ROS-mediated apoptosis of HAPI microglia through p53 signaling following PFOS exposure

Cao

et al. 2021

Preprint

Background and Aims: Ulcerative colitis(UC) is a chronic inflammatory bowel disorder with highly cellular heterogeneity. Mass cytometry(Cy-TOF) and single-cell RNA sequencing (scRNA-seq) have revealed cellular heterogeneity of UC. However, comprehensive elucidation of tissue topological changes within the UC ecosystem is still missing. And we aimed to illustrate compositional and spatial changes of the UC ecosystem.Methods: Imaging mass cytometry (IMC) and scRNA-seq were applied to depict the single-cell landscape of colon ecosystem.Results: We noticed tissue topological changes featured with macrophage disappearance reaction (MDR) in UC region. MDR only occurred for CD163+ tissue-resident macrophages. We found reactive oxygen species (ROS) level were higher in UC region but ROS scavenging enzyme SOD1/2 were barely detected in resident macrophages, resulting selective oxidative protection for inflammatory macrophages and resident macrophage disappearance reaction. Furthermore, inflammatory macrophages replaced resident macrophages during UC, which played a key role in forming the inflammatory cellular network by producing TNF-α and IL-1β. Conclusions: Our study dissected the microenvironment of UC lesions at single-cell resolution while preserving its architecture, based on which, we discovered the mechanism of MDR in UC region and resident macrophage specific MDR resulted in infiltration of inflammatory macrophage, which formed the cytokine producing network within the local cellular neighborhood.

Section: Uneven Expression Of Ros Scavenging Enzyme Sod1/2 Resulted Ros Induced Resident Macrophage Apoptosissupporting

confidence: 91%

Selective oxidative protection leads to tissue topological changes orchestrated by macrophage during ulcerative colitis

Cao

et al. 2021

Preprint

“…Further, ROS, IL-17A, and HMGB1 all can regulate the microglial cell proliferation through p53 and PI3K/Akt pathways. Ge et al ( 2016 ) indicated that NAC inhibited p53 expression, and decreased the apoptosis of HAPI microglia. Chen et al ( 2016 ) found that hypoxia/reperfusion can evoke autophagy-activated microglia apoptosis/death via an ROS-regulated Akt/mTOR signaling pathway, which can be reversed by catechin.…”

Section: Discussionmentioning

confidence: 99%

IL-17A Enhances Microglial Response to OGD by Regulating p53 and PI3K/Akt Pathways with Involvement of ROS/HMGB1

Yang

et al. 2017

Front. Mol. Neurosci.

Cerebral ischemia-reperfusion injury (IRI) has a complex pathogenesis, and interleukin-17 (IL-17) is a newly identified class of the cytokine family that plays an important role in ischemic inflammation. An oxygen-glucose deprivation (OGD) model showed that IL-17A expression was significantly up-regulated in microglial cells. After IL-17A siRNA transfection, the inhibition of proliferation, and the increased apoptosis in microglial cells, induced by OGD/reperfusion, was improved, and the elevation of Caspase-3, Caspase-8, Caspase-9, and poly ADP ribose polymerase (PARP) activities was inhibited. Mass spectrometry demonstrated that IL-17A functioned through a series of factors associated with oxidative stress and apoptosis and regulated Caspase-3 activity and apoptosis in microglial cells via the p53 and PI3K/Akt signaling pathways. IL-17A, HMGB1, and ROS were regulated mutually to exhibit a synergistic effect in the OGD model of microglial cells, but the down-regulation of IL-17A or HMGB1 expression did not completely inhibit the production of ROS. These findings demonstrated that ROS might be located upstream of IL-17A and HMGB1 so that ROS can regulate HMGB1/IL-17A expression to affect the p53 and PI3K/Akt signaling pathways and therefore promote the occurrence of apoptosis in microglial cells. These findings provide a novel evidence for the role of IL-17A in ischemic cerebral diseases.

“…multiple proteins. The p53 protein, a nuclear transcription factor, plays an important role in regulating a wide variety of genes[50][51][52].A downstream response factor of p53, p21 expression is significantly increased following p53 activation, leading to cell cycle arrest. In the mitochondria-induced apoptosis pathway, p53 can activate the apoptosis regulator, Bcl-2-like protein 4, Bax, to form a heterodimer with Bcl-2 as an apoptotic activator[53,54].Bax increases the anion channel open probability, and induces loss of mitochondrial membrane potential (Δψ m ), ultimately promotes release of cytochrome c (Cyt c).…”

mentioning

confidence: 99%

Designing anticancer copper(II) complexes by optimizing 2-pyridine-thiosemicarbazone ligands

Deng

European Journal of Medicinal Chemistry

et al. 2018

To develop potential next-generation metal anticancer agents, we designed and synthesised five Cu(II) 2-pyridine-thiosemicarbazone complexes by modifying the hydrogen atom at the N-4 position of ligands, and then investigated their structure-activity relationships and anticancer mechanisms. Modification of the N-4 position with different groups caused significant differences in cellular uptake and produced superior antitumor activity. Cu complexes arrested the cell cycle at S phase, leading to down-regulation of levels of cyclin and cyclin-dependent kinases and up-regulation of expression of cyclin-dependent kinase inhibitors. Cu complexes exerted chemotherapeutic effects via activating p53 and inducing production of reactive oxygen species to regulate expression of the B-cell lymphoma-2 family of proteins, causing a change in the mitochondrial membrane potential and release of cytochrome c to form a dimer with apoptosis protease activating factor-1, resulting in activation of caspase-9/3 to induce apoptosis. In addition, Cu complexes inhibited telomerase by down-regulating the c-myc regulator gene and expression of the human telomerase reverse transcriptase.