Translational research : the journal of laboratory and clinical medicine
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Despite optimal medical therapy, many patients with diabetic kidney disease (DKD) progress to end-stage renal disease. The identification of new biomarkers and drug targets for DKD is required for the development of more effective therapies. The apoptosis of renal tubular epithelial cells is a key feature of the pathogenicity associated with DKD. ⋯ Based on transcriptome sequencing, molecular mechanism exploration revealed that SIK2 overexpression reduces endoplasmic reticulum (ER) stress-mediated tubular epithelial apoptosis by inhibiting the histone acetyltransferase activity of p300 to activate HSF1/Hsp70. Furthermore, the specific restoration of SIK2 in tubules blunts tubular and interstitial impairments in diabetic and vancomycin-induced kidney disease mice. Together, these findings indicate that SIK2 protects against renal tubular injury and the progression of kidney disease, and make a compelling case for targeting SIK2 for therapy in DKD.
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Human body fluids have become an indispensable resource for clinical research, diagnosis and prognosis. Urine is widely used to discover disease-specific glycoprotein biomarkers because of its recurrently non-invasive collection and disease-indicating properties. While urine is an unstable fluid in that its composition changes with ingested nutrients and further as it is excreted through micturition, urinary proteins are more stable and their abnormal glycosylation is associated with diseases. ⋯ In this article, we evaluate the clinical applications of urine, introduce methods for urine glycosylation analysis, and discuss urine glycoprotein biomarkers. We emphasize the importance of mining urinary glycoproteins and searching for disease-specific glycosylation in various diseases (including cancer, neurodegenerative diseases, diabetes, and viral infections). With advances in mass spectrometry-based glycomics/glycoproteomics/glycopeptidomics, characterization of disease-specific glycosylation will optimistically lead to the discovery of disease-related urinary biomarkers with better sensitivity and specificity in the near future.
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Multicenter Study
Expression and function of α4β7 integrin predict the success of vedolizumab treatment in inflammatory bowel disease.
Inflammatory bowel diseases are medically intractable and require constant therapy in many cases. While a growing number of biologicals and small molecules is available for treatment, a substantial portion of patients experiences primary non-response to these compounds and head-to-head evidence for therapy selection is scarce. Thus, approaches to predict treatment success in individual patients are a huge unmet need. ⋯ Moreover, high dynamic adhesion of CD4+ T cells to MAdCAM-1 and high reduction of adhesion by vedolizumab in vitro at baseline were associated with clinical remission. These data substantiate the potential of α4β7 integrin function and expression to forecast outcomes of vedolizumab therapy. Further translational efforts are necessary to improve the performance of the assays and to implement the concept in clinical practice.
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Nephrotoxicity is a major side effect of cisplatin, a widely used cancer therapy drug. However, the mechanism of cisplatin nephrotoxicity remains unclear and no effective kidney protective strategies are available. Here, we report the induction of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) in both in vitro cell culture and in vivo mouse models of cisplatin nephrotoxicity. ⋯ Mechanistically, we demonstrated the interaction of PFKFB3 with cyclin-dependent kinase 4 (CDK4) during cisplatin treatment, resulting in CDK4 activation and consequent phosphorylation and inactivation of retinoblastoma tumor suppressor (Rb). Inhibition of CDK4 reduced cisplatin-induced apoptosis in RPTCs and kidney injury in mice. Collectively, this study unveils a novel pathological role of PFKFB3 in cisplatin nephrotoxicity through the activation of the CDK4/Rb pathway, suggesting a new kidney protective strategy for cancer patients by blocking PFKFB3.