Bioscience Evidence 2024, Vol.14, No.3, 110-121 http://bioscipublisher.com/index.php/be 117 7.2 Analysis of the association between citric acid cycle genes and colorectal cancer Colorectal cancer is a common malignant tumor worldwide, and energy metabolism plays a crucial role in its development. The citric acid cycle is central to cellular energy metabolism, and the polymorphisms in genes involved in this cycle may be associated with susceptibility to colorectal cancer. Cho et al. (2020) evaluated the association between the polymorphisms of citric acid cycle-related genes and the risk of colorectal cancer, as well as the interaction between these gene polymorphisms and energy balance factors such as obesity, physical activity, and energy intake. The researchers conducted a nested case-control study, selecting 3 523 colorectal cancer cases and 10 522 matched controls from the UK Biobank. They used conditional logistic regression models to assess the relationship between citric acid cycle gene polymorphisms and colorectal cancer risk. The study found that the rs35494829 locus in the SUCLG2 gene was significantly associated with the risk of colorectal cancer, particularly colon cancer. Additionally, significant interactions were observed between citric acid cycle genes and factors such as obesity, energy intake, and vigorous physical activity. The close association between citric acid cycle gene polymorphisms and colorectal cancer risk, along with their interaction with energy balance factors, may provide new insights into the bioenergetic mechanisms of colorectal cancer (Yu et al., 2019; Cho et al., 2020). The findings offer important evidence for understanding the relationship between energy metabolism and the development of colorectal cancer, contributing to the formulation of personalized cancer prevention strategies. 7.3 Comparative analysis of citric acid cycle activity in different tissue types The activity of the citric acid cycle varies significantly across different tissue types, reflecting their distinct metabolic demands and functions. For instance, highly oxidative tissues such as the heart and skeletal muscles exhibit robust TCA activity to meet their high energy requirements. In contrast, tissues with lower energy demands, such as adipose tissue, show relatively lower TCA activity (Zhelev et al., 2022). This differential activity is also evident in pathological conditions. In cancerous tissues, the TCA is often reprogrammed to support anabolic processes and rapid cell division, whereas in metabolic diseases like obesity and diabetes, dysregulated TCA activity can contribute to altered energy homeostasis and metabolic dysfunction (Cho et al., 2020; Luo et al., 2020; Kim et al., 2022). Understanding these variations is crucial for developing targeted therapeutic strategies that address tissue-specific metabolic needs and dysfunctions. 8 Therapeutic Interventions Targeting the Citric Acid Cycle 8.1 Potential drug targets within the citric acid cycle The citric acid cycle (TCA) is a central hub in cellular metabolism, making it an attractive target for therapeutic interventions. Several enzymes within the TCA have been identified as potential drug targets. For instance, succinate dehydrogenase and fumarate reductase are key enzymes that link the TCA to the respiratory chain, and inhibitors targeting these enzymes could disrupt both metabolic and respiratory processes in pathogens like Mycobacterium tuberculosis (Hards et al., 2019). Additionally, enzymes such as isocitrate dehydrogenase, pyruvate dehydrogenase kinase, and α-ketoglutarate dehydrogenase have been identified as promising targets in cancer therapy, with agents like CPI-613 showing potential in clinical trials (Neitzel et al., 2020). The regulation of carnitine palmitoyltransferase I (CPT1A), a key enzyme in fatty acid oxidation, also presents a therapeutic opportunity, particularly in metabolic disorders and cancers (Schlaepfer and Joshi, 2020). 8.2 Nutritional interventions to modulate cycle activity Nutritional interventions can significantly influence the activity of the citric acid cycle. For example, dietary components that affect the balance of glucose metabolism can modulate the TCA. Cinnamaldehyde, a compound found in cinnamon, has been shown to enhance the TCA by targeting α-enolase, thereby improving mitochondrial efficiency and reducing blood glucose levels (Zhang et al., 2020).
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