bims-ho1def 2023-07-16 papers

Issue of 2023‒07‒16
two papers selected by
Julien H. Park
Universitätsklinikum Münster

Brain Res. 2023 Jul 11. pii: S0006-8993(23)00253-6. [Epub ahead of print] 148482

Nrf2/HO-1 Blocks TXNIP/NLRP3 interaction via elimination of ROS in Oxygen-glucose Deprivation-induced Neuronal Necroptosis.

Zhihan Liu, Ping Cheng, Tao Feng, Zhiyuan Xie, Meifang Yang, Zhiren Chen, Shuqun Hu, Dong Han, Weiwei Chen.

Acute ischemic stroke (AIS) is known to trigger a cascade of inflammatory events that induces secondary tissue damages. As a type of regulated inflammatory cell death, necroptosis is associated with AIS, whilst its regulation during neuroinflammation is not well understood. In particular, the actual function of NOD-like-receptor family pyrin domain-containing-3(NLRP3) inflammasome in cortical neuronal necroptosis still not clear. Herein, we explored the function of nuclear factor erythroid-2 related factor-2 (Nrf2)/ heme oxygenase-1 (HO-1) in oxygen-glucose deprivation (OGD) induced neuronal necroptosis and its underlying mechanism. To establish an in vitro model of neuronal necrosis, we used OGD/caspase-8 inhibitors (Q-VD-OPh, QVD) to treat rat primary cortical neurons (PCNs) after reoxygenation, wherein we found that the model cause an elevated ROS levels by mediating TXNIP/NLRP3 interactions, which in turn activated the NLRP3 inflammasome. Also, we observed that regulation of nuclear factor erythroid-2 related factor-2 (Nrf2) promoted heme oxygenase-1 (HO-1) expression and decreased TXNIP (a protein that relate oxidative stress to activation of inflammasome) and ROS levels, which negatively regulated the expression of OGD-induced activation of NLRP3 inflammasomes. In addition, HO-1 weakened NLRP3 inflammation body activation, which suggests that Nrf2-regulated HO-1 could block the interaction between TXNIP and NLRP3 in OGD/R-treated cortical neurons by inhibiting ROS production. Our study has discovered the importance of Nrf2/HO-1 signaling cascade for inhibiting inflammasome of NLRP3, which negatively regulated necrosis. Therefore, NLRP3 is considered a potential target for a novel neuroprotective approach, which can expand the therapeutic windows of stroke drugs.

Keywords: NLRP3 inflammasome; Nrf2/HO-1; ROS; necroptosis; neuron

DOI: https://doi.org/10.1016/j.brainres.2023.148482

J Biomol Struct Dyn. 2023 Jul 11. 1-20

Computational screening of pathogenic missense nsSNPs in heme oxygenase 1 (HMOX1) gene and their structural and functional consequences.

Arvind Kumar Yadav, T P Krishna Murthy, Gangaraju Divyashri, Durga Prasad N, Sriraksha Prakash, Vijaya Vaishnavi V, Rohit Shukla, Tiratha Raj Singh.

Heme Oxygenase 1 (HMOX1) is a cytoprotective enzyme, exhibiting the highest activity in the spleen, catalyzing the heme ring breakdown into products of biological significance- biliverdin, CO, and Fe2+. In vascular cells, HMOX1 possesses strong anti-apoptotic, antioxidant, anti-proliferative, anti-inflammatory, and immunomodulatory actions. The majority of these activities are crucial for the prevention of atherogenesis. Single amino acid substitutions in proteins generated by missense non-synonymous single nucleotide polymorphism (nsSNPs) in the protein-encoding regions of genes are potent enough to cause significant medical challenges due to the alteration of protein structure and function. The current study aimed at characterizing and analyzing high-risk nsSNPs associated with the human HMOX1 gene. Preliminary screening of the total available 288 missense SNPs was performed through the lens of deleteriousness and stability prediction tools. Finally, a total of seven nsSNPs (Y58D, A131T, Y134H, F166S, F167S, R183S and M186V) were found to be most deleterious by all tools that are present at highly conserved positions. Molecular dynamics simulations (MDS) analysis explained the mutational effects on the dynamic action of the wild-type and mutant proteins. In a nutshell, R183S (rs749644285) was identified as a highly detrimental mutation that could significantly render the enzymatic activity of HMOX1. The finding of this computational analysis might help subject the experimental confirmatory analysis to characterize the role of nsSNPs in HMOX1.Communicated by Ramaswamy H. Sarma.

Keywords: HMOX1; In-silico analysis; missense mutations; molecular dynamics simulations; non-synonymous SNPs

DOI: https://doi.org/10.1080/07391102.2023.2231553