Inhibition of Dyrk1A Attenuates LPS-Induced Neuroinflammation via the TLR4/NF-κB P65 Signaling Pathway

Mechanism of DYRK1a in myocardial ischemia–reperfusion injury by regulating ferroptosis of cardiomyocytes

“…to ROS generation during neuroinflammation. 37 Animal experiments in the current study offered additional evidence demonstrating that DYRK1a knockdown not only reduced MI size and pathological damage but also blocked ferroptosis. The primary results of this study showed that the increase in the apoptosis rate and the levels of In summary, this study proposes a novel target DYRK1a against ferroptosis in MIRI, which may contribute to the development of potential cardioprotective therapies.…”

“…Although the levels of cell cycle‐related genes are increased in DYRK1a‐deficient cardiomyocytes after MI, both pharmacological inhibition and cardiomyocyte‐specific ablation of DYRK1a can cause baseline hyperplasia and improve cardiac function after MIRI 18 . Although a direct relationship between DYRK1a and ferroptosis has not yet been reported, DYRK1a has been linked to ROS generation during neuroinflammation 37 . Animal experiments in the current study offered additional evidence demonstrating that DYRK1a knockdown not only reduced MI size and pathological damage but also blocked ferroptosis.…”

Development of Novel Fluorinated Polyphenols as Selective Inhibitors of DYRK1A/B Kinase for Treatment of Neuroinflammatory Diseases including Parkinson’s Disease

“…A recent study showed that DYRK1A inhibition reduced neuroinflammation, decreased microglial activation, and attenuated inflammation-induced neuronal damage in an LPS-induced neuroinflammatory model. Inhibition of DYRK1A attenuated neuroinflammation stimulated by LPS by suppressing the TLR4/NF-κB p65 signaling pathway both in vitro and in vivo [ 15 ]. Collectively, these data suggest that DYRK1A is a potentially viable target for the treatment of neurodegenerative diseases involving a neuroinflammatory component, such as in PD.…”

“…DYRK1A is a proline-directed serine/threonine kinase for which many proteins have been shown as substrates [ 11 ]. DYRK1A activity may be involved in PD and PD-D pathogenesis because (1) it is robustly expressed in CNS neurons [ 42 ]; (2) it increase the clearance of neurotoxic protein aggregates by directly phosphorylating parkin and septin 4 [ 9 , 10 ]; (3) it directly attenuates inflammation by targeting Nrf2, GFAP, and TLR4/NF-κB p65 [ 15 , 16 , 43 ]; (4) it directly phosphorylates the key protein APP and increases the secretase-mediated cleavage of APP into Aβ peptides [ 44 ]; (5) Aβ peptides stimulate DYRK1A expression in a positive feedback loop [ 45 ]; (6) DYRK1A is a kinase for which tau serves as a substrate [ 46 ]; and (7) its presence is associated with increased phosphorylation of tau [ 47 ]. These findings support our hypothesis that the inhibition of DYRK1A activity has a disease-modifying effect and can significantly impact the lives of those with PD and PD-D. We now report the discovery of novel and potent DYRK1A allosteric inhibitors in our ongoing medicinal chemistry effort [ 48 ].…”

“…Inhibition of DYRK1A could tilt the balance to T reg , leading to a reduction in inflammation. Likewise, inhibition of DYRK1A could diminish neuroinflammation elicited by LPS, probably through suppression of the TLR4/NF-κB pathway [ 15 ]. It has been shown that DYRK1A phosphorylates cyclin D1, leading to a decrease in p21 in the cells and, ultimately, to reduced expression of Nrf2, a transcription factor that induces the expression of genes involved in antioxidant pathways, which reduce ROS levels.…”