Translational research : the journal of laboratory and clinical medicine
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During the progression of diabetic kidney disease (DKD), renal lactate metabolism is rewired. The relationship between alterations in renal lactate metabolism and renal fibrosis in patients with diabetes has only been partially established due to a lack of biopsy tissues from patients with DKD and the intricate mechanism of lactate homeostasis. The role of lactate dehydrogenase A (LDHA)-mediated lactate generation in renal fibrosis and dysfunction in human and animal models of DKD was explored in this study. ⋯ We found that the pathogenesis of DKD is linked to hypoxia-mediated lactic acidosis, which leads to fibrosis and mitochondrial abnormalities. The pathogenic characteristics of DKD were significantly reduced when aerobic glycolysis or LDHA expression was inhibited. Further studies will aim to investigate whether local acidosis caused by renal LDHA might be exploited as a therapeutic target in patients with DKD.
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Chronic oxidative stress, which is caused by aberrant non-receptor tyrosine kinase (c-Abl) signaling, plays a key role in the progression of β-cell loss in diabetes mellitus. Recent studies, however, have linked ferroptotic-like death to the β-cell loss in diabetes mellitus. Here, we report that oxidative stress-driven reduced/oxidized glutathione (GSH/GSSG) loss and proteasomal degradation of glutathione peroxidase 4 (GPX4) promote ferroptotic-like cell damage through increased lipid peroxidation. ⋯ Inhibition of GLS1 suppresses the ERRγ agonist DY131-induced GSH/GSSG ratio linked to ferroptotic-like death owing to the loss of GPX4. Furthermore, immunohistochemical analysis showed enhanced ERRγ and GPX4 expression in the pancreatic islets of GNF2-treated mice compared to that in streptozotocin-treated mice. Altogether, our results provide the first evidence that the orphan nuclear receptor ERRγ-induced GLS1 expression augments the glutathione antioxidant system, and its downstream signaling leads to improved β-cell function and survival under oxidative stress conditions.
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Patients with sickle cell disease (SCD) have ongoing hemolysis that promotes endothelial injury, complement activation, inflammation, vaso-occlusion, ischemia-reperfusion pathophysiology, and pain. Complement activation markers are increased in SCD in steady-state and further increased during vaso-occlusive crisis (VOC). However, the mechanisms driving complement activation in SCD have not been completely elucidated. ⋯ Importantly, MASP-2 or MASP-3 mAb pretreatment significantly inhibited microvascular stasis (vaso-occlusion) induced by hypoxia-reoxygenation or hemoglobin. These studies suggest that the LP and the AP are both playing a role in promoting inflammation and vaso-occlusion in SCD. Inhibiting complement activation via the LP or the AP might inhibit inflammation and prevent VOC in SCD patients.
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As an anti-inflammatory strategy, MAPK-activated protein kinase-2 (MK2) inhibition can potentially avoid the clinical failures seen for direct p38 inhibitors, especially tachyphylaxis. CC-99677, a selective targeted covalent MK2 inhibitor, employs a rare chloropyrimidine that bonds to the sulfur of cysteine 140 in the ATP binding site via a nucleophilic aromatic substitutions (SNAr) mechanism. This irreversible mechanism translates biochemical potency to cells shown by potent inhibition of heat shock protein 27 (HSP27) phosphorylation in LPS-activated monocytic THP-1 cells. ⋯ Dosed orally, CC-99677 is efficacious in a rat model of ankylosing spondylitis. Single doses, 3 to 400 mg, in healthy human volunteers show linear pharmacokinetics and apparent sustained tumor necrosis factor-α inhibition, with a favorable safety profile. These results support further development of CC-99677 for autoimmune diseases like ankylosing spondylitis.