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BACKGROUND: Epidermal growth factor receptor exon 20 insertion (EGFR ex20ins), an uncommon mutation in non-small cell lung cancer (NSCLC), can induce poor patient response to EGFR tyrosine kinase inhibitors (EGFR-TKI). However, the clinical features and prognosis of patients with EGFR ex20ins are not clearly understood. This study investigated the clinical characteristics and prognosis of advanced NSCLC patients with EGFR ex20ins. METHODS: Advanced NSCLC patients treated at Fujian Cancer Hospital were consecutively recruited from June 1, 2014 to December 20, 2021 and retrospectively examined. EGFR ex20ins was identified by polymerase chain reaction (PCR) or next-generation sequencing (NGS). The clinical characteristics, treatment methods, and patient outcomes were retrieved from the hospital database. The progression-free survival (PFS) and overall survival (OS) were assessed by Kaplan-Meier analysis. RESULTS: Fourteen mutation subtypes of EGFR ex20ins were identified in the 24 enrolled patients, with EGFR ex20ins mutation more prevalent in non-smoking women. A763_Y764insFQEA and A767_V769dup (12.5% for both) were the most common mutation subtypes. Notably, no significant differences in PFS and OS were found between the first-line targeted therapy group [PFS: 257 days, 95% confidence interval (CI): 116-397 days; OS: not reached] and chemotherapy-based combination therapy group (PFS: 182 days, 95% CI: 156-207 days; OS: 998 days, 95% CI: 674-1321 days). TP53 mutation was the commonest concomitant mutation (62%), followed by EGFR amplification (25%). Chemotherapy combined with immunotherapy improved the prognosis of patients with high PD-L1 expression. CONCLUSION: For NSCLC patients with EGFR ex20ins, limited therapeutic benefits can be gleaned from either EGFR-TKIs or chemotherapy-based combination therapy.
EGFR-TKIs have limited efficacy in NSCLC patients with EGFR ex20ins. Combining chemotherapy with immunotherapy may represent a promising treatment approach for individuals with positive ex20ins and high PD-L1 expression.
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Carcinoma de Pulmón de Células no Pequeñas , Receptores ErbB , Exones , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Femenino , Masculino , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Persona de Mediana Edad , Pronóstico , Receptores ErbB/genética , Estudios Retrospectivos , Anciano , Exones/genética , Mutación , Adulto , Inhibidores de Proteínas Quinasas/uso terapéutico , Supervivencia sin Progresión , Mutagénesis InsercionalRESUMEN
BACKGROUND: The association between lipid metabolism disorder and carcinogenesis is well-established, but there is limited research on the connection between lipid metabolism-related genes (LRGs) and lung adenocarcinoma (LUAD). The objective of our research was to identify LRGs as the potential biomarkers for prognosis and assess their impact on immune cell infiltration in LUAD. METHODS: We identified novel prognostic LRGs for LUAD patients via the bioinformatics analysis. CYP27A1 expression level was systematically evaluated via various databases, such as TCGA, UALCAN, and TIMER. Subsequently, LinkedOmics was utilized to perform the CYP27A1 co-expression network and GSEA. ssGSEA was conducted to assess the association between infiltration of immune cells and CYP27A1 expression. CYP27A1's expression level was validated by qRT-PCR analysis. RESULTS: CYP27A1 expression was decreased in LUAD. Reduced CYP27A1 expression was linked to unfavorable prognosis in LUAD. Univariate and multivariate analyses indicated that CYP27A1 was an independent prognostic biomarker for LUAD patients. GSEA results revealed a positive correlation between CYP27A1 expression and immune-related pathways. Furthermore, CYP27A1 expression was positively correlated with the infiltration levels of most immune cells. CONCLUSION: CYP27A1 is a potential biomarker for LUAD patients, and our findings provided a novel perspective to develop the prognostic marker for LUAD patients.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Humanos , Transcriptoma , Pronóstico , Adenocarcinoma del Pulmón/diagnóstico , Adenocarcinoma del Pulmón/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Biomarcadores , Colestanotriol 26-MonooxigenasaRESUMEN
PURPOSE: To explore the impact of intrathecal pemetrexed (IP) on the survival of lung adenocarcinoma (LUAC) patients with leptomeningeal metastasis (LM). METHODS: We analyzed patients with LUAC and LM who received systemic therapy after LM diagnosis at the Fujian Cancer Hospital between July 2018 and March 2022. Patients who underwent IP were assigned to the IP group; those without IP treatment were designated as the non-IP group. Propensity score matching (PSM) was performed between the two groups. RESULTS: 165 patients were enrolled: 83 and 82 in the IP and non-IP groups, respectively. After 1:1 PSM, we included 114 patients in the matched cohort. Median overall survival (OS) was 13.2 months (95% CI 10.8-15.6 months) in the IP group versus 10.1 months (95% CI 5.3-14.9 months) in the non-IP group (P = 0.488). Only Eastern Cooperative Oncology Group Performance Status (ECOG PS) was confirmed as an independent predictor for OS in the matched cohort (hazard ratio (HR) 2.03; P = 0.023). Multivariate competing-risks analysis showed that IP significantly correlated with central nervous system-related death (HR 0.31; P = 0.046). When stratified by ECOG PS, IP improved survival in patients with poor ECOG PS (PS = 2) (14.3 months vs. 1.6 months; P = 0.003). CONCLUSIONS: Intrathecal pemetrexed did not enhance OS for the entire LUAC patient with LM compared to non-intrathecal chemotherapy. However, it exhibited the potential to reduce the risk of central nervous system-related mortality and improve survival in patients with poor ECOG PS.
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Adenocarcinoma del Pulmón , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinomatosis Meníngea , Humanos , Pemetrexed/uso terapéutico , Neoplasias Pulmonares/patología , Puntaje de Propensión , Adenocarcinoma del Pulmón/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinomatosis Meníngea/tratamiento farmacológico , Carcinomatosis Meníngea/etiología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Although the key role of renal fibrosis in the progression of chronic kidney disease (CKD) is well known, the causes of renal fibrosis are not fully clarified. In this study, interferon regulatory factor 1 (IRF-1), a mammalian transcription factor, was highly expressed in fibrotic kidney of CKD patients. Concordantly, the expression level of IRF-1 was significantly elevated in the kidney of unilateral ureteral obstruction (UUO) and Adriamycin nephropathy (ADR) mice. In tubular epithelial cells, overexpression of IRF-1 could induce profibrotic markers expression, which accompanied by dramatic downregulation of Klotho, an important inhibitor of renal fibrosis. Luciferase reporter analysis and ChIP assay revealed that IRF-1 repressed Klotho expression by downregulation of C/EBP-ß, which regulates Klotho gene transcription via directly binding to its promoter. Further investigation showed that tumor necrosis factor-alpha may be an important inducement for the increase of IRF-1 in tubular epithelial cells after UUO and genetic deletion of IRF-1 attenuated renal fibrosis in UUO mice. Hence, these findings demonstrate that IRF-1 contributes to the pathogenesis of renal fibrosis by downregulation of Klotho, and suppresses IRF-1 may be a potential therapeutic target for CKD.
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Glucuronidasa/metabolismo , Factor 1 Regulador del Interferón/metabolismo , Riñón/metabolismo , Riñón/patología , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/patología , Animales , Western Blotting , Línea Celular , Inmunoprecipitación de Cromatina , Glucuronidasa/genética , Células HEK293 , Humanos , Inmunoprecipitación , Factor 1 Regulador del Interferón/genética , Riñón/efectos de los fármacos , Proteínas Klotho , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Biológicos , Ratas , Reacción en Cadena en Tiempo Real de la Polimerasa , Factor de Necrosis Tumoral alfa/farmacología , Obstrucción Ureteral/metabolismo , Obstrucción Ureteral/patologíaRESUMEN
Medial arterial calcification associated with hyperphosphatemia is a main cause of cardiovascular mortality in patients with chronic kidney disease (CKD), but the mechanisms underlying high phosphate-induced vascular calcification remain largely unknown. Here, we observed a significant decrease in the expression of peroxisome proliferator-activated receptor-gamma (PPARγ) in calcified arteries both in CKD patients and in a mouse model of CKD with hyperphosphatemia. In vitro, high phosphate treatment led to a decreased expression of PPARγ in mouse vascular smooth muscle cells (VMSCs), accompanied by apparent osteogenic differentiation and calcification. Pretreatment with PPARγ agonist rosiglitazone significantly reversed high phosphate-induced VSMCs calcification. Further investigation showed that methyl-CpG binding protein 2 (Mecp2)-mediated epigenetic repression was involved in high phosphate-induced PPARγ downregulation. Moreover, the expression of Klotho that has the ability to inhibit vascular calcification by regulating phosphate uptake decreased with the PPARγ reduction in VSMCs after high phosphate treatment, and rosiglitazone failed to inhibit high phosphate-induced calcification in VSMCs with knockdown of Klotho or in aortic rings from Klotho-deficient (kl/kl) mice. Finally, an in vivo study demonstrated that oral administration of rosiglitazone could increase Klotho expression and protect against high phosphate-induced vascular calcification in CKD mice. These findings suggest that the inhibition of PPARγ expression may contribute to the pathogenesis of high phosphate-induced vascular calcification, which may provide a new therapeutic target for vascular calcification in CKD patients.
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Regulación hacia Abajo/efectos de los fármacos , PPAR gamma/metabolismo , Fosfatos/efectos adversos , Insuficiencia Renal Crónica/complicaciones , Calcificación Vascular/etiología , Calcificación Vascular/metabolismo , Adolescente , Adulto , Anciano , Animales , Línea Celular , Dieta , Conducta Alimentaria , Femenino , Glucuronidasa/metabolismo , Humanos , Proteínas Klotho , Proteína 2 de Unión a Metil-CpG/metabolismo , Ratones , Persona de Mediana Edad , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/metabolismo , PPAR gamma/agonistas , ARN Interferente Pequeño/metabolismo , Rosiglitazona/farmacología , Adulto JovenRESUMEN
Nuclear factor-kappa B (NF-κB) as a prognostic marker remains unclear in non-small cell lung cancer (NSCLC). Here, we studied NF-κB-p65 (p65) expression and phosphorylated NF-κB-p105 (p-p105) expression in NSCLC and correlated the finding with overall survival (OS) and clinicopathological features. A total of 186 archival samples from patients with surgically resectable NSCLC were probed with p65 and p-p105 (Ser 932). The p65-positive expression and p-p105-positive expression were defined as distinct nuclear p65 and cytoplasmic p-p105 labelling in at least 1% of tumour cells, respectively. The positive staining of p65 alone, p-p105 alone and co-expression of p65 and p-p105 were observed in 61 (32.8%), 90 (48.4%) and 35 (18.8%) patients, respectively. Co-expression of p65 and p-p105 but not of either p65 or p-p105 alone was associated with a poor prognosis. Patients with co-expression of p65 and p-p105 had a shorter OS than others, median OS 26.5 months versus 64.1 months, HR 1.85 (95% CI: 1.18-2.91), P = 0.007. There was no statistically significant association between clinicopathological characteristics and either p65 or p-p105 alone or co-expression of p65 and p-p105. This indicates that co-expression of p65 and p-p105 was a poor prognostic factor, and pathologic studies of NF-κB expression could include multiple pathway components in NSCLC.
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Adenocarcinoma/genética , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Células Escamosas/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , Subunidad p50 de NF-kappa B/genética , Factor de Transcripción ReIA/genética , Adenocarcinoma/diagnóstico , Adenocarcinoma/mortalidad , Adenocarcinoma/cirugía , Adulto , Anciano , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/cirugía , Femenino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana Edad , Subunidad p50 de NF-kappa B/metabolismo , Fosforilación , Pronóstico , Estudios Prospectivos , Transducción de Señal , Análisis de Supervivencia , Factor de Transcripción ReIA/metabolismoRESUMEN
Abnormal angiogenesis plays a pathological role in diabetic nephropathy (DN), contributing to glomerular hypertrophy and microalbuminuria. Slit2/Robo1 signaling participates in angiogenesis in some pathological contexts, but whether it is involved in glomerular abnormal angiogenesis of early DN is unclear. The present study evaluated the effects of Slit2/Robo1 signaling pathway on angiogenesis of human renal glomerular endothelial cells (HRGECs) exposed to a diabetic-like environment or recombinant Slit2-N. To remove the effect of Slit2 derived from mesangial cells, human renal mesangial cells (HRMCs) grown in high glucose (HG) medium (33 mM) were transfected with Slit2 siRNA and then the HG-HRMCs-CM with Slit2 depletion was collected after 48 h. HRGECs were cultured in the HG-HRMCs-CM or recombinant Slit2-N for 0, 6, 12, 24, or 48 h. The mRNA and protein expressions of Slit2/Robo1, PI3K/Akt and HIF-1α/VEGF signaling pathways were detected by quantitative real-time PCR, western blotting, and ELISA, respectively. The CCK-8 cell proliferation assay, flow cytometry and the scratch wound-healing assay were used to assess cell proliferation, cycles, and migration, respectively. Matrigel was used to perform a tubule formation assay. Our results showed that the HG-HRMCs-CM with Slit2 depletion enhanced the activation of Slit2/Robo1, PI3K/Akt, and HIF-1α/VEGF signaling in HRGECs in time-dependent manner (0-24 h post-treatment). In addition, the HG-HRMCs-CM with Slit2 depletion significantly promoted HRGECs proliferation, migration, and tube formation. Pretreatment of HRGECs with Robo1 siRNA suppressed the activation of PI3K/Akt and HIF-1α/VEGF signaling and inhibited angiogenesis, whereas PI3K inhibitor suppressed HIF-1α/VEGF signaling, without influencing Robo1 expression. In the HRGECs treated with Slit2-N, Slit2-N time-dependently enhanced the activation of Robo1/PI3K/Akt/VEGF pathway but not HIF-1α activity, and promoted HRGECs proliferation, migration, and tube formation. The effects induced by Slit2 were also abolished by Robo1 siRNA and PI3K inhibitor. Taken together, our findings indicate that in a diabetic-like environment, in addition to mesangial cells, autocrine activation of Slit2/Robo1 signaling of HRGECs may contribute to angiogenesis of HRGECs through PI3K/Akt/VEGF pathway; therefore, Slit2/Robo1 signaling may be a potent therapeutic target for the treatment of abnormal angiogenesis in early DN and may have broad implications for the treatment of other diseases dependent on pathologic angiogenesis.
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Diabetes Mellitus/metabolismo , Células Endoteliales/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Glomérulos Renales/metabolismo , Neovascularización Patológica/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Receptores Inmunológicos/metabolismo , Transducción de Señal , Diabetes Mellitus/genética , Diabetes Mellitus/patología , Células Endoteliales/patología , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Glomérulos Renales/patología , Neovascularización Patológica/genética , Neovascularización Patológica/patología , Proteínas del Tejido Nervioso/genética , Receptores Inmunológicos/genética , Proteínas RoundaboutRESUMEN
BACKGROUND: ALK rearrangement-advanced NSCLC patients respond to crizotinib. ALK rearrangement is currently determined with RT-PCR. VENTANA IHC is a standard method to identify ALK protein overexpression in NSCLC; however, VENTANA IHC has rarely been used to determine the response to crizotinib in Chinese patients with NSCLC and ALK overexpression. To better clarify the clinical implication of VENTANA IHC to detect ALK rearrangements, we conducted this study to analyze VENTANA IHC and RT-PCR in a large cohort of Chinese patients with NSCLC undergoing screening for ALK rearrangements. METHODS: A total of 1720 patients with NSCLC who had ALK rearrangements detected by VENTANA IHC and/or RT-PCR were included in this analysis. We compared the efficacy and survival of ALK-positive patients detected by VENTANA IHC and RT-PCR. We used NGS to identify patients in whom the two methods were inconsistent. RESULTS: Among 1720 patients, 187 (10.87%) were shown to be ALK-positive by VENTANA IHC and/or RT-PCR, and 66 received crizotinib treatment. We identified 10.27% (172/1674) of patients as ALK-positive by the VENTANA IHC method, and 12.73% (41/322) of patients had ALK rearrangements by the RT-PCR method. Twenty-nine of 276 (10.51%) ALK-positive patients were simultaneously analyzed using VENTANA IHC and RT-PCR. The overall response rates were 65.90% (29/44) by VENTANA IHC and 55.88% (19/34) by RT-PCR. The disease control rates were 86.36% (38/44) by VENTANA IHC and 76.47% (26/34) by RT-PCR. In contrast, the median progression-free survival for VENTANA IHC and RT-PCR was 8.5 and 9.2 months, respectively. The VENTANA IHC and RT-PCR results obtained for 6 of 17 ALK-positive patients were inconsistent based on NGS; specifically, 4 patients had EML4-ALK fusions, 2 patients had non EML4-ALK fusions, 1 patient had a KCL1-ALK fusion, and one patient had a FBXO36-ALK fusion. CONCLUSIONS: VENTANA IHC is a reliable and rapid screening tool used in routine pathologic laboratories for the identification of suitable candidates for ALK-targeted therapy. VENTANA IHC has moderate sensitivity and a slightly higher association with response to therapy with ALK inhibitors, and some VENTANA IHC-positive, but RT-PCR-negative cases may benefit from crizotinib.
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Quinasa de Linfoma Anaplásico/genética , Pueblo Asiatico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Crizotinib/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/enzimología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Crizotinib/farmacología , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Adulto JovenRESUMEN
BACKGROUND/AIMS: Geriatric nutritional risk index (GNRI) was developed as a "nutrition-related" risk index and was reported in different populations as associated with the risk of all-cause and cardiovascular morbidity and mortality. Therefore, GNRI can be used to classify patients according to a risk of complications in relation to conditions associated with protein-energy wasting (PEW). However, not all reports pointed to the prognostic ability of the GNRI. The purpose of this study was to assess the associations of GNRI with mortality in chronic hemodialysis patients. METHODS: We electronically searched original articles published in peer-reviewed journals from their inception to September 2018 in The PubMed, Embase, and the Cochrane Library databases. The primary outcome was all-cause and cardiovascular mortality. We pooled unadjusted and adjusted odds ratios (ORs) with 95% confidence intervals (95% CIs) using Review Manager 5.3 software. RESULTS: A total of 10,739 patients from 19 cohort studies published from 2010 to 2018 were included. A significant negative association was found between the GNRI and all-cause mortality in patients with chronic hemodialysis (OR, 0.90; 95% CI, 0.84-0.97, p=0.004) (per unit increase) and (OR, 2.15; 95% CI, 1.88-2.46, pï¼0.00001) (low vs. high GNRI). Moreover, there was also a significant negative association between the GNRI (per unit increase) and cardiovascular events (OR, 0.98; 95% CI, 0.97-1.00, p=0.01), as well as cardiovascular mortality (OR, 0.89; 95% CI, 0.80-0.99, p=0.03). CONCLUSION: Our findings supported the hypothesis that the low GNRI is associated with an increased risk of all-cause and cardiovascular mortality in chronic hemodialysis patients. Based on our literature review, GNRI has been found to be an effective tool for identifying patients with nutrition-related risk of all-cause and cardiovascular disease.
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Evaluación Geriátrica/métodos , Fallo Renal Crónico/etiología , Estado Nutricional , Anciano , Anciano de 80 o más Años , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/mortalidad , Humanos , Fallo Renal Crónico/mortalidad , Desnutrición Proteico-Calórica/complicaciones , Medición de RiesgoRESUMEN
BACKGROUND RET rearrangements have been reported in 30% of papillary thyroid carcinomas and 1-2% of non-small cell lung cancer (NSCLC). In these tumors, RET gene fusion product provides a constitutively active tyrosine kinase (TKR), leading to uncontrolled cellular proliferation, differentiation, and migration. In this investigation we assessed the positivity rate of RET gene rearrangement in primary and metastatic non-small cell lung cancer and explored their relationships. MATERIAL AND METHODS Between January 2013 and May 2015, we collected 384 cases of primary metastatic non-small cell lung cancer, which included 246 matched metastatic tumors cases from multiple centers. The RET rearrangement uniformity in metastatic lymph nodes and tumor specimens were contrasted and the relationships between RET rearrangement and patients' clinical features were investigated. RESULTS For those 384 cases, 7 (1.82%) cases had tumors with identified RET rearrangement. Among the 246 paired cases, 3 (1.22%) cases of primary tumor had identified RET rearrangement and 2 (0.81%) cases of metastases had identified RET rearrangement. The sensitivity was 66.67% (2/3) and the specificity was 100% (243/243). CONCLUSIONS The results of this research indicate that the metastases of non-small cell lung cancer can predict RET rearrangement of the primary tumor tissue in the majority of cases. Testing for RET rearrangement in metastases can be used as an alternative to testing of primary tumor tissue if it is inaccessible.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogénicas c-ret/genética , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Femenino , Reordenamiento Génico , Humanos , Neoplasias Pulmonares/enzimología , Masculino , Persona de Mediana Edad , TransfecciónRESUMEN
BACKGROUND: Hyperuricemia is an independent risk factor for causing chronic kidney disease and contributes to kidney fibrosis. After urate crystals get deposited in the kidney, they can cause hyperuricemia nephropathy, leading to glomerular hypertrophy and renal tubular interstitial fibrosis. Recent data showed that uric acid (UA) could induce epithelial mesenchymal transition (EMT) of renal tubular cells, in which NRLP3 inflammatory pathway was involved. However, whether TLR4/NF-κB signaling pathway is also involved in EMT of renal tubular cells induced by UA is not clear. METHODS: Human renal tubular epithelial cells (HK-2) were directly treated with UA and the phenotypic transition was detected by morphological changes and the molecular markers of EMT. The activation of the TLR4/NF-κB signaling pathway induced by UA was measured by Western blot and its involvement was further confirmed by the inhibition of NF-κB activation or knockdown of toll like receptor 4 (TLR4) expression. RESULTS: UA induced obvious morphological changes of HK-2 cell, accompanied with altered molecular markers of EMT including fibronectin, α-SMA and E-cadherin. In addition, UA significantly upregulated the gene expression of interleukin-1ß and tumor necrosis factor-α in a time- and dose-dependent manner. Furthermore, UA significantly activated the TLR4/NF-κB signaling pathway in HK-2 cells, while the inhibition of the TLR4 expression by siRNA and NF-κB activation by PDTC significantly attenuated EMT induced by UA in HK-2 cells. CONCLUSIONS: UA can induce EMT in renal tubular epithelial cells by the activation of the TLR4/NF-κB signaling pathway, and the targeted intervention of the TLR4/NF-κB signaling pathway might effectively inhibit UA-induced renal interstitial fibrosis mediated by EMT.
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Transición Epitelial-Mesenquimal , FN-kappa B/metabolismo , Transducción de Señal , Receptor Toll-Like 4/metabolismo , Ácido Úrico/metabolismo , Actinas/metabolismo , Antígenos CD , Biomarcadores/metabolismo , Cadherinas/metabolismo , Línea Celular , Citocinas/metabolismo , Células Epiteliales/metabolismo , Fibronectinas , Humanos , Hiperuricemia/complicaciones , Hiperuricemia/metabolismo , Hiperuricemia/fisiopatología , Interleucina-1beta/metabolismo , Túbulos Renales/citología , Terapia Molecular Dirigida/métodos , FN-kappa B/antagonistas & inhibidores , Nefritis Intersticial/tratamiento farmacológico , Nefritis Intersticial/etiología , Pirrolidinas/farmacología , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Tiocarbamatos/farmacología , Receptor Toll-Like 4/antagonistas & inhibidores , Receptor Toll-Like 4/genética , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia ArribaRESUMEN
BACKGROUND/AIMS: Hyperphosphatemia is one of the most notable features of chronic kidney disease (CKD). Numerous epidemiological and clinical studies have found that high serum phosphate concentrations are associated with calcification in the coronary arteries. However, the mechanisms underlying the vascular calcification induced by high phosphate have not been understood fully. METHODS: Vascular smooth muscle cells (VSMCs) were cultured in high-phosphate media to induce vascular calcification, which was detected by Alizarin red S staining. Gene expression and protein levels of differentiation markers were determined by real-time RT-PCR and western blotting, respectively. Protein levels of phosphorylated NF-κB and TLR4 were detected by western blotting, and the role of NF-κB/TLR4 was further confirmed by using an NF-κB inhibitor or TLR4 siRNA. RESULTS: Our results showed that high-phosphate media induced obvious calcification of VSMCs. Simultaneously, VSMC differentiation was confirmed by the increased expression of bone morphogenetic protein-2 and Runt-related transcription factor 2 and decreased expression of the VSMC-specific marker SM22α, which was accompanied by the increased expression of inflammatory cytokines. Moreover, a significant upregulation of TLR4 and phosphorylated NF-κB was also detected in VSMCs with high-phosphate media. In contrast, VSMC calcification and the increased expression of inflammatory cytokines were markedly attenuated by pretreatment with TLR4 siRNA and pyrrolidine dithiocarbamic acid, an NF-κB inhibitor. CONCLUSION: These data suggest that high-phosphate conditions directly induce vascular calcification via the activation of TLR4/NF-κB signaling in VSMCs. Moreover, inhibition of the TLR4/NF-κB signaling pathway might be a key intervention to prevent vascular calcification in patients with CKD.
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Músculo Liso Vascular/metabolismo , Fosfatos/química , Fosfatos/farmacología , Calcificación Vascular/inducido químicamente , Células Cultivadas , Humanos , Hiperfosfatemia/complicaciones , FN-kappa B/metabolismo , Insuficiencia Renal Crónica/metabolismo , Transducción de Señal , Receptor Toll-Like 4/metabolismoRESUMEN
Increased basic fibroblast growth factor-2 (FGF2) and reduced Klotho have both been reported to be closely associated with renal fibrosis. However, the relationship between Klotho and FGF2 remains unclear. We demonstrate that FGF2 induced tubulo-epithelial plasticity in cultured HK-2 cells, accompanied by a reduction in Klotho expression, whereas recombinant Klotho protein could inhibit the action of FGF2. The FGF2 effects required extracellular signal-regulated protein kinase 1/2 activation, which was suppressed by Klotho. Moreover, Klotho also restrained FGF2-induced fibroblast proliferation and activation. The inhibitory effect of Klotho on the activity of FGF2 was likely due to its potent ability to compete with FGF2 binding to FGF receptor 1. Unilateral ureteral obstruction (UUO)-induced renal fibrosis was associated with an increase in FGF2 and a reduction in Klotho expression in wild-type mice, whereas FGF2(-/-) mice largely preserved Klotho expression and developed only mild renal fibrosis after obstructive injury. Furthermore, administration of Klotho protein in UUO mice significantly reduced renal fibrosis, concomitant with a marked suppression of FGF2 production and signalling. These studies demonstrate a feedback loop between Klotho depletion and FGF2 activation in renal fibrosis. Our results also suggest that Klotho treatment reduces renal fibrosis, at least in part, by inhibiting FGF2 signalling.
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Factor 2 de Crecimiento de Fibroblastos/metabolismo , Glucuronidasa/metabolismo , Riñón/patología , Transducción de Señal/fisiología , Animales , Western Blotting , Línea Celular , Modelos Animales de Enfermedad , Fibrosis/metabolismo , Fibrosis/patología , Técnica del Anticuerpo Fluorescente , Humanos , Inmunoprecipitación , Riñón/metabolismo , Proteínas Klotho , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Reacción en Cadena en Tiempo Real de la Polimerasa , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/patologíaRESUMEN
BACKGROUND: There are few reports of IgA nephropathy (IgAN) with antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. METHODS: The authors report the clinical and pathological findings in 14 patients with IgAN and ANCA seropositivity. RESULTS: These retrospective cases consisted of 4 men and 10 women with a mean age of 44.4 ± 12.7 years. ANCA-positivity was documented by EUROBlot kits and indirect immunofluorescence in all patients. The results of EUROBlot kits were positive in 14 patients (12 MPO-ANCA, 2 PR3-ANCA). Indirect immunofluorescence was positive in 14 patients (12 P-ANCA, 2 C-ANCA). Three of 14 IgAN with ANCA-positive patients showed severe clinical manifestations with crescents involving a mean of 56% glomeruli, including heavy proteinuria (mean 24-hour urine protein: 3.8 g/d), hematuria and acute renal failure (mean creatinine: 4.5 ± 3.7 mg/dL). The remaining 11 patients with no crescents showed various degrees of proteinuria (mean 24-hour urine protein: 2.4 ± 2.4 g/d), hematuria and serum creatinine levels (median creatinine: 0.9 (IQR, 0.5 - 1.4) mg/dL). The follow-up period for 10 patients had an average length of 14.0 ± 11.2 months. Among the three patients with crescents who had been treated with steroids and cyclophosphamide, one patient became dialysis dependent at the time of biopsy and remained on dialysis after treatment, another died of acute heart failure, and the last one showed improvement in renal function after treatment and did not develop end-stage renal disease (ESRD) 26 months after renal biopsy. The remaining 7 patients with no crescents were treated with steroids, cyclophosphamide, renin-angiotensin system inhibitors, and/or Traditional Chinese Medicine; 6 had stabilized or improved renal function and one progressed to ESRD with worsening renal function. CONCLUSIONS: These findings suggest not all ANCAs are involved in the pathology of IgAN. In patients with IgAN and ANCAs, identification of pathogenic vs. non-pathogenic ANCAs is recommended.
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Anticuerpos Anticitoplasma de Neutrófilos/sangre , Glomerulonefritis por IGA , Lesión Renal Aguda , Adulto , Femenino , Glomerulonefritis por IGA/sangre , Glomerulonefritis por IGA/epidemiología , Glomerulonefritis por IGA/fisiopatología , Hematuria , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Nephrotoxicity is a common complication of cisplatin chemotherapy and thus limits the use of cisplatin in clinic. The purinergic 2X7 receptor (P2X7R) plays important roles in inflammation and apoptosis in some inflammatory diseases; however, its roles in cisplatin-induced nephrotoxicity remain unclear. In this study, we first assessed the expression of P2X7R in cisplatin-induced nephrotoxicity in C57BL/6 mice, and then we investigated the changes of renal function, histological injury, inflammatory response, and apoptosis in renal tissues after P2X7R blockade in vivo using an antagonist A-438079. Moreover, we measured the changes of nod-like receptor family, pyrin domain containing proteins (NLRP3) inflammasome components, oxidative stress, and proapoptotic genes in renal tissues in cisplatin-induced nephrotoxicity after treatment with A-438079. We found that the expression of P2X7R was significantly upregulated in the renal tubular epithelial cells in cisplatin-induced nephrotoxicity compared with that of the normal control group. Furthermore, pretreatment with A-438079 markedly attenuated the cisplatin-induced renal injury while lightening the histological damage, inflammatory response and apoptosis in renal tissue, and improved the renal function. These effects were associated with the significantly reduced levels of NLRP3 inflammasome components, oxidative stress, p53 and caspase-3 in renal tissues in cisplatin-induced nephrotoxicity. In conclusions, our studies suggest that the upregulated activity of P2X7R might play important roles in the development of cisplatin-induced nephrotoxicity, and P2X7R blockade might become an effective therapeutic strategy for this disease.
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Lesión Renal Aguda/metabolismo , Caspasa 3/metabolismo , Cisplatino/toxicidad , Inflamasomas/metabolismo , Estrés Oxidativo/fisiología , Antagonistas del Receptor Purinérgico P2X/farmacología , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/prevención & control , Animales , Relación Dosis-Respuesta a Droga , Inflamasomas/antagonistas & inhibidores , Masculino , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Antagonistas del Receptor Purinérgico P2X/uso terapéutico , Piridinas/farmacología , Piridinas/uso terapéutico , Receptores Purinérgicos P2X7/metabolismo , Tetrazoles/farmacología , Tetrazoles/uso terapéuticoRESUMEN
The aim was to explore the effects of rapamycin on autophagy and injury of podocytes in streptozocin (STZ)-induced type 1 diabetic mice, and its role in delaying progression of diabetic nephropathy. In this study, male Balb/c mice were divided into three groups: control (n = 12), STZ-induced diabetic (n = 12), and rapamycin-treated diabetic (DM + Rapa) (n = 12), which received intraperitoneal injection of rapamycin (2 mg/kg/48 h) after induction of DM. Levels of urinary albumin (UA), blood urea nitrogen, serum creatinine, and kidney weight/body weight were measured at week 12. Renal pathologic changes, number of podocytes autophagy, and organelles injury were investigated by PAS staining, transmission electron microscopy, and immunofluorescence staining, respectively. Western blot was performed to determine the expression of LC3 (a podocyte autophagy marker), phosphorylated mammalian target of rapamycin, p-p70S6K, bax, and caspase-3 protein. Podocytes count was evaluated by immunofluorescence staining and Wilms tumor 1 immunohistochemistry, and Western blot of nephrin and podocin. The results indicated that rapamycin could reduce the kidney weight/body weight and UA secretion. It could alleviate podocyte foot process fusion, glomerular basement membrane thickening, and matrix accumulation, and increase the number of autophagosomes, and LC3-expressing podocytes. Down-regulation of bax and caspase-3 protein, and up-regulation of nephrin and podocin protein were observed in the glomeruli of diabetic mice after administration of rapamycin. In conclusion, rapamycin can ameliorate renal injury in diabetic mice by increasing the autophagy activity and inhibition of apoptosis of podocytes.
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Autofagia/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Nefropatías Diabéticas/prevención & control , Podocitos/efectos de los fármacos , Sirolimus/farmacología , Albuminuria/etiología , Albuminuria/prevención & control , Animales , Biomarcadores/sangre , Nitrógeno de la Urea Sanguínea , Caspasa 3/metabolismo , Citoprotección , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/complicaciones , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/patología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Ratones Endogámicos BALB C , Proteínas Asociadas a Microtúbulos/metabolismo , Podocitos/metabolismo , Podocitos/ultraestructura , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Factores de Tiempo , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Purpose: We compared pulmonary function indices and quantitative CT parameters of airway remodeling, air trapping, and emphysema in asthmatic patients and patients with COPD and asthma-COPD overlap (ACO) and explored their relationships with airflow limitation. Patients and Methods: Patients with asthma (n=48), COPD (n=52), and ACO (n=30) and controls (n=54) who completed pulmonary function tests and HRCT scans were retrospectively enrolled in our study. Quantitative CT analysis software was used to assess emphysema (LAA%), airway wall dimensions (wall area (WA), luminal area (LA), and wall area percentage (WA%)), and air trapping ((relative volume change of -860 HU to -950 HU (RVC-860 to-950) and the expiration-to-inspiration ratio of the mean lung density (MLDE/I))). Differences in pulmonary function and HRCT parameters were compared among the groups. Spearman correlation analysis and regression analysis were utilized to explore structureâfunction relationships. Results: The LAA% in COPD and ACO patients was significantly greater than that in asthmatic patients and controls. The WA% and WA in COPD and ACO patients were greater than those in controls, whereas the WA% and LA between asthmatic patients and controls reached statistical significance. The RVC-860 to -950 levels decreased in the following order: ACO, COPD, and asthma. RVC-860 to -950 independently predicted FEV1% in asthmatic patients; LAA% and MLDE/I in COPD patients; and LAA%, WA% and RVC-860 to -950 in ACO patients. Conclusion: Comparable emphysema was observed in patients with COPD and ACO but not in asthmatic patients. All patients exhibited proximal airway remodeling. The bronchi were thickened outward in COPD and ACO patients but are thickened inward in asthmatic patients. Furthermore, air trapping in ACO patients was the most severe among all the groups. Indirect lung densitometry measurements might be more predictive of the degree of airflow limitation than direct airway measurements in obstructive airway diseases.
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Remodelación de las Vías Aéreas (Respiratorias) , Síndrome de Superposición de la Enfermedad Pulmonar Obstructiva Crónica-Asmática , Asma , Pulmón , Valor Predictivo de las Pruebas , Enfermedad Pulmonar Obstructiva Crónica , Enfisema Pulmonar , Humanos , Masculino , Femenino , Persona de Mediana Edad , Pulmón/fisiopatología , Pulmón/diagnóstico por imagen , Estudios Retrospectivos , Asma/fisiopatología , Asma/diagnóstico por imagen , Asma/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico por imagen , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Anciano , Enfisema Pulmonar/fisiopatología , Enfisema Pulmonar/diagnóstico por imagen , Volumen Espiratorio Forzado , Síndrome de Superposición de la Enfermedad Pulmonar Obstructiva Crónica-Asmática/fisiopatología , Síndrome de Superposición de la Enfermedad Pulmonar Obstructiva Crónica-Asmática/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Adulto , Capacidad Vital , Pruebas de Función Respiratoria , Tomografía Computarizada MultidetectorRESUMEN
BACKGROUND: It is well established that residence migration can negatively affect the mental health of adolescents. However, the related factors that mediate the association between residence migration and depression are still uncertain. METHODS: The participants were 16,037 adolescents in junior middle schools. A self-administered questionnaire was used for the survey. In addition to collecting general demographic characteristics of the participants, including age, gender, local residence status, only child status, parental marriage status and parent-child relationship, the questionnaire also contained the 9-item Patient Health Questionnaire, the short form of the Childhood Trauma Questionnaire and the Connor-Davidson Resilience Scale. Data analysis was conducted using SPSS software. RESULTS: A total of 14,059 valid questionnaires were collected, resulting in 12,122 local adolescents, defined as being born and raised locally, and 1937 migrant adolescents, defined as being transferred from other regions. Meanwhile, 53.3 % of local adolescents and 58.2 % of migrant adolescents reported depressive symptoms. This result indicated that residence migration might contribute to depression symptoms(OR = 1.136, 95%CI: 1.013-1.273, p < 0.05). Childhood maltreatment and parental divorce are risk factors for depression in migrant adolescents. For all adolescents, resilience and a good parent-child relationship may reduce the risk of depression. Childhood maltreatment completely mediates residence migration-related depression(95 % bootstrap CI = 0.146, 0.323). CONCLUSION: This study revealed that residence migration could contribute to adolescent depression, and childhood maltreatment may largely mediate this process, providing new insight into the relationship between adolescent depressive symptoms and residence migration. Reducing childhood maltreatment may effectively improve the depressive symptoms of migrant adolescents.
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Maltrato a los Niños , Depresión , Humanos , Adolescente , Niño , Depresión/epidemiología , Depresión/psicología , Maltrato a los Niños/psicología , Encuestas y Cuestionarios , Instituciones Académicas , Factores de RiesgoRESUMEN
Mesenchymal stem cells (MSC) attenuate albuminuria and preserve normal renal histology in diabetic mice. However, the effects of MSC on glomerular podocyte injury remain uncertain. The aim of this study was to evaluate the effects of MSC on podocyte injury in streptozotocin (STZ)-induced diabetic rats. Thirty days after diabetes induction by STZ injection (65 mg/kg, intraperitoneally) in Sprague-Dawley rats, the diabetic rats received medium or 2 × 10(6) enhanced green fluorescent protein-labeled MSC via the renal artery. In vivo tracking of MSC was followed by immunofluorescence analysis. Diabetes-related physical and biochemical parameters were measured on day 60 after the MSC infusion. The expression of podocyte markers (nephrin and podocin), podocyte survival factors (VEGF and BMP-7), and the ultrastructural pathology of podocytes were also assessed. MSC were only detected in the glomeruli from the left kidney receiving MSC infusion. Compared with medium-treated diabetic rats, rats treated with MSC showed a suppressed increase in kidney weight, kidney to body weight index, creatinine clearance rate, and urinary albumin to creatinine ratio; however, the treatment had no effect on blood glucose or body weight levels. Furthermore, the MSC treatment reduced the loss of podocytes, effacement of foot processes, widening of foot processes, thickening of glomerular basal membrane (GBM), and loss of glomerular nephrin and podocin. Most important, MSC-injected kidneys expressed higher levels of BMP-7 but not of VEGF. Our results clearly demonstrated that intra-arterial administration of MSC prevented the development of albuminuria as well as any damage to or loss of podocytes, though there was no improvement in blood sugar levels. The protective effects of MSC may be mediated in part by increasing BMP-7 secretion.
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Diabetes Mellitus Experimental/patología , Nefropatías Diabéticas/prevención & control , Riñón/patología , Células Madre Mesenquimatosas/citología , Podocitos/patología , Proteinuria/patología , Proteinuria/prevención & control , Animales , Biomarcadores/metabolismo , Glucemia/metabolismo , Proteína Morfogenética Ósea 7/genética , Proteína Morfogenética Ósea 7/metabolismo , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/terapia , Nefropatías Diabéticas/inducido químicamente , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Expresión Génica , Genes Reporteros , Proteínas Fluorescentes Verdes , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Riñón/metabolismo , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/metabolismo , Ratones , Podocitos/metabolismo , Proteinuria/inducido químicamente , Proteinuria/metabolismo , Ratas , Ratas Sprague-Dawley , Estreptozocina , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Age is closely related to human health and disease risks. However, chronologically defined age often disagrees with biological age, primarily due to genetic and environmental variables. Identifying effective indicators for biological age in clinical practice and self-monitoring is important but currently lacking. The human lens accumulates age-related changes that are amenable to rapid and objective assessment. Here, using lens photographs from 20 to 96-year-olds, we develop LensAge to reflect lens aging via deep learning. LensAge is closely correlated with chronological age of relatively healthy individuals (R2 > 0.80, mean absolute errors of 4.25 to 4.82 years). Among the general population, we calculate the LensAge index by contrasting LensAge and chronological age to reflect the aging rate relative to peers. The LensAge index effectively reveals the risks of age-related eye and systemic disease occurrence, as well as all-cause mortality. It outperforms chronological age in reflecting age-related disease risks (p < 0.001). More importantly, our models can conveniently work based on smartphone photographs, suggesting suitability for routine self-examination of aging status. Overall, our study demonstrates that the LensAge index may serve as an ideal quantitative indicator for clinically assessing and self-monitoring biological age in humans.