Up-regulation of Dyrk1b promote astrocyte activation following lipopolysaccharide-induced neuroinflammation

He, Mingqing; Gu, Jun; Zhu, Jinzhou; Wang, Xiaoyan; Wang, Chengniu; Duan, Chengwei; Ni, Yingjie; Lü, Xiang; Li, Jianzhong

doi:10.1016/j.npep.2018.04.008

Cited by 10 publications

(8 citation statements)

References 47 publications

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“…Dyrk1b is an arginine-directed serine/threonine protein kinase which is highly expressed in many cancers. Increased levels of Dyrk1b have been found to interact with STAT3 to modulate the activation of astrocyte cells in LPS-induced neuroinflammation [ 66 ]. Furthermore, ULK4 has been associated with primary biliary cholangitis (PBC); expression levels of ULK4 were found to be significantly higher in PBC patients than in healthy controls, suggesting a potential relationship between ULK4 and inflammation [ 67 ].…”

Section: Discussionmentioning

confidence: 99%

Salmonella Enteritidis GalE Protein Inhibits LPS-Induced NLRP3 Inflammasome Activation

Huang

Guo

et al. 2022

Microorganisms

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Microbial infection can trigger the assembly of inflammasomes and promote secretion of cytokines, such as IL-1β and IL-18. It is well-known that Salmonella modulates the activation of NLRC4 (NLR family CARD domain-containing protein 4) and NLRP3 (NLR family pyrin domain-containing 3) inflammasomes, however the mechanisms whereby Salmonella avoids or delays inflammasome activation remain largely unknown. Therefore, we used Salmonella Enteritidis C50336ΔfliC transposon library to screen for genes involved in modulating inflammasomes activation. The screen revealed the galactose metabolism-related gene galE to be essential for inflammasome activation. Here, we found that inflammasome activation was significantly increased in J774A.1 cells or wild-type bone marrow-derived macrophages (BMDMs) during infection by ΔfliCΔgalE compared to cells infected with ΔfliC. Importantly, we found that secretion of IL-1β was Caspase-1-dependent, consistent with canonical NLRP3 inflammasome activation. Furthermore, the virulence of ΔfliCΔgalE was significantly decreased compared to ΔfliC in a mouse model. Finally, RNA-seq analysis showed that multiple signaling pathways related to the inflammasome were subject to regulation by GalE. Taken together, our results suggest that GalE plays an important role in the regulatory network of Salmonella evasion of inflammasome activation.

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Section: Discussionmentioning

confidence: 99%

Salmonella Enteritidis GalE Protein Inhibits LPS-Induced NLRP3 Inflammasome Activation

Huang

Guo

et al. 2022

Microorganisms

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“…Like with DYRK1A, DYRK1B inhibition leads to the proliferation of pancreatic, insulin-producing β-cells. DYRK1B is involved in neuroinflammation [ 115 ]. Targeting DYRK1B provides a new rationale for treatment of various solid cancers such as liposarcoma or breast cancers (reviews: [ 116 , 117 ]) as well as in chronic myeloid leukemia (CML).…”

Section: Dyrks and Human Diseasementioning

confidence: 99%

Dual-Specificity, Tyrosine Phosphorylation-Regulated Kinases (DYRKs) and cdc2-Like Kinases (CLKs) in Human Disease, an Overview

Lindberg

Meijer

2021

IJMS

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Dual-specificity tyrosine phosphorylation-regulated kinases (DYRK1A, 1B, 2-4) and cdc2-like kinases (CLK1-4) belong to the CMGC group of serine/threonine kinases. These protein kinases are involved in multiple cellular functions, including intracellular signaling, mRNA splicing, chromatin transcription, DNA damage repair, cell survival, cell cycle control, differentiation, homocysteine/methionine/folate regulation, body temperature regulation, endocytosis, neuronal development, synaptic plasticity, etc. Abnormal expression and/or activity of some of these kinases, DYRK1A in particular, is seen in many human nervous system diseases, such as cognitive deficits associated with Down syndrome, Alzheimer’s disease and related diseases, tauopathies, dementia, Pick’s disease, Parkinson’s disease and other neurodegenerative diseases, Phelan-McDermid syndrome, autism, and CDKL5 deficiency disorder. DYRKs and CLKs are also involved in diabetes, abnormal folate/methionine metabolism, osteoarthritis, several solid cancers (glioblastoma, breast, and pancreatic cancers) and leukemias (acute lymphoblastic leukemia, acute megakaryoblastic leukemia), viral infections (influenza, HIV-1, HCMV, HCV, CMV, HPV), as well as infections caused by unicellular parasites (Leishmania, Trypanosoma, Plasmodium). This variety of pathological implications calls for (1) a better understanding of the regulations and substrates of DYRKs and CLKs and (2) the development of potent and selective inhibitors of these kinases and their evaluation as therapeutic drugs. This article briefly reviews the current knowledge about DYRK/CLK kinases and their implications in human disease.

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“…Previously, Flt3 has been linked to dendritic cell-mediated immune responses, which may be possibly involved in regulation of inflammatory factors in the PD model. Moreover, both DYRK1B and GSK3β have been identified as potential targets for PD and other neurodegenerative diseases. , These off-targets may not only help to interpret the efficacy of 23 in the MPTP-induced PD mouse models but also suggest new possible directions (e.g., multiple-targeting IDO/TDO and GSK3β) to develop agents for PD treatment.…”

Section: Resultsmentioning

confidence: 99%

X-ray Structure-Guided Discovery of a Potent, Orally Bioavailable, Dual Human Indoleamine/Tryptophan 2,3-Dioxygenase (hIDO/hTDO) Inhibitor That Shows Activity in a Mouse Model of Parkinson’s Disease

Ning

Huo

et al. 2021

J. Med. Chem.

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Human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan 2,3-dioxygenase (hTDO) have been closely linked to the pathogenesis of Parkinson's disease (PD); nevertheless, development of dual hIDO1 and hTDO inhibitors to evaluate their potential efficacy against PD is still lacking. Here, we report biochemical, biophysical, and computational analyses revealing that 1H-indazole-4-amines inhibit both hIDO1 and hTDO by a mechanism involving direct coordination with the heme ferrous and ferric states. Crystal structure-guided optimization led to 23, which manifested IC 50 values of 0.64 and 0.04 μM to hIDO1 and hTDO, respectively, and had good pharmacokinetic properties and brain penetration in mice. 23 showed efficacy against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse motor coordination deficits, comparable to Madopar, an anti-PD medicine. Further studies revealed that different from Madopar, 23 likely has specific anti-PD mechanisms involving lowering IDO1 expression, alleviating dopaminergic neurodegeneration, reducing inflammatory cytokines and quinolinic acid in mouse brain, and increasing kynurenic acid in mouse blood.

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Up-regulation of Dyrk1b promote astrocyte activation following lipopolysaccharide-induced neuroinflammation

Cited by 10 publications

References 47 publications

Salmonella Enteritidis GalE Protein Inhibits LPS-Induced NLRP3 Inflammasome Activation

Salmonella Enteritidis GalE Protein Inhibits LPS-Induced NLRP3 Inflammasome Activation

Dual-Specificity, Tyrosine Phosphorylation-Regulated Kinases (DYRKs) and cdc2-Like Kinases (CLKs) in Human Disease, an Overview

X-ray Structure-Guided Discovery of a Potent, Orally Bioavailable, Dual Human Indoleamine/Tryptophan 2,3-Dioxygenase (hIDO/hTDO) Inhibitor That Shows Activity in a Mouse Model of Parkinson’s Disease

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