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Antioxidants
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Exploring Endoplasmic Reticulum Stress in Disease: The Therapeutic Potential of...
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Exploring Endoplasmic Reticulum Stress in Disease: The Therapeutic Potential of Natural Pro- and Antioxidant Compounds in Redox Modulation

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 (20 April 2025) | Viewed by 9256

Special Issue Editors

Dr. Giacomo Pepe

E-Mail Website
Guest Editor
Department of Pharmacy, University of Salerno, Via G. Paolo II, Fisciano, 84084 Salerno, Italy
Interests: agro-industrial by-products; bioactive compounds; antioxidants; foods; green extraction
Dr. Vincenzo Vestuto

E-Mail Website
Guest Editor
Department of Pharmacy, University of Salerno, Via G. Paolo II, Fisciano, 84084 Salerno, Italy
Interests: protein misfolding disorders; ER stress; antioxidants; nutraceuticals; biochemistry of cancer
Special Issues, Collections and Topics in MDPI journals
Dr. Manuela Giovanna Basilicata

E-Mail Website
Guest Editor Assistant
Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, Naples, Italy
Interests: chromatography; mass spectrometry; hyphenated analytical techniques; peptidomics; natural compounds; pharmacokinetics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The endoplasmic reticulum (ER) is responsible for folding and modifying proteins before transporting them within the cell. Pathological conditions like nutrient deprivation, oxidative stress, and changes in calcium levels can lead to ER stress due to an imbalance between protein-folding capacity and the demand for properly folded proteins. ER stress is implicated in various diseases, including neurodegenerative diseases, metabolic disorders (e.g., obesity, type 2 diabetes), cardiovascular diseases (e.g., atherosclerosis, heart failure, ischemia–reperfusion injury), inflammatory dis-orders (e.g., inflammatory bowel disease, rheumatoid arthritis, asthma), and cancer.

Understanding the role of ER stress in disease pathogenesis may drive novel therapeutic strategies targeting the ER stress response. Natural products are gaining attention for their potential to either mitigate or trigger oxidative and ER stress, yet further research is needed to fully understand their biochemical mechanisms in ER stress modulation to develop effective treatments.

We invite researchers to submit their original research and review articles aimed at deepening the understanding of and providing new perspectives on the effectiveness of plant-derived compounds, nutraceuticals, and functional foods in modulating ER stress for the treatment of associated diseases. Additionally, we welcome innovative methods for isolating and characterizing bioactive natural compounds and their mechanisms, uncovering new biological targets associated with ER stress, and elucidating their pharmacological effects.

Dr. Giacomo Pepe
Dr. Vincenzo Vestuto
Dr. Manuela Giovanna Basilicata
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. 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

  • bioactive compounds
  • endoplasmic reticulum stress
  • inflammation
  • natural products
  • nutraceuticals
  • oxidative stress
  • protein misfolding
  • ROS
  • omics sciences

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Published Papers (5 papers)

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Research

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14 pages, 3616 KiB  
Article
A Structural Effect of the Antioxidant Curcuminoids on the Aβ(1–42) Amyloid Peptide
by Angelo Santoro, Antonio Ricci, Manuela Rodriquez, Michela Buonocore and Anna Maria D’Ursi
Antioxidants 2025, 14(1), 53; https://doi.org/10.3390/antiox14010053 - 5 Jan 2025
Cited by 1 | Viewed by 895
Abstract
Investigating amyloid–β (Aβ) peptides in solution is essential during the initial stages of developing lead compounds that can influence Aβ fibrillation while the peptide is still in a soluble state. The tendency of the Aβ(1–42) peptide to misfold in solution, correlated to the [...] Read more.
Investigating amyloid–β (Aβ) peptides in solution is essential during the initial stages of developing lead compounds that can influence Aβ fibrillation while the peptide is still in a soluble state. The tendency of the Aβ(1–42) peptide to misfold in solution, correlated to the aetiology of Alzheimer’s disease (AD), is one of the main hindrances to characterising its aggregation kinetics in a cell-mimetic environment. Moreover, the Aβ(1–42) aggregation triggers the unfolded protein response (UPR) in the endoplasmic reticulum (ER), leading to cellular dysfunction and multiple cell death modalities, exacerbated by reactive oxygen species (ROS), which damage cellular components and trigger inflammation. Antioxidants like curcumin, a derivative of Curcuma longa, help mitigate ER stress by scavenging ROS and enhancing antioxidant enzymes. Furthermore, evidence in the literature highlights the effect of curcumin on the secondary structure of Aβ(1–42). This explorative study investigates the Aβ(1–42) peptide conformational behaviour in the presence of curcumin and six derivatives using circular dichroism (CD) to explore their interactions with lipid bilayers, potentially preventing aggregate formation. The results suggest that the synthetic tetrahydrocurcumin (THC) derivative interacts with the amyloid peptide in all the systems presented, while cyclocurcumin (CYC) and bisdemethoxycurcumin (BMDC) only interact when the peptide is in a less stable conformation. Molecular dynamics simulations helped visualise the curcuminoids’ effect in an aqueous system and hypothesise the importance of the peptide surface exposition to the solvent, differently modulated by the curcumin derivatives. Full article
(This article belongs to the Special Issue Exploring Endoplasmic Reticulum Stress in Disease: The Therapeutic Potential of Natural Pro- and Antioxidant Compounds in Redox Modulation)
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16 pages, 67650 KiB  
Article
Tanshinone IIA Inhibits the Endoplasmic Reticulum Stress-Induced Unfolded Protein Response by Activating the PPARα/FGF21 Axis to Ameliorate Nonalcoholic Steatohepatitis
by Dajin Pi, Zheng Liang, Jinyue Pan, Jianwei Zhen, Chuiyang Zheng, Wen Fan, Qingliang Song, Maoxing Pan, Qinhe Yang and Yupei Zhang
Antioxidants 2024, 13(9), 1026; https://doi.org/10.3390/antiox13091026 - 23 Aug 2024
Cited by 1 | Viewed by 1834
Abstract
Nonalcoholic steatohepatitis (NASH) is a critical stage in the progression of nonalcoholic fatty liver disease (NAFLD). Tanshinone IIA (TIIA) is a tanshinone extracted from Salvia miltiorrhiza; due to its powerful anti-inflammatory and antioxidant biological activities, it is commonly used for treating cardiovascular and [...] Read more.
Nonalcoholic steatohepatitis (NASH) is a critical stage in the progression of nonalcoholic fatty liver disease (NAFLD). Tanshinone IIA (TIIA) is a tanshinone extracted from Salvia miltiorrhiza; due to its powerful anti-inflammatory and antioxidant biological activities, it is commonly used for treating cardiovascular and hepatic diseases. A NASH model was established by feeding mice a methionine and choline-deficient (MCD) diet. Liver surface microblood flow scanning, biochemical examination, histopathological examination, cytokine analysis through ELISA, lipidomic analysis, transcriptomic analysis, and Western blot analysis were used to evaluate the therapeutic effect and mechanism of TIIA on NASH. The results showed that TIIA effectively reduced lipid accumulation, fibrosis, and inflammation and alleviated endoplasmic reticulum (ER) stress. Lipidomic analysis revealed that TIIA normalized liver phospholipid metabolism in NASH mice. A KEGG analysis of the transcriptome revealed that TIIA exerted its effect by regulating the PPAR signalling pathway, protein processing in the ER, and the NOD-like receptor signalling pathway. These results suggest that TIIA alleviates NASH by activating the PPARα/FGF21 axis to negatively regulate the ER stress-induced unfolded protein response (UPR). Full article
(This article belongs to the Special Issue Exploring Endoplasmic Reticulum Stress in Disease: The Therapeutic Potential of Natural Pro- and Antioxidant Compounds in Redox Modulation)
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30 pages, 2543 KiB  
Article
Anticancer Therapies Based on Oxidative Damage: Lycium barbarum Inhibits the Proliferation of MCF-7 Cells by Activating Pyroptosis through Endoplasmic Reticulum Stress
by Maria Rosaria Miranda, Manuela Giovanna Basilicata, Vincenzo Vestuto, Giovanna Aquino, Pasquale Marino, Emanuela Salviati, Tania Ciaglia, Gloria Domínguez-Rodríguez, Ornella Moltedo, Pietro Campiglia, Giacomo Pepe and Michele Manfra
Antioxidants 2024, 13(6), 708; https://doi.org/10.3390/antiox13060708 - 11 Jun 2024
Cited by 7 | Viewed by 2149
Abstract
Lycium barbarum, commonly recognized as goji berry or wolfberry, is highly appreciated not only for its organoleptic and nutritional properties but also as an important source of bioactive compounds such as polysaccharides, carotenoids, phenolics, and various other non-nutritive compounds. These constituents give [...] Read more.
Lycium barbarum, commonly recognized as goji berry or wolfberry, is highly appreciated not only for its organoleptic and nutritional properties but also as an important source of bioactive compounds such as polysaccharides, carotenoids, phenolics, and various other non-nutritive compounds. These constituents give it a multitude of health benefits, including antioxidant, anti-inflammatory, and anticancer properties. However, the precise biochemical mechanisms responsible for its anticancer effects remain unclear, and the comprehensive composition of goji berry extracts is often insufficiently explored. This study aimed to investigate the biochemical pathways modulated in breast cancer cells by an ethanolic extract of Lycium barbarum fruit (LBE). Following metabolomic profiling using UHPLC-HRMS/MS, we assessed the antitumoral properties of LBE on different breast cancer cell lines. This investigation revealed that LBE exhibited cytotoxic effects, inducing a pro-oxidant effect that triggered pyroptosis activation through endoplasmic reticulum (ER) stress and subsequent activation of the P-IRE1α/XBP1/NLRP3 axis in MCF-7 cells. In addition, LBE did not display cytotoxicity toward healthy human cells but demonstrated antioxidant properties by neutralizing ROS generated by doxorubicin. These findings underscore the potential of LBE as a highly promising natural extract in cancer therapy. Full article
(This article belongs to the Special Issue Exploring Endoplasmic Reticulum Stress in Disease: The Therapeutic Potential of Natural Pro- and Antioxidant Compounds in Redox Modulation)
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Review

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25 pages, 1523 KiB  
Review
Exploring Endocannabinoid System: Unveiling New Roles in Modulating ER Stress
by Ilaria Capolupo, Maria Rosaria Miranda, Simona Musella, Veronica Di Sarno, Michele Manfra, Carmine Ostacolo, Alessia Bertamino, Pietro Campiglia and Tania Ciaglia
Antioxidants 2024, 13(11), 1284; https://doi.org/10.3390/antiox13111284 - 24 Oct 2024
Cited by 1 | Viewed by 2079
Abstract
The endoplasmic reticulum (ER) is the organelle mainly involved in maintaining cellular homeostasis and driving correct protein folding. ER-dependent defects or dysfunctions are associated with the genesis/progression of several pathological conditions, including cancer, inflammation, and neurodegenerative disorders, that are directly or indirectly correlated [...] Read more.
The endoplasmic reticulum (ER) is the organelle mainly involved in maintaining cellular homeostasis and driving correct protein folding. ER-dependent defects or dysfunctions are associated with the genesis/progression of several pathological conditions, including cancer, inflammation, and neurodegenerative disorders, that are directly or indirectly correlated to a wide set of events collectively named under the term “ER stress”. Despite the recent increase in interest concerning ER activity, further research studies are needed to highlight all the mechanisms responsible for ER failure. In this field, recent discoveries paved the way for the comprehension of the strong interaction between ER stress development and the endocannabinoid system. The activity of the endocannabinoid system is mediated by the activation of cannabinoid receptors (CB), G protein-coupled receptors that induce a decrease in cAMP levels, with downstream anti-inflammatory effects. CB activation drives, in most cases, the recovery of ER homeostasis through the regulation of ER stress hallmarks PERK, ATF6, and IRE1. In this review, we focus on the CB role in modulating ER stress, with particular attention to the cellular processes leading to UPR activation and oxidative stress response extinguishment, and to the mechanisms underlying natural cannabinoids’ modulation of this complex cellular machine. Full article
(This article belongs to the Special Issue Exploring Endoplasmic Reticulum Stress in Disease: The Therapeutic Potential of Natural Pro- and Antioxidant Compounds in Redox Modulation)
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Other

Jump to: Research, Review

20 pages, 5471 KiB  
Systematic Review
Relevant Serum Endoplasmic Reticulum Stress Biomarkers in Type 2 Diabetes and Its Complications: A Systematic Review and Meta-Analysis
by José Rafael Villafan-Bernal, Francisco Barajas-Olmos, Iris Paola Guzmán-Guzmán, Angélica Martínez-Hernández, Cecilia Contreras-Cubas, Humberto García-Ortiz, Monserrat I. Morales-Rivera, Raigam Jafet Martínez-Portilla and Lorena Orozco
Antioxidants 2024, 13(12), 1564; https://doi.org/10.3390/antiox13121564 - 19 Dec 2024
Viewed by 1329
Abstract
Endoplasmic reticulum stress (ERS) is activated in all cells by stressors such as hyperglycemia. However, it remains unclear which specific serum biomarkers of ERS are consistently altered in type 2 diabetes (T2D). We aimed to identify serum ERS biomarkers that are consistently altered [...] Read more.
Endoplasmic reticulum stress (ERS) is activated in all cells by stressors such as hyperglycemia. However, it remains unclear which specific serum biomarkers of ERS are consistently altered in type 2 diabetes (T2D). We aimed to identify serum ERS biomarkers that are consistently altered in T2D and its complications, and their correlation with metabolic and anthropometric variables. We performed a systematic review and meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-Analyses and Systematic Reviews of Observational Studies (MOOSE). The risk of bias was assessed using the Newcastle–Ottawa scale. Random-effects models weighted by the inverse variance were employed to estimate the standardized mean difference and correlations as effect size measures. Indicators of heterogeneity and meta-regressions were evaluated. Of the 1206 identified studies, 22 were finally included, representing 11,953 subjects (2224 with T2D and 9992 non-diabetic controls). Most studies were of high quality. Compared with controls, subjects with T2D had higher circulating levels of heat shock protein 70 (HSP70; SMD: 2.30, 95% CI 1.13–3.46; p < 0.001) and secretagogin (SMD: 0.60, 95%CI 0.19–1.01; p < 0.001). They also had higher serum levels of peroxiredoxin-1, -2, -4, and -6. Secretagogin inversely correlated with HOMA-IR, yet positively correlated with HOMA-B, HbA1c, and FPG. PRX4 negatively correlated with HbA1c and FPG, while HSP70 positively correlated with HbA1c. In conclusion, six ERS biomarkers are consistently elevated in human T2D and correlate with glycemic control, insulin resistance, and β-cell function. Emerging evidence links serum ERS biomarkers to diabetes complications, but further research should evaluate their prognostic implications. Full article
(This article belongs to the Special Issue Exploring Endoplasmic Reticulum Stress in Disease: The Therapeutic Potential of Natural Pro- and Antioxidant Compounds in Redox Modulation)
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