Browsing by Subject "Glycation"

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    Mechanism of increased clearance of glycated albumin by proximal tubule cells
    (The American Physiological Society, 2016-05-01) Wagner, Mark C.; Myslinski, Jered; Pratap, Shiv; Flores, Brittany; Rhodes, George; Campos-Bilderback, Silvia B.; Sandoval, Ruben M.; Kumar, Sudhanshu; Patel, Monika; Ashish; Molitoris, Bruce A.; Medicine, School of Medicine
    Serum albumin is the most abundant plasma protein and has a long half-life due to neonatal Fc receptor (FcRn)-mediated transcytosis by many cell types, including proximal tubule cells of the kidney. Albumin also interacts with, and is modified by, many small and large molecules. Therefore, the focus of the present study was to address the impact of specific known biological albumin modifications on albumin-FcRn binding and cellular handling. Binding at pH 6.0 and 7.4 was performed since FcRn binds albumin strongly at acidic pH and releases it after transcytosis at physiological pH. Equilibrium dissociation constants were measured using microscale thermophoresis. Since studies have shown that glycated albumin is excreted in the urine at a higher rate than unmodified albumin, we studied glucose and methylgloxal modified albumins (21 days). All had reduced affinity to FcRn at pH 6.0, suggesting these albumins would not be returned to the circulation via the transcytotic pathway. To address why modified albumin has reduced affinity, we analyzed the structure of the modified albumins using small-angle X-ray scattering. This analysis showed significant structural changes occurring to albumin with glycation, particularly in the FcRn-binding region, which could explain the reduced affinity to FcRn. These results offer an explanation for enhanced proximal tubule-mediated sorting and clearance of abnormal albumins.
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    Oncostatin M Improves Cutaneous Wound Re-Epithelialization and Is Deficient under Diabetic Conditions
    (Elsevier, 2022) Das, Amitava; Madeshiya, Amit K.; Biswas, Nirupam; Ghosh, Nandini; Gorain, Mahadeo; Rawat, Atul; Mahajan, Sanskruti P.; Khanna, Savita; Sen, Chandan K.; Roy, Sashwati; Surgery, School of Medicine
    Impaired re-epithelialization characterized by hyperkeratotic non-migratory wound epithelium is a hallmark of non-healing diabetic wounds. In chronic wounds, copious release of oncostatin M (OSM) from wound macrophages is evident. OSM is a potent keratinocyte activator. This work sought to understand the signal transduction pathway responsible for wound-re-epithelialization, the primary mechanism underlying wound closure. Daily topical treatment of full-thickness excisional wounds of C57bl/6 mice with recombinant murine OSM improved wound re-epithelialization and accelerated wound closure by bolstering keratinocyte proliferation and migration. OSM activated the JAK-STAT pathway as manifested by STAT3 phosphorylation. Such signal transduction in the human keratinocyte induced TP63, the master regulator of keratinocyte function. Elevated TP63 induced integrin beta 1, a known effector of keratinocyte migration. In diabetic wounds, OSM was more abundant compared to the level in non-diabetic wounds. However, in diabetic wounds OSM activity was compromised by glycation. Aminoguanidine, a deglycation agent, rescued compromised keratinocyte migration caused by glycated OSM. Finally, topical application of recombinant OSM improved keratinocyte migration and accelerated wound closure in db/db mice. This work recognizes that despite its abundance at the wound-site, OSM is inactivated by glycation and topical delivery of exogenous OSM is likely to be productive in accelerating diabetic wound closure.