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Bioactive Molecules from Plants: Discovery and Pharmaceutical Applications, 3rd Edition

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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (10 August 2024) | Viewed by 12522

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Dr. Javier Garcia-Pardo

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Institut de Biotecnologia i de Biomedicina (IBB), Universitat Autónoma de Barcelona, 08193 Bellaterra, Barcelona, Spain
Interests: bioactive compounds; cell signaling; drug delivery; drug discovery; enzymology; high-throughput screening; metalloproteases; molecular pharmacology; nanoparticles; neuropeptides; neurodegenerative diseases; parkinson's disease; protein-protein interaction inhibitors; protein engineering; protein structure; protease inhibitors; protein folding and aggregation; substrate specificity; X-ray crystallography
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Dear Colleagues,

Plants have historically proven their value as a source of bioactive molecules with pharmaceutical potential, and due to increasing demand for chemical diversity in pharmaceutical screening programs, the identification of novel therapeutic drugs from natural sources represents an interesting approach. Indeed, plants are extremely rich sources of bioactive molecules that are useful for a multitude of applications in the fields of biomedicine, cosmetics, and the food industry.

The focus of this Special Issue is the identification, extraction, purification, characterization and formulation of novel bioactive molecules derived from plants. The topics include, but are not limited to, bioactive compounds as supplements for functional foods and cosmetics, novel molecules with antioxidant properties, bioactive compounds targeting cell survival and cell signaling pathways, novel protein and non-protein protease inhibitors from plants, bioactive molecules with anti-bacterial, anti-fungal, or antiviral properties, and compounds with immunomodulatory effects.

Dr. Javier Garcia-Pardo
Guest Editor

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Keywords

antioxidants
antimicrobial activity
antiviral agent
bioactive molecules
cell signaling
drug discovery
functional foods
high-throughput screening
medicinal chemistry
medicinal plants
protease inhibitor
phytotherapy
phytochemicals
drug delivery
formulation

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Related Special Issues

Bioactive Molecules from Plants: Discovery and Pharmaceutical Applications in Pharmaceutics (34 articles)
Bioactive Molecules from Plants: Discovery and Pharmaceutical Applications (Volume II) in Pharmaceutics (16 articles)

Published Papers (8 papers)

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Research

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16 pages, 2076 KiB

Open AccessArticle

Chemical Composition and Bioactivity Dataset Integration to Identify Antiproliferative Compounds in Phyllanthus Plants

by Luis Diaz, Taylor H. Díaz-Herrera and Ericsson Coy-Barrera

Pharmaceutics 2024, 16(11), 1381; https://doi.org/10.3390/pharmaceutics16111381 - 27 Oct 2024

Viewed by 574

Abstract

Background/Objectives: Phyllanthus species are renowned in traditional medicine for their diverse therapeutic properties, including potential anticancer activities. This study explored the antiproliferative potential of six Phyllanthus species by integrating chemical composition with bioactivity assays to identify key antiproliferative compounds. Methods: The integration of liquid chromatography–mass spectrometry (LC-MS)-based chemical composition data with antiproliferative activity against three cancer cell lines—PC-3 (prostate adenocarcinoma), SiHa (cervical carcinoma), and A549 (lung carcinoma)—as well as a normal mouse fibroblast line (L929) was performed by covariate analysis. These compounds were subsequently isolated and structurally characterized using spectroscopic methods. Results: Through covariate statistics, seven m/z features were found to be plausible active compounds, and after isolation, they were related to butyrolactone and arylnaphthalide lignans. Among the active isolates, an unreported compound, (+)-phyllanlathyrin 6, was discovered in the aerial part of Phyllanthus lathyroides. The isolated compounds exhibited moderate to good antiproliferative activity (IC₅₀ < 20 µM) with selectivity to SiHa, validating the covariate-based identification approach. Conclusions: These findings highlight the potential of Phyllanthus species as sources of novel anticancer agents, with specific arylnaphthalide lignans showing promising cytotoxic effects that could be further developed into therapeutic leads. Additionally, this study underscores the value of combining advanced analytical techniques with bioactivity testing to uncover bioactive compounds from natural sources. The results contribute to the growing body of evidence supporting the therapeutic relevance of Phyllanthus species and provide a foundation for future drug development efforts targeting cancer treatment. Full article

(This article belongs to the Special Issue Bioactive Molecules from Plants: Discovery and Pharmaceutical Applications, 3rd Edition)

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20 pages, 6135 KiB

Open AccessArticle

Targeting 7KCh-Induced Cell Death Response Mediated by p38, P2X7 and GSDME in Retinal Pigment Epithelium Cells with Sterculic Acid

by Ana Pariente, Rafael Peláez, Rodrigo Ochoa, Álvaro Pérez-Sala, Ángela Villanueva-Martínez, Miriam Bobadilla and Ignacio M. Larráyoz

Pharmaceutics 2023, 15(11), 2590; https://doi.org/10.3390/pharmaceutics15112590 - 5 Nov 2023

Viewed by 1323

Abstract

Age-related macular degeneration (AMD) is the main cause of blindness in developed countries. AMD is characterized by the formation of drusen, which are lipidic deposits, between retinal pigment epithelium (RPE) and the choroid. One of the main molecules accumulated in drusen is 7-Ketocholesterol (7KCh), an oxidized-cholesterol derivative. It is known that 7KCh induces inflammatory and cytotoxic responses in different cell types and the study of its mechanism of action is interesting in order to understand the development of AMD. Sterculic acid (SA) counteracts 7KCh response in RPE cells and could represent an alternative to improve currently used AMD treatments, which are not efficient enough. In the present study, we determine that 7KCh induces a complex cell death signaling characterized by the activation of necrosis and an alternative pyroptosis mediated by P2X7, p38 and GSDME, a new mechanism not yet related to the response to 7KCh until now. On the other hand, SA treatment can successfully attenuate the activation of both necrosis and pyroptosis, highlighting its therapeutic potential for the treatment of AMD. Full article

(This article belongs to the Special Issue Bioactive Molecules from Plants: Discovery and Pharmaceutical Applications, 3rd Edition)

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23 pages, 8765 KiB

Open AccessArticle

Development and Evaluation of a Self-Nanoemulsifying Drug Delivery System for Sinapic Acid with Improved Antiviral Efficacy against SARS-CoV-2

by Hani A. Alhadrami, Ahmed S.G. Srag El-Din, Hossam M. Hassan, Ahmed M. Sayed, Albaraa H. Alhadrami, Mostafa E. Rateb and Demiana M. Naguib

Pharmaceutics 2023, 15(11), 2531; https://doi.org/10.3390/pharmaceutics15112531 - 25 Oct 2023

Cited by 2 | Viewed by 1844

Abstract

This study aimed to develop a self-nanoemulsifying drug delivery system (SNE) for sinapic acid (SA) to improve its solubility and antiviral activity. Optimal components for the SA-SNE formulation were selected, including Labrafil as the oil, Cremophor EL as the surfactant, and Transcutol as the co-surfactant. The formulation was optimized using surface response design, and the optimized SA-SNE formulation exhibited a small globule size of 83.6 nm, high solubility up to 127.1 ± 3.3, and a 100% transmittance. In vitro release studies demonstrated rapid and high SA release from the formulation. Pharmacokinetic analysis showed improved bioavailability by 2.43 times, and the optimized SA-SNE formulation exhibited potent antiviral activity against SARS-CoV-2. The developed SA-SNE formulation can enhance SA’s therapeutic efficacy by improving its solubility, bioavailability, and antiviral activity. Further in silico, modeling, and Gaussian accelerated molecular dynamics (GaMD)-based studies revealed that SA could interact with and inhibit the viral main protease (M^pro). This research contributes to developing effective drug delivery systems for poorly soluble drugs like SA, opening new possibilities for their application via nebulization in SARS-CoV-2 therapy. Full article

(This article belongs to the Special Issue Bioactive Molecules from Plants: Discovery and Pharmaceutical Applications, 3rd Edition)

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16 pages, 9410 KiB

Open AccessArticle

Bio-Fabricated Silver Nanoparticles from the Leaf Extract of the Poisonous Plant, Holigarna arnottiana: Assessment of Antimicrobial, Antimitotic, Anticancer, and Radical-Scavenging Properties

by Anthyalam Parambil Ajaykumar, Ovungal Sabira, Valiyaparambil Sivadasan Binitha, Sudhir Rama Varma, Anjaly Mathew, Kodangattil Narayanan Jayaraj, Pandikkadan Ayyappan Janish, Koladath Vasu Zeena, Padannappurath Sheena, Veena Venugopal, Priyanka Palakkapparambil and Aswathi

Pharmaceutics 2023, 15(10), 2468; https://doi.org/10.3390/pharmaceutics15102468 - 15 Oct 2023

Cited by 4 | Viewed by 1749

Abstract

This study presents a novel approach to fabricate silver nanoparticles (AgNPs) using the poisonous plant, Holigarna arnottiana leaf extract. The formation of AgNPs was confirmed by a color change from green to dark brown and validated by UV analysis. FTIR analysis identified functional groups on the AgNPs, while Zeta potential analysis assessed their stability. TEM analysis established an average diameter of 18 nm and a spherical morphology for the nanoparticles. LC MS analysis coupled with database searches revealed the presence of diverse bioactive compounds, including flavonoids, nucleotides, dipeptides, enzymes, and glycosides. These compounds are postulated to act as reducing agents in the leaf extract-mediated synthesis process. Moreover, the bio-fabricated AgNPs exhibited noteworthy anticancer properties against DLA cells. In addition, AgNPs displayed substantial antimitotic effects in an assay involving Allium cepa root cells. These findings underscore the potential of the AgNPs as cytotoxic agents. The biosynthesized AgNPs showed antimicrobial activity against various bacterial pathogens, including Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus. Furthermore, the AgNPs exhibited outstanding radical-scavenging properties in the DPPH assay, suggesting their potential application in antioxidant therapies. The study collectively highlights the successful synthesis of AgNPs through a green, biocompatible approach, and demonstrates their promising potential for anticancer, antimitotic, and radical-scavenging applications. Full article

(This article belongs to the Special Issue Bioactive Molecules from Plants: Discovery and Pharmaceutical Applications, 3rd Edition)

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19 pages, 10118 KiB

Open AccessArticle

The Neuroprotective Effects of Flavonoid Fisetin against Corticosterone-Induced Cell Death through Modulation of ERK, p38, and PI3K/Akt/FOXO3a-Dependent Pathways in PC12 Cells

by Pei-Rong Chang, Je-Wen Liou, Pei-Yi Chen, Wan-Yun Gao, Chia-Ling Wu, Ming-Jiuan Wu and Jui-Hung Yen

Pharmaceutics 2023, 15(10), 2376; https://doi.org/10.3390/pharmaceutics15102376 - 23 Sep 2023

Cited by 4 | Viewed by 1695

Abstract

The overactive hypothalamic–pituitary–adrenal (HPA) axis is believed to trigger the overproduction of corticosterone, leading to neurotoxicity in the brain. Fisetin is a flavonoid commonly found in fruits and vegetables. It has been suggested to possess various biological activities, including antioxidant, anti-inflammatory, and neuroprotective effects. This study aims to explore the potential neuroprotective properties of fisetin against corticosterone-induced cell death and its underlying molecular mechanism in PC12 cells. Our results indicate that fisetin, at concentrations ranging from 5 to 40 μM, significantly protected PC12 cells against corticosterone-induced cell death. Fisetin effectively reduced the corticosterone-mediated generation of reactive oxygen species (ROS) in PC12 cells. Fisetin treatments also showed potential in inhibiting the corticosterone-induced apoptosis of PC12 cells. Moreover, inhibitors targeting MAPK/ERK kinase 1/2 (MEK1/2), p38 MAPK, and phosphatidylinositol 3-kinase (PI3K) were found to significantly block the increase in cell viability induced by fisetin in corticosterone-treated cells. Consistently, fisetin enhanced the phosphorylation levels of ERK, p38, Akt, and c-AMP response element-binding protein (CREB) in PC12 cells. Additionally, it was found that the diminished levels of p-CREB and p-ERK by corticosterone can be restored by fisetin treatment. Furthermore, the investigation of crosstalk between ERK and CREB revealed that p-CREB activation by fisetin occurred through the ERK-independent pathway. Moreover, we demonstrated that fisetin effectively counteracted the corticosterone-induced nuclear accumulation of FOXO3a, an apoptosis-triggering transcription factor, and concurrently promoted FOXO3a phosphorylation and its subsequent cytoplasmic localization through the PI3K/Akt pathway. In conclusion, our findings indicate that fisetin exerts its neuroprotective effect against corticosterone-induced cell death by modulating ERK, p38, and the PI3K/Akt/FOXO3a-dependent pathways in PC12 cells. Fisetin emerges as a promising phytochemical for neuroprotection. Full article

(This article belongs to the Special Issue Bioactive Molecules from Plants: Discovery and Pharmaceutical Applications, 3rd Edition)

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23 pages, 4165 KiB

Open AccessArticle

(-)-5-Demethoxygrandisin B a New Lignan from Virola surinamensis (Rol.) Warb. Leaves: Evaluation of the Leishmanicidal Activity by In Vitro and In Silico Approaches

by Steven Souza Paes, João Victor Silva-Silva, Paulo Wender Portal Gomes, Luely Oliveira da Silva, Ana Paula Lima da Costa, Manoel Leão Lopes Júnior, Daiana de Jesus Hardoim, Carla J. Moragas-Tellis, Noemi Nosomi Taniwaki, Alvaro Luiz Bertho, Fábio Alberto de Molfetta, Fernando Almeida-Souza, Lourivaldo Silva Santos and Kátia da Silva Calabrese

Pharmaceutics 2023, 15(9), 2292; https://doi.org/10.3390/pharmaceutics15092292 - 7 Sep 2023

Cited by 1 | Viewed by 1497

Abstract

Leishmaniasis is a complex disease caused by infection with different Leishmania parasites. The number of medications used for its treatment is still limited and the discovery of new drugs is a valuable approach. In this context, here we describe the in vitro leishmanicidal activity and the in silico interaction between trypanothione reductase (TryR) and (-)-5-demethoxygrandisin B from the leaves of Virola surinamensis (Rol.) Warb. The compound (-)-5-demethoxygrandisin B was isolated from V. surinamensis leaves, a plant found in the Brazilian Amazon, and it was characterized as (7R,8S,7′R,8′S)-3,4,5,3′,4′-pentamethoxy-7,7′-epoxylignan. In vitro antileishmanial activity was examined against Leishmania amazonensis, covering both promastigote and intracellular amastigote phases. Cytotoxicity and nitrite production were gauged using BALB/c peritoneal macrophages. Moreover, transmission electron microscopy was applied to probe ultrastructural alterations, and flow cytometry assessed the shifts in the mitochondrial membrane potential. In silico methods such as molecular docking and molecular dynamics assessed the interaction between the most stable configuration of (-)-5-demethoxygrandisin B and TryR from L. infantum (PDB ID 2JK6). As a result, the (-)-5-demethoxygrandisin B was active against promastigote (IC₅₀ 7.0 µM) and intracellular amastigote (IC₅₀ 26.04 µM) forms of L. amazonensis, with acceptable selectivity indexes. (-)-5-demethoxygrandisin B caused ultrastructural changes in promastigotes, including mitochondrial swelling, altered kDNA patterns, vacuoles, vesicular structures, autophagosomes, and enlarged flagellar pockets. It reduced the mitochondria membrane potential and formed bonds with important residues in the TryR enzyme. The molecular dynamics simulations showed stability and favorable interaction with TryR. The compound targets L. amazonensis mitochondria via TryR enzyme inhibition. Full article

(This article belongs to the Special Issue Bioactive Molecules from Plants: Discovery and Pharmaceutical Applications, 3rd Edition)

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14 pages, 7732 KiB

Open AccessArticle

Coleon U, Isolated from Plectranthus mutabilis Codd., Decreases P-Glycoprotein Activity Due to Mitochondrial Inhibition

by Sofija Jovanović Stojanov, Epole N. Ntungwe, Jelena Dinić, Ana Podolski-Renić, Milica Pajović, Patrícia Rijo and Milica Pešić

Pharmaceutics 2023, 15(7), 1942; https://doi.org/10.3390/pharmaceutics15071942 - 12 Jul 2023

Cited by 1 | Viewed by 1380

Abstract

Multidrug resistance in cancer is often mediated by P-glycoprotein. Natural compounds have been suggested as a fourth generation of P-glycoprotein inhibitors. Coleon U, isolated from Plectranthus mutabilis Codd., was reported to modulate P-glycoprotein activity but the underlying mechanism has not yet been revealed. Therefore, the effects of Coleon U on cell viability, proliferation, and cell death induction were studied in a non-small-cell lung carcinoma model comprising sensitive and multidrug-resistant cells with P-glycoprotein overexpression. P-glycoprotein activity and mitochondrial membrane potential were assessed by flow cytometry upon Coleon U, sodium-orthovanadate (an ATPase inhibitor), and verapamil (an ATPase stimulator) treatments. SwissADME was used to identify the pharmacokinetic properties of Coleon U, while P-glycoprotein expression was studied by immunofluorescence. Our results showed that Coleon U is not a P-glycoprotein substrate and is equally efficient in sensitive and multidrug-resistant cancer cells. A decrease in P-glycoprotein activity observed with Coleon U and verapamil after 72 h is antagonized in combination with sodium-orthovanadate. Coleon U induced a pronounced effect on mitochondrial membrane depolarization and showed a tendency to decrease P-glycoprotein expression. In conclusion, Coleon U-delayed effect on the decrease in P-glycoprotein activity is due to P-glycoprotein’s functioning dependence on ATP production in mitochondria. Full article

(This article belongs to the Special Issue Bioactive Molecules from Plants: Discovery and Pharmaceutical Applications, 3rd Edition)

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Review

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16 pages, 1639 KiB

Open AccessEditor’s ChoiceReview

Plant Protease Inhibitors as Emerging Antimicrobial Peptide Agents: A Comprehensive Review

by Mónica G. Parisi, Brenda Ozón, Sofía M. Vera González, Javier García-Pardo and Walter David Obregón

Pharmaceutics 2024, 16(5), 582; https://doi.org/10.3390/pharmaceutics16050582 - 24 Apr 2024

Cited by 1 | Viewed by 1394

Abstract

Antimicrobial peptides (AMPs) are important mediator molecules of the innate defense mechanisms in a wide range of living organisms, including bacteria, mammals, and plants. Among them, peptide protease inhibitors (PPIs) from plants play a central role in their defense mechanisms by directly attacking pathogens or by modulating the plant’s defense response. The growing prevalence of microbial resistance to currently available antibiotics has intensified the interest concerning these molecules as novel antimicrobial agents. In this scenario, PPIs isolated from a variety of plants have shown potential in inhibiting the growth of pathogenic bacteria, protozoans, and fungal strains, either by interfering with essential biochemical or physiological processes or by altering the permeability of biological membranes of invading organisms. Moreover, these molecules are active inhibitors of a range of proteases, including aspartic, serine, and cysteine types, with some showing particular efficacy as trypsin and chymotrypsin inhibitors. In this review, we provide a comprehensive analysis of the potential of plant-derived PPIs as novel antimicrobial molecules, highlighting their broad-spectrum antimicrobial efficacy, specificity, and minimal toxicity. These natural compounds exhibit diverse mechanisms of action and often multifunctionality, positioning them as promising molecular scaffolds for developing new therapeutic antibacterial agents. Full article

(This article belongs to the Special Issue Bioactive Molecules from Plants: Discovery and Pharmaceutical Applications, 3rd Edition)

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