ADD (Metabolic Pharmaceuticals)

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by neurofibrillary tangles (NFTs), senile plaques from Aβ deposits, neuronal inflammation, oxidative stress, and impaired neuronal transmission involving acetylcholine and glutamate. Diabetes patients are at a higher risk of developing AD-like pathology due to shared pathological and molecular mechanisms, including insulin resistance, oxidative stress, formation of advanced glycation end products (AGEs), and overactive immune systems. Current treatments of AD typically address only one aspect of the disease, rather than treating it as a multifactorial process. Targeting cerebral glucose-insulin metabolism has emerged as a promising strategy for AD management. Numerous studies show positive correlations between anti-diabetic drugs and AD management. Among these, DPP IV inhibitors have demonstrated significant therapeutic benefits against AD in experimental settings. DPP IV inhibitors have been shown to significantly reduce Aβ oligomerization, phosphorylated tau (p-tau), oxidative stress, and inflammatory markers, presenting a potentially effective approach for targeting AD-like pathology. Although preclinical data are promising, clinical trials are needed to validate these findings and establish the safety and efficacy of DPP IV inhibitors as a therapeutic intervention for AD. This could represent a novel approach for addressing both the metabolic and neurodegenerative aspects of AD.

Preeclampsia (PE) is a serious pregnancy complication characterized by elevated blood pressure and a major cause of maternal and perinatal morbidities, also known to increase the risk of chronic kidney disease. Mechanisms underlying PE-induced kidney injury remain unclear. Anti-angiotensin II type 1 receptor agonistic autoantibody (AT1-AA) is reported to participate in the pathogenesis of PE-induced kidney injury. Our previous study replicated the major features of PE in pregnant mice by administration of intravenous injection of AT1-AA and found that podocyte senescence plays a role in PE-induced kidney injury. Elevated levels of N-acetyl-β-D glucosaminidase (NAG) and kidney injury molecule-1 (KIM-1) in the urine of patients with PE have been reported, indicating renal tubular injury. In this study, we identified the role of renal proximal tubular epithelial cells (PTECs) in PE-induced kidney injury and the therapeutic value of empagliflozin, an anti-diabetic agent, in a murine model of AT1-AA-induced PE. In our study, higher tubular injury score (Control vs. PE: P < 0.0001) show that PTECs are damaged in AT1-AA-induced PE. We identified ferroptosis as one of the cause of AT1-AA-induced PTEC injury by RNAseq, and confirmed the involvement of ferroptosis by detecting ferrous iron (Control vs. PE: P < 0.0001), reduced glutathione (GSH) (Control vs. PE: P < 0.0001) and lipid peroxidation (Control vs. PE: P < 0.0001). Empagliflozin ameliorates AT1-AA-induced PTEC ferroptosis and injury in PE. Furthermore, we demonstrated that tazarotene-induced gene 1 is involved in AT1-AA-induced PTEC injury. These findings suggest that renal tubules are injured in PE and empagliflozin has therapeutic potential for PE-induced PTEC injury.