ABSTRACT
OBJECTIVE: Renal ischemia/reperfusion injury (IRI) is a major cause of acute kidney injury (AKI), which is associated with high incidence and mortality. AST-120 is an oral carbonaceous adsorbent that can alleviate kidney damage. This study aimed to explore the effects of AST-120 on renal IRI and the molecular mechanism. METHODS: A renal IRI mouse model was established and administrated AST-120, and differentially expressed genes were screened using RNA sequencing. Renal function and pathology were analyzed in mice. Hypoxia/reoxygenation (H/R) cell model was generated, and glycolysis was evaluated by detecting lactate levels and Seahorse analysis. Histone lactylation was analyzed by western blotting, and its relationship with hexokinase 2 (HK2) was assessed using chromatin immunoprecipitation. RESULTS: The results showed that HK2 expression was increased after IRI, and AST-120 decreased HK2 expression. Knockout of HK2 attenuated renal IRI and inhibits glycolysis. AST-120 inhibited renal IRI in the presence of HK2 rather than HK2 absence. In proximal tubular cells, knockdown of HK2 suppressed glycolysis and H3K18 lactylation caused by H/R. H3K18 lactylation was enriched in HK2 promoter and upregulated HK2 levels. Rescue experiments revealed that lactate reversed IRI that suppressed by HK2 knockdown. CONCLUSIONS: In conclusion, AST-120 alleviates renal IRI via suppressing HK2-mediated glycolysis, which suppresses H3K18 lactylation and further reduces HK2 levels. This study proposes a novel mechanism by which AST-120 alleviates IRI.
Subject(s)
Carbon , Disease Models, Animal , Glycolysis , Hexokinase , Oxides , Reperfusion Injury , Reperfusion Injury/metabolism , Reperfusion Injury/drug therapy , Animals , Hexokinase/metabolism , Hexokinase/genetics , Glycolysis/drug effects , Mice , Male , Oxides/pharmacology , Acute Kidney Injury/metabolism , Acute Kidney Injury/drug therapy , Acute Kidney Injury/etiology , Acute Kidney Injury/pathology , Kidney/metabolism , Kidney/pathology , Kidney/drug effects , Mice, Inbred C57BL , Histones/metabolism , Humans , Cell LineABSTRACT
CTBP1 has been demonstrated as a co-repressor in the transcriptional regulation of downstream genes and is involved in various cell process. However, the mechanism of CTBP1 in the progression of prostate cancer is still unclear. Here, we aim to investigate how CTBP1 exerts its role in prostate cancer progression, especially how CTBP1 was regulated by the upstream genes. We found that CTBP1 was highly expressed in prostate cancer and promoted the cell viability, migration, invasion and glycolysis of prostate cancer cells. CDH1 was verified to be the target of CTBP1. We determined that CTBP1 could directly bind with SP1 to inhibit the transcription of CDH1. Moreover, succinylation of CTBP1 was found to be up-regulated in prostate cancer cell. Further studies demonstrated that KAT2A promotes the succinylation of CTBP1 and mediates the transcription suppressing activity of it. In addition, the K46 and K280 was confirmed to be the two sites that regulated by KAT2A. In vivo studies further indicated that CTBP1 could promote the growth of prostate cancer, and this effect of CTBP1 could be partially reversed by KAT2A knockdown. Taken together, we found that succinylation of CTBP1 mediated by KAT2A suppresses the inhibitory activity of CTBP1 on the transcription of CDH1, thus act as an oncogene.
Subject(s)
DNA-Binding Proteins , Prostatic Neoplasms , Humans , Male , Alcohol Oxidoreductases/metabolism , Antigens, CD , Cadherins/metabolism , Cell Line, Tumor , DNA-Binding Proteins/metabolism , Gene Expression Regulation, Neoplastic , Histone Acetyltransferases/metabolism , Prostatic Neoplasms/genetics , Transcription Factors/metabolismABSTRACT
BACKGROUND: This study aims to explore the combined effect of frailty and the estimated glomerular filtration rate (eGFR) and non-elective hospital readmission in elderly inpatients. METHODS: A total of 400 elderly patients were selected. The Fried scale was used to assess frailty. The patients were divided into a non-frailty group and a frailty group. They were divided into a normal eGFR group and a eGFR decreased group. Finally, the patients were divided into the following four groups: Group A (no frailty + eGFR normal); Group B (no frailty + eGFR decreased); Group C (frailty + eGFR normal); and Group D (frailty + eGFR decreased). RESULTS: The results of the follow-up survival analysis showed the non-elective hospital readmission within 6 months of discharge. Group A, Group B, Group C, and Group D had an incidence of 21%, 26%, 24%, and 36%, respectively. The Kaplan-Meier curves showed the event-free survival rates of Group A and Group C were higher than that of Group D, and there was no significant difference between Group B and Group D. The risk of non-elective hospital readmission within 6 months in patients with a decreased eGFR was 1.777 times higher than that in patients with a normal eGFR [95% confidence interval (CI): 1.001-3.154], while the risk of non-elective hospital readmission within 6 months in frail patients and non-frail patients did not differ significantly. The multivariate Cox regression analysis showed that the risk of non-elective hospital readmission in Group D was 2.295 times higher than that in Group A (95% CI: 1.096-4.810), and the difference was statistically significant. The risk of non-elective hospital readmission in Group B was 1.401 times of that in Group A (95% CI: 0.665-2.953), while that in Group C was 91.8% (95% CI: 0.403-2.092), but the differences were not statistically significant. CONCLUSIONS: A decline in eGFR is associated with non-elective hospital readmission in elderly inpatients within 6 months; however, frailty is not associated with non-elective hospital readmission. The combined effect of frailty and eGFR in elderly inpatients is related to non-elective hospital readmission.