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Modulation of Autophagy by Dietary Polyphenols: Mechanisms and Health Benefits

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A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 50299

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Special Issue Editor

Dr. Elzbieta Janda

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Guest Editor

Health Sciences Department, Magna Graecia University, Catanzaro, Italy

Special Issue Information

Dear Colleagues,

Recent years have provided plenty of evidence that health benefits of dietary polyphenols are mediated not only by their potent antioxidant and antiinflammatory properties, but also via the modulation of autophagy. Different forms of autophagy play a critical role in cellular homeostasis, while related genetic and acquired defects lead to disease. For this reason, the process of autophagy has been recognized as a pharmacological target. However, little is known about the molecular mechanisms underlying the crosstalk of polyphenol-mediated pathways with autophagy machinery.

We invite you to submit your latest research or review article to this Special issue that will gather novel evidence on the signaling and/or epigenetic mechanisms triggered by dietary polyphenols in various models of human disease characterized by oxidative imbalance and/or inflammation. In particular, papers addressing the relationship between antioxidant and anti-inflammatory pathways and autophagy are welcome.

The Special Issue is not restricted to a specific pathology but will focus on novel and consolidating insights into mechanisms of autophagy regulation and the pharmacology of natural flavonoids and related compounds found in dietary sources.

We are looking forward to your contribution to this fast evolving research area.

Dr. Elzbieta Janda
Guest Editor

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. Antioxidants 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

natural polyphenols
autophagy
mechanisms
oxidative stress
inflammation
nutraceutical approaches
disease models

Published Papers (10 papers)

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Research

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26 pages, 5328 KiB

Open AccessArticle

Thunbergia laurifolia Leaf Extract Inhibits Glutamate-Induced Neurotoxicity and Cell Death through Mitophagy Signaling

by Wudtipong Vongthip, Chanin Sillapachaiyaporn, Kyu-Won Kim, Monruedee Sukprasansap and Tewin Tencomnao

Antioxidants 2021, 10(11), 1678; https://doi.org/10.3390/antiox10111678 - 25 Oct 2021

Cited by 8 | Viewed by 3502

Abstract

Oxidative stress plays a crucial role in neurodegeneration. Therefore, reducing oxidative stress in the brain is an important strategy to prevent neurodegenerative disorders. Thunbergia laurifolia (Rang-jued) is well known as an herbal tea in Thailand. Here, we aimed to determine the protective effects of T. laurifolia leaf extract (TLE) on glutamate-induced oxidative stress toxicity and mitophagy-mediated cell death in mouse hippocampal cells (HT-22). Our results reveal that TLE possesses a high level of bioactive antioxidants by LC–MS technique. We found that the pre-treatment of cells with TLE prevented glutamate-induced neuronal death in a concentration-dependent manner. TLE reduced the intracellular ROS and maintained the mitochondrial membrane potential caused by glutamate. Moreover, TLE upregulated the gene expression of antioxidant enzymes (SOD1, SOD2, CAT, and GPx). Interestingly, glutamate also induced the activation of the mitophagy process. However, TLE could reverse this activity by inhibiting autophagic protein (LC3B-II/LC3B-I) activation and increasing a specific mitochondrial protein (TOM20). Our results suggest that excessive glutamate can cause neuronal death through mitophagy-mediated cell death signaling in HT-22 cells. Our findings indicate that TLE protects cells from neuronal death by stimulating the endogenous antioxidant enzymes and inhibiting glutamate-induced oxidative toxicity via the mitophagy–autophagy pathway. TLE might have potential as an alternative or therapeutic approach in neurodegenerative diseases. Full article

(This article belongs to the Special Issue Modulation of Autophagy by Dietary Polyphenols: Mechanisms and Health Benefits)

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11 pages, 5487 KiB

Open AccessArticle

Quercetin in Tartary Buckwheat Induces Autophagy against Protein Aggregations

by Sumiko Ikari, Qiang Yang, Shiou-Ling Lu, Yuancai Liu, Feike Hao, Guoqiang Tong, Shiguang Lu and Takeshi Noda

Antioxidants 2021, 10(8), 1217; https://doi.org/10.3390/antiox10081217 - 29 Jul 2021

Cited by 2 | Viewed by 4675

Abstract

Tartary buckwheat is used as an ingredient in flour and tea, as well as in traditional Chinese medicine for its antioxidant effects. Here, we found that an ethanol extract of tartary buckwheat (TBE) potently induced autophagy flux in HeLa cells by suppressing mTORC1 activity, as revealed by dephosphorylation of the mTORC1 substrates Ulk1, S6K, and 4EBP, as well as by the nuclear translocation of transcriptional factor EB. In addition to non-selective bulk autophagy, TBE also induced aggrephagy, which is defined as autophagy against aggregated proteins. Quercetin is a flavonol found at high levels in TBE. We showed that quercetin induced both non-selective bulk autophagy and aggrephagy. These effects were also observed in Huh-7 cells derived from hepatocytes. Thus, aggrephagy induction by TBE and quercetin may relieve alcoholic hepatitis, which is closely linked to the accumulation of protein aggregations called Mallory–Denk bodies. Full article

(This article belongs to the Special Issue Modulation of Autophagy by Dietary Polyphenols: Mechanisms and Health Benefits)

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19 pages, 41207 KiB

Open AccessArticle

Green Tea Polyphenol Catechins Inhibit Coronavirus Replication and Potentiate the Adaptive Immunity and Autophagy-Dependent Protective Mechanism to Improve Acute Lung Injury in Mice

by Chih-Ching Yang, Chang-Jer Wu, Chen-Yen Chien and Chiang-Ting Chien

Antioxidants 2021, 10(6), 928; https://doi.org/10.3390/antiox10060928 - 7 Jun 2021

Cited by 32 | Viewed by 9286

Abstract

Effective antiviral therapeutics are urgently required to fight severe acute respiratory syndrome (SARS) caused by a SARS coronavirus (SARS-CoV). Because polyphenol catechins could confer antioxidative, anti-inflammatory, antiviral, and antimicrobial activities, we assessed the therapeutic effects of catechins against SARS-CoV replication in Vero E6 cells, the preventive effect of catechins on CD25/CD69/CD94/CD8⁺ cytotoxic T lymphocytes-mediated adaptive immunity, and the protective effect on lipopolysaccharide-induced acute lung injury (ALI) in mice. We found that catechins containing 32.8% epigallocatechin gallate, 15.2% epicatechin gallate, 13.2 epicatechin, 10.8% epigallocatechin, 10.4% gallocatechin, and 4.4% catechin directly inhibited SARS-CoV replication at sub-micromolecular concentrations. Four-week catechins ingestion increased CD8⁺ T cell percentage, upregulated CD69⁺/CD25⁺/CD94-NKG2A/CD8⁺ T lymphocytes-mediated adaptive immunity, and increased type I cytokines release responding to ovalbumin/alum. Catechins significantly reduced lipopolysaccharide-induced cytokine storm and oxidative stress and ALI by inhibiting PI3K/AKT/mTOR signaling to upregulate Beclin-1/Atg5-Atg12/LC3-II-mediated autophagy mechanism. Pretreatment of autophagy inhibitor 3-Methyladenine reversed the inhibiting effects of catechins on the cytokines and oxidative stress levels and ALI. In conclusion, our data indicated that catechins directly inhibited SARS-CoV replication, potentiated the CD25/CD69/CD94/CD8⁺ T lymphocytes-mediated adaptive immunity and attenuated lipopolysaccharide-induced ALI and cytokine storm by PI3K/AKT/mTOR-signaling-mediated autophagy, which may be applied to prevent and/or treat SARS-CoV infection. Full article

(This article belongs to the Special Issue Modulation of Autophagy by Dietary Polyphenols: Mechanisms and Health Benefits)

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15 pages, 18688 KiB

Open AccessArticle

Apigenin and Luteolin Regulate Autophagy by Targeting NRH-Quinone Oxidoreductase 2 in Liver Cells

by Elzbieta Janda, Concetta Martino, Concetta Riillo, Maddalena Parafati, Antonella Lascala, Vincenzo Mollace and Jean A. Boutin

Antioxidants 2021, 10(5), 776; https://doi.org/10.3390/antiox10050776 - 13 May 2021

Cited by 14 | Viewed by 4362

Abstract

Dietary flavonoids stimulate autophagy and prevent liver dysfunction, but the upstream signaling pathways triggered by these compounds are not well understood. Certain polyphenols bind directly to NRH-quinone oxidoreductase 2 (NQO2) and inhibit its activity. NQO2 is highly expressed in the liver, where it participates in quinone metabolism, but recent evidence indicates that it may also play a role in the regulation of oxidative stress and autophagy. Here, we addressed a potential role of NQO2 in autophagy induction by flavonoids. The pro-autophagic activity of seven flavonoid aglycons correlated perfectly with their ability to inhibit NQO2 activity, and flavones such as apigenin and luteolin showed the strongest activity in all assays. The silencing of NQO2 strongly reduced flavone-induced autophagic flux, although it increased basal LC3-II levels in HepG2 cells. Both flavones induced AMP kinase (AMPK) activation, while its reduction by AMPK beta (PRKAB1) silencing inhibited flavone-induced autophagy. Interestingly, the depletion of NQO2 levels by siRNA increased the basal AMPK phosphorylation but abrogated its further increase by apigenin. Thus, NQO2 contributes to the negative regulation of AMPK activity and autophagy, while its targeting by flavones releases pro-autophagic signals. These findings imply that NQO2 works as a flavone receptor mediating autophagy and may contribute to other hepatic effects of flavonoids. Full article

(This article belongs to the Special Issue Modulation of Autophagy by Dietary Polyphenols: Mechanisms and Health Benefits)

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21 pages, 26089 KiB

Open AccessArticle

Targeting AKT/mTOR and Bcl-2 for Autophagic and Apoptosis Cell Death in Lung Cancer: Novel Activity of a Polyphenol Compound

by Sucharat Tungsukruthai, Onrapak Reamtong, Sittiruk Roytrakul, Suchada Sukrong, Chanida Vinayanwattikun and Pithi Chanvorachote

Antioxidants 2021, 10(4), 534; https://doi.org/10.3390/antiox10040534 - 29 Mar 2021

Cited by 13 | Viewed by 3660

Abstract

Autophagic cell death (ACD) is an alternative death mechanism in resistant malignant cancer cells. In this study, we demonstrated how polyphenol stilbene compound PE5 exhibits potent ACD-promoting activity in lung cancer cells that may offer an opportunity for novel cancer treatment. Cell death caused by PE5 was found to be concomitant with dramatic autophagy induction, as indicated by acidic vesicle staining, autophagosome, and the LC3 conversion. We further confirmed that the main death induction caused by PE5 was via ACD, since the co-treatment with an autophagy inhibitor could reverse PE5-mediated cell death. Furthermore, the defined mechanism of action and upstream regulatory signals were identified using proteomic analysis. Time-dependent proteomic analysis showed that PE5 affected 2142 and 1996 proteins after 12 and 24 h of treatment, respectively. The crosstalk network comprising 128 proteins that control apoptosis and 25 proteins involved in autophagy was identified. Protein–protein interaction analysis further indicated that the induction of ACD was via AKT/mTOR and Bcl-2 suppression. Western blot analysis confirmed that the active forms of AKT, mTOR, and Bcl-2 were decreased in PE5-treated cells. Taken together, we demonstrated the novel mechanism of PE5 in shifting autophagy toward cell death induction by targeting AKT/mTOR and Bcl-2 suppression. Full article

(This article belongs to the Special Issue Modulation of Autophagy by Dietary Polyphenols: Mechanisms and Health Benefits)

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20 pages, 1848 KiB

Open AccessArticle

Neuroprotection by Phytoestrogens in the Model of Deprivation and Resupply of Oxygen and Glucose In Vitro: The Contribution of Autophagy and Related Signaling Mechanisms

by Giuseppe Abbruzzese, Javier Morón-Oset, Sabela Díaz-Castroverde, Nuria García-Font, Cesáreo Roncero, Francisco López-Muñoz, José Luis Marco Contelles and María Jesús Oset-Gasque

Antioxidants 2020, 9(6), 545; https://doi.org/10.3390/antiox9060545 - 22 Jun 2020

Cited by 13 | Viewed by 3203

Abstract

Phytoestrogens can have a neuroprotective effect towards ischemia-reperfusion-induced neuronal damage. However, their mechanism of action has not been well described. In this work, we investigate the type of neuronal cell death induced by oxygen and glucose deprivation (OGD) and resupply (OGDR) and pinpoint some of the signaling mechanisms whereby the neuroprotective effects of phytoestrogens occur in these conditions. First, we found that autophagy initiation affords neuronal protection upon neuronal damage induced by OGD and OGDR. The mammalian target of rapamycin/ribosomal S6 kinase (mTOR/S6K) pathway is blocked in these conditions, and we provide evidence that this is mediated by modulation of both the 5′ AMP-activated protein kinase (AMPK) and phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathways. These are dampened up or down, respectively, under OGDR-induced neuronal damage. In contrast, the MAPK-Erk kinase/extracellular signal-regulated kinase (MEK/ERK) pathway is increased under these conditions. Regarding the pathways affected by phytoestrogens, we show that their protective properties require autophagy initiation, but at later stages, they decrease mitogen-activated protein kinase (MAPK) and AMPK activation and increase mTOR/S6K activation. Collectively, our results put forward a novel mode of action where phytoestrogens play a dual role in the regulation of autophagy by acting as autophagy initiation enhancers when autophagy is a neuroprotective and pro-survival mechanism, and as autophagy initiation inhibitors when autophagy is a pro-death mechanism. Finally, our results support the therapeutic potential of phytoestrogens in brain ischemia by modulating autophagy. Full article

(This article belongs to the Special Issue Modulation of Autophagy by Dietary Polyphenols: Mechanisms and Health Benefits)

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Review

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15 pages, 2190 KiB

Open AccessReview

The Multifaceted Role of Flavonoids in Cancer Therapy: Leveraging Autophagy with a Double-Edged Sword

by Zhe Zhang, Jiayan Shi, Edouard C. Nice, Canhua Huang and Zheng Shi

Antioxidants 2021, 10(7), 1138; https://doi.org/10.3390/antiox10071138 - 19 Jul 2021

Cited by 30 | Viewed by 4130

Abstract

Flavonoids are considered as pleiotropic, safe, and readily obtainable molecules. A large number of recent studies have proposed that flavonoids have potential in the treatment of tumors by the modulation of autophagy. In many cases, flavonoids suppress cancer by stimulating excessive autophagy or impairing autophagy flux especially in apoptosis-resistant cancer cells. However, the anti-cancer activity of flavonoids may be attenuated due to the simultaneous induction of protective autophagy. Notably, flavonoids-triggered protective autophagy is becoming a trend for preventing cancer in the clinical setting or for protecting patients from conventional therapeutic side effects in normal tissues. In this review, focusing on the underlying autophagic mechanisms of flavonoids, we hope to provide a new perspective for clinical application of flavonoids in cancer therapy. In addition, we highlight new research ideas for the development of new dosage forms of flavonoids to improve their various pharmacological effects, establishing flavonoids as ideal candidates for cancer prevention and therapy in the clinic. Full article

(This article belongs to the Special Issue Modulation of Autophagy by Dietary Polyphenols: Mechanisms and Health Benefits)

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22 pages, 4777 KiB

Open AccessReview

Dietary Polyphenols in Metabolic and Neurodegenerative Diseases: Molecular Targets in Autophagy and Biological Effects

by Ana García-Aguilar, Olga Palomino, Manuel Benito and Carlos Guillén

Antioxidants 2021, 10(2), 142; https://doi.org/10.3390/antiox10020142 - 20 Jan 2021

Cited by 27 | Viewed by 4523

Abstract

Polyphenols represent a group of secondary metabolites of plants which have been analyzed as potent regulators of multiple biological processes, including cell proliferation, apoptosis, and autophagy, among others. These natural compounds exhibit beneficial effects and protection against inflammation, oxidative stress, and related injuries including metabolic diseases, such as cardiovascular damage, obesity and diabetes, and neurodegeneration. This review aims to summarize the mechanisms of action of polyphenols in relation to the activation of autophagy, stimulation of mitochondrial function and antioxidant defenses, attenuation of oxidative stress, and reduction in cell apoptosis, which may be responsible of the health promoting properties of these compounds. Full article

(This article belongs to the Special Issue Modulation of Autophagy by Dietary Polyphenols: Mechanisms and Health Benefits)

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19 pages, 2129 KiB

Open AccessReview

Modulation of Autophagy in Cancer Cells by Dietary Polyphenols

by Claudia Musial, Kamila Siedlecka-Kroplewska, Zbigniew Kmiec and Magdalena Gorska-Ponikowska

Antioxidants 2021, 10(1), 123; https://doi.org/10.3390/antiox10010123 - 16 Jan 2021

Cited by 40 | Viewed by 5114

Abstract

The role of autophagy is to degrade damaged or unnecessary cellular structures. Both in vivo and in vitro studies suggest a dual role of autophagy in cancer—it may promote the development of neoplasms, but it may also play a tumor protective function. The mechanism of autophagy depends on the genetic context, tumor stage and type, tumor microenvironment, or clinical therapy used. Autophagy also plays an important role in cell death as well as in the induction of chemoresistance of cancer cells. The following review describes the extensive autophagic cell death in relation to dietary polyphenols and cancer disease. The review documents increasing use of polyphenolic compounds in cancer prevention, or as agents supporting oncological treatment. Polyphenols are organic chemicals that exhibit antioxidant, anti-inflammatory, anti-angiogenic, and immunomodulating properties, and can also initiate the process of apoptosis. In addition, polyphenols reduce oxidative stress and protect against reactive oxygen species. This review presents in vitro and in vivo studies in animal models with the use of polyphenolic compounds such as epigallocatechin-3-gallate (EGCG), oleuropein, punicalgin, apigenin, resveratrol, pterostilbene, or curcumin and their importance in the modulation of autophagy-induced death of cancer cells. Full article

(This article belongs to the Special Issue Modulation of Autophagy by Dietary Polyphenols: Mechanisms and Health Benefits)

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35 pages, 3939 KiB

Open AccessFeature PaperReview

Cell Clearing Systems as Targets of Polyphenols in Viral Infections: Potential Implications for COVID-19 Pathogenesis

by Fiona Limanaqi, Carla Letizia Busceti, Francesca Biagioni, Gloria Lazzeri, Maurizio Forte, Sonia Schiavon, Sebastiano Sciarretta, Giacomo Frati and Francesco Fornai

Antioxidants 2020, 9(11), 1105; https://doi.org/10.3390/antiox9111105 - 10 Nov 2020

Cited by 32 | Viewed by 6142

Abstract

The novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has generated the ongoing coronavirus disease-2019 (COVID-19) pandemic, still with an uncertain outcome. Besides pneumonia and acute lung injury (ALI) or acute respiratory distress syndrome (ARDS), other features became evident in the context of COVID-19. These includes endothelial and coagulation dysfunction with disseminated intravascular coagulation (DIC), and multiple organ dysfunction syndrome (MODS), along with the occurrence of neurological alterations. The multi-system nature of such viral infection is a witness to the exploitation and impairment of ubiquitous subcellular and metabolic pathways for the sake of its life-cycle, ranging from host cell invasion, replication, transmission, up to a cytopathic effect and overt systemic inflammation. In this frame, alterations in cell-clearing systems of the host are emerging as a hallmark in the pathogenesis of various respiratory viruses, including SARS-CoV-2. Indeed, exploitation of the autophagy and proteasome pathways might contribute not only to the replication of the virus at the site of infection but also to the spreading of either mature virions or inflammatory mediators at both cellular and multisystem levels. In this frame, besides a pharmacological therapy, many researchers are wondering if some non-pharmacological substances might counteract or positively modulate the course of the infection. The pharmacological properties of natural compounds have gained increasing attention in the field of alternative and adjunct therapeutic approaches to several diseases. In particular, several naturally-occurring herbal compounds (mostly polyphenols) are reported to produce widespread antiviral, anti-inflammatory, and anti-oxidant effects while acting as autophagy and (immuno)-proteasome modulators. This article attempts to bridge the perturbation of autophagy and proteasome pathways with the potentially beneficial effects of specific phytochemicals and flavonoids in viral infections, with a focus on the multisystem SARS-CoV-2 infection. Full article

(This article belongs to the Special Issue Modulation of Autophagy by Dietary Polyphenols: Mechanisms and Health Benefits)

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