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The Role of Phytochemicals in Aging and Aging-Related Diseases

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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Natural Products".

Deadline for manuscript submissions: 15 August 2025 | Viewed by 12578

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Special Issue Editors

Prof. Dr. Giovanni Scapagnini

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Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
Interests: phytochemicals; dietary supplementation; nutrition; natural compounds; antioxidants; aging
Special Issues, Collections and Topics in MDPI journals

Dr. Sergio Davinelli

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Guest Editor

Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
Interests: nutrition and dietetics; health promotion; aging; functional foods; food phytochemicals; dietary polyphenols
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Dr. Alessandro Medoro

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Guest Editor

Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
Interests: phytochemicals; plant-based diet; dietary supplementation; pharma-nutrition; aging; nutrition; aging-related diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Aging is an inevitable process influenced by genetic, lifestyle, and environmental factors. Recent non-pharmacological approaches for the improvement and, possibly, for the reverse/delay of the aging process shed new light on this topic. Among the variegated class of anti-aging molecules, phytochemicals and their metabolites have been suggested to improve aging and aging-related diseases. They comprise a large family of plant-derived metabolites with highly diverse chemical structures that are not directly involved in the growth and development of plants but are synthesized to increase their survival fitness. A growing body of evidence suggests that phytochemicals can not only act as simple antioxidant agents that neutralize free radicals, but that they can also modulate one or more cellular pathways associated with lifespan, aging, and disease prevention. Indeed, these bioactive molecules exert anti-aging effects via different mechanisms, such as the inhibition of cell senescence and mitochondrial dysfunction and the reduction of telomere shortening, epigenetic alterations, and genomic instability. Finally, their excellent safety profile and large structural diversity make phytochemicals particularly attractive for drug discovery processes.

This Special Issue will collect publications on topics including (but not limited to):

Biological effects of phytochemicals associated with aging-related pathways and diseases;
Molecular pharmacology techniques to identify potential anti-aging phytochemicals;
Bioavailability of dietary phytochemicals (e.g., gut microbiota, additive/synergistic effects) in the context of aging;
Dietary phytochemicals and the design of new drugs/derivatives to target aging-related mechanisms;
Dietary phytochemicals and human intervention trials against aging-related disease.

Prof. Dr. Giovanni Scapagnini
Dr. Sergio Davinelli
Dr. Alessandro Medoro
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

phytochemicals
plant-based diet
dietary supplementation
pharma-nutrition
aging
aging-related diseases
prevention

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Published Papers (7 papers)

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Research

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16 pages, 4770 KiB

Open AccessArticle

The Immunomodulatory Effects of Apigenin and Quercetin on Cytokine Secretion by the Human Gingival Fibroblast Cell Line and Their Potential Link to Alzheimer’s Disease

by Anna Kurek-Górecka, Małgorzata Kłósek, Radosław Balwierz, Grażyna Pietsz and Zenon P. Czuba

Pharmaceuticals 2025, 18(5), 628; https://doi.org/10.3390/ph18050628 - 26 Apr 2025

Viewed by 577

Abstract

Background: The link between periodontal pathogens, inflammation, and neurodegenerative processes, including Alzheimer’s disease (AD), is evident. Porphyromonas gingivalis and Treponema denticola release lipopolysaccharide (LPS), constituting a virulence factor that takes part in the brain inflammatory process. Human gingival fibroblasts (HGF-1) are a source of pro-inflammatory cytokines released during periodontal diseases. Propolis is a rich source of quercetin and apigenin, which exhibit anti-inflammatory and immunomodulatory activities, influencing the concentration of pro-inflammatory cytokines. Considering this aspect, models with stimulated HGF-1, followed by LPS and/or interferon-α (IFN-α), were used. Aim: This study was designed to evaluate the concentrations of selected cytokines produced by HGF-1, which may influence brain inflammation. The immunomodulatory effects of apigenin and quercetin were investigated by measuring the concentration of interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-15 (IL-15), and tumour necrosis factor (TNF-α). This study’s novelty is based on insights into the immunomodulatory effects of selected flavonoids by correlating the secretion of pro-inflammatory cytokines by gingival fibroblasts during periodontal disease with inflammatory processes in the brain. The cytotoxicity of apigenin and quercetin was estimated using the MTT assay. Fibroblasts were stimulated with LPS at 200 ng/mL and/or IFN-α at 100 U/mL concentration, followed by incubation with apigenin (25–50 µg/mL) and quercetin (25–50 µg/mL). Cytokine concentrations were measured using the xMAP technology. Results: The most pronounced and statistically significant reduction in cytokine levels, particularly IL-6 and IL-15, was observed for quercetin in both concentrations (25 µg/mL and 50 µg/mL), especially following LPS stimulation. Apigenin in both analysed concentrations also significantly decreased the level of IL-6. These results suggest that quercetin and apigenin may indirectly act as potential immunomodulators in preventing brain inflammation by inhibiting the inflammatory process in periodontitis; however, this should be confirmed in further studies. Full article

(This article belongs to the Special Issue The Role of Phytochemicals in Aging and Aging-Related Diseases)

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19 pages, 6563 KiB

Open AccessArticle

Immunomodulatory Effects of a Standardized Botanical Mixture Comprising Angelica gigas Roots and Pueraria lobata Flowers Through the TLR2/6 Pathway in RAW 264.7 Macrophages and Cyclophosphamide-Induced Immunosuppression Mice

by Seo-Yun Jang, Hyeon-A Song, Min-Ji Park, Kyung-Sook Chung, Jong Kil Lee, Eun Yeong Jang, Eun Mi Sun, Min Cheol Pyo and Kyung-Tae Lee

Pharmaceuticals 2025, 18(3), 336; https://doi.org/10.3390/ph18030336 - 27 Feb 2025

Viewed by 789

Abstract

Background: As the population ages, enhancing immune function is crucial to mitigating age-related physiological decline. Since immunostimulant drugs are known to have potential side effects, medicinal plants emerge as promising candidates offering a safer alternative. To leverage the advantages of medicinal plants with fewer side effects and develop a potent immune-enhancing agent, we investigated the efficacy of a novel immunomodulatory candidate derived from the combination of Angelica gigas and Pueraria lobata (CHL). Methods: In vitro, CHL was treated in RAW 264.7 macrophages at various time points, and the experiments conducted in the study were performed using ELISA, Western blot, and RT-qPCR analysis. In vivo, C57BL/6 mice were administrated CHL for 16 days (p.o.) and CTX on the three days (i.p.), and experiments were conducted with ELISA, western blot, RT-qPCR analysis, H&E staining, flow cytometry, gut microbiome, and correlation analysis. Results: In vitro, CHL has upregulated NO and cytokines expression, substantially enhancing the NF-κB and MAPK activation. Furthermore, CHL promoted the TAK1, TRAF6, and MyD88 via TLR2/6 signaling. In vivo, the CHL improved the reduced body weight and immune organs’ indices and recovered various cytokines expression, NK cell cytotoxicity activity, and immune cell population. CHL also improved the histological structure and tight junction markers, mucin-2, and TLR2/6 in the intestines of CTX-induced mice. Conclusions: Overall, CHL demonstrated immunostimulatory potential by enhancing immune responses and restoring immune function, suggesting its promise as a safe and effective immune-enhancing agent. Full article

(This article belongs to the Special Issue The Role of Phytochemicals in Aging and Aging-Related Diseases)

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14 pages, 9728 KiB

Open AccessArticle

Exploring the Anti-Osteoporotic Effects of n-Hexane Fraction from Cotoneaster wilsonii Nakai: Activation of Runx2 and Osteoblast Differentiation In Vivo

by Soyeon Hong, Hee Ju Lee, Da Seul Jung, Saruul Erdenebileg, Hoseong Hwang, Hak Cheol Kwon, Jaeyoung Kwon and Gyhye Yoo

Pharmaceuticals 2025, 18(1), 45; https://doi.org/10.3390/ph18010045 - 3 Jan 2025

Viewed by 969

Abstract

Background: Osteoporosis is characterized by the microstructural depletion of bone tissue and decreased bone density, leading to an increased risk of fractures. Cotoneaster wilsonii Nakai, an endemic species of the Korean Peninsula, grows wild in Ulleungdo. In this study, we aimed to investigate the effects of C. wilsonii and its components on osteoporosis. Methods and Results: The alkaline phosphatase (ALP) activity of C. wilsonii extracts and fractions was evaluated in MC3T3-E1 pre-osteoblasts, and the n-hexane fraction (CWH) showed the best properties for ALP activity. The effects of the CWH on bone formation were assessed in MC3T3-E1 cells and ovariectomized mice. Biochemical assays and histological analyses focused on the signaling activation of osteoblast differentiation and osteogenic markers, such as ALP, collagen, and osterix. The CWH significantly activated TGF-β and Wnt signaling, enhancing osteoblast differentiation and bone matrix formation. Notably, CWH treatment improved micro-CT indices, such as femoral bone density, and restored serum osteocalcin levels compared to OVX controls. Conclusions: These results highlight the potential of the C. wilsonii Nakai n-hexane fraction as a promising therapeutic agent for managing osteoporosis. Full article

(This article belongs to the Special Issue The Role of Phytochemicals in Aging and Aging-Related Diseases)

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17 pages, 4794 KiB

Open AccessArticle

White Tea Reduces Dyslipidemia, Inflammation, and Oxidative Stress in the Aortic Arch in a Model of Atherosclerosis Induced by Atherogenic Diet in ApoE Knockout Mice

by Merve Huner Yigit, Mehtap Atak, Ertugrul Yigit, Zehra Topal Suzan, Mehmet Kivrak and Huseyin Avni Uydu

Pharmaceuticals 2024, 17(12), 1699; https://doi.org/10.3390/ph17121699 - 17 Dec 2024

Viewed by 1064

Abstract

Objective: In this study, we aimed to evaluate the potential effects of white tea (WT) in the atherosclerosis process characterized by oxidative stress, inflammation, and dyslipidemia. Methods: In our study, apolipoprotein E knockout (ApoE^−/−) mice (RRID: IMSR_JAX:002052) and C57BL/6J mice (RRID: IMSR_JAX:000664) were used. In the atherosclerosis model induced by an atherogenic diet (AD), WT was administered via oral gavage at two different concentrations. The animals were sacrificed by decapitation under anesthesia, and their serum and aortic tissues were collected. Total cholesterol (TC), triglyceride (TG), interleukin (IL)-1β, IL-6, IL-10, IL-12, tumor necrosis factor-α (TNF-α), interferon-γ, myeloperoxidase, paraoxonase-1, lipoprotein-associated phospholipase A2, oxidized low-density lipoprotein (Ox-LDL), lectin-like oxidized LDL receptor (LOX-1), a disintegrin, and metalloprotease (ADAM) 10 and 17 activities were determined via colorimetric, enzyme-linked immunoassay, and fluorometric methods. Results: WT supplementation decreased serum Ox-LDL, LOX-1, TC, and TG levels by approximately 50%. TNF- and IL-6 levels were reduced by approximately 30% in the aortic arch. In addition, ADAM10/17 enzyme activities were found to be reduced by approximately 25%. However, no change in the AD-induced fibrotic cap structure was observed in the aortic root. Conclusions: The findings indicate that white tea effectively reduced oxidative stress, inflammation, and dyslipidemia in atherosclerosis but does not affect atheroma plaque morphology. Full article

(This article belongs to the Special Issue The Role of Phytochemicals in Aging and Aging-Related Diseases)

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15 pages, 2547 KiB

Open AccessArticle

Carotenoid Interactions with PCSK9: Exploring Novel Cholesterol-Lowering Strategies

by Alessandro Medoro, Giovanni Scapagnini, Simone Brogi, Tassadaq Hussain Jafar, Truong Tan Trung, Luciano Saso and Sergio Davinelli

Pharmaceuticals 2024, 17(12), 1597; https://doi.org/10.3390/ph17121597 - 27 Nov 2024

Cited by 2 | Viewed by 1215

Abstract

Background/Objectives: This study investigated the potential of green algae-derived carotenoids as natural inhibitors of the proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of cholesterol metabolism. PCSK9 promotes the degradation of low-density lipoprotein receptors (LDLR), thereby increasing blood cholesterol levels and elevating the risk of cardiovascular diseases. Methods/Results: We screened the pharmacophore fit score of 27 carotenoids with PCSK9 and identified 14 that were analyzed for binding affinity and molecular interactions. Astaxanthin, siphonaxanthin, and prasinoxanthin were identified as the top candidates, demonstrating strong binding affinity (−10.5, −10.3, and −9.4 Kcal/mol, respectively) and stable interactions with several known key residues within the active site of PCSK9, including Pro-331, Arg-357, Cys-358, Val-359, Asp-360, Ile-416, Leu-436, Thr-437, Pro-438, Leu-440, Arg-458, Val-460, Trp-461, Arg-476, Cys-477, Ala-478, Ala-649, Val-650, and Asp-651. Density functional theory analysis confirmed the stability of astaxanthin and its favorable electronic properties, suggesting its potential as an effective inhibitor. Molecular dynamics simulations of the PCSK9–astaxanthin complex revealed sustained structural stability and key interactions critical for maintaining the functional integrity of the protein. Conclusions: These findings provide evidence that specific carotenoids, particularly astaxanthin, may offer a cost-effective alternative to existing PCSK9 inhibitors, providing a potential approach for managing cholesterol levels and reducing cardiovascular risk. Pre-clinical and clinical validations are required to confirm the therapeutic potential of these compounds. Full article

(This article belongs to the Special Issue The Role of Phytochemicals in Aging and Aging-Related Diseases)

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15 pages, 3945 KiB

Open AccessArticle

Physcion Mitigates LPS-Induced Neuroinflammation, Oxidative Stress, and Memory Impairments via TLR-4/NF-кB Signaling in Adult Mice

by Sareer Ahmad, Kyonghwan Choe, Haroon Badshah, Riaz Ahmad, Waqar Ali, Inayat Ur Rehman, Tae Ju Park, Jun Sung Park and Myeong Ok Kim

Pharmaceuticals 2024, 17(9), 1199; https://doi.org/10.3390/ph17091199 - 11 Sep 2024

Cited by 3 | Viewed by 2198

Abstract

Alzheimer’s disease (AD) is the most predominant cause of dementia, considered a progressive decline in cognitive function that ultimately leads to death. AD has posed a substantial challenge in the records of medical science over the past century, representing a predominant etiology of dementia with a high prevalence rate. Neuroinflammation is a common characteristic of various central nervous system (CNS) pathologies like AD, primarily mediated by specialized brain immune and inflammatory cells, such as astrocytes and microglia. The present study aims to elucidate the potential mechanism of physcion that mitigates LPS-induced gliosis and assesses oxidative stress in mice. Physcion reduced the reactivity of Iba-1- and GFAP-positive cells and decreased the level of inflammatory cytokines like TNF-α and IL-1β. Physcion also reversed the effect of LPS-induced oxidative stress by upregulating the expression of Nrf2 and HO-1. Moreover, physcion treatment reversed LPS-induced synaptic disorder by increasing the level of presynaptic protein SNAP-23 and postsynaptic protein PSD-95. Our findings may provide a contemporary theoretical framework for clinical investigations aimed at examining the pathogenic mechanisms and therapeutic approaches for neuroinflammation and AD. Full article

(This article belongs to the Special Issue The Role of Phytochemicals in Aging and Aging-Related Diseases)

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Review

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16 pages, 802 KiB

Open AccessReview

Alkaloids as Natural NRF2 Inhibitors: Chemoprevention and Cytotoxic Action in Cancer

by Darinka Gjorgieva Ackova, Viktorija Maksimova, Katarina Smilkov, Brigitta Buttari, Marzia Arese and Luciano Saso

Pharmaceuticals 2023, 16(6), 850; https://doi.org/10.3390/ph16060850 - 7 Jun 2023

Cited by 14 | Viewed by 3701

Abstract

Being a controller of cytoprotective actions, inflammation, and mitochondrial function through participating in the regulation of multiple genes in response to stress-inducing endogenous or exogenous stressors, the transcription factor Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) is considered the main cellular defense mechanism to maintain redox balance at cellular and tissue level. While a transient activation of NRF2 protects normal cells under oxidative stress, the hyperactivation of NRF2 in cancer cells may help them to survive and to adapt under oxidative stress. This can be detrimental and related to cancer progression and chemotherapy resistance. Therefore, inhibition of NRF2 activity may be an effective approach for sensitizing cancer cells to anticancer therapy. In this review, we examine alkaloids as NRF2 inhibitors from natural origin, their effects on cancer therapy, and/or as sensitizers of cancer cells to anticancer chemotherapeutics, and their potential clinical applications. Alkaloids, as inhibitor of the NRF2/KEAP1 signaling pathway, can have direct (berberine, evodiamine, and diterpenic aconitine types of alkaloids) or indirect (trigonelline) therapeutic/preventive effects. The network linking alkaloid action with oxidative stress and NRF2 modulation may result in an increased NRF2 synthesis, nuclear translocation, as well in a downstream impact on the synthesis of endogenous antioxidants, effects strongly presumed to be the mechanism of action of alkaloids in inducing cancer cell death or promoting sensitivity of cancer cells to chemotherapeutic agents. In this regard, the identification of additional alkaloids targeting the NRF2 pathway is desirable and the information arising from clinical trials will reveal the potential of these compounds as a promising target for anticancer therapy. Full article

(This article belongs to the Special Issue The Role of Phytochemicals in Aging and Aging-Related Diseases)

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