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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: 20 December 2024 | Viewed by 10779

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Prof. Dr. Letteria Minutoli

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Guest Editor

Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy
Interests: preclinical pharmacology; inflammation; oxidative stress; natural products; flavonoids; cannabinoids
Special Issues, Collections and Topics in MDPI journals

Dr. Giovanni Pallio

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Guest Editor

Department of Biomedical and Dental Sciences and Morphological and Functional Imaging, University of Messina, Via C. Valeria, 98125 Messina, Italy
Interests: preclinical pharmacology; inflammation; oxidative stress; natural products; flavonoids; cannabinoids
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our previous successful Special Issue “New Insights in Natural Bioactive Compounds”.

Natural bioactive compounds are small molecules produced naturally by several plants, including primary and secondary metabolites. Natural bioactive compounds have a wide range of possible applications and can be useful in the treatment and management of various kinds of human diseases due to their outstanding biological properties. Moreover, bioactive compounds and pharmaceuticals derived from natural products have received increasing attention due to their considerable benefits for human health. This Special Issue will shape the future research direction of important natural products, as well as related bioactives. Our purpose is to feature high-quality, advanced research and knowledge contributed by various research groups working on natural products from all around the world. We cordially invite authors to contribute original articles, as well as review papers on the functional and medicinal properties of natural products for preventing and managing human diseases.

Prof. Dr. Letteria Minutoli
Dr. Giovanni Pallio
Guest Editors

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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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

inflammation
cytokines
ROS
oxidative stress
natural products
flavonoids
cannabinoids

Related Special Issues

New Insights in Natural Bioactive Compounds in International Journal of Molecular Sciences (19 articles)
New Insights in Natural Bioactive Compounds 2.0 in International Journal of Molecular Sciences (17 articles)

Published Papers (10 papers)

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Research

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36 pages, 7923 KiB

Open AccessArticle

The Ethyl Acetate Extract of Phyllanthus emblica L. Alleviates Diabetic Nephropathy in a Murine Model of Diabetes

by Cheng-Hsiu Lin and Chun-Ching Shih

Int. J. Mol. Sci. 2024, 25(12), 6686; https://doi.org/10.3390/ijms25126686 - 18 Jun 2024

Viewed by 736

Abstract

Oil-Gan is the fruit of the genus Phyllanthus emblica L. The fruits have excellent effects on health care and development values. There are many methods for the management of diabetic nephropathy (DN). However, there is a lack of effective drugs for treating DN throughout the disease course. The primary aim of this study was to examine the protective effects (including analyses of urine and blood, and inflammatory cytokine levels) and mechanisms of the ethyl acetate extract of P. emblica (EPE) on db/db mice, an animal model of diabetic nephropathy; the secondary aim was to examine the expression levels of p- protein kinase Cα (PKCα)/t-PKCα in the kidney and its downregulation of vascular endothelial growth factor (VEGF) and fibrosis gene transforming growth factor-β1 (TGF-β1) by Western blot analyses. Eight db/m mice were used as the control group. Forty db/db mice were randomly divided into five groups. Treatments included a vehicle, EPE1, EPE2, EPE3 (at doses of 100, 200, or 400 mg/kg EPE), or the comparative drug aminoguanidine for 8 weeks. After 8 weeks of treatment, the administration of EPE to db/db mice effectively controlled hyperglycemia and hyperinsulinemia by markedly lowering blood glucose, insulin, and glycosylated HbA1c levels. The administration of EPE to db/db mice decreased the levels of BUN and creatinine both in blood and urine and reduced urinary albumin excretion and the albumin creatine ratio (UACR) in urine. Moreover, EPE treatment decreased the blood levels of inflammatory cytokines, including kidney injury molecule-1 (KIM-1), C-reactive protein (CRP), and NLR family pyrin domain containing 3 (NLRP3). Our findings showed that EPE not only had antihyperglycemic effects but also improved renal function in db/db mice. A histological examination of the kidney by immunohistochemistry indicated that EPE can improve kidney function by ameliorating glomerular morphological damage following glomerular injury; alleviating proteinuria by upregulating the expression of nephrin, a biomarker of early glomerular damage; and inhibiting glomerular expansion and tubular fibrosis. Moreover, the administration of EPE to db/db mice increased the expression levels of p- PKCα/t-PKCα but decreased the expression levels of VEGF and renal fibrosis biomarkers (TGF-β1, collagen IV, p-Smad2, p-Smad3, and Smad4), as shown by Western blot analyses. These results implied that EPE as a supplement has a protective effect against renal dysfunction through the amelioration of insulin resistance as well as the suppression of nephritis and fibrosis in a DN model. Full article

(This article belongs to the Special Issue New Insights in Natural Bioactive Compounds 3.0)

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16 pages, 4357 KiB

Open AccessArticle

Effects of 3-(4-Hydroxy-3-methoxyphenyl)propionic Acid on Enhancing Grip Strength and Inhibiting Protein Catabolism Induced by Exhaustive Exercise

by Yishan Tong, Jiapeng Huang, Shuo Wang, Riyo Awa, Takashi Tagawa, Ziwei Zhang, Tiehan Cao, Haruki Kobori and Katsuhiko Suzuki

Int. J. Mol. Sci. 2024, 25(12), 6627; https://doi.org/10.3390/ijms25126627 - 16 Jun 2024

Viewed by 704

Abstract

3-(4-Hydroxy-3-methoxyphenyl)propionic acid (HMPA), also known as dihydroferulic acid, is a hydroxycinnamic acid derivative that can be derived from the microbial transformation of dietary polyphenols or naturally obtained from fermented foods. Although numerous studies have documented its antioxidant and anti-obesity effects, the effect of HMPA on muscle function remains unknown. This study investigated the effects of HMPA on muscle strength and exercise endurance capacity. Mice were orally administered low and high doses of HMPA for 14 days and subjected to grip force and treadmill exhaustion tests to evaluate muscle function. Our results showed that HMPA-administered groups significantly enhanced absolute grip strength (p = 0.0256) and relative grip strength (p = 0.0209), and low-dose HMPA decreased the plasma level of blood urea nitrogen after exercise (p = 0.0183), but HMPA did not affect endurance performance. Low-dose HMPA administration increased Myf5 expression in sedentary mice (p = 0.0106), suggesting that low-dose HMPA may promote muscle development. Additionally, HMPA improved hepatic glucose and lipid metabolism, and inhibited muscular lipid metabolism and protein catabolism, as indicated by changes in mRNA expression levels of related genes. These findings suggest that HMPA may be a promising dietary supplement for muscle health and performance. Full article

(This article belongs to the Special Issue New Insights in Natural Bioactive Compounds 3.0)

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11 pages, 809 KiB

Open AccessArticle

Antibacterial Effect of Spanish Honeys of Different Botanical Origins against Staphylococcus epidermidis

by Vanesa Núñez-Gómez, Marta San Mateo, Lorena Sánchez-Martínez and María Jesús Periago

Int. J. Mol. Sci. 2024, 25(12), 6590; https://doi.org/10.3390/ijms25126590 - 15 Jun 2024

Viewed by 383

Abstract

Honey is traditionally used for its medicinal properties attributed to its antibacterial and antioxidant effects. It is considered a natural alternative to conventional antibiotics. This effect has been attributed to their physico-chemical properties, as various chemical parameters can synergistically influence this effect. The aim of this study is to assess Spanish honeys of diverse botanical origins for their antibacterial efficacy against Staphylococcus epidermidis, correlating their physico-chemical attributes, (poly)phenol content, and antioxidant activity. The methods included colour determination via two methodologies, acidity, pH, moisture content, and sugar concentration. (Poly)phenol content was quantified using the Folin-Ciocalteau method, while antioxidant activity was evaluated via the FRAP method. Subsequently, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against S. epidermidis were investigated with different concentrations of honeys. The results revealed a direct relationship between honey darkness, (poly)phenol concentration, antioxidant activity, and antibacterial efficacy. Darker honeys exhibited higher (poly)phenol levels, greater antioxidant activity, and consequently, lower MIC and MBC values, showing enhanced antibacterial properties. These findings underscore the potential of honey as a therapeutic agent against S. epidermidis, particularly in wound healing applications to avoid infection. Further research into honey’s multifaceted properties is warranted to unveil novel therapeutic avenues in healthcare. Full article

(This article belongs to the Special Issue New Insights in Natural Bioactive Compounds 3.0)

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14 pages, 2656 KiB

Open AccessArticle

Generation of Porcine and Rainbow Trout 3D Intestinal Models and Their Use to Investigate Astaxanthin Effects In Vitro

by Sharon Arcuri, Georgia Pennarossa, Rolando Pasquariello, Madhusha Prasadani, Fulvio Gandolfi and Tiziana A. L. Brevini

Int. J. Mol. Sci. 2024, 25(11), 5966; https://doi.org/10.3390/ijms25115966 - 29 May 2024

Viewed by 506

Abstract

Astaxanthin (AST) is a natural compound derived from shellfish, microorganisms, and algae, with several healthy properties. For this reason, it is widely used in the diet of humans and animals, such as pigs, broilers, and fish, where its addition is related to its pigmenting properties. Moreover, AST’s ability to reduce free radicals and protect cells from oxidative damage finds application during the weaning period, when piglets are exposed to several stressors. To better elucidate the mechanisms involved, here we generate ad hoc pig and rainbow trout in vitro platforms able to mimic the intestinal mucosa. The morphology is validated through histological and molecular analysis, while functional properties of the newly generated intestinal barriers, both in porcine and rainbow trout models, are demonstrated by measuring trans-epithelial electrical resistance and analyzing permeability with fluorescein isothiocyanate–dextran. Exposure to AST induced a significant upregulation of antioxidative stress markers and a reduction in the transcription of inflammation-related interleukins. Altogether, the present findings demonstrate AST’s ability to interact with the molecular pathways controlling oxidative stress and inflammation both in the porcine and rainbow trout species and suggest AST’s positive role in prevention and health. Full article

(This article belongs to the Special Issue New Insights in Natural Bioactive Compounds 3.0)

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22 pages, 4138 KiB

Open AccessArticle

Mechanochemical Approach to Obtaining a Multicomponent Fisetin Delivery System Improving Its Solubility and Biological Activity

by Natalia Rosiak, Ewa Tykarska and Judyta Cielecka-Piontek

Int. J. Mol. Sci. 2024, 25(7), 3648; https://doi.org/10.3390/ijms25073648 - 25 Mar 2024

Cited by 1 | Viewed by 936

Abstract

In this study, binary amorphous solid dispersions (ASDs, fisetin-Eudragit^®) and ternary amorphous solid inclusions (ASIs, fisetin-Eudragit^®-HP-β-cyclodextrin) of fisetin (FIS) were prepared by the mechanochemical method without solvent. The amorphous nature of FIS in ASDs and ASIs was confirmed using XRPD (X-ray powder diffraction). DSC (Differential scanning calorimetry) confirmed full miscibility of multicomponent delivery systems. FT-IR (Fourier-transform infrared analysis) confirmed interactions that stabilize FIS’s amorphous state and identified the functional groups involved. The study culminated in evaluating the impact of amorphization on water solubility and conducting in vitro antioxidant assays: 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)—ABTS, 2,2-diphenyl-1-picrylhydrazyl—DPPH, Cupric Reducing Antioxidant Capacity—CUPRAC, and Ferric Reducing Antioxidant Power—FRAP and in vitro neuroprotective assays: inhibition of acetylcholinesterase—AChE and butyrylcholinesterase—BChE. In addition, molecular docking allowed for the determination of possible bonds and interactions between FIS and the mentioned above enzymes. The best preparation turned out to be ASI_30_EPO (ASD fisetin-Eudragit^® containing 30% FIS in combination with HP-β-cyclodextrin), which showed an improvement in apparent solubility (126.5 ± 0.1 µg∙mL⁻¹) and antioxidant properties (ABTS: IC₅₀ = 10.25 µg∙mL⁻¹, DPPH: IC₅₀ = 27.69 µg∙mL⁻¹, CUPRAC: IC_0.5 = 9.52 µg∙mL⁻¹, FRAP: IC_0.5 = 8.56 µg∙mL⁻¹) and neuroprotective properties (inhibition AChE: 39.91%, and BChE: 42.62%). Full article

(This article belongs to the Special Issue New Insights in Natural Bioactive Compounds 3.0)

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15 pages, 2970 KiB

Open AccessArticle

Vitexicarpin Induces Apoptosis and Inhibits Metastatic Properties via the AKT-PRAS40 Pathway in Human Osteosarcoma

by Hyung-Mun Yun, Hyun Sook Kwon, Joon Yeop Lee and Kyung-Ran Park

Int. J. Mol. Sci. 2024, 25(7), 3582; https://doi.org/10.3390/ijms25073582 - 22 Mar 2024

Viewed by 966

Abstract

Osteosarcoma, which has poor prognosis after metastasis, is the most common type of bone cancer in children and adolescents. Therefore, plant-derived bioactive compounds are being actively developed for cancer therapy. Artemisia apiacea Hance ex Walp. is a traditional medicinal plant native to Eastern Asia, including China, Japan, and Korea. Vitexicarpin (Vitex), derived from A. apiacea, has demonstrated analgesic, anti-inflammatory, antitumour, and immunoregulatory properties; however, there are no published studies on Vitex isolated from the aerial parts of A. apiacea. Thus, this study aimed to evaluate the antitumour activity of Vitex against human osteosarcoma cells. In the present study, Vitex (>99% purity) isolated from A. apiacea induced significant cell death in human osteosarcoma MG63 cells in a dose- and time-dependent manner; cell death was mediated by apoptosis, as evidenced by the appearance of cleaved-PARP, cleaved-caspase 3, anti-apoptotic proteins (Survivin and Bcl-2), pro-apoptotic proteins (Bax), and cell cycle-related proteins (Cyclin D1, Cdk4, and Cdk6). Additionally, a human phosphokinase array proteome profiler revealed that Vitex suppressed AKT-dependent downstream kinases. Further, Vitex reduced the phosphorylation of PRAS40, which is associated with autophagy and metastasis, induced autophagosome formation, and suppressed programmed cell death and necroptosis. Furthermore, Vitex induced antimetastatic activity by suppressing the migration and invasion of MMP13, which is the primary protease that degrades type I collagen for tumour-induced osteolysis in bone tissues and preferential metastasis sites. Taken together, our results suggest that Vitex is an attractive target for treating human osteosarcoma. Full article

(This article belongs to the Special Issue New Insights in Natural Bioactive Compounds 3.0)

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16 pages, 1434 KiB

Open AccessArticle

Caffeic Acid Phosphanium Derivatives: Potential Selective Antitumor, Antimicrobial and Antiprotozoal Agents

by Miloš Lukáč, Lívia Slobodníková, Martin Mrva, Aneta Dušeková, Mária Garajová, Martin Kello, Dominika Šebová, Martin Pisárčik, Marián Kojnok, Andrej Vrták, Elena Kurin and Silvia Bittner Fialová

Int. J. Mol. Sci. 2024, 25(2), 1200; https://doi.org/10.3390/ijms25021200 - 18 Jan 2024

Viewed by 1059

Abstract

Caffeic acid (CA) is one of the most abundant natural compounds present in plants and has a broad spectrum of beneficial pharmacological activities. However, in some cases, synthetic derivation of original molecules can expand their scope. This study focuses on the synthesis of caffeic acid phosphanium derivatives with the ambition of increasing their biological activities. Four caffeic acid phosphanium salts (CAPs) were synthesized and tested for their cytotoxic, antibacterial, antifungal, and amoebicidal activity in vitro, with the aim of identifying the best area for their medicinal use. CAPs exhibited significantly stronger cytotoxic activity against tested cell lines (HeLa, HCT116, MDA-MB-231 MCF-7, A2058, PANC-1, Jurkat) in comparison to caffeic acid. Focusing on Jurkat cells (human leukemic T cell lymphoma), the IC₅₀ value of CAPs ranged from 0.9 to 8.5 μM while IC₅₀ of CA was >300 μM. Antimicrobial testing also confirmed significantly higher activity of CAPs against selected microbes in comparison to CA, especially for Gram-positive bacteria (MIC 13–57 μM) and the yeast Candida albicans (MIC 13–57 μM). The anti-Acanthamoeba activity was studied against two pathogenic Acanthamoeba strains. In the case of A. lugdunensis, all CAPs revealed a stronger inhibitory effect (EC₅₀ 74–3125 μM) than CA (>10⁵ µM), while in A. quina strain, the higher inhibition was observed for three derivatives (EC₅₀ 44–291 μM). The newly synthesized quaternary phosphanium salts of caffeic acid exhibited selective antitumor action and appeared to be promising antimicrobial agents for topical application, as well as potential molecules for further research. Full article

(This article belongs to the Special Issue New Insights in Natural Bioactive Compounds 3.0)

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Review

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20 pages, 2002 KiB

Open AccessReview

Plant-Based HSP90 Inhibitors in Breast Cancer Models: A Systematic Review

by Ilham Zarguan, Sonia Ghoul, Lamiae Belayachi and Abdelaziz Benjouad

Int. J. Mol. Sci. 2024, 25(10), 5468; https://doi.org/10.3390/ijms25105468 - 17 May 2024

Viewed by 727

Abstract

Breast cancer, the most invasive cancer in women globally, necessitates novel treatments due to prevailing limitations of therapeutics. Search of news anticancer targets is more necessary than ever to tackle this pathology. Heat-Shock Protein 90 (HSP90), a chaperone protein, is implicated in breast cancer pathogenesis, rendering it an appealing target. Looking for alternative approach such as Plant-based compounds and natural HSP90 inhibitors offer promising prospects for innovative therapeutic strategies. This study aims to identify plant-based compounds with anticancer effects on breast cancer models and elucidate their mechanism of action in inhibiting the HSP90 protein. A systematic review was conducted and completed in January 2024 and included in vitro, in vivo, and in silico studies that investigated the effectiveness of plant-based HSP90 inhibitors tested on breast cancer models. Eleven studies were included in the review. Six plants and 24 compounds from six different classes were identified and proved to be effective against HSP90 in breast cancer models. The studied plant extracts showed a dose- and time-dependent decrease in cell viability. Variable IC50 values showed antiproliferative effects, with the plant Tubocapsicum anomalum demonstrating the lowest value. Withanolides was the most studied class. Fennel, Trianthema portulacastrum, and Spatholobus suberectus extracts were shown to inhibit tumor growth and angiogenesis and modulate HSP90 expression as well as its cochaperone interactions in breast cancer mouse models. The identified plant extracts and compounds were proven effective against HSP90 in breast cancer models, and this inhibition showed promising effects on breast cancer biology. Collectively, these results urge the need of further studies to better understand the mechanism of action of HSP90 inhibitors using comparable methods for preclinical observations. Full article

(This article belongs to the Special Issue New Insights in Natural Bioactive Compounds 3.0)

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23 pages, 1689 KiB

Open AccessReview

Therapeutic Potential of Chlorogenic Acid in Chemoresistance and Chemoprotection in Cancer Treatment

by Nicole Cortez, Cecilia Villegas, Viviana Burgos, Leandro Ortiz, Jaime R. Cabrera-Pardo and Cristian Paz

Int. J. Mol. Sci. 2024, 25(10), 5189; https://doi.org/10.3390/ijms25105189 - 10 May 2024

Viewed by 851

Abstract

Chemotherapeutic drugs are indispensable in cancer treatment, but their effectiveness is often lessened because of non-selective toxicity to healthy tissues, which triggers inflammatory pathways that are harmful to vital organs. In addition, tumors’ resistance to drugs causes failures in treatment. Chlorogenic acid (5-caffeoylquinic acid, CGA), found in plants and vegetables, is promising in anticancer mechanisms. In vitro and animal studies have indicated that CGA can overcome resistance to conventional chemotherapeutics and alleviate chemotherapy-induced toxicity by scavenging free radicals effectively. This review is a summary of current information about CGA, including its natural sources, biosynthesis, metabolism, toxicology, role in combatting chemoresistance, and protective effects against chemotherapy-induced toxicity. It also emphasizes the potential of CGA as a pharmacological adjuvant in cancer treatment with drugs such as 5-fluorouracil, cisplatin, oxaliplatin, doxorubicin, regorafenib, and radiotherapy. By analyzing more than 140 papers from PubMed, Google Scholar, and SciFinder, we hope to find the therapeutic potential of CGA in improving cancer therapy. Full article

(This article belongs to the Special Issue New Insights in Natural Bioactive Compounds 3.0)

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22 pages, 1914 KiB

Open AccessReview

Oxidative Stress: The Role of Antioxidant Phytochemicals in the Prevention and Treatment of Diseases

by Adele Muscolo, Oliva Mariateresa, Torello Giulio and Russo Mariateresa

Int. J. Mol. Sci. 2024, 25(6), 3264; https://doi.org/10.3390/ijms25063264 - 13 Mar 2024

Cited by 9 | Viewed by 2992

Abstract

Oxidative stress, characterized by an imbalance favouring oxidants over antioxidants, is a key contributor to the development of various common diseases. Counteracting these oxidants is considered an effective strategy to mitigate the levels of oxidative stress in organisms. Numerous studies have indicated an inverse correlation between the consumption of vegetables and fruits and the risk of chronic diseases, attributing these health benefits to the presence of antioxidant phytochemicals in these foods. Phytochemicals, present in a wide range of foods and medicinal plants, play a pivotal role in preventing and treating chronic diseases induced by oxidative stress by working as antioxidants. These compounds exhibit potent antioxidant, anti-inflammatory, anti-aging, anticancer, and protective properties against cardiovascular diseases, diabetes mellitus, obesity, and neurodegenerative conditions. This comprehensive review delves into the significance of these compounds in averting and managing chronic diseases, elucidating the key sources of these invaluable elements. Additionally, it provides a summary of recent advancements in understanding the health benefits associated with antioxidant phytochemicals. Full article

(This article belongs to the Special Issue New Insights in Natural Bioactive Compounds 3.0)

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