Translational research : the journal of laboratory and clinical medicine
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Glomeruli stand at the center of nephrons to accomplish filtration and albumin interception. Podocytes and mesangial cells are the major constituents in the glomeruli. However, their interdependency in glomerular injury has rarely been reported. ⋯ In cultured mesangial cells, AngII treatment induced the expression of SDF-1α, which was secreted into the supernatant to further promote oxidative stress and cell injury in podocytes. Collectively, these results demonstrate that the CXCR4-AT1 axis plays a vital role in glomerular injury via mediating pathologic crosstalk between podocytes and mesangial cells. Our findings uncover a novel pathogenic mechanism by which the CXCR4-AT1 axis promotes glomerular injury.
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Orthotopic liver transplantation (OLT) is a lifesaving procedure. However, grafts may fail due to primary nonfunction (PNF). In the past, we demonstrated PNFs to be mainly associated with fatty allografts, and given its unpredictable nature, the development of a disease model is urgently needed. ⋯ Thus, lipid-laden hepatocytes fail to perform gluconeogenesis via lactate reutilization, and the resultant hyperlactatemia and lactic acidosis causes cardiac arrhythmogenicity and death. Furthermore, the genomic and immunohistochemistry investigations underscore a dysfunctional Krebs cycle with impaired energy metabolism in lipid-burdened mitochondria. Together, we show fatty allografts to be highly vulnerable towards ischemia/reperfusion-injury, and stabilizing the Cori cycle is of critical importance to avert PNFs.
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Diabetic nephropathy (DN) is one of the complications of diabetes. Long-term hyperglycemia in the kidney results in renal insufficiency, and eventually leads to end-stage renal disease. Epigenetic factor ASH2L has long been identified as a transcriptional activator, and we previously indicated that ASH2L aggravated fibrosis and inflammation in high glucose-induced glomerular mesangial cells, but the pathophysiological relevance and the mechanism of ASH2L-mediated H3K4me3 in DN is not well understood. ⋯ Loss of ASH2L protected glomerular injury caused by hyperglycemia, as evidenced by reduced albuminuria, preserved structure, decreased glomerular extracellular matrix deposition, and lowered renal glomerular expression of proinflammatory and profibrotic markers in db/db mice. Furthermore, we demonstrated that enrichment of ASH2L-mediated H3K4me3 on the promoter regions of ADAM17 and HIPK2 triggered their transcription, leading to aberrant activation of Notch1 signaling pathway, thereby contributing to fibrosis and inflammation in DN. The findings of this study provide compelling evidence for targeting ASH2L as a potential therapeutic strategy to prevent or slow down the progression of DN.
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To investigate the role of S-palmitoylation in pyroptosis following acute myocardial infarction (AMI). Myocardial ischemic injury is mainly related to the death of terminally differentiated cardiomyocytes. Pyroptosis is a new form of programmed cell death and recently is identified a potential mechanism of cardiomyocyte loss. ⋯ The short-term palmitic acid dietary intake or ML348 deteriorates myocardial pyroptosis, infarct size and cardiac function in AMI mice by GSDMD palmitoylation. Disulfiram antagonizes Cys192 palmitoylation of GSDMD-N-terminal and reduces myocardial pyroptosis and injury in AMI mice. We identifies ZHDDC14 induced palmitoylation as a crucial node for modulating GSDMD-N-terminal cytomembrane localization and establishes Disulfiram targeting GSDMD Cys192 palmitoylation as a potential clinical intervention for myocardial pyroptosis.
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To reveal dysregulated metabolism hallmark that was associated with a severe acute pancreatitis (SAP) phenotype. In this study, LC-MS/MS-based targeted metabolomics was used to analyze plasma samples from 106 acute pancreatitis (AP) patients (34 mild, 38 moderate, and 34 severe) admitted within 48 hours from abdominal pain onset and 41 healthy controls. Temporal metabolic profiling was performed on days 1, 3, and 7 after admission. ⋯ The abnormally expressed arginase2 and ornithine transcarboxylase were further discovered in combination with time-course metabolic profiling in the SAP animal models, the decreased ornithine catabolites were found at a late stage of inflammation, but ornithine-associated metabolic enzymes were activated during the inflammatory process. The plasma metabolome of AP patients is distinctive, which shows promise for early SAP diagnosis. AP aggravation is linked to the activated ornithine metabolic pathway and its inadequate levels of catabolites in in-situ lesion.