Synergic Combination of Natural Bioactive Compounds for Preventing and Treating Human Diseases

Maria Maisto^1*Anis Ben Hsouna²Gian Carlo Tenore¹

• ¹Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
• ²2Departement of Environmental Sciences and Nutrition, Higher Institute of Applied Sciences and Technology of Mahdia, University of Monastir-Tunisia, Mahdia, Tunisia., Mahdia, Tunisia

In recent years, the focus on natural molecules and their potential to manage chronic diseases has grown exponentially(1–3), highlighting the complex interactions these substances have with biological pathways and their potential synergistic effects when used in combination(4). This editorial delves into the specifics of several key studies that demonstrated the potential of natural compound combinations as alternative therapies for treating different kinds of human diseases (Figure 1). Specifically, a recent study included in this research topic explored the combined effects of 3'-sialyl lactose and osteopontin, two human milk oligosaccharides, on influenza virus infection in vitro model of human laryngeal carcinoma cells (HEP-2). The study highlighted the reduction in pro-inflammatory cytokines, such as TNF- and interleukin-6 (IL-6), suggesting that the synergy between these molecules could enhance the immune system's response to viral infections https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1271926/full ). In the realm of metabolic diseases, a study recently published in the current collection, focused on the role of diosgenin, extracted from fenugreek, in a diabetic rat model. The diosgenin ability to modulate diabetic condition was investigated by evaluating its effects on the expression of the main molecular modulators implicated in glycemic control. Diosgenin appears to modulate the activity of GLUT4, facilitating increased glucose uptake into cells, as well as, diosgenin affecting the insulin signaling cascade by activating IRS and PI3K, leading to the phosphorylation and activation of Akt, that in turn inhibits GSK-3β, which results in enhanced glycogen synthesis. (https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2024.1280100/full). Continuing in the context of diabetes, another study of this research topic has investigated the effects of multicomponent formulation derived from ancient traditional medicine on the management of senile diabetic conditions. The authors find that the formulation tested, composed of a combination of 13 different plant-based extracts can ameliorate diabetes by reducing islet cell apoptosis and resisting oxidative stress by regulating the insulin-mediated PI3K/AKT/GSK-3β pathway (https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1339758/full). Continuing the discussion about diabetes, a recent review has reported the valuable synergic effects of the different bioactive molecules of Phyllanthus emblica fruit extract, highlighting that these compounds could potentially enhance diabetic treatment outcomes by leveraging their antioxidant and anti-inflammatory properties.(https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1288618/full). Moved to a completely different pathological background, a comprehensive review investigated the roles of vitamins A, C, D, and E in cancer prevention and therapy delving into the multifaceted mechanisms by which these vitamins contribute to oncological health. By synthesizing data from a wide range of preclinical and clinical studies, the review highlighted how these vitamins act synergistically to combat cancer progression through several biological pathways implicated. The authors described that, while vitamins C and E can provide a valuable defense against oxidative stress, vitamins A, plays a crucial role in epigenetic regulation of oncogenes and tumor suppressor genes expression, influencing cancer development and progression, as well as, Vitamin D, have been shown to modulate the inflammatory response by regulating cytokine production and inhibiting pathways that lead to inflammation. On the basis of such considerations, the authors suppose that the synergic combination of vitamins could be a useful multifunctional tool to prevent the progression of cancer condition (https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1271926/full). In line with this trend, other authors have investigated the effects of a nutraceutical formulation containing a blend of three polyphenolic standardized extracts: rosemary (Rosmarinus officinalis L.), ashwagandha (Withania somnifera L.), and sesame (Sesamum indicum L.) seed, to alleviate back pain. The formulation was tested in a single-center randomized double-blind study with three parallel arms. The study resulted in valuable benefits in improving the treated patients' health-related quality of life, mood, and sleep quality https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2024.1403108/full). On the same trend, other authors have investigated the effects of multicomponent formulation, composite of a mix of various natural extracts, i.e., Angelica sinensis (Oliv.), Carthamus tinctorius L., Saposhnikovia divaricata, Schischk, g; Arisaema erubescens, and Angelica dahurica on the soft tissue injury. After only 10 days of oral treatment, a valuable pain reduction was assessed in the treated group (https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2024.1413937/full). Another example of a synergistic combination of natural bioactive compounds are the association of melatonin and palmitoylethanolamide in a nutraceutical formulation used for the prevention and treatment of immune disease. The results highlight that such combinations are able to reduce the release of immune-inflammatory modulators in the human mast cell line (HMC- 1.2) at their bioaccessible concentration. Additionally, the nutraceutical formulation tested can reduce COX-2 mRNA transcription levels in stimulated HMC-1.2 and to contract COX-2 enzymatic activity directly. https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2024.1417747/full Differently, other authors have investigated the correlation between the Composite Dietary Antioxidant Index (CDAI) and the prevalence and recurrence of kidney stones. In the study, the CDAI was derived by standardizing the intake of dietary antioxidants from 24-hour dietary recalls. The study assessed the prevalence and recurrence of kidney stones based on questionnaire responses. The association between the CDAI and both the prevalence and recurrence of kidney stones was investigated using multivariable logistic regression. The student results suggest that individuals in the top tertile had a 23% lower prevalence of kidney stones (OR = 0.77, 95% CI: 0.66, 0.90, p = 0.0011) and a 39% lower recurrence rate (OR = 0.61, 95% CI: 0.47, 0.80, p = 0.0003) than those in the bottom tertile. Finally, other studies have investigated the heathy effects of Catalpol (CA), derived from Rehmannia Radix, on blood deficiency syndrome (BDS), using 16S rRNA gene sequencing and metabolomic analysis of serum and spleen (https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1280049/full). Another pivotal study investigated the impact of catalpol, a natural compound derived from Rehmannia Radix, on blood deficiency syndrome induced by chemotherapy drugs. This research demonstrated catalpol’s effectiveness in mitigating the detrimental effects of these drugs on blood parameters in rats. (https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1280049/full). Finally, the multitarget activity of Ophiopogon D, a key natural organic compound found in Ophiopogon japonicus, to differently modulate the cardiovascular protection, immune modulation, anti-cancer, anti-atherosclerosis, anti-inflammatory properties, and effectiveness against NAFLD (Non-Alcoholic Fatty Liver Disease), was investigated in a systematic review (https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1401627/full) . In conclusion, the synergy observed among various natural bioactive compounds offers a promising frontier for the integrative management of health and disease. By harnessing the combined effects of these compounds, it is possible to enhance therapeutic outcomes and provide a basis for the development of novel treatment strategies that are both effective and sustainable. The future of medical treatment could very well rely on our ability to integrate these natural elements seamlessly with traditional medical practices, leading to holistic approaches that are not only preventive but also curative.