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Background: Diabetic kidney disease (DKD) is an intricate complication of diabetes with limited treatment options. Anoikis, a programmed cell death activated by loss of cell anchorage to the extracellular matrix, participated in various physiological and pathological processes. Our study aimed to elucidate the role of anoikis-related genes in DKD pathogenesis. Methods: Differentially expressed genes (DEGs) associated with anoikis in DKD were identified. Weighted gene co-expression network analysis (WGCNA) was conducted to identify DKD-correlated modules and assess their functional implications. A diagnostic model for DKD was developed using LASSO regression and Gene set variation analysis (GSVA) was performed for enrichment analysis. Experimental validation was employed to validate the significance of selected genes in the progression of DKD. Results: We identified 10 anoikis-related DEGs involved in key signaling pathways impacting DKD progression. WGCNA highlighted the yellow module's significant enrichment in immune response and regulatory pathways. Correlation analysis further revealed the association between immune infiltration and anoikis-related DEGs. Our LASSO regression-based diagnostic model demonstrated a well-predictive efficacy with seven identified genes. GSVA indicated that gene function in the high-risk group was primarily associated with immune regulation. Further experimental validation using diabetic mouse models and data analysis in the single-cell dataset confirmed the significance of PYCARD and SFN in DKD progression. High glucose stimulation in RAW264.7 and TCMK-1 cells showed significantly increased expression levels of both Pycard and Sfn. Co-expression analysis demonstrated distinct functions of PYCARD and SFN, with KEGG pathway analysis showing significant enrichment in immune regulation and cell proliferation pathway. Conclusion: In conclusion, our study provides valuable insights into the molecular mechanisms involved in DKD pathogenesis, specifically highlighting the role of anoikis-related genes in modulating immune infiltration. These findings suggest that targeting these genes may hold promise for future diagnostic and therapeutic approaches in DKD management.
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BACKGROUND AND PURPOSE: Hypertension significantly contributes to stroke. Previous research has indicated a connection between daytime napping and stroke. Research on the connection between daytime napping duration and first stroke in hypertensive individuals is lacking nevertheless. METHODS: This research, which ran from 24 August 2013 to 31 December 2022, recruited 11,252 individuals with hypertension and without a history of stroke from the China Stroke Primary Prevention Trial. To determine the relationship between daytime napping duration and stroke onset in hypertensive individuals, we conducted analyses for threshold effects, multivariate-adjusted Cox proportional hazard regression models, and Kaplan-Meier survival curves. RESULTS: The duration of daytime napping (<75 min) was positively correlated with stroke risk; beyond 75 min, the risk did not increase further. When compared to hypertensive individuals who napped for 1-30 min, daytime napping 31-60 min (hazard ratio [HR] = 1.27, 95% confidence interval [CI] = 1.06-1.53) and >60 min (HR = 1.37, 95% CI = 1.14-1.65) were substantially related with a greater risk of first stroke. Additionally, this correlation was absent in cases of hemorrhagic stroke, but present in cases of ischemic stroke, specifically for hypertensive individuals who napped for 31-60 min or >60 min (p < 0.05). Kaplan-Meier survival curves displayed that hypertensive individuals who extended daytime napping had an elevated incidence of stroke. CONCLUSIONS: Hypertensive individuals who take longer daytime naps (>30 min) are at an elevated risk of stroke onset, particularly ischemic stroke, irrespective of other factors.
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Hipertensión , Sueño , Accidente Cerebrovascular , Humanos , Masculino , Hipertensión/epidemiología , Hipertensión/complicaciones , Femenino , Persona de Mediana Edad , Sueño/fisiología , Anciano , Accidente Cerebrovascular/epidemiología , China/epidemiología , Factores de Tiempo , Factores de Riesgo , Accidente Cerebrovascular Isquémico/epidemiologíaRESUMEN
INTRODUCTION: Sepsis, a syndrome of organ dysfunction caused by an unregulated host response to infection. This study aimed to develop a novel sepsis diagnostic model of hematological parameters and evaluate its effectiveness in the early identification and prognosis of sepsis in emergency departments. METHODS: A retrospective study was conducted in Emergency Department. Cell population data parameters related to monocytes and neutrophils were obtained using the Mindary BC-6800 plus hematology analyzer. Receiver operating characteristic (ROC) curve analysis, logistic regression analysis was performed to assess the performance of the parameters and establish a diagnostic and prognostic model of sepsis, which was then verified with a validation cohort. RESULTS: Mon_XW exhibited the best diagnostic performance (area under the ROC curve [AUC] = 0.848, 95% confidence interval [CI]: 0.810-0.885, p < 0.001), followed by Neu_Y and Neu_YW (AUC = 0.777 95% CI: 0.730-0.824, p < 0.001). Logistic regression analysis identified Mon_XW and Neu_Y as independent predictors, which were used to establish a diagnostic model named hematological parameter for sepsis (HPS). HPS demonstrated the best diagnostic performance with an AUC of 0.862 (95% CI: 0.826-0.898, p < 0.001), sensitivity of 70.0%, and specificity of 87.1%, compared to C-reactive protein (CRP) and procalcitonin (PCT). The validation cohort also found that the positive predictive value of HPS was 70.4% and the negative predictive value was 92.2%. CONCLUSION: The developed HPS model showed promising diagnostic efficacy for sepsis in the emergency department, which outperformed CRP and PCT in terms of sensitivity and specificity. By enabling early identification and prognosis of sepsis, that contributes to reducing sepsis-related mortality.
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Sepsis , Humanos , Estudios Retrospectivos , Sepsis/diagnóstico , Pronóstico , Polipéptido alfa Relacionado con Calcitonina , Proteína C-Reactiva/análisis , Curva ROC , Servicio de Urgencia en HospitalRESUMEN
Background: Diabetic nephropathy (DN) is one of the primary causes of end-stage renal disease, yet effective therapeutic targets remain elusive. This study aims to identify novel diagnostic biomarkers and potential therapeutic candidates for DN. Methods: Differentially expressed genes (DEGs) in GSE96804 and GSE142025 were identified and functional enrichment analysis was performed. Diagnostic biomarkers were selected using machine learning algorithms and evaluated by Receiver Operating Characteristic analysis. c-Fos expression was validated in an established DN mouse model. Immune infiltration levels were assessed with Single-Sample Gene Set Enrichment Analysis. Co-expression analysis revealed regulatory relationships involving FOS. cMAP predicted potential therapeutic candidates. Transcriptome sequencing and experiments in RAW264.7 cells was performed to investigate molecular mechanisms of emetine. Results: In both datasets, we identified 44 upregulated and 74 downregulated DEGs involved in focal adhesion, ECM-receptor interaction, and the PI3K-Akt signaling pathway. FOS emerged as a robust diagnostic marker with decreased expression in DN patients and DN mouse. Co-expression analysis revealed potential regulatory mechanisms of FOS, implicating the MAPK signaling pathway, regulation of cell proliferation and apoptotic signaling pathways. Immune dysregulation was observed in DN patients. Notably, emetine was identified as a potential therapeutic candidate. Transcriptome sequencing and experimental validation demonstrated emetine suppressed M1 macrophage polarization by inhibiting the activation of NF-κB signaling pathway, as well as reducing the expression of Il-18 and Ccl5. Conclusion: In conclusion, our study identified FOS as a promising diagnostic biomarker and emetine as a potential therapeutic candidate for DN. These findings enhance our understanding of DN pathogenesis and present novel prospects for therapeutic strategies.
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Extracellular vesicles (EVs) can facilitate essential communication among cells in a range of pathophysiological conditions including cancer metastasis and progression, immune regulation, and neuronal communication. EVs are membrane-enclosed vesicles generated through endocytic origin and contain many cellular components, including proteins, lipids, nucleic acids, and metabolites. Over the past few years, the intravesicular content of EVs has proven to be a valuable biomarker for disease diagnostics, involving cancer, cardiovascular diseases, and central nervous system diseases. This review aims to provide insight into EV biogenesis, composition, function, and isolation, present a comprehensive overview of emerging techniques for EV cargo analysis, highlighting their major technical features and limitations, and summarize the potential role of EV cargos as biomarkers in disease diagnostics. Further, progress and remaining challenges will be discussed for clinical diagnostic outlooks.
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Vesículas Extracelulares , Neoplasias , Ácidos Nucleicos , Humanos , Vesículas Extracelulares/metabolismo , Proteínas/metabolismo , Biomarcadores/metabolismo , Neoplasias/patología , Ácidos Nucleicos/metabolismoRESUMEN
Background: Colon cancer (CC) is one of the most common cancers with high morbidity globally. Ubiquitination is involved in the characterization of multiple biological processes, and some ubiquitinated enzymes are associated with the prognosis of CC. However, the prognostic model associated with ubiquitination-related genes (URGs) for CC is unavailable. Methods: Gene expression data, somatic mutations, transcriptome profiles, microsatellite instability status (MSI) status, and clinical information for CC were obtained from The Cancer Genome Atlas (TCGA) dataset. Seven URGs were used for establishing a prognostic prediction model, which was constructed and validated in GSE17538. Besides, genomic variance analysis (GSVA) was used to explore further the differences in biological pathway activation status between the high-risk and low-risk groups. Finally, the single-sample gene set enrichment analysis (ssGSEA) and ESTIMATE algorithm analysis were used to characterize the cellular infiltration in the microenvironment. Results: A seven-URG prognostic signature was established, based on which patients in the training and test groups could be divided into high-risk and low-risk groups. The results demonstrated that the model has a solid ability to predict the prognosis of CC patients. Conclusions: We established a prognostic prediction model for CC based on ubiquitination. Then we analyzed the genetic characteristics associated with ubiquitination and the tumor microenvironment (TME) cell infiltration in CC. These results are worthy of exploring new clinical treatment strategies for CC.
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Background: Severe community-acquired pneumonia (sCAP) is a condition where infection-induced lung tissue inflammation intensifies to a certain stage, resulting in organ dysfunction and even life-threatening disease. When sCAP occurs, neutrophils and monocytes will be activated and released into the peripheral blood to kill bacteria. There are significant morphological changes in these activated neutrophils and monocytes. Haematological parameters can reflect these morphological changes, and indicate the occurrence of sCAP and the severity of infection. This study is designed to establish a new haematological model and explore its clinical value in the diagnosis and prognosis of sCAP. Methods: Patients who fulfilled the diagnostic criteria of common pneumonia (CP) and sCAP were enrolled in this study. Healthy body check-up patients were also enrolled as a control group. Characteristic information and 28-day survival of patients were recorded. Haematological results, C-reactive protein (CRP) and procalcitonin (PCT) were calculated by BC-6800 Plus automated haematology analyser and cobas E601 automated biochemical immunoassay analyser. Results: A total of 100 check-ups patients, 100 CP patients, and 111 sCAP patients were enrolled in this study. The new haematological model WBC & Mon-XW, combining WBC (white blood cell count) and Mon-XW (monocytes complexity distribution width), was significantly elevated in the sCAP group and significantly higher than in the control group and the CP group. The new model had good diagnostic efficacy for sCAP, with an area under the receiver operating characteristic curve (ROC-AUC) of 0.842, which was higher than that of CRP (0.633) and PCT (0.750). Moreover, WBC & Mon-XW was effective for survival prognostic evaluations of sCAP, with an ROC-AUC of 0.748. The new model was the independent predictors for the death of pneumonia with an OR (odds ratio) value of 1.82. The 28-day mortality rate was approximately 40% in the WBC & Mon-XW ≥8.9 group, which was approximately 15% higher than that in the WBC & Mon-XW <8.9 group. Conclusions: The new haematological model can be used as an indicator for sCAP diagnosis and prognosis.
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Necrotizing enterocolitis (NEC) is one of the most prevalent neonatal gastrointestinal disorders. Despite ongoing breakthroughs in its treatment and prevention, the incidence and mortality associated with NEC remain high. New therapeutic approaches, such as breast milk composition administration, stem cell therapy, immunotherapy, and fecal microbiota transplantation (FMT) have recently evolved the prevention and the treatment of NEC. This study investigated the most recent advances in NEC therapeutic approaches and discussed their applicability to bring new insight to NEC treatment.
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Background: Icariin presents protective effect in several kidney diseases. However, the role of icariin in contrast-induced acute kidney injury (CIAKI) is still unclear. This study aimed to investigate the effect of icariin in CIAKI, as well as exploring the underlying mechanism from the aspect of interaction between protein-coding genes and non-coding RNAs. Methods: The effect of icariin was evaluated in both in vivo and in vitro CIAKI models. Rat kidneys were collected for genome-wide sequencing. The differentially expressed genes (DEGs) were screened and visualized by R software. The function annotation of DEGs was analyzed by Metascape. By Cytoscape software, the competing endogenous RNA (ceRNA) network was constructed, and hub genes were selected. Expressions of hub genes were validated by PCR. Association of hub genes in the ceRNA network and renal function was also examined. Results: Icariin protected against CIAKI in both in vivo and in vitro models. Based on DEGs in icariin pretreated CIAKI rats, lncRNA- and circRNA-associated ceRNA networks were constructed, respectively. Function annotation showed the ceRNA networks were enriched in ERK1 and ERK2 cascade, MAPK signaling and NF-κB signaling. Further, two circRNAs, six lncRNAs, four miRNAs and nine mRNAs were selected as hub genes of the ceRNA network. Among them, eight mRNAs (Acot1, Cbwd1, Ly6i, Map3k14, Mettl2b, Nyap1, Set and Utp20) were negatively correlated with renal function, while one mRNA (Tmem44) was positively correlated with renal function. Conclusion: Icariin presented a protective effect against CIAKI. The ceRNA network, involving Acot1, Cbwd1, Ly6i, Map3k14, Mettl2, Nyap1, Set, Tmem44 and Utp20, might partially contribute to the underlying mechanism of icariin protection by regulation of ERK1 and ERK2 cascade, MAPK signaling and NF-κB signaling.
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Lesión Renal Aguda , MicroARNs , ARN Largo no Codificante , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/genética , Lesión Renal Aguda/prevención & control , Animales , Flavonoides , Redes Reguladoras de Genes , MicroARNs/metabolismo , FN-kappa B/genética , ARN Circular , ARN Largo no Codificante/metabolismo , ARN Mensajero/genética , RatasRESUMEN
Background: Degenerative diseases in orthopaedics have become a significant global public health issue with the aging of the population worldwide. The traditional medical interventions, including physical therapy, pharmacological therapy and even surgery, hardly work to modify degenerative progression. Stem cell-based therapy is widely accepted to treat degenerative orthopaedic disease effectively but possesses several limitations, such as the need for strict monitoring of production and storage and the potential risks of tumorigenicity and immune rejection in clinical translation. Furthermore, the ethical issues surrounding the acquisition of embryonic stem cells are also broadly concerned. Exosome-based therapy has rapidly grown in popularity in recent years and is regarded as an ideal alternative to stem cell-based therapy, offering a promise to achieve 'cell-free' tissue regeneration. Methods: Traditionally, the native exosomes extracted from stem cells are directly injected into the injured site to promote tissue regeneration. Recently, several modified exosome-based strategies were developed to overcome the limitations of native exosomes, which include mainly exogenous molecule loading and exosome delivery through scaffolds. In this paper, a systematic review of the exosome-based strategy for degenerative disease in orthopaedics is presented. Results: Treatment strategies based on the native exosomes are effective but with several disadvantages such as rapid diffusion and insufficient and fluctuating functional contents. The modified exosome-based strategies can better match the requirements of the regeneration in some complex healing processes. Conclusion: Exosome-based strategies hold promise to manage degenerative disease in orthopaedics prior to patients reaching the advanced stage of disease in the future. The timely summary and highlights offered herein could provide a research perspective to promote the development of exosome-based therapy, facilitating the clinical translation of exosomes in orthopaedics. Translational potential of this article: Exosome-based therapy is superior in anti-senescence and anti-inflammatory effects and possesses lower risks of tumorigenicity and immune rejection relative to stem cell-based therapy. Exosome-based therapy is regarded as an ideal alternative to stem cell-based therapy, offering a promise to achieve 'cell-free' tissue regeneration.
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Efficient transfection of therapeutic agents and timely potency testing are two key factors hindering the development of cellular therapy. Here we present a cellular-nanoporation and exosome assessment device, a quantitative platform for nanochannel-based cell electroporation and exosome-based in situ RNA expression analysis. In its application to transfection of anti-miRNAs and/or chemotherapeutics into cells, we have systematically described the differences in RNA expression in secreted exosomes and assessed cellular therapies in real time.
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Exosomas , MicroARNs , MicroARNs/genética , MicroARNs/metabolismo , TransfecciónRESUMEN
Rapid and specific quantitation of a variety of RNAs with low expression levels in early-stage cancer is highly desirable but remains a challenge. Here, we present a dual signal amplification strategy consisting of the CRISPR/Cas13a system and a catalytic hairpin DNA circuit (CHDC), integrated on a reusable electrochemical biosensor for rapid and accurate detection of RNAs. Signal amplification is accomplished through the unique combination of the CRISPR/Cas13a system with CHDC, achieving a limit of detection of 50 aM within a readout time of 6 min and an overall process time of 36 min, using a measuring volume of 10 µL. Enzymatic regeneration of the sensor surface and ratiometric correction of background signal allow up to 37 sequential RNA quantifications by square-wave voltammetry on a single biosensor chip without loss of sensitivity. The reusable biosensor platform could selectively (specificity = 0.952) and sensitively (sensitivity = 0.900) identify low expression RNA targets in human serum, distinguishing early-stage patients (n = 20) suffering from non-small-cell lung carcinoma (NSCLC) from healthy subjects (n = 30) and patients with benign lung disease (n = 12). Measurement of six NSCLC-related RNAs (miR-17, miR-155, TTF-1 mRNA, miR-19b, miR-210 and EGFR mRNA) shows the ability of the electrochemical CRISPR/CHDC system to be a fast, low-cost and highly accurate tool for early cancer diagnostics.
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Técnicas Biosensibles , Carcinoma de Pulmón de Células no Pequeñas , ADN Catalítico , Neoplasias Pulmonares , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genéticaRESUMEN
In recent years hydrogen sulfide (H2S) has demonstrated vasculoprotective effects against cell death, which suggests its promising therapeutic potential for numerous types of disease. Additionally, a protective effect of exogenous H2S in HGinduced injuries in HUVECs was demonstrated, suggesting a potential protective effect for diabetic vascular complications. The present study aimed to investigate the mechanism accounting for the cytoprotective role of exogenous H2S against high glucose [HG (40 mM glucose)]induced injury and inflammation in human umbilical vein endothelial cells (HUVECs). HUVECs were exposed to HG for 24 h to establish an in vitro model of HGinduced cytotoxicity. The cells were pretreated with sodium hydrosulfide (NaHS), a donor of H2S, or inhibitors of necroptosis and p38 MAPK prior to the exposure to HG. Cell viability, intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP), IL1ß, IL6, IL8, TNFα, phosphorylated(p)38 and receptorinteracting protein 3 (RIP3) expression levels were detected using the indicated methods, including Cell Counting Kit 8, fluorescence detection, western blotting, immunofluorescence assay and ELISAs. The results demonstrated that necroptosis and the p38 MAPK signaling pathway mediated HGinduced injury and inflammation. Notably, NaHS was discovered to significantly ameliorate p38 MAPK/necroptosismediated injury and inflammation in response to HG, as evidenced by an increase in cell viability, a decrease in ROS generation and loss of MMP, as well as the reduction in the secretion of proinflammatory cytokines. In addition, the upregulated expression of RIP3 induced by HG was repressed by treatment with SB203580, while the HGinduced upregulation of pp38 expression levels were significantly downregulated following the treatment of Nec1 and RIP3siRNA. In conclusion, the findings of the present study indicated that NaHS may protect HUVECs against HGinduced injury and inflammation by inhibiting necroptosis via the p38 MAPK signaling pathway, which may represent a promising drug for the therapy of diabetic vascular complications.
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Células Endoteliales de la Vena Umbilical Humana , Inflamación , Sistema de Señalización de MAP Quinasas , Necroptosis , Sustancias Protectoras , Sulfuros , Humanos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Angiopatías Diabéticas/genética , Angiopatías Diabéticas/prevención & control , Glucosa/toxicidad , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/patología , Inflamación/inducido químicamente , Inflamación/prevención & control , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Necroptosis/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Sustancias Protectoras/farmacología , Especies Reactivas de Oxígeno/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Transducción de Señal/efectos de los fármacos , Sulfuros/farmacología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: Immunotherapy offers a novel approach for the treatment of cutaneous melanoma, but the clinical efficiency varies for individual patients. In consideration of the high cost and adverse effects of immunotherapy, it is essential to explore the predictive biomarkers of outcomes. Recently, the tumor mutation burden (TMB) has been proposed as a predictive prognosticator of the immune response. METHOD: RNA-seq and somatic mutation datasets of 472 cutaneous melanoma patients were downloaded from The Cancer Genome Atlas (TCGA) database to analyze mutation type and TMB. Differently expressed genes (DEGs) were identified for functional analysis. TMB-related signatures were identified via LASSO and multivariate Cox regression analysis. The association between mutants of signatures and immune cells was evaluated from the TIMER database. Furthermore, the Wilcox test was applied to assess the difference in immune infiltration calculated by the CIBERSORT algorithm in risk groupings. RESULTS: C>T substitutions and TTN were the most common SNV and mutated gene, respectively. Patients with low TMB presented poor prognosis. DEGs were mainly implicated in skin development, cell cycle, DNA replication, and immune-associated crosstalk pathways. Furthermore, a prognostic model consisting of eight TMB-related genes was developed, which was found to be an independent risk factor for treatment outcome. The mutational status of eight TMB-related genes was associated with a low level of immune infiltration. In addition, the immune infiltrates of CD4+ and CD8+ T cells, NK cells, and M1 macrophages were higher in the low-risk group, while those of M0 and M2 macrophages were higher in the high-risk group. CONCLUSION: Our study demonstrated that a higher TMB was associated with favorable survival outcome in cutaneous melanoma. Moreover, a close association between prognostic model and immune infiltration was identified, providing a new potential target for immunotherapy.
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Biomarcadores de Tumor/genética , Melanoma/genética , Mutación , Neoplasias Cutáneas/genética , Biomarcadores de Tumor/inmunología , Biología Computacional , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunoterapia , Estimación de Kaplan-Meier , Linfocitos Infiltrantes de Tumor/inmunología , Melanoma/inmunología , Melanoma/terapia , Modelos Genéticos , Modelos Inmunológicos , Polimorfismo de Nucleótido Simple , Pronóstico , Modelos de Riesgos Proporcionales , Factores de Riesgo , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/terapiaRESUMEN
Background: Papillary renal cell carcinoma (PRCC), although the second-most common type of renal cell carcinoma, still lacks specific biomarkers for diagnosis, treatment, and prognosis. TopBP1-interacting checkpoint and replication regulator (TICRR) is a DNA replication initiation regulator upregulated in various cancers. We aimed to evaluate the role of TICRR in PRCC tumorigenesis and prognosis. Methods: Based on the Kidney Renal Papillary cell carcinoma Project (KIRP) on The Cancer Genome Atlas (TCGA) database, we determined the expression of TICRR using the Wilcoxon rank sum test. The biological functions of TICRR were evaluated using the Metascape database and Gene Set Enrichment Analysis (GSEA). The association between TICRR and immune cell infiltration was investigated by single sample GSEA. Logistic analysis was applied to study the correlation between TICRR expression and clinicopathological characteristics. Finally, Cox regression analysis, Kaplan-Meier analysis, and nomograms were used to determine the predictive value of TICRR on clinical outcomes in PRCC patients. Results: TICRR expression was significantly elevated in PRCC tumors (P < 0.001). Functional annotation indicated enrichment with negative regulation of cell division, cell cycle, and corresponding pathways in the high TICRR expression phenotype. High TICRR expression in PRCC was associated with female sex, younger age, and worse clinical stages. Cox regression analysis revealed that TICRR was a risk factor for overall survival [hazard ratio (HR): 2.80, P = 0.002], progression-free interval (HR: 2.86, P < 0.001), and disease-specific survival (HR: 7.03, P < 0.001), especially in patients with male sex, age below 60 years, clinical stages II-IV and clinical T stage T1-T2. Conclusion: Increased TICRR expression in PRCC might play a role in tumorigenesis by regulating the cell cycle and has prognostic value for clinical outcomes.
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Acetaminophen (APAP) is a widely used over-the-counter analgesic and antipyretic. It can cause hepatotoxicity. Recent studies demonstrated that hydrogen sulfide (H2 S) exhibits cell protection in several cell types. This study was designed to investigate whether H 2 S ameliorated APAP-induced acute liver injury and to elucidate its mechanisms. In this study, we analyzed the detailed biological and molecular processes of APAP-induced hepatotoxicity using a bioinformatics analysis, which showed that apoptosis and the c-Jun N-terminal kinase (JNK)/mitogen-activated protein kinase pathway were confirmed to play critical roles in these processes. We further investigated the protective effects of H 2 S on APAP-induced hepatotoxicity. In vivo, we observed that the exogenous supplement of H 2 S ameliorated APAP-induced liver injury. Cystathionine-ß-synthase (CBS) and cystathionine-γ-lyase (CSE) systems were the endogenous pathway of H 2 S. The expression of CBS/CSE was decreased in APAP-treated mice, while H 2 S could significantly restore it. In addition, APAP-induced JNK activation was inhibited by H 2 S in vivo. In vitro, H 2 S abolished the active effects of APAP on caspase3, Bax, and Bcl-2 expressions as well as JNK phosphorylation in hepatocytes. It was found through flow cytometry that the amount of APAP-induced apoptotic hepatocytes was decreased in the presence of H 2 S. In conclusion, our results suggested that H 2 S attenuated APAP-induced apoptosis in hepatocytes through JNK/MAPK siganaling pathway.
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Acetaminofén/efectos adversos , Apoptosis/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Hepatocitos/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Acetaminofén/farmacología , Animales , Proteínas Reguladoras de la Apoptosis/metabolismo , Línea Celular , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Hepatocitos/patología , Humanos , Sulfuro de Hidrógeno , MAP Quinasa Quinasa 4/metabolismo , Masculino , Ratones , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismoRESUMEN
Cardiac inflammation and oxidative stress play a key role in the pathogenesis of diabetic cardiomyopathy (DCM). The anti-aging protein Klotho has been found to protect cells from inflammation and oxidative stress. The current study aimed to explore the cardioprotective effects of Klotho on DCM and the underlying mechanisms. H9c2 cells and neonatal cardiomyocytes were incubated with 33mM glucose in the presence or absence of Klotho. Klotho pretreatment effectively inhibited high glucose-induced inflammation, ROS generation, apoptosis, mitochondrial dysfunction, fibrosis and hypertrophy in both H9c2 cells and neonatal cardiomyocytes. In STZ-induced type 1 diabetic mice, intraperitoneal injection of Klotho at 0.01mg/kg per 48h for 3months completely suppressed cardiac inflammatory cytokines and oxidative stress and prevented cardiac cell death and remodeling, which subsequently improved cardiac dysfunction without affecting hyperglycemia. This study revealed that Klotho may exert its protective effects by augmenting nuclear factor erythroid 2-related factor 2 (Nrf2) expression and inactivating nuclear factor κB (NF-κB) activation both in vitro and in vivo. Thus, this work demonstrated for the first time that the anti-aging protein Klotho may be a potential therapeutic agent to treat DCM by inhibiting oxidative stress and inflammation. We also demonstrated the critical roles of the Nrf2 and NF-κB pathways in diabetes-stimulated cardiac injuries and indicated that they may be key therapeutic targets for diabetic complications.
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Cardiotónicos/farmacología , Cardiomiopatías Diabéticas/prevención & control , Glucosa/efectos adversos , Glucuronidasa/farmacología , Corazón/efectos de los fármacos , Miocarditis/prevención & control , Miocitos Cardíacos/efectos de los fármacos , Animales , Células Cultivadas , Citoprotección/efectos de los fármacos , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/patología , Hiperglucemia/complicaciones , Hiperglucemia/inmunología , Hiperglucemia/metabolismo , Inflamación/metabolismo , Inflamación/patología , Inflamación/prevención & control , Proteínas Klotho , Masculino , Ratones , Ratones Endogámicos C57BL , Miocarditis/metabolismo , Miocarditis/patología , Miocitos Cardíacos/fisiología , FN-kappa B/metabolismo , Ratas , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Abstract Background: Although a proportion of CSX patients have impaired brachial artery flow-mediated dilatation (FMD) in response to hyperemia, suggesting that endothelial dysfunction in these patients may be systemic and not just confined to the coronary circulation; the underlying mechanisms triggering endothelial dysfunction in these patients are still incompletely understood. Objectives: To assess the association of the index of Microcirculatory Resistance (IMR) with endothelial dysfunction and inflammation in patients with CSX. Methods: We studied 20 CSX patients and 20 age and gender-matched control subjects. Thermodilution-derived coronary flow reserve (CFR) and IMR were measured using a pressure-temperature sensor-tipped guidewire. Brachial artery FMD was measured using high-resolution, two-dimensional ultrasound images obtained with a Doppler ultrasound device (HDI-ATL 5000, USA) with a 5 MHz to 12 MHz linear-array transducer. Results: Compared with in control subjects, CFR was significantly lower (2.42 ± 0.78 vs. 3.59 ± 0.79, p < 0.001); IMR was higher (32.2 ± 8.0 vs. 19.5 ± 5.5, p < 0.001); the concentration of hs-CRP and FMD was higher (4.75 ± 1.62 vs. 2.75 ± 1.50; 5.24 ± 2.41 vs. 8.57 ± 2.46, p < 0.001) in CSX patients. The Duke treadmill score (DTS) was correlated positively to CFR and FMD (0.489 and 0.661, p < 0.001), it was negative to IMR and hsCRP (-0.761 and -0.087, p < 0.001) in CSX patients. Conclusions: The main finding in this study is that the DTS measured in patients with CSX was associated to hsCRP and FMD. Moreover, the independent effects of exercise tolerance can significantly impair FMD and hsCRP in CSX patients; especially it is particularly important to whom where FMD was associated negatively with IMR.
Resumo Fundamentos: Embora uma proporção de pacientes com SCX tenha dilatação mediada por fluxo da artéria braquial (DMF) prejudicada em resposta à hiperemia, sugerindo que a disfunção endotelial nestes pacientes pode ser sistémica e não limitar-se à circulação coronariana, os mecanismos subjacentes que desencadeiam a disfunção endotelial nestes pacientes ainda não são completamente compreendidos. Objetivos: Avaliar a associação do índice de resistência microcirculatória (IMR) com a disfunção endotelial e a inflamação em pacientes com SCX. Métodos: Estudaram-se 20 pacientes com SCX e 20 sujeitos de controle emparelhados em idade e género. A reserva de fluxo coronariano derivada da termodiluição (RFC) e a IMR forma medidas usando um fio guia com ponta de sensor de temperatura e pressão. A DMF da artéria braquial foi medida utilizando imagens ultrassónicas bidimensionais de alta resolução obtidas com um aparelho de ultrassom Doppler (HDI-ATL 5000, EE.UU.) com transdutor linear de 5 MHz a 12 MHz. Resultados: Em comparação com os sujeitos de controle, a RFC foi significativamente menor (2,42 ± 0,78 vs 3,59 ± 0,79, p < 0,001); o IMR foi maior (32,2 ± 8,0 frente a 19,5 ± 5,5, p < 0,001); a concentração de PCR-as e DMF foi maior (4,75 ± 1,62 frente a 2,75 ± 1,50, 5,24 ± 2,41 diante de 8,57 ± 2,46, p < 0,001) em pacientes com SCX. A escore de Duke (ED) se correlacionou positivamente com RFC e DMF (0,489 e 0,661, p < 0,001), foi negativa para IMR e PCR-as (-0,761 e -0,087, p < 0,001) em pacientes com SCX. Conclusões: O principal achado neste estudo é que o ED medido em pacientes com SCX esteve associado a PCR-as e DMF. Por outra parte, os efeitos independentes da tolerância ao exercício podem piorar significativamente a DMF e a PCR-as em pacientes com SCX especialmente, é particularmente importante que a DMF se associou negativamente com a RIM.
Asunto(s)
Humanos , Masculino , Femenino , Persona de Mediana Edad , Resistencia Vascular/fisiología , Endotelio Vascular/fisiopatología , Angina Microvascular/fisiopatología , Circulación Coronaria/fisiología , Inflamación/fisiopatología , Microcirculación/fisiología , Estudios de Casos y Controles , Estudios ProspectivosRESUMEN
BACKGROUND: Although a proportion of CSX patients have impaired brachial artery flow-mediated dilatation (FMD) in response to hyperemia, suggesting that endothelial dysfunction in these patients may be systemic and not just confined to the coronary circulation; the underlying mechanisms triggering endothelial dysfunction in these patients are still incompletely understood. OBJECTIVES: To assess the association of the index of Microcirculatory Resistance (IMR) with endothelial dysfunction and inflammation in patients with CSX. METHODS: We studied 20 CSX patients and 20 age and gender-matched control subjects. Thermodilution-derived coronary flow reserve (CFR) and IMR were measured using a pressure-temperature sensor-tipped guidewire. Brachial artery FMD was measured using high-resolution, two-dimensional ultrasound images obtained with a Doppler ultrasound device (HDI-ATL 5000, USA) with a 5 MHz to 12 MHz linear-array transducer. RESULTS: Compared with in control subjects, CFR was significantly lower (2.42 ± 0.78 vs. 3.59 ± 0.79, p < 0.001); IMR was higher (32.2 ± 8.0 vs. 19.5 ± 5.5, p < 0.001); the concentration of hs-CRP and FMD was higher (4.75 ± 1.62 vs. 2.75 ± 1.50; 5.24 ± 2.41 vs. 8.57 ± 2.46, p < 0.001) in CSX patients. The Duke treadmill score (DTS) was correlated positively to CFR and FMD (0.489 and 0.661, p < 0.001), it was negative to IMR and hsCRP (-0.761 and -0.087, p < 0.001) in CSX patients. CONCLUSIONS: The main finding in this study is that the DTS measured in patients with CSX was associated to hsCRP and FMD. Moreover, the independent effects of exercise tolerance can significantly impair FMD and hsCRP in CSX patients; especially it is particularly important to whom where FMD was associated negatively with IMR.
Asunto(s)
Circulación Coronaria/fisiología , Endotelio Vascular/fisiopatología , Inflamación/fisiopatología , Microcirculación/fisiología , Angina Microvascular/fisiopatología , Resistencia Vascular/fisiología , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
BACKGROUND: Contrast-induced acute kidney injury (CIAKI) is a common cause of hospital-acquired acute kidney injury (AKI). S100A8/A9-TLR4-NLRP3 inflammasome pathway triggers inflammation, apoptosis and tissue injury in several AKI models. Nevertheless, the underlying mechanism of S100A8/A9-TLR4-NLRP3 inflammasome pathway in CIKAI is not clear. We aimed to investigate the possible role of S100A8/A9-TLR4-NLRP3 inflammasome in the pathophysiology of CIAKI. METHODS: We treated male rats and NRK-52E cells by iopromide to establish in vivo and in vitro models of CIAKI. We collected serum and urine samples to detect renal function. We obtained kidney tissue for histological analysis and detection of protein concentration. We used inhibitor of TLR4 and NLRP3-siRNA to further testify their role in CIAKI in NRK-52E cells. RESULTS: Iopromide caused elevation of SCr, BUN and NGAL level, decrease of endogenous creatinine clearance, morphological injury and tubular apoptosis, enhanced IL-1ß and IL-18 expression, and increased expression of S100A8/A9, TLR4 and NLRP3 inflammsome. In NRK-52E cells, iopromide caused enhanced apoptotic rates and ROS generation, which could be ameliorated by inhibitor of TLR4 and NLRP3-siRNA. Moreover, inhibition of TLR4 dampened NLRP3 expression. CONCLUSION: S100A8/A9-TLR4-NLRP3 inflammasome pathway represented a key mechanism of CI-AKI, which provided a potential therapeutic target.