한빛사 논문
Zeeshan Ahmad Khan a,b,c, Dewan Md. Sumsuzzman a,b,c, Jeonghyun Choi a,b,c, Yonggeun Hong a,b,c,d,*
a Department of Physical Therapy, College of Healthcare Medical Science & Engineering, Gimhae 50834, South Korea b Research Center for Aged-Life redesign, Inje University, Gimhae 50834, South Korea c Biohealth Products Research Center (BPRC), Inje University, Gimhae 50834, South Korea d Department of Rehabilitation Science, Graduate School of Inje University, Gimhae 50834, South Korea
*Corresponding author.
Abstract
Cerebral hypoxia-ischemia (CHI) causes brain aging, neurological disorders, cognitive decline, motor function impairment, and mortality. Inhibiting death-associated protein kinase 1 (DAPK1) has shown therapeutic potential against CHI, but several reports contradict its protective function, mechanism of activation, and signal transduction. Here, we systematically reviewed the role and the activation mechanism of DAPK1, and quantitatively assess the efficacy of DAPK1 inhibition (DI) methods in neuroprotection, following a CHI in animal models. Embase and PubMed were searched for relevant studies. Overall, 13 studies met the inclusion criteria, and the SYRCLE Risk of bias tool (RoB) tool was used to assess RoB. StataSE 16 was used for meta-analysis and network meta-analysis (NMA). Standardized mean differences (SMD) with 95% confidence intervals (CI) were calculated to estimate the effect size. DI was associated with the reduction of brain infarct volume (BIV) [SMD = −1.70, 95% CI (−2.10, −1.30); p = 0.00], neurological score (N.S.), neuronal degeneration, with no change in the level of in cell death [SMD = −0.83, 95% CI (−2.00, 0.35); p = 0.17], indicating the protective role of DI against CHI. No differences were found in DAPK1 mRNA and protein levels [SMD = 0.50, 95% CI (−0.05, 1.04); p = 0.07] {single-study driven; upregulated after exclusion (p = 0.01, I2 = 36.43)}, whereas phospho-DAPK1 [SMD = −2.22, 95% CI (−3.69, −0.75); p = 0.00] was downregulated and phosphorylated myosin light chain [SMD = 3.37, 95% CI (2.51, 4.96); p = 0.00] was upregulated between CHI and sham groups. Furthermore, we performed NMA to understand the molecular level at which DI offers maximum protection against BIV. Post-transcriptional inhibition (PTI; SUCRA, 82.6%) and gene knockout showed best (KO; SUCRA, 81.3%), signal transduction inhibition (STI; SUCRA, 49.5%) offered 3rd best, while catalytic activity inhibition (CAI; SUCRA, 0.3%) exhibited the lowest reduction in BIV against CHI. The results demonstrate that DI has a neuroprotective effect against CHI and DAPK1 might be regulated at the post-transcriptional and post-translational levels after CHI. Inhibiting DAPK1 at the post-transcriptional level and blocking multiple signal transduction pathways of DAPK1 could lead to better functional recovery against CHI.
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