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Cell Metabolism and Small Natural Compounds

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

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 17769

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Special Issue Editors

Dr. Francesca Oppedisano

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Institute of Research for Food Safety and Health (IRC-FSH), Department of Health Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
Interests: nutraceuticals; mitochondria; membrane proteins; cell metabolism; cardiovascular disease; metabolic syndrome; omics sciences
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Dr. Salvatore Nesci

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Department of Veterinary Medical Sciences, Alma Mater Studiorum-Università di Bologna, Ozzano Emilia, Italy
Interests: mitochondria; bioenergetics; ATP synthase; permeability transition pore; mitochondrial supercomplexes; cell metabolism
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Dr. Anna Spagnoletta

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ENEA, Italian National Agency for New Technologies, Energy and Sustainable Economic Development, Department of Sustainability, Trisaia Research Center, Rotondella, Italy
Interests: mitochondria; protein purification; antioxidant activity; biomolecules extraction; agricultural waste valorization; novel food
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cellular metabolism and especially its dysregulation plays a key role in the physiology of the onset of many diseases, such as cancer, diabetes, metabolic syndrome, cardiovascular and neurodegenerative diseases.

Over the years, only through in-depth studies of biochemistry and molecular biology it has been possible to better understand the correlation between cellular mechanisms and the various chemical mediators.

In particular, the knowledge and the study of the mechanisms that involve the alteration of energy metabolism, the overproduction of reactive oxygen species (ROS) and nitrogen species (RNS), the imbalance between proliferation and cell death, the interaction between enzymes and substrates, represent a useful and fundamental tool to create new therapeutic approaches, more effective and ensuring a better quality of life.

Therefore, the detailed study of potential natural mediators of cellular metabolism both endogenous and exogenous (extracted from animal and plant sources) becomes an interesting research topic to be enriched with information. The multiplicity of bioactive molecules present in nature which is associated with a potential therapeutic effect and increased tolerability and bioavailability is an excellent alternative to synthetic drugs.

The increased knowledge of altered metabolic pathways and the ability of natural compounds to modulate them is an achievement and a great step forward for science.

Given the particular historical moment we are living, this special issue aims to focus more attention of the entire scientific community on the great therapeutic potential of natural compounds, and especially on their safety for health.

In particular, we encourage the submission of original manuscripts and reviews that bring new insights and information on the biochemical interaction of known or novel natural compounds with cellular metabolism, in health and disease, to design new and innovative therapeutic approaches.

Dr. Francesca Oppedisano
Dr. Salvatore Nesci
Dr. Anna Spagnoletta
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

cell metabolism
mitochondria
ROS
RNS
proliferation and cell death
metabolic pathways
natural compounds
bioactive molecules
human pathology

Related Special Issue

Cell Metabolism and Small Natural Compounds 2.0 in International Journal of Molecular Sciences (1 article)

Published Papers (9 papers)

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Editorial

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3 pages, 190 KiB

Open AccessEditorial

Cell Metabolism Therapy by Small Natural Compounds

by Salvatore Nesci, Anna Spagnoletta and Francesca Oppedisano

Int. J. Mol. Sci. 2023, 24(18), 13776; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241813776 - 07 Sep 2023

Viewed by 652

Abstract

Cellular metabolism therapy counteracting metabolic dysfunction performs a preeminent role in the pathophysiology of different diseases, such as cancer, diabetes, metabolic syndrome, and cardiovascular and neurodegenerative diseases [...] Full article

(This article belongs to the Special Issue Cell Metabolism and Small Natural Compounds)

Research

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22 pages, 3636 KiB

Open AccessArticle

The Oligostilbene Gnetin H Is a Novel Glycolysis Inhibitor That Regulates Thioredoxin Interacting Protein Expression and Synergizes with OXPHOS Inhibitor in Cancer Cells

by Shivendra Singh, Flavia De Carlo, Mohamed A. Ibrahim, Patrice Penfornis, Alan J. Mouton, Siddharth K. Tripathi, Ameeta K. Agarwal, Linda Eastham, David S. Pasco, Premalatha Balachandran and Pier Paolo Claudio

Int. J. Mol. Sci. 2023, 24(9), 7741; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24097741 - 23 Apr 2023

Cited by 2 | Viewed by 1747

Abstract

Since aerobic glycolysis was first observed in tumors almost a century ago by Otto Warburg, the field of cancer cell metabolism has sparked the interest of scientists around the world as it might offer new avenues of treatment for malignant cells. Our current study claims the discovery of gnetin H (GH) as a novel glycolysis inhibitor that can decrease metabolic activity and lactic acid synthesis and displays a strong cytostatic effect in melanoma and glioblastoma cells. Compared to most of the other glycolysis inhibitors used in combination with the complex-1 mitochondrial inhibitor phenformin (Phen), GH more potently inhibited cell growth. RNA-Seq with the T98G glioblastoma cell line treated with GH showed more than an 80-fold reduction in thioredoxin interacting protein (TXNIP) expression, indicating that GH has a direct effect on regulating a key gene involved in the homeostasis of cellular glucose. GH in combination with phenformin also substantially enhances the levels of p-AMPK, a marker of metabolic catastrophe. These findings suggest that the concurrent use of the glycolytic inhibitor GH with a complex-1 mitochondrial inhibitor could be used as a powerful tool for inducing metabolic catastrophe in cancer cells and reducing their growth. Full article

(This article belongs to the Special Issue Cell Metabolism and Small Natural Compounds)

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14 pages, 6653 KiB

Open AccessArticle

A Picrocrocin-Enriched Fraction from a Saffron Extract Affects Lipid Homeostasis in HepG2 Cells through a Non-Statin-like Mode

by Luca Frattaruolo, Federica Marra, Graziantonio Lauria, Carlo Siciliano, Rosita Curcio, Luigina Muto, Matteo Brindisi, Donatella Aiello, Anna Napoli, Giuseppe Fiermonte, Anna Rita Cappello, Marco Fiorillo, Amer Ahmed and Vincenza Dolce

Int. J. Mol. Sci. 2023, 24(4), 3060; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043060 - 04 Feb 2023

Cited by 3 | Viewed by 1554

Abstract

Dyslipidemia is a lipid metabolism disorder associated with the loss of the physiological homeostasis that ensures safe levels of lipids in the organism. This metabolic disorder can trigger pathological conditions such as atherosclerosis and cardiovascular diseases. In this regard, statins currently represent the main pharmacological therapy, but their contraindications and side effects limit their use. This is stimulating the search for new therapeutic strategies. In this work, we investigated in HepG2 cells the hypolipidemic potential of a picrocrocin-enriched fraction, analyzed by high-resolution ¹H NMR and obtained from a saffron extract, the stigmas of Crocus sativus L., a precious spice that has already displayed interesting biological properties. Spectrophotometric assays, as well as expression level of the main enzymes involved in lipid metabolism, have highlighted the interesting hypolipidemic effects of this natural compound; they seem to be exerted through a non-statin-like mechanism. Overall, this work provides new insights into the metabolic effects of picrocrocin, thus confirming the biological potential of saffron and paving the way for in vivo studies that could validate this spice or its phytocomplexes as useful adjuvants in balancing blood lipid homeostasis. Full article

(This article belongs to the Special Issue Cell Metabolism and Small Natural Compounds)

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19 pages, 3648 KiB

Open AccessArticle

The Mycotoxin Patulin Inhibits the Mitochondrial Carnitine/Acylcarnitine Carrier (SLC25A20) by Interaction with Cys136 Implications for Human Health

by Nicola Giangregorio, Annamaria Tonazzi, Cosima Damiana Calvano, Ciro Leonardo Pierri, Giovanna Incampo, Tommaso R. I. Cataldi and Cesare Indiveri

Int. J. Mol. Sci. 2023, 24(3), 2228; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032228 - 23 Jan 2023

Cited by 1 | Viewed by 1252

Abstract

The effect of mycotoxin patulin (4-hydroxy-4H-furo [3,2c] pyran-2 [6H] -one) on the mitochondrial carnitine/acylcarnitine carrier (CAC, SLC25A20) was investigated. Transport function was measured as [³H]-carnitine_ex/carnitine_in antiport in proteoliposomes reconstituted with the native protein extracted from rat liver mitochondria or with the recombinant CAC over-expressed in E. coli. Patulin (PAT) inhibited both the mitochondrial native and recombinant transporters. The inhibition was not reversed by physiological and sulfhydryl-reducing reagents, such as glutathione (GSH) or dithioerythritol (DTE). The IC₅₀ derived from the dose–response analysis indicated that PAT inhibition was in the range of 50 µM both on the native and on rat and human recombinant protein. The kinetics process revealed a competitive type of inhibition. A substrate protection experiment confirmed that the interaction of PAT with the protein occurred within a protein region, including the substrate-binding area. The mechanism of inhibition was identified using the site-directed mutagenesis of CAC. No inhibition was observed on Cys mutants in which only the C136 residue was mutated. Mass spectrometry studies and in silico molecular modeling analysis corroborated the outcomes derived from the biochemical assays. Full article

(This article belongs to the Special Issue Cell Metabolism and Small Natural Compounds)

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14 pages, 4530 KiB

Open AccessArticle

Santolina pinnata Viv. Exerts Promising Antitumor Activity against Breast Cancer Cells and Anti-Inflammatory Effects in LPS-Stimulated RAW 264.7 Cells

by Matteo Brindisi, Luca Frattaruolo, Vincenzo Sicari, Monica Rosa Loizzo, Gianni Bedini, Vittoria Rago, Rosa Tundis and Anna Rita Cappello

Int. J. Mol. Sci. 2022, 23(21), 12885; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232112885 - 25 Oct 2022

Cited by 2 | Viewed by 1428

Abstract

Cancer is one of the largest causes of mortality in the world, and due to its incidence, the discovery of novel anticancer drugs is of great importance. Many successful anticancer drugs used in clinical practices are derived from natural products. The genus Santolina is a group of species distributed in the Mediterranean area and used in traditional medicine for their biological properties. The aim of this work was to investigate, for the first time, the multi-target biological potential of Italian Santolina pinnata in relation to their chemical profile, by which an interesting natural source of valuable phytochemicals endowed with anticancer and anti-inflammatory features could be assessed. n-Hexane (EHSP) and methanol (EMSP) extracts were investigated by gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS) and ultra-high-performance liquid chromatography (UHPLC), respectively. Anti-proliferative activity was analyzed on MCF-7 and MDA-MB-231 breast cancer cells, as well as on non-tumorigenic MCF-10A cells, by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Apoptotic death was assessed by comet assay. Cell motility and invasive features were examined in highly invasive MDA-MB-231 by wound-healing scratches, while, in both breast cancer cell lines, by gel-zymography experiments. The anti-inflammatory potential was analyzed by nitric oxide (NO) production and the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) staining experiments in bacterial lipopolysaccharides (LPS) which stimulated RAW 264.7 cells. EHSP and EMSP extracts exhibited anticancer activity against breast cancer cells, promoting apoptotic death, as well as decreasing cell migration and invasive behaviours. The highest activity (IC₅₀ of 15.91 μg/mL) was detected against MDA-MB-231 cells, a highly invasive breast cancer cell line. Both extracts were also able to promote anti-inflammatory effects (IC₅₀ values ranging from 27.5 to 61.14 μg/mL), as well as to reduce NO levels by inducing inhibitory effects on NF-κB nuclear translocation in LPS-stimulated RAW 264.7 cells. The different biological behaviours found between the extracts could be related to their different chemical compositions. Herein, the multi-target biological potential of S. pinnata in inducing antitumor and anti-inflammatory effects was comprehensively demonstrated. These findings will provide important stepping-stones for further investigations and may lead to the development of highly effective S. pinnata extract-based treatments for breast cancer and inflammatory processes. Full article

(This article belongs to the Special Issue Cell Metabolism and Small Natural Compounds)

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11 pages, 1796 KiB

Open AccessCommunication

The Impairment of Cell Metabolism by Cardiovascular Toxicity of Doxorubicin Is Reversed by Bergamot Polyphenolic Fraction Treatment in Endothelial Cells

by Cristina Algieri, Chiara Bernardini, Francesca Oppedisano, Debora La Mantia, Fabiana Trombetti, Ernesto Palma, Monica Forni, Vincenzo Mollace, Giovanni Romeo, Ilaria Troisio and Salvatore Nesci

Int. J. Mol. Sci. 2022, 23(16), 8977; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23168977 - 11 Aug 2022

Cited by 7 | Viewed by 1491

Abstract

The beneficial effects of bergamot polyphenolic fraction (BPF) on the mitochondrial bioenergetics of porcine aortic endothelial cells (pAECs) were verified under the cardiotoxic action of doxorubicin (DOX). The cell viability of pAECs treated for 24 h with different concentrations of DOX was reduced by 50%, but the negative effect of DOX was reversed in the presence of increasing doses of BPF (100 µg/mL and 200 µg/mL BPF). An analysis of the protective effect of BPF on the toxic action of DOX was also carried out on cell respiration. We observed the inhibition of the mitochondrial activity at 10 µM DOX, which was not restored by 200 µg/mL BPF. Conversely, the decrease in basal respiration and ATP production caused by 0.5 or 1.0 µM DOX were improved in the presence of 100 or 200 µg/mL BPF, respectively. After 24 h of cell recovery with 100 µg/mL or 200 µg/mL BPF on pAECs treated with 0.5 µM or 1.0 µM DOX, respectively, the mitochondrial parameters of oxidative metabolism impaired by DOX were re-boosted. Full article

(This article belongs to the Special Issue Cell Metabolism and Small Natural Compounds)

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Review

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22 pages, 2194 KiB

Open AccessReview

Hyaluronic Acid: A Powerful Biomolecule with Wide-Ranging Applications—A Comprehensive Review

by Giorgia Natalia Iaconisi, Paola Lunetti, Nunzia Gallo, Anna Rita Cappello, Giuseppe Fiermonte, Vincenza Dolce and Loredana Capobianco

Int. J. Mol. Sci. 2023, 24(12), 10296; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241210296 - 18 Jun 2023

Cited by 11 | Viewed by 2842

Abstract

Hyaluronic acid (HA) is a glycosaminoglycan widely distributed in the human body, especially in body fluids and the extracellular matrix of tissues. It plays a crucial role not only in maintaining tissue hydration but also in cellular processes such as proliferation, differentiation, and the inflammatory response. HA has demonstrated its efficacy as a powerful bioactive molecule not only for skin antiaging but also in atherosclerosis, cancer, and other pathological conditions. Due to its biocompatibility, biodegradability, non-toxicity, and non-immunogenicity, several HA-based biomedical products have been developed. There is an increasing focus on optimizing HA production processes to achieve high-quality, efficient, and cost-effective products. This review discusses HA’s structure, properties, and production through microbial fermentation. Furthermore, it highlights the bioactive applications of HA in emerging sectors of biomedicine. Full article

(This article belongs to the Special Issue Cell Metabolism and Small Natural Compounds)

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25 pages, 3499 KiB

Open AccessReview

Inflammation, Mitochondria and Natural Compounds Together in the Circle of Trust

by Salvatore Nesci, Anna Spagnoletta and Francesca Oppedisano

Int. J. Mol. Sci. 2023, 24(7), 6106; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24076106 - 24 Mar 2023

Cited by 8 | Viewed by 2819

Abstract

Human diseases are characterized by the perpetuation of an inflammatory condition in which the levels of Reactive Oxygen Species (ROS) are quite high. Excessive ROS production leads to DNA damage, protein carbonylation and lipid peroxidation, conditions that lead to a worsening of inflammatory disorders. In particular, compromised mitochondria sustain a stressful condition in the cell, such that mitochondrial dysfunctions become pathogenic, causing human disorders related to inflammatory reactions. Indeed, the triggered inflammation loses its beneficial properties and turns harmful if dysregulation and dysfunctions are not addressed. Thus, reducing oxidative stress with ROS scavenger compounds has proven to be a successful approach to reducing inflammation. Among these, natural compounds, in particular, polyphenols, alkaloids and coenzyme Q₁₀, thanks to their antioxidant properties, are capable of inhibiting the activation of NF-κB and the expression of target genes, including those involved in inflammation. Even more, clinical trials, and in vivo and in vitro studies have demonstrated the antioxidant and anti-inflammatory effects of phytosomes, which are capable of increasing the bioavailability and effectiveness of natural compounds, and have long been considered an effective non-pharmacological therapy. Therefore, in this review, we wanted to highlight the relationship between inflammation, altered mitochondrial oxidative activity in pathological conditions, and the beneficial effects of phytosomes. To this end, a PubMed literature search was conducted with a focus on various in vitro and in vivo studies and clinical trials from 2014 to 2022. Full article

(This article belongs to the Special Issue Cell Metabolism and Small Natural Compounds)

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27 pages, 2281 KiB

Open AccessReview

The Generation of Nitric Oxide from Aldehyde Dehydrogenase-2: The Role of Dietary Nitrates and Their Implication in Cardiovascular Disease Management

by Jessica Maiuolo, Francesca Oppedisano, Cristina Carresi, Micaela Gliozzi, Vincenzo Musolino, Roberta Macrì, Federica Scarano, Annarita Coppoletta, Antonio Cardamone, Francesca Bosco, Rocco Mollace, Carolina Muscoli, Ernesto Palma and Vincenzo Mollace

Int. J. Mol. Sci. 2022, 23(24), 15454; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232415454 - 07 Dec 2022

Cited by 3 | Viewed by 2755

Abstract

Reduced bioavailability of the nitric oxide (NO) signaling molecule has been associated with the onset of cardiovascular disease. One of the better-known and effective therapies for cardiovascular disorders is the use of organic nitrates, such as glyceryl trinitrate (GTN), which increases the concentration of NO. Unfortunately, chronic use of this therapy can induce a phenomenon known as “nitrate tolerance”, which is defined as the loss of hemodynamic effects and a reduction in therapeutic effects. As such, a higher dosage of GTN is required in order to achieve the same vasodilatory and antiplatelet effects. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is a cardioprotective enzyme that catalyzes the bio-activation of GTN to NO. Nitrate tolerance is accompanied by an increase in oxidative stress, endothelial dysfunction, and sympathetic activation, as well as a loss of the catalytic activity of ALDH2 itself. On the basis of current knowledge, nitrate intake in the diet would guarantee a concentration of NO such as to avoid (or at least reduce) treatment with GTN and the consequent onset of nitrate tolerance in the course of cardiovascular diseases, so as not to make necessary the increase in GTN concentrations and the possible inhibition/alteration of ALDH2, which aggravates the problem of a positive feedback mechanism. Therefore, the purpose of this review is to summarize data relating to the introduction into the diet of some natural products that could assist pharmacological therapy in order to provide the NO necessary to reduce the intake of GTN and the phenomenon of nitrate tolerance and to ensure the correct catalytic activity of ALDH2. Full article

(This article belongs to the Special Issue Cell Metabolism and Small Natural Compounds)

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