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Role of Natural Compounds in Human Health and Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Bioactives and Nutraceuticals".

Deadline for manuscript submissions: closed (24 April 2026) | Viewed by 26721

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Special Issue Editors

Dr. Jaewon Shim

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Guest Editor

Department of Biochemistry, Kosin University College of Medicine, Busan 49267, Republic of Korea
Interests: natural product

Dr. Wook-bin Lee

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Guest Editor

Natural Product Research Center, Korea Institute of Science & Technology, Gangneung 25451, Republic of Korea
Interests: natural product

Special Issue Information

Dear Colleagues,

Natural Compounds have been used for a long time in traditional medicine to treat different illnesses. Recently, there has been more interest in these natural compounds because they might have health benefits and fewer side effects compared to synthetic drugs. Their antioxidant, anti-inflammatory, antimicrobial, and immunomodulatory properties offer a wide range of therapeutic applications, including anti-cancer, anti-cardiovascular disease, anti-neurodegenerative diseases, and anti-metabolic disorders. For example, curcumin has been extensively studied for its ability to inhibit tumor growth and metastasis. Omega-3 fatty acids from fish oil, flavonoids from dark chocolate, and polyphenols from red wine have been shown to improve heart health by reducing blood pressure, improving lipid profiles, and enhancing endothelial function. Ginkgo biloba is believed to improve cognitive function and slow the progression of neurodegenerative diseases due to its antioxidant and anti-inflammatory properties. Berberine, found in several plants, has been shown to regulate glucose and lipid metabolism, making it a potential treatment for type 2 diabetes.

This special issue explores the role of natural compounds in promoting human health and fighting diseases, highlighting their mechanisms of action, therapeutic potential, and the challenges associated with their use.

Importantly, the exact active ingredient of natural origin extract must be reported in the submitted research manuscript, since papers describing the effects of mixed extraction from natural origin are not in the scope of the journal.

Dr. Jaewon Shim
Dr. Wook-bin Lee
Guest Editors

Manuscript Submission Information

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Keywords

natural compound
therapeutic applications
action mechanisms of natural compounds
traditional medicine

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Published Papers (10 papers)

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Research

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17 pages, 3084 KB

Open AccessArticle

Neuromodulatory Effects of Arecoline on Anxiety-like Behavior in Mice Exposed to Chronic Unpredictable Mild Stress

by Xiangfei Zhang, Danyang Wang, Jingwen Cui, Bei Fan, Fengzhong Wang and Cong Lu

Int. J. Mol. Sci. 2026, 27(1), 371; https://doi.org/10.3390/ijms27010371 - 29 Dec 2025

Cited by 1 | Viewed by 610

Abstract

Chronic stress disrupts neuroendocrine regulation, neurotransmitter balance, and neuronal redox homeostasis, thereby contributing to the development of anxiety-related neuropathology. Arecoline, the predominant alkaloid of Areca catechu L., displays diverse neuropharmacological properties, yet its role in stress-induced emotional dysfunction has not been fully elucidated. This study examined the anxiolytic-like and neuroprotective effects of arecoline in mice exposed to chronic unpredictable mild stress (CUMS). Arecoline administration markedly improved behavioral outcomes, reflected by increased central exploration in the open-field test, prolonged time in the light compartment, and enhanced open-arm activity in the elevated plus maze. These behavioral benefits were accompanied by normalization of serum corticosterone levels, restoration of hippocampal neurotransmitters, reinforcement of antioxidant enzyme activities, and attenuation of pro-inflammatory cytokines. At the molecular level, arecoline elevated brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), cAMP response element-binding protein (CREB), N-methyl-D-aspartate receptor (NMDAR), and Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), indicating enhanced synaptic plasticity, while concurrently diminishing oxidative and inflammatory stress. Collectively, the findings suggest that arecoline exerts multifaceted neuroprotective actions under chronic stress by coordinating neuroendocrine modulation, neurotransmitter homeostasis, antioxidant defenses, and synaptic plasticity. This study provides new mechanistic evidence supporting the potential relevance of arecoline as a functional neuroactive compound for managing stress-induced anxiety disorders. Full article

(This article belongs to the Special Issue Role of Natural Compounds in Human Health and Disease)

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14 pages, 876 KB

Open AccessArticle

Inhibition of (p)ppGpp Synthesis and Membrane Fluidity Modulation by Diosgenin: A Strategy to Suppress Staphylococcus aureus Persister Cells

by Yena Seo, Minjun Kim and Tae-Jong Kim

Int. J. Mol. Sci. 2025, 26(13), 6335; https://doi.org/10.3390/ijms26136335 - 30 Jun 2025

Cited by 2 | Viewed by 1302

Abstract

Persister cells are a subset of bacterial cells that exhibit transient antibiotic tolerance without genetic resistance, contributing to the persistence of chronic infections. This study investigates the ability of diosgenin, a naturally occurring steroidal saponin, to inhibit persister cell formation in Staphylococcus aureus through metabolic suppression and membrane modulation. Diosgenin treatments at 80 µM and 160 µM significantly reduced persister cell survival under oxacillin, ciprofloxacin, and gentamicin stress, with reductions ranging from 82% to 94% after 3 h diosgenin pre-exposure. Gene expression analysis revealed that diosgenin downregulated relP and relQ, key genes involved in (p)ppGpp synthesis, by up to 60%, accompanied by 36–38% decreases in intracellular ATP levels. Diosgenin did not significantly alter membrane permeability or membrane potential but reduced membrane fluidity by 35% and 41% at 80 µM and 160 µM, respectively. Taken together, our findings suggest that diosgenin exerts a dual-action regulatory effect on persister cell formation by disrupting metabolic pathways essential for dormancy and altering membrane dynamics, potentially affecting membrane-associated signaling. This study provides a framework for the further exploration of diosgenin as a potential anti-persister agent with particular promise for use in combination with conventional antibiotics to enhance therapeutic efficacy against chronic bacterial infections. Full article

(This article belongs to the Special Issue Role of Natural Compounds in Human Health and Disease)

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16 pages, 4219 KB

Open AccessArticle

Protocatechualdehyde Induced Breast Cancer Stem Cell Death via the Akt/Sox2 Signaling Pathway

by Seung-Yeon Ko, Seonghee Park and Youn-Hee Choi

Int. J. Mol. Sci. 2025, 26(5), 1811; https://doi.org/10.3390/ijms26051811 - 20 Feb 2025

Cited by 1 | Viewed by 1774

Abstract

Breast cancer (BC) is most frequently recognized in women and characterized by histological and molecular heterogeneity. Among the various subtypes, triple-negative BC remains the most challenging disease owing to the lack of effective molecular targets and the high frequency of breast cancer stem cells (BCSCs), which account for both recurrence and resistance to conventional treatments. Despite the availability of hormonal therapies and targeted treatments, patients still face early and late relapses, necessitating new cytotoxic and selective treatment strategies. Our study focuses on investigating the effects of protocatechualdehyde (PCA), a potent bioactive compound derived from Artemisia princeps, on CSCs in BC cells. PCA inhibited BC growth and mammosphere formation as the concentration increased. This agent decreased the fraction of the CD44⁺/CD24⁻ population, the aldehyde dehydrogenase 1A-expressing population, and the protein level of Sox2 in breast CSCs by downregulating Akt and pAkt. Moreover, PCA treatment reduced the tumor volume and weight in 4T1-challenged BALB/c mice. Collectively, our findings support the anti-tumor effect of Akt/Sox2-targeting PCA, suggesting a novel utilization of PCA in BC therapy. Full article

(This article belongs to the Special Issue Role of Natural Compounds in Human Health and Disease)

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19 pages, 3951 KB

Open AccessArticle

Retinal Protective Effect of Mono-Ethyl Fumarate in Experimental Age-Related Macular Degeneration via Anti-Oxidative and Anti-Apoptotic Alterations

by Hara Lee, Siqi Zhang, Hong Ryul Ahn, Taejung Kim, Jiyool Kim, Heesu Lee, Sang Hoon Jung and Joonki Kim

Int. J. Mol. Sci. 2025, 26(4), 1413; https://doi.org/10.3390/ijms26041413 - 7 Feb 2025

Cited by 3 | Viewed by 1786

Abstract

Age-related macular degeneration (AMD) is a leading cause of vision impairment in people over the age of 60. Currently, the FDA-approved drugs for AMD have various side effects, and there is a notable lack of drug development for dry AMD. This study aimed to explore the therapeutic effects of mono-ethyl fumarate (MEF) on AMD. MEF effectively protected ARPE-19 cells from cell death induced by a combination of A2E and blue light exposure. In a C57BL/6J mouse model of retinal degeneration caused by sodium iodate, MEF played a role in preserving retinal thickness and maintaining the layered structure of the retina. It was assessed via fundus imaging, optical coherence tomography, and hematoxylin and eosin staining. Treatment with MEF significantly increased the expression of antioxidant proteins such as HO-1, NQO1, and SOD1 in ARPE-19 cells. Additionally, treatment with MEF significantly increased the levels of the antioxidant proteins SOD1 and GPX4 in the mouse retina. Concurrently, it significantly reduced the levels of apoptosis-related factors, such as the Bax/Bcl-2 ratio and Caspase -3 cleavage. These findings suggest that MEF may represent a promising therapeutic candidate for the management of AMD. Full article

(This article belongs to the Special Issue Role of Natural Compounds in Human Health and Disease)

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14 pages, 3656 KB

Open AccessCommunication

Effects of Antioxidant Amino Acids on Cancer Sarcopenia

by Shota Nukaga, Rina Fujiwara-Tani, Takuya Mori, Isao Kawahara, Ryoichi Nishida, Yoshihiro Miyagawa, Kei Goto, Hitoshi Ohmori, Kiyomu Fujii, Takamitsu Sasaki, Chie Nakashima, Yi Luo, Shingo Kishi, Ruiko Ogata and Hiroki Kuniyasu

Int. J. Mol. Sci. 2025, 26(1), 272; https://doi.org/10.3390/ijms26010272 - 31 Dec 2024

Cited by 1 | Viewed by 1825

Abstract

Cancer sarcopenia is highly prevalent in patients with advanced cancer, which is closely related to the disease prognosis. Overcoming cancer sarcopenia is important for cancer treatment. Cystine and theanine (CT), antioxidant amino acids, have been applied to the nutritional intervention of various diseases but their effects remain unclear on cancer sarcopenia. We attempt to examine the effect of CT on cancer sarcopenia. Both mouse and in vitro cachexia models showed that CT reduced oxidative stress, inhibited autophagy and apoptosis, improved oxidative phosphorylation and the suppression of high mobility group box-1 production, and improved sarcopenia and muscle maturity. When treated with 5-fluorouracil in a mouse cachexia model, tumor weight decreased but oxidative stress increased and muscle weight and muscle maturity were suppressed regardless of diet. However, in the CT group, oxidative stress was reduced and the exacerbation of sarcopenia by 5-fluorouracil was suppressed. Thus, in cancer cachexia, oxidative stress plays a major role in skeletal muscle damage, and CT, which has an anti-oxidative stress effect, has a strong protective effect on skeletal muscle. In the future, it will be important to conduct clinical studies on nutritional intervention for cancer sarcopenia using CT. Full article

(This article belongs to the Special Issue Role of Natural Compounds in Human Health and Disease)

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13 pages, 1876 KB

Open AccessArticle

Development and Evaluation of ABI-171, a New Fluoro-Catechin Derivative, for the Treatment of Idiopathic Pulmonary Fibrosis

by Gian Luca Araldi, Yu-Wen Hwang and Ganesh Raghu

Int. J. Mol. Sci. 2024, 25(21), 11827; https://doi.org/10.3390/ijms252111827 - 4 Nov 2024

Cited by 2 | Viewed by 2797

Abstract

The persistent challenge of idiopathic pulmonary fibrosis (IPF), characterized by disease progression and high mortality, underscores the urgent need for innovative therapeutic strategies. We have developed a novel small molecule—catechin derivative ABI-171—selectively targeting dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) and proviral integration site for Moloney murine leukemia virus 1 (PIM1) kinases, crucial in the pathogenesis of fibrotic processes. We employed the Bleomycin-induced (intratracheal) mouse model of pulmonary fibrosis (PF) to evaluate the therapeutic efficacy of ABI-171. Mice with induced PF were treated QD with ABI-171, either prophylactically or therapeutically, using oral and intranasal routes. Pirfenidone (100 mg/kg, TID) and Epigallocatechin gallate (EGCG, 100 mg/kg, QD), a natural catechin currently in a Phase 1 clinical trial, were used as reference compounds. ABI-171, administered prophylactically, led to a significant reduction in hydroxyproline levels and fibrotic tissue formation compared to the control group. Treatment with ABI-171 improved body weight, indicating mitigation of disease-related weight loss. Additionally, ABI-171 demonstrated anti-inflammatory activity, reducing lymphocyte and neutrophil infiltration. In the therapeutic setting, ABI-171, administered 7 days post-induction, reduced mortality rates (p = 0.04) compared with the bleomycin and EGCG control groups. ABI-171 also ameliorated the severity of lung injuries assessed by improved Masson’s trichrome scores when administered both orally and intranasally. ABI-171 significantly decreases bleomycin-induced PF and improves survival in mice, showcasing promising therapeutic potential beyond current medications like pirfenidone and EGCG for patients with IPF. Based on these results, further studies with ABI-171 are ongoing in preclinical studies. Full article

(This article belongs to the Special Issue Role of Natural Compounds in Human Health and Disease)

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14 pages, 2454 KB

Open AccessArticle

Vitex agnus castus Extract Ze 440: Diterpene and Triterpene’s Interactions with Dopamine D2 Receptor

by Jakob K. Reinhardt, Lukas Schertler, Hendrik Bussmann, Manuel Sellner, Martin Smiesko, Georg Boonen, Olivier Potterat, Matthias Hamburger and Veronika Butterweck

Int. J. Mol. Sci. 2024, 25(21), 11456; https://doi.org/10.3390/ijms252111456 - 25 Oct 2024

Cited by 4 | Viewed by 8307

Abstract

Pre-clinical studies suggest that extracts prepared from the fruits of Vitex agnus castus (VAC) interact with dopamine D2 receptors, leading to reduced prolactin secretion. In previous experiments, dopaminergic activity was mostly evaluated using radioligand binding assays or via the inhibition of prolactin release from rat pituitary cells. Diterpenes featuring a clerodadienol scaffold were identified as major active compounds, but no conclusive data regarding their potency and intrinsic activity are available. Utilising advances in chromatography, we re-examined this topic using HPLC-based tracking of bioactivity via microfractionation of the VAC extract Ze 440. Using a cAMP-based assay, we measured dopaminergic activity in CHO-K1 cells that overexpress the human D2 receptor. Six diterpenes were isolated from two active HPLC microfractions. Viteagnusin I emerged as the most potent diterpene (EC₅₀: 6.6 µM), followed by rotundifuran (EC₅₀: 12.8 µM), whereas vitexilactone was inactive (EC₅₀: >50 µM). Interestingly, triterpenes were also identified as active, with 3-epi-maslinic acid being the most active compound (EC₅₀: 5.1 µM). To better understand these interactions at the molecular level, selected diterpenes and triterpenes were analysed through molecular docking against D2 receptor structures. Our data show that the dopaminergic activity of VAC diterpenes seems to depend on the configuration and on ring substitution in the side chain. This study also highlights for the first time the dopaminergic contribution of triterpenes such as 3-epi-maslinic acid. Full article

(This article belongs to the Special Issue Role of Natural Compounds in Human Health and Disease)

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Review

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24 pages, 2708 KB

Open AccessReview

Berberine: A Negentropic Modulator for Multi-System Coordination

by Xiaolian Tian, Qingbo Chen, Yingying He, Yangyang Cheng, Mengyu Zhao, Yuanbin Li, Meng Yu, Jiandong Jiang and Lulu Wang

Int. J. Mol. Sci. 2026, 27(2), 747; https://doi.org/10.3390/ijms27020747 - 12 Jan 2026

Viewed by 1881

Abstract

Berberine (BBR), a protoberberine alkaloid with a long history of medicinal use, has consistently demonstrated benefits in glucose–lipid metabolism and inflammatory balance across both preclinical and human studies. These diverse effects are not mediated by a single molecular target but by BBR’s capacity to restore network coordination among metabolic, immune, and microbial systems. At the core of this regulation is an AMP-activated Protein Kinase (AMPK)-centered mechanistic hub, integrating signals from insulin and nutrient sensing, Sirtuin 1/3 (SIRT1/3)-mediated mitochondrial adaptation, and inflammatory pathways such as nuclear Factor Kappa-light-chain-enhancer of Activated B cells (NF-κB) and NOD-, LRR- and Pyrin Domain-containing Protein 3 (NLRP3). This hub is dynamically regulated by system-level inputs from the gut, mitochondria, and epigenome, which in turn strengthen intestinal barrier function, reshape microbial and bile-acid metabolites, improve redox balance, and potentially reverse the epigenetic imprint of metabolic stress. These interactions propagate through multi-organ axes, linking the gut, liver, adipose, and vascular systems, thus aligning local metabolic adjustments with systemic homeostasis. Within this framework, BBR functions as a negentropic modulator, reducing metabolic entropy by fostering a coordinated balance among these interconnected systems, thereby restoring physiological order. Combination strategies, such as pairing BBR with metformin, Sodium-Glucose Cotransporter 2 (SGLT2) inhibitors, and agents targeting the microbiome or inflammation, have shown enhanced efficacy and substantial translational potential. Berberine ursodeoxycholate (HTD1801), an ionic-salt derivative of BBR currently in Phase III trials and directly compared with dapagliflozin, exemplifies the therapeutic promise of such approaches. Within the hub–axis paradigm, BBR emerges as a systems-level modulator that recouples energy, immune, and microbial circuits to drive multi-organ remodeling. Full article

(This article belongs to the Special Issue Role of Natural Compounds in Human Health and Disease)

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17 pages, 400 KB

Open AccessReview

A Comprehensive Review of Robinetin: Distribution, Biological Activity and Pharmacokinetic Parameters

by Katarzyna Jakimiuk

Int. J. Mol. Sci. 2025, 26(19), 9546; https://doi.org/10.3390/ijms26199546 - 30 Sep 2025

Viewed by 1367

Abstract

Robinetin, a naturally occurring polyhydroxylated flavonol, has gained attention due to its broad spectrum of biological activities and potential therapeutic applications. This review presents a comprehensive summary of the current knowledge concerning the natural occurrence, extraction, spectroscopic characterization, and pharmacological properties of robinetin. Ethnobotanical evidence highlights its presence in various medicinal plants, particularly within the Fabaceae family, where it contributes to traditional treatments of infections, inflammation, and metabolic disorders. Robinetin exhibits diverse bioactivities, including antiviral, antibacterial, antiparasitic, antioxidant, anti-mutagenic, and enzyme-inhibitory effects. Notably, it inhibits HIV-1 integrase and acetylcholinesterase and demonstrates moderate antiproliferative activity in cancer cell lines. Despite limited water solubility, its redox behavior and metal-chelating capabilities support its antioxidant potential. Recent in vivo studies indicate its hepatoprotective and metabolic regulatory effects. Additionally, computational models reveal promising interactions with molecular targets such as CDK1. Collectively, these findings underscore the multifaceted therapeutic potential of robinetin and advocate for further pharmacokinetic and clinical investigations to validate its efficacy as a lead compound for the development of phytochemically derived pharmaceuticals. Full article

(This article belongs to the Special Issue Role of Natural Compounds in Human Health and Disease)

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16 pages, 602 KB

Open AccessReview

Nutritional Characteristics, Health-Related Properties, and Food Application of Teff (Eragrostis tef): An Overview

by Boyiza Samson Abebe, Iuliana Aprodu, Daniela Ionela Istrati and Camelia Vizireanu

Int. J. Mol. Sci. 2025, 26(19), 9293; https://doi.org/10.3390/ijms26199293 - 23 Sep 2025

Cited by 7 | Viewed by 3353

Abstract

Teff [Eragrostis tef (Zucc.) Trotter] is a globally recognized ancient grain renowned for its attractive nutritional profile and diverse potential applications. Considering its physicochemical characteristics, nutritional value, and probable applications is essential for optimizing its benefits across various food industries. This review aims to comprehensively investigate teff, its physicochemical characteristics, diverse dietary applications, and health benefits. Teff is rich in macro- and micronutrients, making it an excellent addition to various food products. Bioactive compounds, such as flavonoids and phenolic acids, also enhance their functionality. Therefore, teff appears to be a whole grain with favorable technological characteristics and nutritional benefits for various food applications. Also, being gluten-free, teff is acceptable for individuals with celiac disease or gluten sensitivity. Also, it reduces cholesterol levels, supports heart health, stabilizes blood sugar levels, strengthens bone density and strength, and provides immune system support. In conclusion, teff shows excellent potential for developing innovative and nutritious solutions to meet the growing needs of consumers. Full article

(This article belongs to the Special Issue Role of Natural Compounds in Human Health and Disease)

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