence of delirium ranged from 9.1% to 25%. The pooled sensitivity and specificity were 0.92 (95% confidence interval [CI] 0.87-0.95) and 0.95 (95% CI 0.92-0.97), respectively. The pooled positive likelihood ratio was 18.6 (95% CI 12.2-28.2), the negative likelihood ratio was 0.09 (95% CI 0.06-0.14) and the diagnostic odds ratio was 211 (95% CI 128-349). Moreover, the area under the curve was 0.97 (95% CI 0.95-0.98). CONCLUSIONS: The 3D-CAM has good diagnostic accuracy for delirium detection in different care settings. Further analyses illustrated that it had comparable diagnostic accuracy in older adults and patients with dementia or known baseline cognitive impairment. In conclusion, the 3D-CAM is recommended for clinical delirium detection.
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Delirio , Humanos , Anciano , Delirio/diagnóstico , Sensibilidad y Especificidad , Unidades de Cuidados Intensivos , Hospitales , Habitaciones de PacientesRESUMEN
Renal interstitial fibrosis is the pathological basis of end-stage renal disease, in which the heterogeneity of macrophages in renal microenvironment plays an important role. However, the molecular mechanisms of macrophage plasticity during renal fibrosis progression remain unclear. In this study, we found for the first time that increased expression of Twist1 in macrophages was significantly associated with the severity of renal fibrosis in IgA nephropathy patients and mice with unilateral ureteral obstruction (UUO). Ablation of Twist1 in macrophages markedly alleviated renal tubular injury and renal fibrosis in UUO mice, accompanied by a lower extent of macrophage infiltration and M2 polarization in the kidney. The knockdown of Twist1 inhibited the chemotaxis and migration of macrophages, at least partially, through the CCL2/CCR2 axis. Twist1 downregulation inhibited M2 macrophage polarization and reduced the secretion of the profibrotic factors Arg-1, MR (CD206), IL-10, and TGF-ß. Galectin-3 was decreased in the macrophages of the conditional Twist1-deficient mice, and Twist1 was shown to directly activate galectin-3 transcription. Up-regulation of galectin-3 recovered Twist1-mediated M2 macrophage polarization. In conclusion, Twist1/galectin-3 signaling regulates macrophage plasticity (M2 phenotype) and promotes renal fibrosis. This study could suggest new strategies for delaying kidney fibrosis in patients with chronic kidney disease.
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Fibrosis/patología , Galectina 3/metabolismo , Enfermedades Renales/patología , Activación de Macrófagos , Proteína 1 Relacionada con Twist/metabolismo , Obstrucción Ureteral/complicaciones , Animales , Fibrosis/etiología , Fibrosis/metabolismo , Galectina 3/genética , Humanos , Enfermedades Renales/etiología , Enfermedades Renales/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Transducción de Señal , Proteína 1 Relacionada con Twist/genéticaRESUMEN
BACKGROUND: Infection is the leading cause of multiple organ dysfunction syndrome (MODS) in the elderly. Red blood cell distribution width (RDW) was considered to be associated with many diseases. We aimed to explore whether RDW was associated with MODS in elderly infected patients. METHODS: We retrospectively collected data from elderly patients (≥ 65 years old) with infection. In this study, we conducted a 1:3 case-control match based on age and gender and utilized binary Logistic regression to investigate the impact of variables such as RDW on MODS. RESULTS: A total of 576 eligible patients were included in this study. RDW in the case group was significantly higher than that in control group (p < 0.001). Multivariate analysis found that RDW was an independent risk factor for MODS in elderly infected patients (OR = 1.397, 95% CI: 1.166-1.674, p < 0.001). CONCLUSIONS: RDW was an independent risk factor for MODS in elderly patients with infection.
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Índices de Eritrocitos , Insuficiencia Multiorgánica , Humanos , Anciano , Estudios de Casos y Controles , Estudios Retrospectivos , Factores de Riesgo , EritrocitosRESUMEN
BACKGROUND: Gut dysbiosis is postulated to participate in the pathogenesis of IgA nephropathy (IgAN). However, the key bacterial taxa closely associated with IgAN onset and treatment response have not been identified. METHODS: We recruited 127 patients with IgAN who were treatment naive and 127 matched healthy controls (HCs) who were randomly divided into discovery and validation cohorts to investigate the characteristics of their gut microbiota and establish a bacterial diagnosis model for IgAN. A separate cohort of 56 patients and HCs was investigated to assess crossregional validation. A further 40 patients with primary membranous nephropathy (MN) were enrolled to probe disease-specific validation. A subgroup of 77 patients was prospectively followed to further dissect the association between alterations in gut microbiota and treatment response after 6 months of immunosuppressive therapy. Fecal microbiota samples were collected from all participants and analyzed using 16S ribosomal RNA sequencing. RESULTS: Decreased α-diversity (Shannon, P=0.03), altered microbial composition (Adonis, P=0.0001), and a striking expansion of the taxonomic chain Proteobacteria-Gammaproteobacteria-Enterobacteriales-Enterobacteriaceae-Escherichia-Shigella (all P<0.001) were observed in patients with IgAN who were treatment naive, which reversed only in patients who achieved clinical remission after 6 months of immunosuppressive therapy. Importantly, seven operational taxa units, of which Escherichia-Shigella contributed the most, were determined to be the optimal bacterial classifier of IgAN (AUC=0.8635, 0.8551, 0.8026 in discovery, validation, and cross-regional validation sets, respectively), but did not effectively distinguish patients with IgAN versus those with MN (AUC=0.6183). Bacterial function prediction further verified enrichment of the shigellosis infection pathway in IgAN. CONCLUSION: Gut dysbiosis, characterized by a striking expansion of genus Escherichia-Shigella, is a hallmark of patients with IgAN and may serve as a promising diagnostic biomarker and therapeutic target for IgAN. Further studies are warranted to investigate the potential contribution of Escherichia-Shigella in IgAN pathogenesis.
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Glomerulonefritis por IGA , Terapia de Inmunosupresión , Shigella , Humanos , Bacterias , Disbiosis , Escherichia , Glomerulonefritis por IGA/genéticaRESUMEN
BACKGROUND: Emerging evidence suggests that gut microbiota dysbiosis may play a critical role in the development of lupus nephritis (LN). However, the specific characteristics of the gut microbiota in individuals with LN have not been fully clarified. METHODS: The PubMed, Web of Science, and Embase databases were systematically searched for clinical and animal studies related to the relationship between LN and gut microbiota from inception until October 1, 2023. A semiquantitative analysis was used to assess the changes in gut microbial profiles. RESULTS: A total of 15 clinical studies were selected for analysis, which included 138 LN patients, 441 systemic lupus erythematosus patients, and 1526 healthy controls (HCs). Five different types of LN mouse models were included in 5 animal studies. The alpha diversity was decreased in LN patients compared to HCs. A significant decrease in the Firmicutes/Bacteroidetes (F/B) ratio is considered a hallmark of pathological conditions. Specifically, alterations in the abundance of the phylum Proteobacteria, genera Streptococcus and Lactobacillus, and species Ruminococcus gnavus and Lactobacillus reuteri may play a critical role in the pathogenesis of LN. Remarkably, the gut taxonomic chain Bacteroidetes-Bacteroides-Bacteroides thetaiotaomicron was enriched in LN patients, which could be a crucial characteristic of LN patients. The increased level of interleukin-6, imbalance of regulatory T cells and T helper 17 cells, and decreased level of the intestinal tight junction proteins zonula occludens-1 and claudin-1 also might be related to the pathogenesis of LN. CONCLUSIONS: Specific changes in the abundance of gut microbiota such as decreased F/B ratio, and the level of inflammatory indicators, and markers of intestinal barrier dysfunction may play a crucial role in the pathogenesis of LN. These factors could be effective diagnostic and potential therapeutic targets for LN.
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Microbioma Gastrointestinal , Enfermedades Intestinales , Lupus Eritematoso Sistémico , Nefritis Lúpica , Animales , Ratones , Humanos , Interleucina-6RESUMEN
Chronic kidney disease (CKD) is a major public health issue around the world. A significant number of CKD patients originates from acute kidney injury (AKI) patients, namely "AKI-CKD". CKD is significantly related to the consequences of AKI. Damaged renal proximal tubular (PT) cell repair has been widely confirmed to indicate the renal prognosis of AKI. Oxidative stress is a key damage-associated factor and plays a significant role throughout the development of AKI and CKD. However, the relationships between AKI-CKD progression and oxidative stress are not totally clear and the underlying mechanisms in "AKI-CKD" remain indistinct. In this research, we constructed unilateral ischemia-reperfusion injury (UIRI)-model mice and performed single-nucleus RNA sequencing (snRNA-seq) of the kidney samples from UIRI and sham mice. We obtained our snRNA-seq data and validated the findings based on the joint analysis of public databases, as well as a series of fundamental experiments. Proximal tubular cells associated with failed repair express more complete senescence and oxidative stress characteristics compared to other subgroups. Furthermore, oxidative stress-related transcription factors, including Stat3 and Dnmt3a, are significantly more active under the circumstance of failed repair. What is more, we identified abnormally active intercellular communication between PT cells associated with failed repair and macrophages through the APP-CD74 pathway. More notably, we observed that the significantly increased expression of CD74 in hypoxia-treated TECs (tubular epithelial cells) was dependent on adjacently infiltrated macrophages, which was essential for the further deterioration of failed repair in PT cells. This research provides a novel understanding of the process of AKI to CKD progression, and the oxidative stress-related characteristics that we identified might represent a potentially novel therapeutic strategy against AKI.
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Lesión Renal Aguda , Insuficiencia Renal Crónica , Daño por Reperfusión , Ratones , Animales , Túbulos Renales Proximales/metabolismo , Riñón/metabolismo , Insuficiencia Renal Crónica/metabolismo , Lesión Renal Aguda/genética , Lesión Renal Aguda/complicaciones , Estrés Oxidativo , Daño por Reperfusión/metabolismoRESUMEN
Hypoxia-induced extracellular matrix (ECM) deposition is an important cause of renal fibrosis that is triggered by unknown mechanisms. Human epididymis secretory protein 4 (HE4) is a newly discovered key molecule that causes ECM deposition. We used the unilateral ureteral obstruction (UUO) mouse model to investigate the expression and mechanisms of HE4 in the pathogenesis of renal fibrosis. Results were confirmed in the HK2 cell line and in human donors of kidney tissue with chronic kidney disease. Hypoxia significantly increased HE4 in renal tubular epithelial cells. HE4 overexpression activated the NF-κB pathway through the NF-κB transcription-activating group P65 by phosphorylation and nuclear translocation. NF-κB upregulated tissue inhibitor metalloproteinases 1, which may inhibit ECM degradation through inhibition of matrix metallopeptidase 2 activity. Silencing HE4 inhibited hypoxia-induced ECM deposition and alleviated fibrosis in UUO mice in vivo and blocked NF-κB activation in vitro. Expression of HE4 in the tubulointerstitium was positively correlated with tubulointerstitial fibrosis in tissue samples from patients with chronic kidney disease. Our results suggest that hypoxia induces renal fibrosis by upregulating HE4 and activating the HIF-1α/HE4/NF-κB signaling pathway. Uncovering the molecular mechanisms and function of HE4 overexpression in hypoxia-induced renal fibrosis will provide important insights into understanding renal fibrosis and antifibrotic strategies.
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Células Epiteliales/metabolismo , Fibrosis/metabolismo , Hipoxia/metabolismo , Obstrucción Ureteral/metabolismo , Animales , Modelos Animales de Enfermedad , Matriz Extracelular/metabolismo , Enfermedades Renales/patología , Masculino , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Activación Transcripcional/fisiología , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
BACKGROUND: Emerging evidence demonstrates that gut dysbiosis is implicated in the pathogenesis of chronic kidney disease (CKD) with underlying mechanisms involving mucosal and/or systematic immunity or metabolic disorders. However, the profile of gut microbiota in patients with CKD has not been completely explored. METHODS: Databases from their date of inception to 31 March 2020 were systematically searched for case-control or cross-sectional studies comparing the gut microbial profiles in adult patients with CKD or end-stage renal disease (ESRD) with those in healthy controls. Quantitative analysis of alterations in gut microbial profiles was conducted. RESULTS: Twenty-five studies with a total of 1436 CKD patients and 918 healthy controls were included. The present study supports the increased abundance of, phylum Proteobacteria and Fusobacteria, genus Escherichia_Shigella, Desulfovibrio, and Streptococcus, while lower abundance of genus Roseburia, Faecalibacterium, Pyramidobacter, Prevotellaceae_UCG-001, and Prevotella_9 in patients with CKD; and increased abundance of phylum Proteobacteria, and genus Streptococcus and Fusobacterium, while lower abundance of Prevotella, Coprococcus, Megamonas, and Faecalibacterium in patients with ESRD. Moreover, higher concentrations of trimethylamine-N-oxide and p-cresyl sulfate and lower concentrations of short-chain fatty acids were observed. Gut permeability in patients with CKD was not determined due to the heterogeneity of selected parameters. CONCLUSIONS: Specific alterations of gut microbial parameters in patients with CKD were identified. However, a full picture of the gut microbiota could not be drawn from the data due to the differences in methodology, and qualitative and incomplete reporting of different studies.
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Disbiosis/metabolismo , Microbioma Gastrointestinal/genética , Metilaminas/sangre , Insuficiencia Renal Crónica/metabolismo , Bacterias/clasificación , Bacterias/genética , Disbiosis/microbiología , Disbiosis/patología , Humanos , Insuficiencia Renal Crónica/microbiología , Insuficiencia Renal Crónica/patologíaRESUMEN
Hypoxia plays an important role in the development of renal fibrosis. G2/M arrest in renal tubular cells is an important pathway in the development of chronic kidney disease. It is unknown whether hypoxia leads to renal fibrosis via the regulation of G2/M arrest in renal tubular epithelial cells. For the first time, to our knowledge, we showed that hypoxia induces G2/M arrest in renal tubular cells leading to renal fibrosis, and microRNAs are involved in this regulation. We compared microRNA expression between hypoxia and normoxia in HK2 cells and found microRNA (miR)-493 to be highly expressed at 24 and 48 h after hypoxia. The overexpression of miR-493 reduced the expression of the cell cycle regulator, Stathmin (STMN)-1, and increased the percentage of G2/M phase cells and profibrotic factors in HK2 cells. Targeting STMN-1 with short hairpin RNA produced an effect similar to that of miR-493 overexpression. On contrast, the miR-493 inhibitor reversed these effects in vitro. Consistent with these results, miR-493 sponge adeno-associated virus reduced the expression of profibrotic factors and increased STMN-1 in vivo. In summary, these results suggest that the miR-493-STMN-1 pathway contributes to hypoxia-induced tubular epithelial cell G2/M arrest and renal fibrosis. Abrogating G2/M arrest and blocking the miR-493-STMN-1 pathway will provide further insight for the development of antifibrosis therapy.-Liu, T., Liu, L., Liu, M., Du, R., Dang, Y., Bai, M., Zhang, L., Ma, F., Yang, X., Ning, X., Sun, S. MicroRNA-493 targets STMN-1 and promotes hypoxia-induced epithelial cell cycle arrest In G2/M and renal fibrosis.
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Puntos de Control del Ciclo Celular/genética , División Celular , Fase G2 , Hipoxia/metabolismo , Enfermedades Renales/patología , MicroARNs/genética , Estatmina/genética , Adulto , Animales , Línea Celular , Femenino , Fibrosis/patología , Fibrosis/prevención & control , Humanos , Enfermedades Renales/prevención & control , Túbulos Renales/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Adulto JovenRESUMEN
Epithelial-mesenchymal transition (EMT) is a pathological process that occurs in a variety of diseases, including organ fibrosis. Twist1, a basic helix-loop-helix transcription factor, is involved in EMT and plays significant roles in various fibrotic diseases. Suppression of the EMT process represents a promising approach for the treatment of fibrotic diseases. In this review, we discuss the roles and the underlying molecular mechanisms of Twist1 in fibrotic diseases, including those affecting kidney, lung, skin, oral submucosa and other tissues. We aim at providing new insight into the pathogenesis of various fibrotic diseases and facilitating the development of novel diagnostic and therapeutic methods for their treatment.
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Hipoxia/genética , Riñón/metabolismo , Pulmón/metabolismo , Proteínas Nucleares/genética , Fibrosis Pulmonar/genética , Piel/metabolismo , Proteína 1 Relacionada con Twist/genética , Transición Epitelial-Mesenquimal/genética , Fibrosis , Regulación de la Expresión Génica , Humanos , Hipoxia/metabolismo , Hipoxia/patología , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Riñón/patología , Pulmón/patología , Proteínas Nucleares/metabolismo , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/patología , Transducción de Señal , Piel/patología , Factores de Transcripción de la Familia Snail/genética , Factores de Transcripción de la Familia Snail/metabolismo , Proteína 1 Relacionada con Twist/metabolismoRESUMEN
Our previous results showed that calcyclin-binding protein/Siah-1-interacting protein (CacyBP/SIP) inhibits the proliferation and tumorigenicity of gastric cancer; however, the exact mechanism remains unclear, especially from the aspect of cell cycle. The subcellular localization of CacyBP/SIP, Siah-1, and Skp1 in SGC7901 gastric cancer cells was assessed by immunofluorescence after cell cycle synchronization. Levels of CacyBP/SIP, Siah-1, Skp1, ß-catenin, and p-ERK1/2 were analyzed by western blotting. CacyBP/SIP phosphorylation (p-CacyBP/SIP) and the combining capacity of Siah-1 and Skp1 with CacyBP/SIP in nucleoprotein were determined by immunoprecipitation. CacyBP/SIP, Siah-1, and Skp1 were mainly in the cytoplasm in the G1 phase, but translocated to the nucleus during G2. Their expression in total protein was not altered, but elevated in the G2 phase in nucleoprotein. The CacyBP/SIP nucleus translocation of cells transfected with mutant CacyBP/SIP that does not bind S100 (CacyBP-ΔS100) was significantly increased compared with wild-type CacyBP/SIP. In the G2 phase, p-CacyBP/SIP expression and the combining capacity of Siah-1 and Skp1 with CacyBP/SIP were all increased, whereas levels of ß-catenin and p-ERK1/2 reduced, compared with the G1 phase. CacyBP/SIP or CacyBP-ΔS100 overexpression was correlated with constitutively low ß-catenin expression and affected its level through cell cycle. CacyBP/SIP overexpression led to retarded proliferation, G1 arrest, and ß-catenin reduction, which could be abolished by lithium chloride, ß-catenin activator, and further enhanced by the Wnt inhibitor XAV-939. In addition, CacyBP-ΔS100 further suppressed cell proliferation and induced G1 arrest compared with CacyBP/SIP. In conclusion, CacyBP/SIP nuclear localization, dependent on S100 protein, suppresses gastric cancer tumorigenesis through ß-catenin degradation and the dephosphorylation of ERK1/2 during the G2 phase.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas de Unión al Calcio/metabolismo , Fosfoproteínas/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Proteínas Adaptadoras Transductoras de Señales/biosíntesis , Proteínas de Unión al Calcio/biosíntesis , Ciclo Celular/fisiología , Línea Celular Tumoral , Núcleo Celular/metabolismo , Humanos , Proteína Quinasa 1 Activada por Mitógenos/biosíntesis , Proteína Quinasa 3 Activada por Mitógenos/biosíntesis , Proteínas Nucleares/biosíntesis , Proteínas Nucleares/metabolismo , Fosfoproteínas/biosíntesis , Fosforilación , Proteínas Quinasas Asociadas a Fase-S/biosíntesis , Proteínas Quinasas Asociadas a Fase-S/metabolismo , Proteínas S100/metabolismo , Ubiquitina-Proteína Ligasas/biosíntesis , Ubiquitina-Proteína Ligasas/metabolismo , beta Catenina/biosíntesisRESUMEN
BACKGROUND: Our previous studies indicated that Bmi-1 plays an important role in hypoxia-induced tubular epithelial-mesenchymal transition and the development of kidney fibrosis in cellular and animal models. However, circulating Bmi-1 levels in human chronic kidney disease (CKD) and their relation to progression remains unknown. MATERIALS AND METHODS: We conducted a post-hoc analysis of a prospective cohort study. The blood samples and clinical data of 230 patients with glomerular CKD and 67 healthy adults were prospectively collected between January 2010 and June 2012. Serum Bmi-1 was measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: CKD patients had significantly higher serum Bmi-1 concentrations than the healthy controls (496.4 (363.1 - 675.4) pg/mL compared with 257.3 (235.4 - 303.8) pg/mL, p < 0.001). Serum Bmi-1 level inversely correlated with the estimated glomerular filtration rate (eGFR) (r = -0.346, p < 0.001). In addition, positive correlations were identified between serum Bmi-1 levels and serum creatinine, blood urea nitrogen, cystatin C concentration, and the severity of tubulointerstitial fibrosis (r = 0.248, p < 0.001; r = 0.245, p < 0.001; r = 0.273, p < 0.001; r = 0.536, p < 0.001, respectively). Kaplan-Meier survival curves showed that a higher serum Bmi-1 level was associated with a shorter duration of renal survival. Cox multivariate analyses further demonstrated that serum Bmi-1 concentration was an independent prognostic factor for CKD patients (HR = 6.48, p < 0.001). CONCLUSION: Our study showed that high circulating Bmi-1 levels were associated with adverse kidney disease outcome, suggesting that Bmi-1 is a novel biomarker for glomerular CKD progression. More data from larger longitudinal studies are required to validate our findings.â©.
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Complejo Represivo Polycomb 1/sangre , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/patología , Adulto , Anciano , Biomarcadores/sangre , Nitrógeno de la Urea Sanguínea , Estudios de Cohortes , Creatinina/sangre , Cistatina C/sangre , Progresión de la Enfermedad , Femenino , Tasa de Filtración Glomerular , Humanos , Estimación de Kaplan-Meier , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Análisis Multivariante , Insuficiencia Renal Crónica/mortalidadRESUMEN
Renal fibrosis is the common pathological hallmark of progressive chronic kidney disease (CKD) with diverse aetiologies. Recent researches have highlighted the critical role of hypoxia during the development of renal fibrosis as a final common pathway in end-stage kidney disease (ESKD), which joints the scientist's attention recently to exploit the molecular mechanism underlying hypoxia-induced renal fibrogenesis. The scaring formation is a multilayered cellular response and involves the regulation of multiple hypoxia-inducible signalling pathways and complex interactive networks. Therefore, this review will focus on the signalling pathways involved in hypoxia-induced pathogenesis of interstitial fibrosis, including pathways mediated by HIF, TGF-ß, Notch, PKC/ERK, PI3K/Akt, NF-κB, Ang II/ROS and microRNAs. Roles of molecules such as IL-6, IL-18, KIM-1 and ADO are also reviewed. A comprehensive understanding of the roles that these hypoxia-responsive signalling pathways and molecules play in the context of renal fibrosis will provide a foundation towards revealing the underlying mechanisms of progression of CKD and identifying novel therapeutic targets. In the future, promising new effective therapy against hypoxic effects may be successfully translated into the clinic to alleviate renal fibrosis and inhibit the progression of CKD.
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Hipoxia de la Célula/genética , Fibrosis/genética , Fallo Renal Crónico/genética , Riñón/patología , Fibrosis/patología , Humanos , Fallo Renal Crónico/patología , MicroARNs/genética , FN-kappa B/genética , Receptores Notch/genética , Transducción de Señal/genética , Factor de Crecimiento Transformador beta/genéticaRESUMEN
Calcyclin-binding protein/Siah-1-interacting protein (CacyBP/SIP) was initially described as a binding partner of S100A6 in the Ehrlich ascites tumor cells and later as a Siah-1-interacting protein. This 30 kDa protein includes three domains and is involved in cell proliferation, differentiation, cytoskeletal rearrangement, and transcriptional regulation via binding to various proteins. Studies have also shown that the CacyBP/SIP is a critical protein in tumorigenesis. But, its promotion or suppression of cancer progression may depend on the cell type. In this review, the biological characteristics and target proteins of CacyBP/SIP have been described. Moreover, the exact role of CacyBP/SIP in various cancers is discussed.
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Proteínas de Unión al Calcio/fisiología , Transformación Celular Neoplásica , Animales , Carcinoma de Ehrlich/metabolismo , Línea Celular Tumoral , Proteínas del Citoesqueleto/metabolismo , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Proteínas S100/metabolismo , Complejos de Ubiquitina-Proteína Ligasa/metabolismo , beta Catenina/metabolismoRESUMEN
BACKGROUND: Chronic hypoxia-induced epithelial-to-mesenchymal transition (EMT) is a crucial process in renal fibrogenesis. Egr-1, as a transcription factor, has been proven to be important in promoting EMT. However, whether it functions in hypoxia-induced renal tubular EMT has not been fully elucidated. METHODS: Egr-1 were detected at mRNA and protein levels by qPCR and Western blot analysis respectively after renal epithelial cells were subjected to hypoxia treatment. Meanwhile, EMT phenotype was also observed through identification of relevant EMT-specific markers. siRNA was used to knock down Egr-1 expression and subsequent changes were observed. Specific PKC and MAPK/ERK inhibitors were employed to determine the molecular signaling pathway involved in Egr-1-mediated EMT phenotype. In vivo assays using rat remnant kidney model were used to validate the in vitro results. Furthermore, Egr-1 expression was examined in the samples of CKD patients with the clinical relevance revealed. RESULTS: Hypoxia treatment enhanced the mRNA and protein levels of Egr-1 in HK-2 cells, which was accompanied by a reduced expression of the epithelial marker E-cadherin and an enhanced expression of the mesenchymal marker Fsp-1. Downregulation of Egr-1 with siRNA reversed hypoxia-induced EMT. Using the specific inhibitors to protein kinase C (calphostin C) or MAPK/ERK (PD98059), we identified that hypoxia induced Egr-1 expression through the PKC/ERK pathway. In addition, the upregulation of Egr-1 raised endogenous Snail levels, and the downregulation of Snail inhibited Egr-1-mediated EMT in HK-2 cells. Through in vivo assays using rat remnant kidney and CKD patients' kidney tissues, we found that Egr-1 and Snail were overexpressed in tubular epithelial cells with EMT. CONCLUSION: Egr-1 may be an important regulator of the development of renal tubular EMT induced by hypoxia through the PKC/ERK pathway and the activation of Snail. Targeting Egr-1 expression or activity might be a novel therapeutic strategy to control renal fibrosis.
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Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Transición Epitelial-Mesenquimal , Túbulos Renales/patología , Sistema de Señalización de MAP Quinasas , Proteína Quinasa C/metabolismo , Insuficiencia Renal Crónica/metabolismo , Animales , Cadherinas/metabolismo , Proteínas de Unión al Calcio/metabolismo , Hipoxia de la Célula , Células Cultivadas , Proteína 1 de la Respuesta de Crecimiento Precoz/análisis , Proteína 1 de la Respuesta de Crecimiento Precoz/genética , Células Epiteliales , Fibrosis/metabolismo , Flavonoides/farmacología , Técnicas de Silenciamiento del Gen , Humanos , Túbulos Renales/química , Túbulos Renales/metabolismo , Masculino , Naftalenos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , ARN Mensajero/metabolismo , ARN Interferente Pequeño , Ratas , Ratas Sprague-Dawley , Insuficiencia Renal Crónica/patología , Proteína de Unión al Calcio S100A4 , Factores de Transcripción de la Familia Snail , Factores de Transcripción/análisis , Factores de Transcripción/metabolismo , Transfección , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Acute kidney injury (AKI) is a complex clinical syndrome with a poor short-term prognosis, which increases the risk of the development of chronic kidney diseases and end-stage kidney disease. However, the underlying mechanism of AKI remains to be fully elucidated, and effective prevention and therapeutic strategies are still lacking. Given the enormous energy requirements for filtration and absorption, the kidneys are rich in mitochondria, which are unsurprisingly involved in the onset or progression of AKI. Accumulating evidence has recently documented that Sirtuin 3 (SIRT3), one of the most prominent deacetylases highly expressed in the mitochondria, exerts a protective effect on AKI. SIRT3 protects against AKI by regulating energy metabolism, inhibiting oxidative stress, suppressing inflammation, ameliorating apoptosis, inhibiting early-stage fibrosis and maintaining mitochondrial homeostasis. Besides, a number of SIRT3 activators have exhibited renoprotective properties both in animal models and in vitro experiments, but have not yet been applied to clinical practice, indicating a promising therapeutic approach. In this review, we unravel and summarize the recent advances in SIRT3 research and the potential therapy of SIRT3 activators in AKI.