New Drug Targets to Prevent Death Due to Stroke: A Review Based on Results of Protein-Protein Interaction Network, Enrichment, and Annotation Analyses

Abstract

This study used established biomarkers of death from ischemic stroke (IS) versus stroke survival to perform network, enrichment, and annotation analyses. Protein-protein interaction (PPI) network analysis revealed that the backbone of the highly connective network of IS death consisted of IL6, ALB, TNF, SERPINE1, VWF, VCAM1, TGFB1, and SELE. Cluster analysis revealed immune and hemostasis subnetworks, which were strongly interconnected through the major switches ALB and VWF. Enrichment analysis revealed that the PPI immune subnetwork of death due to IS was highly associated with TLR2/4, TNF, JAK-STAT, NOD, IL10, IL13, IL4, and TGF-β1/SMAD pathways. The top biological and molecular functions and pathways enriched in the hemostasis network of death due to IS were platelet degranulation and activation, the intrinsic pathway of fibrin clot formation, the urokinase-type plasminogen activator pathway, post-translational protein phosphorylation, integrin cell-surface interactions, and the proteoglycan-integrin extracellular matrix complex (ECM). Regulation Explorer analysis of transcriptional factors shows: (a) that NFKB1, RELA and SP1 were the major regulating actors of the PPI network; and (b) hsa-mir-26-5p and hsa-16-5p were the major regulating microRNA actors. In conclusion, prevention of death due to IS should consider that current IS treatments may be improved by targeting VWF, the proteoglycan-integrin-ECM complex, TGF-β1/SMAD, NF-κB/RELA and SP1.

Paraoxonase 1 status is a major Janus-faced component of mild and moderate acute ischemic stroke and consequent disabilities

“…AIS risk factors include unmodifiable factors such as age and gender, and modifiable factors such as diabetes mellitus, high systolic blood pressure, high body mass index, heart disease, high levels of low-density lipoprotein (LDL)-cholesterol and low levels of high density lipoprotein (HDL)-cholesterol, atrial fibrillation, transient ischemic attack (TIA), smoking, sedentary lifestyle and nutritional factors (Gorelick, 2019; Maes et al, 2021). AIS is accompanied by increased production of reactive oxygen and nitrogen species (RONS) and activated immune-inflammatory pathways that cause neuronal damage (Orellana-Urza et al, 2020; Maes et al, 2021). As a result, a portion of the brain tissue (core) sustains irreversible neuronal loss due to necrotic cell death, whereas the surrounding tissues contain recoverable and metabolically active cells (penumbra) in which cell death happens more slowly (Khoshnam et al, 2017).…”

Increased lipid peroxidation and lowered lipid-associated antioxidant defenses mediate the effects of the paraoxonase 1 (PON1) Q192R polymorphism on disabilities and final stroke core volume in mild and moderate stroke

“…Acute ischemic stroke (AIS), which accounts for 87% of all strokes worldwide, may be defined as a rapid loss of brain function caused by a significant disruption of blood and oxygen flow in the cerebral arteries due to an embolism or thrombus. AIS results from the cumulative, long-term effects of irreversible factors, including increasing age, sex, genetic factors, and ethnicity, as well as modifiable risk factors, including increased systolic and diastolic blood pressure, atrial fibrillation, transient ischemic attack, type 2 diabetes mellitus, excess alcohol consumption, smoking, sedentary lifestyle, increased body mass index (BMI), increased levels of glucose, triglycerides, low-density lipoprotein (LDL) cholesterol, and lowered levels of high-density lipoprotein (HDL) cholesterol [7][8][9][10][11].…”

“…The copyright holder for this this version posted September 23, 2022. ; https://doi.org/10.1101/2022.09. 19.22280134 doi: medRxiv preprint with free radical-mediated reactions contributing to neuronal cell death [15], whilst reperfusion is accompanied by secondary neurotoxic responses induced by a second burst in reactive oxygen species (ROS) and pro-inflammatory cytokines, such as interleukin (IL)-6, IL-1β and tumor necrosis factor (TNF)-α [11][12][13].…”

“…AIS results in cerebral ischemia and leads to necrotic and excitotoxic cell death in the ischemic core [12, 13], whereby highly connected immune and hemostatis subnetworks and activation of intracellular pathways may lead to post-stroke death [11]. Following AIS, nitro-oxidative and neuroinflammatory (microglia activation) processes are critically involved in the primary insult, leading to neuroapoptosis, neurotoxicity, necrosis or authophagy and consequent brain cell death in the strokecore and secondary neurodegenrative processes in the penumbra [11–14].…”

“…AIS results in cerebral ischemia and leads to necrotic and excitotoxic cell death in the ischemic core [12, 13], whereby highly connected immune and hemostatis subnetworks and activation of intracellular pathways may lead to post-stroke death [11]. Following AIS, nitro-oxidative and neuroinflammatory (microglia activation) processes are critically involved in the primary insult, leading to neuroapoptosis, neurotoxicity, necrosis or authophagy and consequent brain cell death in the strokecore and secondary neurodegenrative processes in the penumbra [11–14]. Ischemia and the consequent excitotoxicity and reperfusion are associated with free radical-mediated reactions contributing to neuronal cell death [15], whilst reperfusion is accompanied by secondary neurotoxic responses induced by a second burst in reactive oxygen species (ROS) and pro-inflammatory cytokines, such as interleukin (IL)-6, IL-1β and tumor necrosis factor (TNF)-α [11–13].…”