Diabetes mellitus (DM), a chronic inflammatory disease, is a significant global health concern. Influenced by both genetic and environmental factors, DM is a metabolic disorder within the endocrine system that can cause extensive damage to various bodily systems including the cardiovascular, nervous, and urinary systems (Ge et al., 2017). As of 2021, over 529 million people worldwide were affected by DM (GBD, 2021 Diabetes Collaborators, 2023), underscoring the urgent need for effective treatments.
Current DM management primarily relies on oral antidiabetic drugs like biguanides, sodium-glucose cotransport inhibitors, glucokinase activators, sulfonylureas, dipeptidyl peptidase-4 inhibitors, and α-glucosidase inhibitors (Krentz and Bailey, 2005; Naghma et al. 2020; Neumiller et al., 2010; Yang et al., 2022; Zhang et al., 2020; Nakamura et al., 2014). However, these treatments often come with various side effects, necessitating the search for safer and more effective alternatives.
Traditional Chinese Medicine (TCM) has been employed for over two millennia to treat DM (Hao et al., 2017). Recent studies have shown that TCM can significantly improve glycemia and clinical indicators in diabetes patients, effectively delaying DM progression (Tian et al., 2019). In particular, flavonoids derived from TCM have shown promise due to their safety and efficacy (Varshney et al., 2019; Gandhi et al., 2020; Chen et al., 2019).
For instance, flavonoids from Astragalus membranaceus and citrus have shown potential in treating DM and its complications (Li et al., 2019a; Gandhi et al., 2020). Moreover, compounds like luteolin from Salvia miltiorrhiza have been found to improve insulin resistance and regulate glucose and lipid metabolism (Zhang et al., 2021b). However, the specific effects and mechanisms of individual flavonoids in DM treatment remain insufficiently explored.
The integration of transcriptomic analysis and network pharmacology has been increasingly used to understand drug mechanisms and predict efficacy (Xie et al., 2022; Lv et al., 2021). For example, the use of biolayer interferometry (BLI) has advanced as a technique to analyze molecular interactions in TCM and targeted therapy (Bao et al., 2016; Chen et al., 2021; Zhang et al., 2021; Guo et al., 2022). BLI helps in understanding interactions between natural small molecules and target proteins, as seen in recent studies identifying potential SARS-Cov-2 entry inhibitors (Zhang et al., 2021a).
Cyclocarya paliurus (C. paliurus), from the Pecanaceae family, has a long history of use in TCM, particularly in treating diabetes (Yi et al., 2001; Kurihara et al., 2003; Li et al., 2012; Wang et al., 2016; Xu et al., 2017; Yoshitomi et al., 2017). Recognized for its broad health benefits, including anti-inflammatory, detoxifying, and immune-modulating properties, C. paliurus has been approved as a novel food resource in China (Chen et al., 2022).
Its leaves contain polysaccharides, flavonoids, and terpenoids, all effective in DM treatment. For example, polysaccharides in C. paliurus have been shown to protect pancreatic islets and decrease oxidative stress and pro-inflammatory cytokines (Li et al., 2019b). Extracts high in flavonoids, such as quercetin-3-O-glucuronide and kaempferol-3-O-glucuronide, have shown antihyperglycemic effects in diabetic mouse models (Liu et al., 2018b). Moreover, the total flavonoids of C. paliurus (CTFs) have prebiotic-like activity and potential in preventing obesity-related metabolic disorders by affecting gut flora and metabolic pathways (Cheng et al., 2019).
This study focuses on extracting CTFs from C. paliurus leaves, analyzing their chemical composition, and evaluating their in vitro effectiveness in DM treatment. Using transcriptomic analysis, the study aims to predict the molecular mechanisms of CTFs in DM treatment. Network pharmacology and molecular docking methods are employed to screen potential individual flavonoids for DM treatment, and BLI is used to analyze compound-protein binding interactions. This comprehensive approach may yield novel insights into developing CTF-based treatments for DM, offering a promising direction in the ongoing battle against this pervasive disease.
DISCUSSION
Unlocking the Antidiabetic Potential of Cyclocarya Paliurus Flavonoids: A Comprehensive Study
In the realm of Type 2 Diabetes Mellitus (T2DM) research, significant strides have been made in understanding the disease’s pathogenesis. Insulin resistance, a hallmark of T2DM, is influenced by factors such as obesity, aging, and physical inactivity, often leading to a compensatory increase in pancreatic islet cell proliferation and insulin secretion (Besic et al., 2015). However, when this compensation is inadequate, T2DM progresses. This study presents groundbreaking findings on the efficacy of Cyclocarya Paliurus Flavonoids (CTFs) in counteracting these developments.
Effectiveness of CTFs in DM Treatment
Our research discovered that CTFs significantly enhance insulin levels and promote the proliferation of beta-TC-6 cells damaged by high glucose. This finding is consistent with previous research on plant flavonoids, such as those from mulberry leaf, Garcinia kola seeds, Bauhinia strychnifolia stem, Hyphaene thebaica epicarp, and Selaginella tamariscina Spring, which have demonstrated substantial antidiabetic effects (Zhang et al., 2019; Adaramoye, 2012; Praparatana et al., 2022; Salib et al., 2013; Zheng et al., 2013). Dietary flavonoids have been linked to reduced diabetes incidence, highlighting their potential as effective antidiabetic agents.
Deciphering Antidiabetic Mechanisms via Comparative Transcriptomic Analysis
T2DM is primarily caused by insulin resistance and the loss of islet beta-cell function. Our comparative transcriptomic analysis revealed that CTF treatment alters gene expression in pathways critical for insulin signal transduction, such as the PI3K-AKT signaling pathway, insulin secretion pathway, insulin signaling pathway, and p53 signaling pathway. This suggests that CTFs could improve cell behaviors related to diabetes, such as glucose uptake, insulin expression, and cell survival, thereby alleviating abnormal glucose metabolism associated with the condition.
Unveiling Target Pathways through Network Pharmacology
Our network pharmacology analysis identified key proteins and pathways critical in the antidiabetic effects of CTFs. Proteins such as PIK3CA, PIK3R1, PIK3CG, PIK3CD, AKT1, IGF1R, and GSK3B were found to play significant roles. These proteins are involved in cellular processes essential for diabetes management, such as cell survival, proliferation, and insulin signaling.
Identifying Key Antidiabetic Flavonoids
The study pinpointed nine core CTF ingredients with anti-inflammatory and antidiabetic properties: velutin, kaempferide, peonidin, apigenin, pelargonidin, 5,6,7-trihydroxyflavone, tangeretin, laricitrin, and 4′-methylnaringenin. These compounds interact with target proteins like PIK3CA and GSK3B, crucial in diabetes management. Molecular docking and BLI assays further validated these interactions, confirming the antidiabetic potential of these flavonoids.
Conclusions
This study provides substantial evidence of the antidiabetic effects of CTFs. Through transcriptomic analysis, network pharmacology, and BLI assays, we have demonstrated that CTFs promote beta-cell proliferation and increase insulin expression by modulating key genes and proteins involved in crucial signaling pathways. These findings underscore the potential of CTFs as a viable treatment option for T2DM, warranting further research to fully understand their mechanisms of action and therapeutic potential.
Reference link : https://www.sciencedirect.com/science/article/pii/S1756464624000331#s0160
