Hypoxia- and Inflammation-Related Transcription Factor SP3 May Be Involved in Platelet Activation and Inflammation in Intracranial Hemorrhage

 I hate useless research like this. Biomarkers rather than figuring out how to prevent such inflammation. This useless crapola is all a result of NO leadership and NO strategy.

Hypoxia- and Inflammation-Related Transcription Factor SP3 May Be Involved in Platelet Activation and Inflammation in Intracranial Hemorrhage

Ding Wan^1,2†, Jin Feng^1†, Peng Wang², Zhenxing Yang¹ and Tao Sun^1,2*

• ¹Department of Neurosurgery, General Hospital of Ningxia Medical University, Yinchuan, China
• ²Ningxia Key Laboratory of Craniocerebral Diseases, Ningxia Medical University, Yinchuan, China

The purpose of this study was to identify the biomarkers implicated in the development of intracranial hemorrhage (ICH) and potential regulatory pathways. In the transcriptomic data for patients with ICH, we identified DEmiRNAs and DEmRNAs related to hypoxia, inflammation, and their transcription factors (TFs). An ICH-based miRNA-TF-mRNA regulatory network was thus constructed, and four biomarkers (TIMP1, PLAUR, DDIT3, and CD40) were screened for their association with inflammation or hypoxia by machine learning. Following this, SP3 was found to be a transcription factor involved in hypoxia and inflammation, which regulates TIMP1 and PLAUR. From the constructed miRNA-TF-mRNA regulatory network, we identified three axes, hsa-miR-940/RUNX1/TIMP1, hsa-miR-571/SP3/TIMP1, and hsa-miR-571/SP3/PLAUR, which may be involved in the development of ICH. Upregulated TIMP1 and PLAUR were validated in an independent clinical cohort 3 days after ICH onset. According to Gene Set Enrichment Analysis (GSEA), SP3 was discovered to be important in interleukin signaling and platelet activation for hemostasis. Transcription factor SP3 associated with hypoxia or inflammation plays an important role in development of ICH. This study provides potential targets for monitoring the severity of inflammation and hypoxia in patients with ICH.

Introduction

Intracranial hemorrhage (ICH) is a condition characterized by bleeding from the brain parenchyma caused by the rupture of blood vessels in the brain, which leads to compression of the surrounding nerve tissue, disruption of the brain function, and triggering of disorders (1). ICH can be triggered by various factors, such as trauma, hypertension, and infection (2, 3). ICH accounts for 10–15% of strokes and is its most lethal subtype (4–8). The formation of a hematoma from ICH can severely disrupt tracts, leading to various dysfunctions and threatening patients' lives, which makes ICH highly disabling and mortal (4). More than 1 million people are affected by ICH each year (9). The mortality rate for patients with ICH range from 30 to 50% at 1 month and 54% at 1 year (10, 11). The unprecedented virus (COVID-19) have also been identified as potential risk factors for ICH (12). Patients with ICH need to be diagnosed and treated early and accurately in order to achieve the best possible outcome.

Neuronal apoptosis, inflammation, oxidative stress, edema formation, and the breakdown of the blood–brain barrier all contribute to ICH development (13, 14). ICH is not only pathologically characterized by inflammation, but it also causes secondary damage to the brain (15, 16). Inflammatory injury can damage the vascular endothelium and, thus, is involved in ICH development (17, 18). The infiltrating leukocytes can release pro-inflammatory factors, which further damage the blood–brain barrier, thereby worsening the secondary brain injury after ICH development (19–21). Meanwhile, hypoxia can be activated through oxidative stress mechanisms, which in turn are involved in the developmental mechanisms of ICH (14, 22). Therefore, we hypothesize that inflammation and hypoxia play important roles in ICH pathogenesis; however, the molecular mechanisms involved are not yet clear.

Because inflammation is involved in secondary damage after ICH, the degree of inflammation can be used to predict the prognosis of patients with ICH (21, 23, 24). Some indicators of inflammation, such as the neutrophil-to-lymphocyte ratio, have been shown to be useful in predicting the prognosis of patients with ICH, and they are predictive of a good outcome (25). Brain tissue can become hypoxic from ICH, causing irreversible damage (26). Genes associated with hypoxia or inflammation, as well as their pathways of action, play an important role in the development and progression of ICH. ICH development is involved in the Nrf2/HO-1 signaling pathway, according to the previous studies (27). KLF6 acts as a transcription factor that mediates SIRT5 inhibition of the Nrf2/HO-1 signaling pathway, which in turn exacerbates neuronal apoptosis and oxidative stress after ICH development (28). KLF6 plays a crucial role in the inflammatory and hypoxic response (27). Inflammation and hypoxia dramatically impact the survival and quality of life of patients with ICH. Thus, identifying the degree of inflammation and hypoxia in ICH is essential for monitoring the prognosis of patients with ICH.

Recent developments in bioinformatics, including the availability of considerable RNA sequencing data resources, have provided a direction for disease diagnosis and treatment (29–32). Gene expression profiles associated with inflammation or hypoxia can be obtained from RNA sequencing data. This study was designed to examine the genes and pathways that are potentially involved in inflammation during ICH.

More at link.