Peripheral origin exosomal micro RNAs aggravate glymphatic system dysfunction in diabetic cognitive impairment

Cognitive dysfunction is one of the common central nervous systems(CNS)complications of diabetes mellitus,which seriously affects the quality of life of patients and results in a huge economic burden.The glymphatic system dysfunction mediated by aquaporin-4(AQP4)loss or redistribution in perivascular astrocyte endfeet plays a crucial role in diabetes-induced cognitive impairment(DCI).However,the mechanism of AQP4 loss or redistribution in the diabetic states remains unclear.Accumulating evidence suggests that peripheral insulin resistance target tissues and CNS communication affect brain homeostasis and that exosomal miRNAs are key mediators.Glucose and lipid metabolism disorder is an important pathological feature of diabetes mellitus,and skeletal muscle,liver and adipose tissue are the key target insulin resistance organs.In this review,the changes in exosomal miRNAs induced by peripheral metabolism disorders in diabetes mellitus were systematically reviewed.We focused on exosomal miRNAs that could induce low AQP4 expression and redistribution in perivascular astrocyte endfeet,which could provide an interorgan communication pathway to illustrate the pathogenesis of DCI.Furthermore,the mechanisms of exosome secretion from peripheral insulin resistance target tissue and absorption to the CNS were summarized,which will be beneficial for proposing novel and feasible strategies to optimize DCI prevention and/or treatment in diabetic patients.

Tu-Xian Decoction ameliorates diabetic cognitive impairment by inhibiting DAPK-1

Tu-Xian decoction(TXD),a traditional Chinese medicine(TCM)formula,has been frequently administered to manage diabetic cognitive impairment(DCI).Despite its widespread use,the mechanisms underlying TXD’s protective effects on DCI have yet to be fully elucidated.As a significant regulator in neurodegenerative conditions,death-associated protein kinase-1(DAPK-1)serves as a focus for understanding the action of TXD.This study was designed to whether TXD mediates its beneficial outcomes by inhibiting DAPK-1.To this end,a diabetic model was established using Sprague-Dawley(SD)rats through a high-fat,high-sugar(HFHS)diet regimen,followed by streptozotocin(STZ)injection.The experimental cohort was stratified into six groups:Control,Diabetic,TC-DAPK6,high-dose TXD,medium-dose TXD,and low-dose TXD groups.Following a 12-week treatment period,various assessments—including blood glucose levels,body weight measurements,Morris water maze(MWM)testing for cognitive function,brain magnetic resonance imaging(MRI),and histological analyses using hematoxylin-eosin(H&E),and Nissl staining—were conducted.Protein expression in the hippocampus was quantified through Western blotting analysis.The results revealed that TXD significantly improved spatial learning and memory abilities,and preserved hippocampal structure in diabetic rats.Importantly,TXD administration led to a down-regulation of proteins indicative of neurological damage and suppressed DAPK-1 activity within the hippocampal region.These results underscore TXD's potential in mitigating DCI via DAPK-1 inhibition,positioning it as a viable therapeutic candidate for addressing this condition.Further investigation into TXD's molecular mechanisms may elucidate new pathways for the treatment of DCI.