Inhibition of Cxcr4 Disrupts Mouse Embryonic Palatal Mesenchymal Cell Migration and Induces Cleft Palate Occurrence

Zheng, Xiaoyu; Zhao, Xige; Wang, Yijia; Chen, Jing; Wang, Xiaotong; Xia, Peng; Ma, Lulu; Du, Juan

doi:10.3390/ijms241612740

Cited by 3 publications

(1 citation statement)

References 60 publications

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“…Interestingly, eNOS can activate the PI3K/Akt pathway in turn and inhibit Rho isoprenylation. Lipid modification of Rho proteins such as RhoA and Cdc42 activates microgliosis and the inflammatory signaling cascade [ 70 , 71 ] and participates in the signaling pathways required for NF-κB activity and helps regulate the transcription of proinflammatory genes. Of Note, the isoprenylation of Rho protein has emerged as a key target of neuroprotective medicines, particularly statins, in illnesses caused by neuroinflammation [ 72 ].…”

Section: Hmgcr-mediated Neuroinflammationmentioning

confidence: 99%

Mechanisms of 3-Hydroxyl 3-Methylglutaryl CoA Reductase in Alzheimer’s Disease

Zhou,

Wu,

Wang

et al. 2023

IJMS

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Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide and has a high incidence in the elderly. Unfortunately, there is no effective therapy for AD owing to its complicated pathogenesis. However, the development of lipid-lowering anti-inflammatory drugs has heralded a new era in the treatment of Alzheimer’s disease. Several studies in recent years have shown that lipid metabolic dysregulation and neuroinflammation are associated with the pathogenesis of AD. 3-Hydroxyl 3-methylglutaryl CoA reductase (HMGCR) is a rate-limiting enzyme in cholesterol synthesis that plays a key role in cholesterol metabolism. HMGCR inhibitors, known as statins, have changed from being solely lipid-lowering agents to neuroprotective compounds because of their effects on lipid levels and inflammation. In this review, we first summarize the main regulatory mechanism of HMGCR affecting cholesterol biosynthesis. We also discuss the pathogenesis of AD induced by HMGCR, including disordered lipid metabolism, oxidative stress, inflammation, microglial proliferation, and amyloid-β (Aβ) deposition. Subsequently, we explain the possibility of HMGCR as a potential target for AD treatment. Statins-based AD treatment is an ascent field and currently quite controversial; therefore, we also elaborate on the current application prospects and limitations of statins in AD treatment.

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Section: Hmgcr-mediated Neuroinflammationmentioning

confidence: 99%

Mechanisms of 3-Hydroxyl 3-Methylglutaryl CoA Reductase in Alzheimer’s Disease

Zhou,

Wu,

Wang

et al. 2023

IJMS

View full text Add to dashboard Cite

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Elucidating tobacco smoke-induced craniofacial deformities: Biomarker and MAPK signaling dysregulation unraveled by cross-species multi-omics analysis

Lin,

Li,

Zheng

et al. 2024

Ecotoxicology and Environmental Safety

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Lhx6 deficiency causes human embryonic palatal mesenchymal cell mitophagy dysfunction in cleft palate

Luo,

Ieong,

et al. 2024

Mol Med

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Background Overconsumption of retinoic acid (RA) or its analogues/derivatives has been linked to severe craniomaxillofacial malformations, such as cleft palate and midface hypoplasia. It has been noted that RA disturbed the proliferation and migration of embryonic palatal mesenchymal (EPM) cells in these malformations, yet the exact mechanisms underlying these disruptions remained unclear. Methods A model of retinoic acid (RA)-induced cleft palate in fetal mice was successfully established. Histological alterations in the palate were evaluated using Hematoxylin and Eosin (H&E) staining and RNA in situ hybridization (RNAscope). Cellular proliferation levels were quantified via the Cell Counting Kit-8 (CCK-8) assay and EdU incorporation assay, while cell migration capabilities were investigated using wound healing and Transwell assays. Mitochondrial functions were assessed through Mito-Tracker fluorescence, mitochondrial reactive oxygen species (ROS) measurement, ATP level quantification, and mitochondrial DNA (mtDNA) copy number analysis. Differential gene expression and associated signaling pathways were identified through bioinformatics analysis. Alterations in the transcriptional and translational levels of Lhx6 and genes associated with mitophagy were quantified using quantitative PCR (qPCR) and Western blot analysis, respectively. Mitochondrial morphology and the mitochondrial autophagosomes within cells were examined through transmission electron microscopy (TEM). Results Abnormal palatal development in mice, along with impaired proliferation and migration of human embryonic palatal mesenchymal (HEPM) cells, was associated with RA affecting mitochondrial function and concomitant downregulation of Lhx6. Knockdown of Lhx6 in HEPM cells resulted in altered cell proliferation, migration, and mitochondrial function. Conversely, the aberrant mitochondrial function, proliferation, and migration observed in RA-induced HEPM cells were ameliorated by overexpression of Lhx6. Subsequent research demonstrated that Lhx6 ameliorated RA-induced dysfunction in HEPM cells by modulating PINK1/Parkin-mediated mitophagy, thereby activating the MAPK signaling pathways. Conclusion Lhx6 is essential for mitochondrial homeostasis via tuning PINK1/Parkin-mediated mitophagy and MAPK signaling pathways. Downregulation of Lhx6 by RA transcriptionally disturbs the mitochondrial homeostasis, which in turn leads to the proliferation and migration defect in HEPM cells, ultimately causing the cleft palate. Graphical abstract

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Inhibition of Cxcr4 Disrupts Mouse Embryonic Palatal Mesenchymal Cell Migration and Induces Cleft Palate Occurrence

Cited by 3 publications

References 60 publications

Mechanisms of 3-Hydroxyl 3-Methylglutaryl CoA Reductase in Alzheimer’s Disease

Mechanisms of 3-Hydroxyl 3-Methylglutaryl CoA Reductase in Alzheimer’s Disease

Elucidating tobacco smoke-induced craniofacial deformities: Biomarker and MAPK signaling dysregulation unraveled by cross-species multi-omics analysis

Lhx6 deficiency causes human embryonic palatal mesenchymal cell mitophagy dysfunction in cleft palate

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