International Journal of Molecular Medical Science 2025, Vol.15 http://medscipublisher.com/index.php/ijmms © 2025 MedSci Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved. -
International Journal of Molecular Medical Science 2025, Vol.15 http://medscipublisher.com/index.php/ijmms © 2025 MedSci Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved. MedSci Publisher is an international Open Access publisher specializing in disease therapy, clinical pharmacology, clinical biochemistry, vaccines, immunology, microbiology at the publishing platform that is operated by Sophia Publishing Group (SPG), founded in British Columbia of Canada. Publisher MedSci Publisher Editedby Editorial Team of International Journal of Molecular Medical Science Email: edit@ijmms.medscipublisher.com Website: http://medscipublisher.com/index.php/ijmms Address: 11388 Stevenston Hwy, PO Box 96016, Richmond, V7A 5J5, British Columbia Canada International Journal of Molecular Medical Science (ISSN 1927-6656) is an open access, peer reviewed journal published online by MedSci Publisher. The journal publishes scientific articles like original research articles, case reports, review articles, editorials, short communications and correspondence of the high quality pertinent to all aspects of human biology, pathophysiology and molecular medical science, including genomics, transcriptomics, proteomics, metabolomics of disease therapy, clinical pharmacology, clinical biochemistry, vaccines, immunology, microbiology, epidemiology, aging, cancer biology, infectious diseases, neurological diseases and myopathies, stem cells and regenerative medicine, vascular and cardiovascular biology, as well as the important implications for human health and clinical practice research. All the articles published in International Journal of Molecular Medical Science are Open Access, and are distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. MedSci Publisher uses CrossCheck service to identify academic plagiarism through the world’s leading plagiarism prevention tool, iParadigms, and to protect the original authors’ copyrights.
International Journal of Molecular Medical Science (online), 2025, Vol. 15, No. 1 ISSN 1927-6656 http://medscipublisher.com/index.php/ijmms © 2025 MedSci Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved. Latest Content Synergistic Effects of Compound Dietary Fiber and Probiotics and Their Application in Functional Beverages Xiaojie Liu, Long Huang International Journal of Molecular Medical Science, 2025, Vol. 15, No. 1, 1-8 Emerging Genomic Biomarkers for Early Detection of Oral Cancer HuaGuo International Journal of Molecular Medical Science, 2025, Vol. 15, No. 1, 9-19 Metabolic Pathways and Therapeutic Interventions in Cystic Fibrosis Tiantian Li, Jie Zhang International Journal of Molecular Medical Science, 2025, Vol. 15, No. 1, 20-32 Genetic Basis and Clinical Significance of Liver Cysts Ruyi Shao, Xudong Lü International Journal of Molecular Medical Science, 2025, Vol. 15, No. 1, 33-41 Genetic Mutations in Familial Hypertensive Heart Disease Huajun Chen International Journal of Molecular Medical Science, 2025, Vol. 15, No. 1, 42-53
International Journal of Molecular Medical Science, 2025, Vol.15, No.1, 1-8 http://medscipublisher.com/index.php/ijmms 1 Review Article Open Access Synergistic Effects of Compound Dietary Fiber and Probiotics and Their Application in Functional Beverages Xiaojie Liu 1, Long Huang2 1 Shanghai Urban Construction Vocational College, Shanghai, 201415, Shanghai, China 2 Changzhou Neober Biotech Co., Ltd., Changzhou, 213100, Jiangsu, China Corresponding author: huanglong@neober.com International Journal of Molecular Medical Science, 2025, Vol.15, No.1 doi: 10.5376/ijmms.2025.15.0001 Received: 04 Nov., 2024 Accepted: 17 Dec., 2024 Published: 03 Jan., 2025 Copyright © 2025 Liu and Huang, This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preferred citation for this article: Liu X.J., and Huang L., 2025, Synergistic effects of compound dietary fiber and probiotics and their application in functional beverages, International Journal of Molecular Medical Science, 15(1): 1-8 (doi: 10.5376/ijmms.2025.15.0001) Abstract This study systematically reviews the classification, functional properties of compound dietary fiber, and its role in promoting intestinal health. It elucidates the physiological functions of probiotics and the challenges of their application in functional beverages. Furthermore, the study deeply analyzes the synergistic mechanisms between the two, including the promotion of probiotic growth by compound dietary fiber and its optimization of intestinal microecology. The research explores the practical applications of compound dietary fiber and probiotics in functional beverages, covering formula design, process optimization, product stability, and health effect evaluation. Through a comparison of functional beverage development cases at home and abroad, the current technical challenges and solutions are summarized. The findings indicate that compound dietary fiber and probiotics hold great potential in the functional beverage industry, yet further improvements are needed in enhancing stability, health functions, and market adoption. This study provides scientific references for the development of functional beverages and contributes to the theoretical foundation and practical guidance for promoting a healthier lifestyle among consumers. Keywords Compound dietary fiber; Probiotics; Synergistic effects; Functional beverages; Health effects 1 Introduction The integration of compound dietary fibers and probiotics in functional beverages has garnered significant attention due to their potential health benefits. Synbiotic products, which combine probiotics and prebiotics, are designed to enhance gut health by fostering a synergistic relationship between the two components. This synergy is believed to optimize the gut microbiota, improve immune function, and provide nutritional benefits (Sun et al., 2021). The use of dietary fibers from various sources, such as fruits and grains, has been shown to enhance the viability of probiotics and improve the nutritional profile of beverages. Additionally, the incorporation of probiotics in non-dairy beverages has expanded the accessibility of these health benefits to a broader audience, including those with dietary restrictions (Lépine and De Vos, 2018). Recent studies have demonstrated the effectiveness of combining dietary fibers with probiotics in various food matrices. For instance, the use of fruit by-product fibers in yogurts has been shown to enhance probiotic viability and improve the fatty acid profile (Lai et al., 2023). Similarly, synbiotic beverages have been developed using oat-based substrates and probiotic strains, resulting in improved sensory acceptance and probiotic survival. The synergistic effects of dietary fibers and probiotics have also been explored in the context of immune modulation, where they have been shown to directly stimulate immune cells and enhance gut health. Furthermore, the development of synbiotic products using anthocyanin-rich fruits has highlighted the potential for these beverages to offer antioxidant and antimicrobial benefits (Dahiya and Nigam, 2022; Pal and Bhowal, 2023). This study explores the synergistic effects of compound dietary fiber and probiotics and their application in functional beverages. By uncovering their impact on gut microecology, the study aims to identify the optimal compound ratio, develop functional beverages with significant health benefits, and enhance their taste, stability, and market adaptability. The results address consumer needs for gut health, providing solutions for issues such as constipation and irritable bowel syndrome, improving public health, and enhancing the competitiveness of the
International Journal of Molecular Medical Science, 2025, Vol.15, No.1, 1-8 http://medscipublisher.com/index.php/ijmms 2 functional beverage market. By integrating scientific exploration with practical applications, this study offers innovative solutions for the functional beverage industry and personalized nutrition, contributing to the improvement of public health. 2 Characteristics of Compound Dietary Fiber and Probiotics 2.1 Classification and function of compound dietary fiber Dietary fiber is a heterogeneous, indigestible carbohydrate primarily derived from plants. Based on its solubility in water, it can be classified into two categories: soluble fiber and insoluble fiber. Soluble fiber, such as pectin and β-glucans, forms viscous gels in water, slowing the digestion and absorption of nutrients, thereby regulating blood sugar levels and cholesterol. Insoluble fiber, including cellulose and lignin, supports gastrointestinal health by increasing stool bulk and promoting regular bowel movements (Macagnan et al., 2016). Compound dietary fibers are created by combining different types of fibers to enhance their functional properties. This approach also improves the sensory characteristics and nutritional value of food products, making them suitable for use in functional beverages (Chen, 2024). Emerging technologies, such as ultrasound and microwave-assisted extraction, are being explored to improve fiber extraction efficiency and reduce processing costs (Tejeda and Kim, 2021). 2.2 Promotion of intestinal health by compound dietary fiber Compound dietary fibers significantly contribute to intestinal health by serving as a major energy source for the gut microbiota. They undergo fermentation in the colon, producing Short-Chain Fatty Acids (SCFAs) that are essential for the nutrition and integrity of colonocytes (Barber et al., 2020). This fermentation process also creates an antioxidant environment in the colon, which can help in reducing inflammation and promoting gut health (Nazhand et al., 2020). Additionally, certain soluble fibers function as prebiotics, positively modulating the intestinal microbiota and enhancing the gut's immune response. The consumption of compound dietary fibers is associated with improved gut motility, reduced risk of colorectal cancer, and overall better gastrointestinal health (Figure 1) (Tejada-Ortigoza et al., 2016). Figure 1 Effect of dietary fiber and probiotics on the intestinal microflora (Adopted from Lai et al., 2023) 2.3 Definition and physiological functions of probiotics Probiotics are defined as live microorganisms that, when consumed in adequate amounts, confer health benefits to the host. Commonly found in genera such as Lactobacillus, Bifidobacterium, and Saccharomyces, probiotics are widely present in fermented dairy and non-dairy foods and beverages (Enujiugha and Badejo, 2017). Once established in the gut, these strains regulate the gut microbiota, providing various health benefits, including inhibition of gastrointestinal infections, enhanced lactose metabolism, reduced serum cholesterol levels, and alleviation of inflammatory bowel diseases (Chen, 2024). Additionally, probiotics stimulate the immune system, exhibit anti-mutagenic and anti-cancer properties, and improve symptoms of functional dyspepsia by generating beneficial metabolites such as short-chain fatty acids (Hossain et al., 2024).
International Journal of Molecular Medical Science, 2025, Vol.15, No.1, 1-8 http://medscipublisher.com/index.php/ijmms 3 2.4 Application prospects of composite dietary fiber and probiotics The combination of composite dietary fiber and probiotics demonstrates significant application potential in the field of health foods, particularly in the development of functional beverages. Composite dietary fiber not only provides a stable growth environment for probiotics, enhancing their activity and stability, but also synergistically improves gut health, immune function, and metabolic regulation by modulating the gut microbiota. Studies have shown that even in non-dairy matrices, composite dietary fiber can effectively support the survival and adaptability of probiotics, making it more flexible and applicable in the development of functional beverages (Otles and Ozyurt, 2019). As consumer interest in gut health, immune enhancement, and chronic disease prevention continues to grow, composite dietary fiber and probiotics-based functional foods are becoming a focal point in the health market. Although challenges remain in improving the survival rate of probiotics, sensory properties, and storage stability of products, advancements in technology and the application of innovative formulations are driving solutions to these issues (Tesfaye et al., 2019). In the future, this combination is expected to not only diversify the development of functional health beverages but also play a critical role in personalized nutrition, chronic disease management, and the global expansion of the health food market. 3 Synergistic Effects of Compound Dietary Fiber and Probiotics 3.1 Promotion of probiotic growth by compound dietary fiber Compound dietary fibers have been shown to enhance the viability and growth of probiotics in various food matrices. For instance, fibers derived from fruit by-products such as apple and banana have been found to increase the viability of probiotics like Lactobacillus acidophilus and Bifidobacterium animalis during the shelf life of yoghurts, demonstrating a synergistic effect that enhances the nutritional profile of the productb (Speranza et al., 2020). Similarly, soluble corn fiber, when combined with Lactobacillus rhamnosus GG, has been shown to positively influence the fecal microbiota, indicating that dietary fibers can act as prebiotics to support probiotic growth and activity (Skrzypczak et al., 2024). 3.2 Optimization of intestinal microecology through synergistic effects The combination of dietary fibers and probiotics can optimize intestinal microecology by modulating gut microbiota composition and enhancing gut health. Studies have shown that synbiotic combinations, such as those involving long-chain inulin and Lactobacillus acidophilus, can directly stimulate immune cells and improve gut health by modulating the gut microbiota. Additionally, synbiotic beverages containing probiotics and prebiotic fibers have been reported to increase the production of beneficial short-chain fatty acids and decrease harmful metabolites, thereby supporting a healthy gut microbiota (Shah et al., 2020). 3.3 Molecular mechanisms of functional enhancement The synergistic effects of compound dietary fiber and probiotics in functional beverages are primarily mediated through their interactions with the gut microbiota and subsequent metabolic processes. Dietary fibers serve as prebiotics, providing substrates for beneficial gut bacteria, which in turn produce Short-Chain Fatty Acids (SCFAs) and other metabolites that enhance gut health and function (Lee, 2024). Probiotics, such as Lactobacillus and Bifidobacterium strains, further modulate the gut microbiota by increasing the abundance of beneficial bacteria and reducing harmful ones, thereby improving the overall microbial balance. The fermentation of dietary fibers by gut bacteria leads to the production of SCFAs, which have been shown to regulate intestinal pH, enhance mineral absorption, and exert anti-inflammatory effects. These SCFAs also play a crucial role in maintaining the integrity of the gut barrier and modulating immune responses, which are essential for preventing gastrointestinal disorders and enhancing overall health (Chu et al., 2019). Additionally, the presence of phenolic compounds in dietary fibers can contribute to antioxidant activities, further supporting gut health and reducing oxidative stress. 4 Application of Compound Dietary Fiber and Probiotics in Functional Beverages 4.1 Market status and demand analysis of functional beverages The functional beverage market is experiencing significant growth due to increasing consumer awareness of health benefits beyond basic nutrition. Functional beverages, which include non-alcoholic drinks enriched with
International Journal of Molecular Medical Science, 2025, Vol.15, No.1, 1-8 http://medscipublisher.com/index.php/ijmms 4 nontraditional ingredients like probiotics, prebiotics, and dietary fibers, are gaining popularity for their convenience, ease of distribution, and shelf stability (Routray and Orsat, 2019). These beverages are particularly appealing for their potential to improve gut health, manage body weight, and enhance overall well-being, making them a preferred choice among health-conscious consumers. 4.2 Formula design and process optimization The design of functional beverages involves selecting appropriate ingredients and optimizing processes to enhance health benefits and sensory properties. For instance, multigrain beverages using millets have been developed with a focus on maintaining low glycemic index and high dietary fiber content, which are crucial for health benefits and consumer acceptance (Freire et al., 2017). The use of probiotics and prebiotics in beverage formulations requires careful consideration of the strains used and their synergistic effects with dietary fibers to ensure product efficacy and stability (He et al., 2021). 4.3 Product stability and sensory evaluation Ensuring the stability and sensory appeal of functional beverages is critical for consumer acceptance. The incorporation of dietary fibers and probiotics can affect the viscosity and taste of beverages, necessitating process adjustments to maintain desirable sensory attributes (Arya and Shakya, 2021). Techniques such as fermentation and the use of specific probiotic strains can enhance the stability and sensory qualities of these beverages, making them more palatable and effective. Sensory evaluations are essential to optimize formulations and ensure that the final product meets consumer expectations. 4.4 Health effect assessment of functional beverages Functional beverages enriched with dietary fibers and probiotics offer numerous health benefits, including improved gut health, enhanced immune function, and potential relief from gastrointestinal disorders like functional dyspepsia and constipation. Clinical trials have demonstrated that beverages containing specific probiotic strains can modulate gut microbiota, leading to improved digestive health and reduced symptoms of gastrointestinal diseases. The health effects of these beverages are attributed to their ability to enhance the bioavailability of nutrients and support a healthy gut microbiome (Raman et al., 2019). 5 Application Cases and Analysis 5.1 Development status of functional beverages at home and abroad The global market for functional beverages is experiencing significant growth, driven by increasing consumer interest in health and wellness. Functional beverages, which include non-alcoholic drinks enriched with nontraditional ingredients, are gaining popularity due to their health benefits beyond basic nutrition. These beverages are designed to improve various health conditions, such as gut health, immune function, and metabolic health, and are particularly appealing due to their convenience and ease of consumption. In Europe, North America, and Asia, the market for probiotic dairy and non-dairy beverages is substantial, with fermented milk and yogurt products being particularly popular. Non-dairy options are also expanding, catering to consumers with lactose intolerance or those following vegan diets (Palencia-Argel et al., 2022). 5.2 Typical cases of compound dietary fiber and probiotics integration The integration of compound dietary fibers and probiotics in functional beverages is a growing trend, with several successful cases highlighting their synergistic benefits. For instance, beverages containing Lactobacillus paracasei LC-37 have been shown to improve functional dyspepsia by modulating the intestinal microbiota and enhancing beneficial metabolites. Another example is the development of a high-fiber, low glycemic index multigrain beverage using millets, which provides dietary fiber and prebiotic benefits (Figure 2) (Shinde et al., 2019). Additionally, cereal-based gluten-free drinks have been explored for their potential to deliver probiotics and dietary fibers, offering health benefits such as improved gut health and nutrient absorption (Tan et al., 2023). 5.3 Technical challenges and solutions in applications The development of functional beverages incorporating dietary fibers and probiotics faces several technical challenges. One major issue is maintaining the viability of probiotic strains during processing and storage, which
International Journal of Molecular Medical Science, 2025, Vol.15, No.1, 1-8 http://medscipublisher.com/index.php/ijmms 5 is crucial for ensuring the health benefits of the final product (Mudgil and Barak, 2019). Solutions include optimizing fermentation conditions and using protective carriers or encapsulation techniques to enhance probiotic stability. Another challenge is the sensory properties of the beverages, as high fiber content can affect texture and taste. This can be addressed by carefully selecting and balancing ingredients to improve palatability without compromising health benefits (Costabile et al., 2017). Additionally, the use of agricultural by-products as sources of bioactive compounds can reduce costs and environmental impact, although this requires careful processing to ensure quality and safety. Figure 2 Changes in fecal metabolites under the action of complex dietary fiber and probiotics (Adopted from Sun et al., 2021) Image caption: A: Partial least squares discriminant analysis (PLS-DA) of different metabolites in Functional Dyspepsia (FD) before and after the beverage containing Lactobacillus paracasei LC-37 (LC-37) intervention for 28 d (C0 vs. C28); B: Hierarchical clustering analysis for the identification of different metabolites in FD before and after the beverage containing LC-37 intervention for 28 d; C: Correlation analysis of significantly changed species and metabolites affected by the beverage containing LC-37 intervention for 28 d. C0 = samples on d 0; C28 = samples on d 28 (Adopted from Sun et al., 2021)
International Journal of Molecular Medical Science, 2025, Vol.15, No.1, 1-8 http://medscipublisher.com/index.php/ijmms 6 6 Concluding Remarks Future research should focus on exploring the synergistic effects of compound dietary fibers and probiotics in functional beverages. This includes investigating the optimal combinations of fibers and probiotic strains that maximize health benefits, such as improving gut microbiota and enhancing immune responses. Additionally, studies should aim to understand the mechanisms by which these combinations influence metabolic activities and gut health, potentially leading to the development of novel formulations that enhance the efficacy of functional beverages. The application potential of compound dietary fibers and probiotics in functional beverages is vast. These beverages can serve as carriers for bioactive components, offering health benefits beyond basic nutrition, such as improved gut health and disease prevention. The development of non-dairy and cereal-based functional beverages is particularly promising, as they cater to diverse consumer preferences, including those with dietary restrictions. Furthermore, incorporating dietary fibers and probiotics into beverages can enhance their functional properties, such as antioxidant activity and gut microbiota modulation, making them appealing to health-conscious consumers. This study concludes that the integration of compound dietary fibers and probiotics in functional beverages offers significant health benefits, including improved gut microbiota and potential relief from gastrointestinal disorders. The synergistic relationship between dietary fibers and probiotics enhances the nutritional value and functional properties of these beverages, making them a viable option for promoting health and well-being. The findings underscore the importance of continued research and innovation in this field to fully harness the potential of functional beverages in improving public health. Acknowledgments We would like to express my heartfelt thanks to all the teachers who provided guidance and assistance for this study. Conflict of Interest Disclosure The authors affirm that this research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest. References Arya S., and Shakya N., 2021, High fiber, low glycaemic index (GI) prebiotic multigrain functional beverage from barnyard, foxtail and kodo millet, Lwt-Food Science and Technology, 135: 109991. https://doi.org/10.1016/j.lwt.2020.109991 Barber T., Kabisch S., Pfeiffer A., and Weickert M., 2020, The health benefits of dietary fibre, Nutrients, 12(10): 3209. https://doi.org/10.3390/nu12103209 Chen S.Y., 2024, Effect of microorganisms on catechin synthesis in Biluochun tea, Journal of Tea Science Research, 14(1): 1-9. https://doi.org/10.5376/jtsr.2024.14.0001 Chen X., and Zhao Y.C., 2024, Unlocking the tea genome: advances in high-quality sequencing and annotation, Journal of Tea Science Research, 14(2): 79-91. https://doi.org/10.5376/jtsr.2024.14.0008 Chu J., Zhao H., Lu Z., Lu F., Bie X., and Zhang C., 2019, Improved physicochemical and functional properties of dietary fiber from millet bran fermented by Bacillus natto, Food Chemistry, 294: 79-86. https://doi.org/10.1016/j.foodchem.2019.05.035 Costabile A., Bergillos-Meca T., Rasinkangas P., Korpela K., De Vos W., and Gibson G., 2017, Effects of soluble corn fiber alone or in synbiotic combination with Lactobacillus rhamnosus GG and the pilus-deficient derivative GG-PB12 on fecal microbiota, metabolism, and markers of immune function: a randomized, double-blind, placebo-controlled, crossover study in healthy elderly (Saimes Study), Frontiers in Immunology, 8: 1443. https://doi.org/10.3389/fimmu.2017.01443 Dahiya D., and Nigam P., 2022, Nutrition and health through the use of probiotic strains in fermentation to produce non-dairy functional beverage products supporting gut microbiota, Foods, 11(18): 2760. https://doi.org/10.3390/foods11182760 Enujiugha V., and Badejo A., 2017, Probiotic potentials of cereal-based beverages, Critical Reviews in Food Science and Nutrition, 57: 790-804. https://doi.org/10.1080/10408398.2014.930018
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International Journal of Molecular Medical Science, 2025, Vol.15, No.1, 9-19 http://medscipublisher.com/index.php/ijmms 9 Research Insight Open Access Emerging Genomic Biomarkers for Early Detection of Oral Cancer HuaGuo 1,2 1 Zhuji People’s Hospital, Zhuji, 311800, Zhejiang, China 2 Zhuji Hospital of Wenzhou Medical University, Zhuji, 311800, Zhejiang, China Corresponding author: guohua0102@163.com International Journal of Molecular Medical Science, 2025, Vol.15, No.1 doi: 10.5376/ijmms.2025.15.0002 Received: 14 Nov., 2024 Accepted: 31 Dec., 2024 Published: 16 Jan., 2025 Copyright © 2025 Guo, This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preferred citation for this article: Guo H., 2025, Emerging genomic biomarkers for early detection of oral cancer, International Journal of Molecular Medical Science, 15(1): 9-19 (doi: 10.5376/ijmms.2025.15.0002) Abstract Oral cancer, particularly Oral Squamous Cell Carcinoma (OSCC), remains a significant global health challenge due to its high mortality rate and late-stage diagnosis. Emerging genomic biomarkers offer a promising path for the early detection and improved management of OSCC. This study highlights recent advances in genomic biomarker research, focusing on DNA-based, RNA-based, and protein-based biomarkers, as well as circulating tumor DNA (ctDNA). The integration of multi-omics approaches, such as genomics, transcriptomics, and proteomics, provides a comprehensive view of the molecular alterations in OSCC, enhancing the precision of early diagnosis. Additionally, Artificial Intelligence (AI) has emerged as a key tool in the discovery and interpretation of complex biomarker data, enabling more accurate predictions of disease outcomes. Despite these advancements, challenges such as technical limitations, tumor heterogeneity, and regulatory hurdles hinder the widespread clinical adoption of genomic diagnostics. This study discusses these barriers and suggests future directions to enhance the clinical utility of genomic biomarkers, aiming to bridge the gap between research and practical implementation for early OSCC detection. Keywords Oral cancer; Genomic biomarkers; Early detection; Multi-omics; Artificial intelligence 1 Introduction Oral cancer is a significant global health issue, with over 300 000 new cases diagnosed annually, particularly prevalent in regions like South and Southeast Asia, including India, Sri Lanka, and Bangladesh. Despite advances in medical technologies and treatment approaches, the overall five-year survival rate for oral cancer remains low, primarily due to late-stage diagnosis. Risk factors such as smoking, alcohol consumption, and high-risk Human Papilloma Virus (HPV) infections are major contributors, especially in developing countries (D’Souza and Saranath, 2017). Traditional diagnostic methods include physical examinations, tissue biopsies, and imaging techniques like CT, MRI, and PET scans. While essential in clinical practice, these methods often fail to detect the disease in its early stages. Biopsies are invasive and can cause patient discomfort, and imaging techniques are usually employed after symptoms manifest, limiting their role in early detection and contributing to the high mortality rate associated with late diagnosis (Khurshid et al., 2018). The limitations of current diagnostic methods highlight the urgent need for new genomic biomarkers to improve diagnostic sensitivity and specificity. Genomic biomarkers, such as DNA mutations, RNA expression profiles, and methylation patterns, can reveal molecular changes occurring at the early stages of cancer, providing a foundation for more accurate diagnosis. Recent advancements in Next-Generation Sequencing (NGS) and liquid biopsy techniques have enabled researchers to detect circulating tumor DNA (ctDNA) and microRNAs (miRNAs) in body fluids like saliva and blood, offering a non-invasive approach for early diagnosis (Falzone et al., 2019). These biomarkers not only aid in early cancer detection but also in monitoring disease progression and assessing therapeutic responses, making them valuable tools for personalized medicine and improving patient outcomes (Sinevici and O'Sullivan, 2016). This study aims to systematically evaluate the potential of various emerging genomic biomarkers for early detection of oral cancer, including DNA, RNA, protein, and circulating tumor DNA (ctDNA) markers. It will focus on understanding the molecular mechanisms of these biomarkers in cancer initiation and progression, and
International Journal of Molecular Medical Science, 2025, Vol.15, No.1, 9-19 http://medscipublisher.com/index.php/ijmms 10 assess their feasibility for clinical application. By exploring new genomic detection technologies and their applications in early diagnosis, this study seeks to promote the development of more efficient, non-invasive, and precise screening methods for oral cancer. The goal is to provide a basis for personalized treatment approaches, ultimately reducing the incidence and mortality rates of oral cancer globally. 2 Emerging Genomic Biomarkers for Early Detection 2.1 DNA-based biomarkers DNA-based biomarkers focus on genetic and epigenetic alterations, such as mutations and methylation changes in tumor suppressor genes, that occur early in oral cancer development. Hypermethylation of tumor suppressor genes like p16INK4a, RASSF1A, TIMP3, and PCQAP/MED15 has been identified as a promising indicator of oral cancer presence. A study by Liyanage et al. (2019) demonstrated that a panel of these methylated genes could differentiate oral cancer patients from healthy controls with high sensitivity and specificity when detected in saliva, emphasizing their potential in non-invasive early detection (Liyanage et al., 2019). Next-Generation Sequencing (NGS) has facilitated the detection of mutations directly from biological fluids, enhancing the ability to identify genetic alterations associated with Oral Squamous Cell Carcinoma (OSCC). Campos-Carrillo et al. (2019) explored the use of targeted DNA sequencing to detect key oncogenic mutations in saliva, revealing that this approach could effectively identify early-stage tumors that traditional methods might miss. This provides a molecular basis for integrating DNA-based biomarker screening into routine clinical practice (Campos-Carrillo et al., 2019). Furthermore, methylation-specific PCR assays have proven effective in identifying aberrant DNA methylation patterns in the promoter regions of critical genes. A meta-analysis by Adeoye et al. (2021) highlighted the potential of using combined methylation markers in saliva for early screening of OSCC, showing a sensitivity of 86.2% and specificity of 90.6% (Adeoye et al., 2021). These findings support the value of DNA-based methylation biomarkers as reliable tools for early diagnosis, particularly in high-risk populations. 2.2 RNA-based biomarkers (MicroRNAs and lncRNAs) MicroRNAs (miRNAs) have emerged as key players in the early detection of oral cancers due to their role in regulating gene expression and tumorigenesis. Certain miRNAs, such as miR-222-3p, miR-150-5p, and miR-423-5p, have been identified as being differentially expressed in plasma samples from patients with OSCC compared to healthy controls. Chang et al. (2018) demonstrated that a three-miRNA panel could distinguish oral leukoplakia from OSCC with high accuracy (AUC=0.88), suggesting its potential as a non-invasive diagnostic tool (Chang et al., 2018). Long non-coding RNAs (lncRNAs) also play a crucial role in the early detection of oral cancers. Recent studies have highlighted the diagnostic potential of lncRNAs such as GHET1 and ZXF2, which are significantly upregulated in OSCC tissues. Li et al. (2020) identified a set of six novel lncRNAs that, when combined into a diagnostic model, could differentiate OSCC patients from healthy individuals with high sensitivity and specificity (Li et al., 2020). These lncRNAs could serve as early biomarkers for OSCC, offering a more targeted approach to early diagnosis. Moreover, combining lncRNAs with miRNAs in a competitive endogenous RNA (ceRNA) network can further enhance diagnostic precision. Yin et al. (2020) constructed a ceRNA network that included lncRNA HCG22, showing its strong potential as a diagnostic marker for oral cancer. This integrative approach allows for a deeper understanding of the molecular interactions in OSCC and offers a promising path for future biomarker development (Yin et al., 2020). 2.3 Protein-based biomarkers Protein-based biomarkers, particularly those detectable in saliva, provide another non-invasive option for the early detection of OSCC. Cytokeratin fragment 21.1 (Cyfra 21.1) has been identified as a potential biomarker, with elevated levels correlating with the presence of oral cancer. Jafari and Hasanzadeh (2020) developed an
International Journal of Molecular Medical Science, 2025, Vol.15, No.1, 9-19 http://medscipublisher.com/index.php/ijmms 11 immunosensor for detecting Cyfra 21.1 directly from saliva, demonstrating high sensitivity and specificity in identifying early-stage OSCC (Jafari and Hasanzadeh, 2020). Beyond individual proteins, multiplexed proteomic approaches can enhance the accuracy of early detection. For example, IL-8 has been studied as a biomarker due to its association with inflammation and tumor progression. Xu et al. (2020) reported that combining IL-8 with other salivary proteins in a diagnostic panel significantly improved the ability to detect early OSCC, highlighting the value of protein panels in non-invasive screening methods (Xu et al., 2020). Advanced proteomic technologies, such as high-multiplex aptamer-based platforms, have also been explored for identifying novel serum biomarkers. Blatt et al. (2023) used such a platform to analyze the serum proteome of OSCC patients, identifying several proteins that could serve as early indicators of the disease. This approach underscores the potential of advanced proteomics for creating personalized diagnostic tools that could greatly enhance early detection strategies (Blatt et al., 2023). 2.4 Circulating tumor DNA (ctDNA) Circulating tumor DNA (ctDNA) analysis has gained attention as a promising method for early cancer detection, including OSCC. ctDNA contains genetic mutations, methylation patterns, and other tumor-specific alterations that can be detected in blood samples. Campos-Carrillo et al. (2019) reviewed the utility of ctDNA in early cancer detection, emphasizing its potential for identifying genetic mutations associated with oral cancers and offering a non-invasive alternative to traditional biopsy methods (Campos-Carrillo et al., 2019). However, the low abundance of ctDNA in the early stages of cancer poses a challenge for detection. Phallen et al. (2017) introduced targeted error correction sequencing (TEC-Seq) to improve the sensitivity of ctDNA assays, enabling the detection of low-frequency mutations with high accuracy. This technique has shown promise for identifying early-stage cancer alterations, providing a valuable tool for early screening and monitoring (Phallen et al., 2017). Combining ctDNA analysis with other biomarkers has further enhanced diagnostic performance. Bronkhorst et al. (2019) suggested that integrating ctDNA detection with multi-omic approaches, such as combining genetic and epigenetic markers, could improve sensitivity and specificity, particularly for early-stage tumors. This synergistic approach may offer a more comprehensive view of the tumor landscape, allowing for earlier intervention and better outcomes (Bronkhorst et al., 2019). 3 Technological Advances in Biomarker Detection 3.1 Next-generation sequencing (NGS) Next-Generation Sequencing (NGS) is a revolutionary technology that enables high-throughput analysis of genetic material, allowing for comprehensive profiling of mutations, copy number variations, and other genomic alterations associated with oral cancer. NGS technologies facilitate whole-genome, whole-exome, and targeted sequencing, providing detailed insights into the genetic landscape of Oral Squamous Cell Carcinoma (OSCC). For example, Zhang et al. (2019) discussed the clinical application of NGS in precision medicine, emphasizing its role in identifying cancer driver mutations and enabling personalized treatment strategies for various cancers, including oral cancer (Zhang et al., 2019). NGS has also been applied in the context of liquid biopsy, allowing for the detection of circulating tumor DNA (ctDNA) and mutations in peripheral blood samples. Chen and Zhao (2019) highlighted the use of NGS in liquid biopsy to sequence ctDNA, offering a non-invasive method to monitor tumor dynamics in real time, which is particularly useful for cancers like OSCC where repeated tissue biopsies are challenging (Chen and Zhao, 2019). This method allows for early detection of molecular changes even before clinical symptoms appear, thus facilitating timely interventions. Moreover, targeted NGS panels have been developed specifically for oral cancer research to focus on frequently mutated genes such as TP53 and NOTCH1. Kim et al. (2020) emphasized the role of NGS in identifying novel
International Journal of Molecular Medical Science, 2025, Vol.15, No.1, 9-19 http://medscipublisher.com/index.php/ijmms 12 biomarkers and therapeutic targets, encouraging researchers to adopt these technologies for better understanding the pathogenesis of OSCC and improving patient outcomes (Kim et al., 2020). 3.2 Liquid biopsy for circulating tumor DNA (ctDNA) and miRNAs Liquid biopsy, a minimally invasive diagnostic technique, has gained significant attention for its ability to detect circulating tumor DNA (ctDNA) and microRNAs (miRNAs) from blood, saliva, and other body fluids. This approach provides a real-time snapshot of the tumor's molecular profile without the need for traditional tissue biopsies. Lin et al. (2021) discussed the advantages of using ctDNA profiling through liquid biopsy, highlighting its utility in monitoring tumor progression and detecting early genetic alterations associated with OSCC (Lin et al., 2021). Circulating miRNAs have also emerged as promising biomarkers for early detection of oral cancer due to their stability in blood and saliva. Roi et al. (2023) reviewed the role of miRNAs as non-invasive biomarkers in oral cancer diagnosis, noting that changes in specific miRNA expression levels in plasma can serve as early indicators of malignant transformation (Roi et al., 2023). For example, miR-21 and miR-31 have been shown to be upregulated in oral cancer patients, providing potential targets for early detection. The integration of ctDNA and miRNA analysis through liquid biopsy has opened new avenues for monitoring therapeutic response and detecting Minimal Residual Disease (MRD). Cescon et al. (2020) emphasized that ctDNA analysis enables clinicians to track the evolution of tumor clones over time and adapt treatment strategies accordingly, making it a valuable tool in personalized medicine for oral cancer (Cescon et al., 2020). 3.3 Proteomics for early cancer detection Proteomics, the large-scale study of proteins, has become an important tool for identifying protein-based biomarkers for the early detection of oral cancer. Advances in mass spectrometry and protein microarray technologies have allowed researchers to profile thousands of proteins simultaneously, identifying specific patterns of protein expression that correlate with disease states. Xu et al. (2020) demonstrated the potential of salivary proteomics in detecting early-stage OSCC, identifying proteins such as IL-8 and Matrix Metalloproteinases (MMPs) that were significantly upregulated in patients compared to healthy controls (Xu et al., 2020). Proteomics approaches have also been used to discover novel therapeutic targets and develop diagnostic panels for clinical use. Blatt et al. (2023) utilized a high-throughput aptamer-based proteomic platform to identify serum proteins that serve as biomarkers for early detection of OSCC. Their findings suggest that combining multiple protein markers can improve diagnostic accuracy and serve as a foundation for developing non-invasive screening tools for clinical settings (Blatt et al., 2023). Furthermore, the integration of proteomics with other omics data, such as genomics and transcriptomics, offers a holistic view of the molecular changes associated with oral cancer. This multi-omics approach can improve the sensitivity and specificity of early detection methods and provide insights into the underlying mechanisms driving OSCC progression. This integrated approach has the potential to identify robust biomarkers that can be applied in routine clinical practice, thus enhancing early detection efforts. 4 Pathogenesis and Molecular Basis of Oral Cancer 4.1 Genomic and epigenomic changes Genomic changes, such as mutations in key oncogenes and tumor suppressor genes, are fundamental to the initiation and progression of OSCC. Frequently mutated genes in OSCC include TP53, NOTCH1, and PIK3CA, which contribute to cell cycle dysregulation, impaired apoptosis, and enhanced cell proliferation (Fang et al., 2015). Beyond single-gene mutations, copy number variations and chromosomal instability also play a role in driving tumorigenesis. For example, amplifications of chromosomal regions containing oncogenes like CCND1 (Cyclin D1) have been associated with advanced stages of OSCC (Auzair et al., 2016).
International Journal of Molecular Medical Science, 2025, Vol.15, No.1, 9-19 http://medscipublisher.com/index.php/ijmms 13 Epigenetic changes, including DNA methylation and histone modifications, are crucial in OSCC pathogenesis. Aberrant methylation patterns, such as hypermethylation of tumor suppressor genes like CDKN2A, contribute to silencing these genes and promote uncontrolled cell proliferation. Epigenetic alterations can also modulate gene expression through changes in chromatin structure, affecting the transcription of genes involved in differentiation and apoptosis (Zhang et al., 2015). Understanding these changes is critical for developing targeted therapies that can reverse epigenetic silencing and restore normal gene function in OSCC. 4.2 MicroRNA dysregulation in tumorigenesis MicroRNAs (miRNAs) are small non-coding RNAs that play a pivotal role in gene regulation, and their dysregulation is a hallmark of many cancers, including OSCC. In OSCC, specific miRNAs function as oncogenes or tumor suppressors, impacting various processes like proliferation, apoptosis, and metastasis. For instance, downregulation of the miR-200 family is associated with the promotion of Epithelial-To-Mesenchymal Transition (EMT), which enhances the invasive potential of cancer cells (Arunkumar et al., 2017). Other miRNAs, such as miR-21 and miR-375, have been identified as potential biomarkers for OSCC diagnosis due to their consistent expression patterns in cancer tissues and body fluids (He et al., 2016). The overexpression of miR-21, for example, is known to target and suppress tumor suppressor genes like PTEN, leading to enhanced cell survival and resistance to apoptosis. Conversely, restoration of tumor-suppressive miRNAs, such as miR-16, has been shown to inhibit OSCC cell proliferation and induce apoptosis by targeting oncogenic pathways. These findings highlight the therapeutic potential of miRNAs as both biomarkers and targets in OSCC treatment. 4.3 Protein expression and tumorigenesis Alterations in protein expression are crucial in the progression of OSCC, as they reflect changes in cellular signaling pathways that drive tumorigenic processes. Overexpression of proteins like S100A9 and Caveolin-1 has been associated with increased invasiveness and poor prognosis in OSCC patients (Fang et al., 2015), (Auzair et al., 2016). S100A9, for example, can promote tumor cell invasion by interacting with the tumor microenvironment and inducing pro-inflammatory cytokine production, which supports tumor growth. The transcription factor Yes-Associated Protein (YAP), a key component of the Hippo signaling pathway, plays an essential role in regulating cell proliferation and apoptosis in OSCC. Figure 1A demonstrates strong YAP expression in well-differentiated OSCC, while Figure 1B shows similar overexpression in moderately differentiated OSCC. The strong immunohistochemical staining indicates that YAP is highly active in both OSCC types, and its elevated expression has been correlated with increased tumor aggressiveness and poor patient outcomes (Figure 1) (Shelke et al., 2019). This highlights YAP's involvement in driving OSCC progression, making it a potential therapeutic target. Figure 1 A and B: Photomicrograph showing strong expression of YAP in different grades of OSCC (Adapted from Shelke et al., 2019) Image caption: (A) Well-differentiated OSCC; (b) Moderately differentiated OSCC (total magnification×400; IHC staining).The strong expression of YAP in both well-differentiated and moderately differentiated OSCC tissues suggests that YAP may play a role in the progression of OSCC, regardless of differentiation grade. This highlights the potential of YAP as a biomarker for OSCC, and possibly a therapeutic target, since its activity may be associated with cancer cell proliferation and survival (Adapted from Shelke et al., 2019)
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