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Investigating the Molecular Mechanism of Action of Natural Bioactive Molecules

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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 (30 November 2023) | Viewed by 11617

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Prof. Dr. Marie-Laure Fauconnier

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Laboratory of Chemistry of Natural Molecules, Gembloux Agro-Bio Tech, University of Liège, Passage des Déportés 2, 5030 Gembloux, Belgium
Interests: essential oil; VOCs; oxylipins for applications in agronomy and food science
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Special Issue Information

Dear Colleagues,

You all know that people have always looked at remedies for diseases and that natural products have therefore emerged as a valuable source of bioactive molecules of natural origin. Natural products have been and remain traditionally used by human populations for their properties and comprise a wide structural diversity of compounds, including alkaloids, phenolics, terpenes, saponins and volatile organic molecules.

Bioactive molecules of natural origin are increasingly used in various sectors including cosmetics, pharmaceuticals and wellness, but also in the food industry where they can be used as food preservatives, in household products and in the field of plant protection products in agronomy. This diversity of application of natural products is explained by their wide range of interesting biological activities, including antioxidant, anti-inflammatory, bactericidal, fungicidal and virucidal properties.

In recent years, an increasing number of publications referring to these compounds has been published, for a wide variety of applications such as the study of their virucidal properties against the very up-to-date SARS-CoV-2, or the search for new treatments in cancer research. However, many of these publications were largely descriptive.

In the present special issue, we aim at filling this gap by investigating the molecular mechanism of action of natural bioactive molecules. We therefore invite researchers to submit reviews or research articles on the understanding of the mode of action of natural bioactive molecules, considering the associated health risks, which may include allergies and toxicity for example. We are confident that this special issue will contribute to a better understanding of these compounds and of their safer use for a wide range of applications.

Prof. Dr. Marie-Laure Fauconnier
Guest Editor

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Keywords

natural products
antioxidant
anti-inflammatory
bactericide
fungicide
virucidal properties
cosmetics
plant protection products

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Published Papers (6 papers)

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Research

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25 pages, 4264 KiB

Open AccessArticle

Hepatoprotective Effect of Allium ochotense Extracts on Chronic Alcohol-Induced Fatty Liver and Hepatic Inflammation in C57BL/6 Mice

by Min Ji Go, Jong Min Kim, Hyo Lim Lee, Tae Yoon Kim, Ju Hui Kim, Han Su Lee, In Young Kim, Seon Jeong Sim and Ho Jin Heo

Int. J. Mol. Sci. 2024, 25(6), 3496; https://doi.org/10.3390/ijms25063496 - 20 Mar 2024

Viewed by 1692

Abstract

This study was performed to investigate the protective effects of Allium ochotense on fatty liver and hepatitis in chronic alcohol-induced hepatotoxicity. The physiological compounds of a mixture of aqueous and 60% ethanol (2:8, w/w) extracts of A. ochotense (EA) were identified as kestose, raffinose, kaempferol and quercetin glucoside, and kaempferol di-glucoside by UPLC Q-TOF MS^E. The EA regulated the levels of lipid metabolism-related biomarkers such as total cholesterol, triglyceride, low-density lipoprotein (LDL), and high-density lipoprotein (HDL)-cholesterol in serum. Also, EA ameliorated the levels of liver toxicity-related biomarkers such as glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), and total bilirubin in serum. EA improved the antioxidant system by reducing malondialdehyde contents and increasing superoxide dismutase (SOD) levels and reduced glutathione content. EA improved the alcohol metabolizing enzymes such as alcohol dehydrogenase, acetaldehyde dehydrogenase, and cytochrome P450 2E1 (CYP2E1). Treatment with EA alleviated lipid accumulation-related protein expression by improving phosphorylation of AMP-activated protein kinase (p-AMPK) expression levels. Especially, EA reduced inflammatory response by regulating the toll-like receptor–4/nuclear factor kappa-light-chain-enhancer of activated B cells (TLR-4/NF-κB) signaling pathway. EA showed an anti-apoptotic effect by regulating the expression levels of B-cell lymphoma 2 (BCl-2), BCl-2-associated X protein (BAX), and caspase 3. Treatment with EA also ameliorated liver fibrosis via inhibition of transforming growth factor-beta 1/suppressor of mothers against decapentaplegic (TGF-β1/Smad) pathway and alpha-smooth muscle actin (α-SMA). Therefore, these results suggest that EA might be a potential prophylactic agent for the treatment of alcoholic liver disease. Full article

(This article belongs to the Special Issue Investigating the Molecular Mechanism of Action of Natural Bioactive Molecules)

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17 pages, 5819 KiB

Open AccessArticle

Linalool, a Fragrance Compound in Plants, Protects Dopaminergic Neurons and Improves Motor Function and Skeletal Muscle Strength in Experimental Models of Parkinson’s Disease

by Wan-Hsuan Chang, Hung-Te Hsu, Chih-Cheng Lin, Li-Mei An, Chien-Hsing Lee, Horng-Huey Ko, Chih-Lung Lin and Yi-Ching Lo

Int. J. Mol. Sci. 2024, 25(5), 2514; https://doi.org/10.3390/ijms25052514 - 21 Feb 2024

Cited by 1 | Viewed by 2103

Abstract

Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), resulting in reduced dopamine levels in the striatum and eventual onset of motor symptoms. Linalool (3,7-dimethyl-1,6-octadien-3-ol) is a monoterpene in aromatic plants exhibiting antioxidant, antidepressant, and anti-anxiety properties. The objective of this study is to evaluate the neuroprotective impacts of linalool on dopaminergic SH-SY5Y cells, primary mesencephalic and cortical neurons treated with 1-methyl-4-phenylpyridinium ion (MPP⁺), as well as in PD-like mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Cell viability, α-tubulin staining, western blotting, immunohistochemistry and behavioral experiments were performed. In MPP⁺-treated SH-SY5Y cells, linalool increased cell viability, reduced neurite retraction, enhanced antioxidant defense by downregulation of apoptosis signaling (B-cell lymphoma 2 (Bcl-2), cleaved caspase-3 and poly ADP-ribose polymerase (PARP)) and phagocyte NADPH oxidase (gp91^phox), as well as upregulation of neurotrophic signaling (brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF)) and nuclear factor-erythroid 2 related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. In MPP⁺-treated primary mesencephalic neurons, linalool enhanced the expressions of tyrosine hydroxylase (TH), Sirtuin 1 (SirT1), and parkin. In MPP⁺-treated primary cortical neurons, linalool upregulated protein expression of SirT1, γ-Aminobutyric acid type A-α1 (GABA_A-α1), and γ-Aminobutyric acid type B (GABA_B). In PD-like mice, linalool attenuated the loss of dopamine neurons in SNpc. Linalool improved the motor and nonmotor behavioral deficits and muscle strength of PD-like mice. These findings suggest that linalool potentially protects dopaminergic neurons and improves the impairment symptoms of PD. Full article

(This article belongs to the Special Issue Investigating the Molecular Mechanism of Action of Natural Bioactive Molecules)

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17 pages, 3782 KiB

Open AccessArticle

Sedanolide Activates KEAP1–NRF2 Pathway and Ameliorates Hydrogen Peroxide-Induced Apoptotic Cell Death

by Yosuke Tabei, Hiroko Abe, Shingo Suzuki, Nobuaki Takeda, Jun-ichiro Arai and Yoshihiro Nakajima

Int. J. Mol. Sci. 2023, 24(22), 16532; https://doi.org/10.3390/ijms242216532 - 20 Nov 2023

Cited by 5 | Viewed by 1501

Abstract

Sedanolide is a bioactive compound with anti-inflammatory and antitumor activities. Although it has been recently suggested that sedanolide activates the nuclear factor E2-related factor 2 (NRF2) pathway, there is little research on its effects on cellular resistance to oxidative stress. The objective of the present study was to investigate the function of sedanolide in suppressing hydrogen peroxide (H₂O₂)-induced oxidative damage and the underlying molecular mechanisms in human hepatoblastoma cell line HepG2 cells. We found that sedanolide activated the antioxidant response element (ARE)-dependent transcription mediated by the nuclear translocation of NRF2. Pathway enrichment analysis of RNA sequencing data revealed that sedanolide upregulated the transcription of antioxidant enzymes involved in the NRF2 pathway and glutathione metabolism. Then, we further investigated whether sedanolide exerts cytoprotective effects against H₂O₂-induced cell death. We showed that sedanolide significantly attenuated cytosolic and mitochondrial reactive oxygen species (ROS) generation induced by exposure to H₂O₂. Furthermore, we demonstrated that pretreatment with sedanolide conferred a significant cytoprotective effect against H₂O₂-induced cell death probably due to preventing the decrease in the mitochondrial membrane potential and the increase in caspase-3/7 activity. Our study demonstrated that sedanolide enhanced cellular resistance to oxidative damage via the activation of the Kelch-like ECH-associated protein 1 (KEAP1)–NRF2 pathway. Full article

(This article belongs to the Special Issue Investigating the Molecular Mechanism of Action of Natural Bioactive Molecules)

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20 pages, 6385 KiB

Open AccessArticle

Tiliroside Protects against Lipopolysaccharide-Induced Acute Kidney Injury via Intrarenal Renin–Angiotensin System in Mice

by Xiaoli Yi, Chuanming Xu, Jing Yang, Chao Zhong, Huiru Yang, Le Tang, Shanshan Song and Jun Yu

Int. J. Mol. Sci. 2023, 24(21), 15556; https://doi.org/10.3390/ijms242115556 - 25 Oct 2023

Cited by 2 | Viewed by 1834

Abstract

Tiliroside, a natural flavonoid, has various biological activities and improves several inflammatory diseases in rodents. However, the effect of Tiliroside on lipopolysaccharide (LPS)-induced acute kidney injury (AKI) and the underlying mechanisms are still unclear. This study aimed to evaluate the potential renoprotective effect of Tiliroside on LPS-induced AKI in mice. Male C57BL/6 mice were intraperitoneally injected with LPS (a single dose, 3 mg/kg) with or without Tiliroside (50 or 200 mg/kg/day for 8 days). Tiliroside administration protected against LPS-induced AKI, as reflected by ameliorated renal dysfunction and histological alterations. LPS-stimulated renal expression of inflammatory cytokines, fibrosis markers, and kidney injury markers in mice was significantly abolished by Tiliroside. This flavonoid also stimulated autophagy flux but inhibited oxidative stress and tubular cell apoptosis in kidneys from LPS-injected mice. Mechanistically, our study showed the regulation of Tiliroside on the intrarenal renin-angiotensin system in LPS-induced AKI mice. Tiliroside treatment suppressed intrarenal AGT, Renin, ACE, and Ang II, but upregulated intrarenal ACE2 and Ang1-7, without affecting plasma Ang II and Ang1-7 levels. Collectively, our data highlight the renoprotective action of Tiliroside on LPS-induced AKI by suppressing inflammation, oxidative stress, and tubular cell apoptosis and activating autophagy flux via the shift towards the intrarenal ACE2/Ang1-7 axis and away from the intrarenal ACE/Ang II axis. Full article

(This article belongs to the Special Issue Investigating the Molecular Mechanism of Action of Natural Bioactive Molecules)

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13 pages, 1781 KiB

Open AccessArticle

Toxic Determination of Cry11 Mutated Proteins Obtained Using Rational Design and Its Computational Analysis

by Miguel O. Suárez-Barrera, Diego F. Herrera-Pineda, Paola Rondón-Villarreal, Efraín Hernando Pinzón-Reyes, Rodrigo Ochoa, Lydia Visser and Nohora Juliana Rueda-Forero

Int. J. Mol. Sci. 2023, 24(10), 9079; https://doi.org/10.3390/ijms24109079 - 22 May 2023

Viewed by 2160

Abstract

Cry11 proteins are toxic to Aedes aegypti, the vector of dengue, chikungunya, and Zika viruses. Cry11Aa and Cry11Bb are protoxins, which when activated present their active-toxin form in two fragments between 30 and 35 kDa respectively. Previous studies conducted with Cry11Aa and Cry11Bb genes using DNA shuffling generated variant 8, which presented a deletion in the first 73 amino acids and one at position 572 and 9 substitutions including L553F and L556W. In this study, variant 8 mutants were constructed using site-directed mutagenesis, resulting in conversion of phenylalanine (F) and tryptophan (W) to leucine (L) at positions 553 and 556, respectively, producing the mutants 8F553L, 8W556L, and 8F553L/8W556L. Additionally, two mutants, A92D and C157R, derived from Cry11Bb were also generated. The proteins were expressed in the non-crystal strain BMB171 of Bacillus thuringiensis and subjected to median-lethal concentration (LC₅₀) tests on first-instar larvae of A. aegypti. LC₅₀ analysis showed that the 8F553L, 8W556L, 8F553L/8W556L, and C157R variants lost their toxic activity (>500 ng·mL⁻¹), whereas the A92D protein presented a loss of toxicity of 11.4 times that of Cry11Bb. Cytotoxicity assays performed using variant 8, 8W556L and the controls Cry11Aa, Cry11Bb, and Cry-negative BMB171 on the colorectal cancer cell line SW480 reported 30–50% of cellular viability except for BMB171. Molecular dynamic simulations performed to identify whether the mutations at positions 553 and 556 were related to the stability and rigidity of the functional tertiary structure (domain III) of the Cry11Aa protein and variant 8 showed the importance of these mutations in specific regions for the toxic activity of Cry11 against A. aegypti. This generates pertinent knowledge for the design of Cry11 proteins and their biotechnological applications in vector-borne disease control and cancer cell lines. Full article

(This article belongs to the Special Issue Investigating the Molecular Mechanism of Action of Natural Bioactive Molecules)

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Review

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27 pages, 2619 KiB

Open AccessReview

Withaferin A and Celastrol Overwhelm Proteostasis

by Nuria Vilaboa and Richard Voellmy

Int. J. Mol. Sci. 2024, 25(1), 367; https://doi.org/10.3390/ijms25010367 - 27 Dec 2023

Cited by 1 | Viewed by 1443

Abstract

Withaferin A (WA) and celastrol (CEL) are major bioactive components of plants that have been widely employed in traditional medicine. The pleiotropic activities of plant preparations and the isolated compounds in vitro and in vivo have been documented in hundreds of studies. Both WA and CEL were shown to have anticancer activity. Although WA and CEL belong to different chemical classes, our synthesis of the available information suggests that the compounds share basic mechanisms of action. Both WA and CEL bind covalently to numerous proteins, causing the partial unfolding of some of these proteins and of many bystander proteins. The resulting proteotoxic stress, when excessive, leads to cell death. Both WA and CEL trigger the activation of the unfolded protein response (UPR) which, if the proteotoxic stress persists, results in apoptosis mediated by the PERK/eIF-2/ATF4/CHOP pathway or another UPR-dependent pathway. Other mechanisms of cell death may play contributory or even dominant roles depending on cell type. As shown in a proteomic study with WA, the compounds appear to function largely as electrophilic reactants, indiscriminately modifying reachable nucleophilic amino acid side chains of proteins. However, a remarkable degree of target specificity is imparted by the cellular context. Full article

(This article belongs to the Special Issue Investigating the Molecular Mechanism of Action of Natural Bioactive Molecules)

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