Aging-US
·
2024
·
IF 3.9
Yun Li,Meijuan Cheng,Jingjing Jin,Dongxue Zhang,Shenglei Zhang,Yaling Bai,Jinsheng Xu
Vascular calcification (VC) is directly related to high mortality in chronic kidney disease (CKD), and cellular apoptosis of vascular smooth muscle cells (VSMCs) is a crucial process in the initiation of VC. Microtubule affinity-regulating kinase 4 (Mark4), known as a serine/threonine protein kinase, can induce cell apoptosis and autophagy by modulating Akt phosphorylation. However, the potential functions and molecular mechanisms of Mark4 in VSMCs apoptosis and calcification need to be further explored. Initially, our data indicated that the mRNA expression of Mark4 was prominently elevated in high phosphorus-stimulated human VSMCs compared with the other members in Marks. Consistently, Mark4 expression was found to be significantly increased in the calcified arteries of both CKD patients and rats. In vitro , silencing Mark4 suppressed apoptosis-specific marker expression by promoting Akt phosphorylation, finally attenuating VSMCs calcification induced by high phosphate. Mechanically, the transcription factor Sp1 was enriched in the Mark4 promoter region and modulated Mark4 transcription. Moreover, SET domain-containing protein 8 (Setd8) was proved to interact with Sp1 and jointly participated in the transcriptional regulation of Mark4. Finally, rescue experiments revealed that Setd8 contributed to VSMCs apoptosis and calcification by modulating Mark4 expression. In conclusion, these findings reveal that Mark4 is transcriptionally activated by Sp1, which is interacted with Setd8, to promote VSMCs calcification through Akt-mediated antiapoptotic effects, suggesting that Mark4 represents a potent and promising therapeutic target for VC in CKD.
研究领域:
分子生物学
·
细胞生物学
·
心血管疾病
·
肾病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2019
·
IF 5.808
Fangfang Li,Zongliang Liu,Heyuan Sun,Chunmei Li,Wenyan Wang,Liang Ye,Chunhong Yan,Jingwei Tian,Hongbo Wang
Gliomas are the most common primary intracranial neoplasms among all brain malignancies, and the microtubule affinity regulating kinases (MARKs) have become potential drug targets for glioma. Here, we report a novel dual small-molecule inhibitor of MARK3 and MARK4, designated as PCC0208017. In vitro, PCC0208017 strongly inhibited kinase activity against MARK3 and MARK4, and strongly reduced proliferation in three glioma cell lines. This compound attenuated glioma cell migration, glioma cell invasion, and angiogenesis. Molecular mechanism studies revealed that PCC0208017 decreased the phosphorylation of Tau, disrupted microtubule dynamics, and induced a G2/M phase cell cycle arrest. In an in vivo glioma model, PCC0208017 showed robust anti-tumor activity, blood–brain barrier permeability, and a good oral pharmacokinetic profile. Molecular docking studies showed that PCC0208017 exhibited high binding affinity to MARK3 and MARK4. Taken together, our study describes for the first time that PCC0208017, a novel MARK3/MARK4 inhibitor, might be a promising lead compound for treatment of glioma.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
神经科学
✓ 已验证
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2025
·
IF 8.2
Kunmei Xie,Jingquan Dong,Xiguang Liu,Xiao Liu,Shasha Zhang,Yan Cao,Long Chen,Wanyi Xu,Panpan Zhao,Zibo Dong
Sepsis is a life-threatening systemic inflammatory response syndrome with high morbidity and mortality. A frequent complication is sepsis-associated encephalopathy (SAE), characterized by neurological impairments. Microglia pyrin domain- containing receptor 3 (NLRP3) inflammasome activation is a pivotal pathogenic mechanism in SAE. Microtubule-affinity regulating kinase 4 (MARK4) has been implicated in neuroinflammatory diseases, but its role in SAE and microglial NLRP3 inflammasome activation is unclear. Sophoridine (SRI), a MARK4 antagonist with anti-inflammatory and neuroprotective properties, has not yet been thoroughly investigated in SAE. Here, we used a cecum ligation puncture (CLP)-induced SAE mouse model and LPS+ATP or LPS+ nigericin (Nig)-treated microglia, to assess the role of MARK4 in SAE. Molecular docking, Nissl staining, the enzyme-linked immunosorbent assay (ELISA), immunofluorescence, and behavioral tests were applied to assess SRI’s effects on SAE. Our findings demonstrate that MARK4 is significantly upregulated in SAE. Knockdown of MARK4 effectively suppressed microglial pyroptosis and pro-inflammatory cytokine release by inhibiting NLRP3 inflammasome activation. SRI binds to MARK4 and enhances its stability. By suppressing MARK4 protein expression, SRI reduces NLRP3 inflammasome-mediated microglia inflammation. In vivo , SRI treatment increased survival, improved neurological behavioral deficits, attenuated blood-brain barrier disruption, and provided neuroprotective effects against brain injury. In summary, MARK4 contributes to microglial pyroptosis and neuroinflammation through NLRP3 pathway in SAE, resulting in neuronal injury and cognitive impairment. SRI alleviates SAE by targeting MARK4. These results suggest MARK4 as a potential therapeutic target and SRI as a promising candidate for treating SAE.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）