A recent study has uncovered significant advancements in the identification of biomarkers for ischemic stroke (IS), spotlighting three mitochondrial-related genes: thiosulfate sulfurtransferase (TST), sulfide quinone oxidoreductase (SQOR), and nardilysin (NRDC). This research, conducted by scientists from Hebei University of Traditional Chinese Medicine, provides new insights on ischemic stroke from a mitochondrial perspective, which could revolutionize diagnostic and therapeutic approaches to the condition.
Ischemic stroke, which results when blood flow to the brain is interrupted, is one of the leading causes of disability and death globally. The World Health Organization estimates the number of IS patients surged from 2.04 million to 3.29 million between 1990 and 2019, with projections indicating this number could reach 4.9 million by 2030. Current treatments, primarily involving tissue plasminogen activator (tPA) injections, are only effective for a small fraction of patients due to time constraints and contraindications. These limitations highlight the urgent need for innovative diagnostic methods and therapeutic targets.
Utilizing datasets from the Gene Expression Omnibus (GEO) database, the researchers standardized and combined existing data to identify differentially expressed genes associated with mitochondrial dysfunction and ischemic stroke. Data processing involved methods such as weighted gene co-expression network analysis (WGCNA), through which the team determined significant gene interactions and identified the intersection of genes as potential biomarkers.
"A total of 42 proteins, 601 transcription factors, and 99 miRNAs related to TST, SQOR, and NRDC were predicted," the authors emphasized. The comprehensive analytical approach allowed them to determine the diagnostic efficacy of the three identified genes.
Further investigation revealed the pivotal immunological roles these genes play. Both SQOR and TST were noted for their involvement with immune cells such as neutrophils, CD4+ T cells, and CD8+ T cells. The correlation between these genes and immune responses is particularly relevant, considering inflammation plays a significant role in the exacerbation of damage caused by ischemic strokes.
The study also revealed the potential of combining TST, SQOR, and NRDC as diagnostic markers for IS, which could improve the classification and diagnosis of patients. Receiver Operating Characteristic (ROC) analyses yielded strong diagnostic model performance, highlighting the accuracy of the three-gene model.
Mitochondrial function is especially significant, as it is intricately linked to neuronal health and survival. Mitochondria-derived ATP, for example, is instrumental for maintaining neuronal excitability and overall brain function. Disruption in this function can lead to apoptosis, autophagy, and inflammation—key pathways implicated during the progression of ischemic conditions.
Through advanced methods like cMAP (Connection Map), the team even identified potential small molecule drugs. Notably, molecular docking suggested the compound W.13 demonstrated the highest binding energy with the three diagnostic genes, paving the path for possible therapeutic interventions aimed at mitochondrial function.
To verify their findings, the researchers conducted experiments using male Sprague-Dawley rats subjected to middle cerebral artery occlusion followed by reperfusion, simulating ischemic conditions. Observations revealed significant mitochondrial damage and associated increases in oxidative stress markers, lending credence to the hypothesis of mitochondrial involvement during ischemic events.
SOD (superoxide dismutase) levels decreased, indicating compromised antioxidant defenses, and MDA (malondialdehyde) levels increased, signaling heightened oxidative stress. These biochemical changes aligned with the observed elevated levels of TST and SQOR and decreased NRDC levels, providing clearer paths for therapeutic targeting.
Moving forward, this study lays the groundwork for future exploration of mitochondrial dysfunction as it pertains to ischemic stroke. The interconnectedness of TST, SQOR, and NRDC opens new avenues for both improving diagnostics and developing targeted therapies catered to metabolic and immune mechanisms involved in IS.
While promising, the researchers acknowledge the limitations of their study, particularly concerning the need for larger clinical cohorts and longitudinal analyses to fully understand the complex interactions between these genes and stroke pathology.
Nonetheless, the identification of mitochondria-related biomarkers signals significant progress for the medical field, offering hope for more effective treatments and enhanced patient outcomes when dealing with ischemic strokes. Future studies will expand upon these findings, confirming the efficacy of TST, SQOR, and NRDC as biomarkers and unlocking new pathways for intervention.