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23 pages, 8569 KiB

Open AccessArticle

Cold Physical Plasma-Mediated Fenretinide Prodrug Activation Confers Additive Cytotoxicity in Epithelial Cells

by Mohsen Ahmadi, Debora Singer, Felix Potlitz, Zahra Nasri, Thomas von Woedtke, Andreas Link, Sander Bekeschus and Kristian Wende

Antioxidants 2023, 12(6), 1271; https://doi.org/10.3390/antiox12061271 - 14 Jun 2023

Cited by 2 | Viewed by 2281

Abstract

Cold physical plasma is a partially ionized gas operated at body temperature and utilized for heat-sensitive technical and medical purposes. Physical plasma is a multi-component system consisting of, e.g., reactive species, ions and electrons, electric fields, and UV light. Therefore, cold plasma technology [...] Read more.

Cold physical plasma is a partially ionized gas operated at body temperature and utilized for heat-sensitive technical and medical purposes. Physical plasma is a multi-component system consisting of, e.g., reactive species, ions and electrons, electric fields, and UV light. Therefore, cold plasma technology is an interesting tool for introducing biomolecule oxidative modifications. This concept can be extended to anticancer drugs, including prodrugs, which could be activated in situ to enhance local anticancer effects. To this end, we performed a proof-of-concept study on the oxidative prodrug activation of a tailor-made boronic pinacol ester fenretinide treated with the atmospheric pressure argon plasma jet kINPen operated with either argon, argon–hydrogen, or argon–oxygen feed gas. Fenretinide release from the prodrug was triggered via Baeyer–Villiger-type oxidation of the boron–carbon bond based on hydrogen peroxide and peroxynitrite, which were generated by plasma processes and chemical addition using mass spectrometry. Fenretinide activation led to additive cytotoxic effects in three epithelial cell lines in vitro compared to the effects of cold plasma treatment alone regarding metabolic activity reduction and an increase in terminal cell death, suggesting that cold physical plasma-mediated prodrug activation is a new direction for combination cancer treatment studies. Full article

(This article belongs to the Special Issue From Nature to Synthetic Small Molecule Antioxidants: New Candidates in Drug Discovery)

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22 pages, 3054 KiB

Open AccessArticle

Rational Design of Multifunctional Ferulic Acid Derivatives Aimed for Alzheimer’s and Parkinson’s Diseases

by Eduardo Gabriel Guzmán-López, Miguel Reina, Luis Felipe Hernández-Ayala and Annia Galano

Antioxidants 2023, 12(6), 1256; https://doi.org/10.3390/antiox12061256 - 11 Jun 2023

Cited by 4 | Viewed by 2597

Abstract

Ferulic acid has numerous beneficial effects on human health, which are frequently attributed to its antioxidant behavior. In this report, many of them are reviewed, and 185 new ferulic acid derivatives are computationally designed using the CADMA-Chem protocol. Consequently, their chemical space was [...] Read more.

Ferulic acid has numerous beneficial effects on human health, which are frequently attributed to its antioxidant behavior. In this report, many of them are reviewed, and 185 new ferulic acid derivatives are computationally designed using the CADMA-Chem protocol. Consequently, their chemical space was sampled and evaluated. To that purpose, selection and elimination scores were used, which are built from a set of descriptors accounting for ADME properties, toxicity, and synthetic accessibility. After the first screening, 12 derivatives were selected and further investigated. Their potential role as antioxidants was predicted from reactivity indexes directly related to the formal hydrogen atom transfer and the single electron transfer mechanisms. The best performing molecules were identified by comparisons with the parent molecule and two references: Trolox and α-tocopherol. Their potential as polygenic neuroprotectors was investigated through the interactions with enzymes directly related to the etiologies of Parkinson’s and Alzheimer’s diseases. These enzymes are acetylcholinesterase, catechol-O-methyltransferase, and monoamine oxidase B. Based on the obtained results, the most promising candidates (FA-26, FA-118, and FA-138) are proposed as multifunctional antioxidants with potential neuroprotective effects. The findings derived from this investigation are encouraging and might promote further investigations on these molecules. Full article

(This article belongs to the Special Issue From Nature to Synthetic Small Molecule Antioxidants: New Candidates in Drug Discovery)

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17 pages, 2692 KiB

Open AccessArticle

Synthesis and Biological Evaluation of O⁶-Aminoalkyl-Hispidol Analogs as Multifunctional Monoamine Oxidase-B Inhibitors towards Management of Neurodegenerative Diseases

by Ahmed H. E. Hassan, Hyeon Jeong Kim, Keontae Park, Yeonwoo Choi, Suyeon Moon, Chae Hyeon Lee, Yeon Ju Kim, Soo Bin Cho, Min Sung Gee, Danbi Lee, Jong-Hyun Park, Jong Kil Lee, Jong Hoon Ryu, Ki Duk Park and Yong Sup Lee

Antioxidants 2023, 12(5), 1033; https://doi.org/10.3390/antiox12051033 - 29 Apr 2023

Cited by 5 | Viewed by 2262

Abstract

Oxidative catabolism of monoamine neurotransmitters by monoamine oxidases (MAOs) produces reactive oxygen species (ROS), which contributes to neuronal cells’ death and also lowers monoamine neurotransmitter levels. In addition, acetylcholinesterase activity and neuroinflammation are involved in neurodegenerative diseases. Herein, we aim to achieve a [...] Read more.

Oxidative catabolism of monoamine neurotransmitters by monoamine oxidases (MAOs) produces reactive oxygen species (ROS), which contributes to neuronal cells’ death and also lowers monoamine neurotransmitter levels. In addition, acetylcholinesterase activity and neuroinflammation are involved in neurodegenerative diseases. Herein, we aim to achieve a multifunctional agent that inhibits the oxidative catabolism of monoamine neurotransmitters and, hence, the detrimental production of ROS while enhancing neurotransmitter levels. Such a multifunctional agent might also inhibit acetylcholinesterase and neuroinflammation. To meet this end goal, a series of aminoalkyl derivatives of analogs of the natural product hispidol were designed, synthesized, and evaluated against both monoamine oxidase-A (MAO-A) and monoamine oxidase-B (MAO-B). Promising MAO inhibitors were further checked for the inhibition of acetylcholinesterase and neuroinflammation. Among them, compounds 3aa and 3bc were identified as potential multifunctional molecules eliciting submicromolar selective MAO-B inhibition, low-micromolar AChE inhibition, and the inhibition of microglial PGE₂ production. An evaluation of their effects on memory and cognitive impairments using a passive avoidance test confirmed the in vivo activity of compound 3bc, which showed comparable activity to donepezil. In silico molecular docking provided insights into the MAO and acetylcholinesterase inhibitory activities of compounds 3aa and 3bc. These findings suggest compound 3bc as a potential lead for the further development of agents against neurodegenerative diseases. Full article

(This article belongs to the Special Issue From Nature to Synthetic Small Molecule Antioxidants: New Candidates in Drug Discovery)

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14 pages, 2606 KiB

Open AccessArticle

Swietenine Alleviates Nonalcoholic Fatty Liver Disease in Diabetic Mice via Lipogenesis Inhibition and Antioxidant Mechanisms

by Kit-Kay Mak, Shiming Zhang, Jestin Chellian, Zulkefeli Mohd, Ola Epemolu, Albena T. Dinkova-Kostova, Madhu Katyayani Balijepalli and Mallikarjuna Rao Pichika

Antioxidants 2023, 12(3), 595; https://doi.org/10.3390/antiox12030595 - 27 Feb 2023

Cited by 3 | Viewed by 2502

Abstract

Our previous studies have reported the effect of swietenine (a major bioactive component of Swietenia macrophylla seeds) in reversing and potentiating the effect of metformin in hyperglycemia and hyperlipidaemia in diabetic rats. Moreover, we reported that the anti-inflammatory effect of swietenine is mediated [...] Read more.

Our previous studies have reported the effect of swietenine (a major bioactive component of Swietenia macrophylla seeds) in reversing and potentiating the effect of metformin in hyperglycemia and hyperlipidaemia in diabetic rats. Moreover, we reported that the anti-inflammatory effect of swietenine is mediated via the activation of nuclear factor erythroid 2-related factor 2 (Nrf2). This study evaluated the effect of swietenine and its mechanisms in nonalcoholic fatty liver disease (NAFLD) in high-fat diet/streptozotocin-induced diabetic mice. The effect was assessed by determining blood biochemical parameters (glucose, cholesterol, triglycerides, alanine transaminase (ALT), asparate transaminase (AST), alkaline phosphatase (ALP), glutathione (GSH), total antioxidant capacity (TAC), and malondialdehyde (MDA)) and liver biochemical parameters (liver index, cholesterol, and triglycerides). Hepatic lipid accumulation (initial causative factor in NAFLD) was determined by oil-O-red staining. Gene expression (qPCR) and immunohistochemical studies were performed to elucidate the mechanism of swietenine’s effect in NAFLD. The critical regulators (genes and proteins) involved in lipogenesis (ACLY, ACC1, FASN, SREBP1c, and ChREBPβ) and oxidative stress (Nrf2, NQO-1 and HO-1) pathways were determined. In mice fed with a high-fat diet followed by streptozotocin injection, the liver cholesterol, triglycerides, and lipids were elevated. These increases were reversed by the oral administration of swietenine, 80 mg/kg body weight, on alternate days for eight weeks. Gene expression and immunohistochemical studies showed that swietenine reversed the elevated levels of crucial enzymes of lipogenesis (ACLY, ACC1 and FASN) and their master transcription factors (SREBP1c and ChREBPβ). Furthermore, swietenine activated the Nrf2 antioxidant defense mechanism, as evidenced by the upregulated levels of Nrf2, NQO-1, and HO-1. It is concluded that swietenine shows beneficial effects in diabetes-induced NAFLD via inhibiting lipogenesis and activating the Nrf2 pathway. Full article

(This article belongs to the Special Issue From Nature to Synthetic Small Molecule Antioxidants: New Candidates in Drug Discovery)

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16 pages, 6591 KiB

Open AccessArticle

Cytoprotective and Antioxidant Effects of Hydrolysates from Black Soldier Fly (Hermetia illucens)

by Kristian Riolo, Archimede Rotondo, Giovanna Loredana La Torre, Ylenia Marino, Gianluca Antonio Franco, Rosalia Crupi, Roberta Fusco, Rosanna Di Paola, Sabrina Oliva, Giuseppe De Marco, Domenico Savastano, Salvatore Cuzzocrea, Enrico Gugliandolo and Alessia Giannetto

Antioxidants 2023, 12(2), 519; https://doi.org/10.3390/antiox12020519 - 18 Feb 2023

Cited by 11 | Viewed by 3350

Abstract

The black soldier fly (BSF), Hermetia illucens, has been recognized as one of the most promising insect species for its ability to valorize organic waste while producing a valuable larval biomass with a great potential as a sustainable source of nutrients, including proteins [...] Read more.

The black soldier fly (BSF), Hermetia illucens, has been recognized as one of the most promising insect species for its ability to valorize organic waste while producing a valuable larval biomass with a great potential as a sustainable source of nutrients, including proteins and bioactive molecules. In the present study, BSF larvae were used to produce and characterize the protein hydrolysates (BPHs) that were then evaluated for their potential biological activity in vitro. The BPHs obtained from the BSF larvae proteins by enzymatic digestion were characterized by Nuclear Magnetic Resonance (NMR) and polyacrylamide gel electrophoresis and assessed for their antioxidant activity (BPHs in the range of 0.1 to 1.5 mg/mL) in L-929 cells. Our findings show that BPHs can exert a dose-dependent cytoprotective role against H₂O₂-iduced oxidative stress in cells. This antioxidant activity relies on the reduction of ROS levels in challenged cells as measured by flow cytometry and fluorescence microscopy, together with the induction and nuclear translocation of Nrf2, as evaluated by qPCR and indirect immunofluorescence analysis, respectively. Overall, our findings on the remarkable biological activity of the BPHs obtained in a large-scale process strongly suggest the application of BPHs as ingredients promoting animal health in feed formulations. Full article

(This article belongs to the Special Issue From Nature to Synthetic Small Molecule Antioxidants: New Candidates in Drug Discovery)

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27 pages, 4260 KiB

Open AccessArticle

Synthesis of New Shogaol Analogues as NRF2 Activators and Evaluation of Their Anti-Inflammatory Activity, Modes of Action and Metabolic Stability

by Kit-Kay Mak, Zhang Shiming, Raghavendra Sakirolla, Madhu Katyayani Balijepalli, Albena T. Dinkova-Kostova, Ola Epemolu, Zulkefeli Mohd and Mallikarjuna Rao Pichika

Antioxidants 2023, 12(2), 475; https://doi.org/10.3390/antiox12020475 - 13 Feb 2023

Cited by 3 | Viewed by 2642

Abstract

6-shogaol is a natural and the most potent bioactive vanilloid in dried Zingiber officinale rhizomes. Many scientific studies have reported the diverse biological activities of 6-shogaol. However, the major drawback of 6-shogaol is its instability at room temperature. We synthesised new shogaol thiophene [...] Read more.

6-shogaol is a natural and the most potent bioactive vanilloid in dried Zingiber officinale rhizomes. Many scientific studies have reported the diverse biological activities of 6-shogaol. However, the major drawback of 6-shogaol is its instability at room temperature. We synthesised new shogaol thiophene compounds (STCs) by replacing the pentyl group in the sidechain with thiophene derivatives. The STCs were tested for their nuclear factor erythroid 2-related factor 2 (NRF2) activation ability in murine hepatoma cells (Hepa1c1c-7) by determining their NAD(P)H quinone oxidoreductase 1 (NQO1) inducing ability and expression of NRF2-associated antioxidant genes. The anti-inflammatory activity of STCs was determined in Escherichia coli lipopolysaccharide (LPS_Ec)-stimulated NR2-proficient and -silenced mouse microglial cells (BV-2) by measuring the inflammatory markers, cytokines, and mediators. The modes of action (interacting with the Kelch domain of KEAP1, covalent bonding with cysteines of KEAP1, and inhibition of GSK-3β enzyme activity) of NRF2 activation by STCs were determined using commercially available kits. The in vitro metabolic stability of the STCs in liver microsomes (humans, rats, and mice) was also investigated. The molecular docking and molecular dynamics studies were conducted to identify the binding poses, stability, and molecular interactions of the STCs in the binding pockets of Kelch and BTB domains of KEAP1 and GSK-3β enzyme. The new STCs were synthesised in good yields of > 85%, with a purity of about 95%, using a novel synthesis method by employing a reusable proline–proline dipeptide catalyst. The STCs are more potent than 6-shogaol in activating NRF2 and reducing inflammation. The nature of substituents on thiophene has a profound influence on the bioactivity of the STCs. Phenylthiophene STC (STC5) is the most potent, while thiophenes containing electron-withdrawing groups showed weaker bioactivity. The bioactivity of 6-shogaol is in the micromolar range, whereas STC5 showed bioactivity in the sub micromolar range. The STCs showed anti-inflammatory effects via NRF2-dependent and NRF2-independent mechanisms. The STCs improved NRF2 activity through multiple (KEAP1-independent and -dependent) mechanisms. The STCs showed decreased reactivity with thiols than 6-shogaol and thus may possess fewer side-effects than 6-shogaol. The STCs were more metabolically stable than 6-shogaol. Full article

(This article belongs to the Special Issue From Nature to Synthetic Small Molecule Antioxidants: New Candidates in Drug Discovery)

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17 pages, 4060 KiB

Open AccessArticle

Mitochondria-Targeted Triphenylphosphonium-Hydroxytyrosol Prevents Lipotoxicity-Induced Endothelial Injury by Enhancing Mitochondrial Function and Redox Balance via Promoting FoxO1 and Nrf2 Nuclear Translocation and Suppressing Inflammation via Inhibiting p38/NF-кB Pathway

by Xuyun Liu, Jing Gao, Yizhen Yan, Eleftheria A. Georgiou, Jing Lou, Mengya Feng, Xing Zhang, Feng Gao, Jiankang Liu, Ioannis K. Kostakis and Lin Zhao

Antioxidants 2023, 12(1), 175; https://doi.org/10.3390/antiox12010175 - 11 Jan 2023

Cited by 3 | Viewed by 2430

Abstract

Hyperlipidemia results in endothelial dysfunction, which is intimately associated with disturbed mitochondrial homeostasis, and is a real risk factor for cardiovascular diseases (CVDs). Triphenylphosphonium (TPP⁺)-HT, constructed by linking a mitochondrial-targeting moiety TPP⁺ to hydroxytyrosol (HT), enters the cell and accumulates in [...] Read more.

Hyperlipidemia results in endothelial dysfunction, which is intimately associated with disturbed mitochondrial homeostasis, and is a real risk factor for cardiovascular diseases (CVDs). Triphenylphosphonium (TPP⁺)-HT, constructed by linking a mitochondrial-targeting moiety TPP⁺ to hydroxytyrosol (HT), enters the cell and accumulates in mitochondria and is thus an important candidate drug for preventing hyperlipidemia-induced endothelial injury. In the present study, we found that TPP-HT has a better anti-inflammatory effect than HT. In vivo, TPP-HT significantly prevented hyperlipidemia-induced adverse changes in the serological lipid panel, as well as endothelial and mitochondrial dysfunction of the thoracic aorta. Similarly, in vitro, TPP-HT exhibited similar protective effects in palmitate (PA)-induced endothelial dysfunction, particularly enhanced expression of the mitochondrial ETC complex II, recovered FoxO1 expression in PA-injured human aorta endothelial cells (HAECs) and promoted FoxO1 nuclear translocation. We further demonstrated that FoxO1 plays a pivotal role in regulating ATP production in the presence of TPP-HT by using the siFoxO1 knockdown technique. Simultaneously, TPP-HT enhanced Nrf2 nuclear translocation, consistent with the in vivo findings of immunofluorescence, and the antioxidant effect of TPP-HT was almost entirely blocked by siNrf2. Concomitantly, TPP-HT’s anti-inflammatory effects in the current study were primarily mediated via the p38 MAPK/NF-κB signaling pathway in addition to the FoxO1 and Nrf2 pathways. In brief, our findings suggest that mitochondria-targeted TPP-HT prevents lipotoxicity induced endothelial dysfunction by enhancing mitochondrial function and redox balance by promoting FoxO1 and Nrf2 nuclear translocation. Full article

(This article belongs to the Special Issue From Nature to Synthetic Small Molecule Antioxidants: New Candidates in Drug Discovery)

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18 pages, 2261 KiB

Open AccessArticle

Antiamnesic Effects of Feralolide Isolated from Aloe vera Resin Miller against Learning Impairments Induced in Mice

by Imran Khan, Tapan Kumar Mohanta, Nuzhat Ihsan, Sobia Ahsan Halim, Ajmal Khan, Najeeb Ur Rehman, Faizullah Khan, Asaad Khalid, Ashraf N. Abdalla, Nasiara Karim and Ahmed Al-Harrasi

Antioxidants 2023, 12(1), 161; https://doi.org/10.3390/antiox12010161 - 10 Jan 2023

Cited by 6 | Viewed by 2358

Abstract

Feralolide, a dihydroisocoumarin, was isolated from the methanolic extract of resin of Aloe vera. The present study aims to investigate the in vivo ability of feralolide to ameliorate memory impairment induced by scopolamine using a battery of in vitro assays, such as antioxidant [...] Read more.

Feralolide, a dihydroisocoumarin, was isolated from the methanolic extract of resin of Aloe vera. The present study aims to investigate the in vivo ability of feralolide to ameliorate memory impairment induced by scopolamine using a battery of in vitro assays, such as antioxidant and acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition, and in vivo animal models, including elevated plus maze, Morris water maze, passive avoidance, and novel object recognition tests. Feralolide caused a concentration-dependent inhibition of AChE and BuChE enzymes with IC₅₀ values of 55 and 52 μg/mL, respectively, and antioxidant activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2, 2′-azinobis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) with IC₅₀ values 170 and 220 μg/mL, respectively. Feralolide reversed the scopolamine-induced amnesia as indicated by a dose-dependent decrease in escape latency, path length, and passing frequency in the Morris water maze test compared with the relevant control. The compound also significantly increased the discrimination index in a dose-dependent manner in NORT and decreased transfer latency in EPM, reflective of its memory-enhancing effect. Furthermore, feralolide also caused significant dose-dependent elevation in the step-down latency (SDL) in the passive avoidance test. The results indicated that feralolide might be a helpful memory restorative mediator in treating cognitive disorders such as Alzheimer’s disease. Full article

(This article belongs to the Special Issue From Nature to Synthetic Small Molecule Antioxidants: New Candidates in Drug Discovery)

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38 pages, 4308 KiB

Open AccessArticle

Seleno-Analogs of Scaffolds Resembling Natural Products a Novel Warhead toward Dual Compounds

by Nora Astrain-Redin, Irene Talavera, Esther Moreno, María J. Ramírez, Nuria Martínez-Sáez, Ignacio Encío, Arun K. Sharma, Carmen Sanmartín and Daniel Plano

Antioxidants 2023, 12(1), 139; https://doi.org/10.3390/antiox12010139 - 6 Jan 2023

Cited by 9 | Viewed by 2760

Abstract

Nowadays, oxidative cell damage is one of the common features of cancer and Alzheimer’s disease (AD), and Se-containing molecules, such as ebselen, which has demonstrated strong antioxidant activity, have demonstrated well-established preventive effects against both diseases. In this study, a total of 39 [...] Read more.

Nowadays, oxidative cell damage is one of the common features of cancer and Alzheimer’s disease (AD), and Se-containing molecules, such as ebselen, which has demonstrated strong antioxidant activity, have demonstrated well-established preventive effects against both diseases. In this study, a total of 39 Se-derivatives were synthesized, purified, and spectroscopically characterized by NMR. Antioxidant ability was tested using the DPPH assay, while antiproliferative activity was screened in breast, lung, prostate, and colorectal cancer cell lines. In addition, as a first approach to evaluate their potential anti-Alzheimer activity, the in vitro acetylcholinesterase inhibition (AChEI) was tested. Regarding antioxidant properties, compound 13a showed concentration- and time-dependent radical scavenging activity. Additionally, compounds 14a and 17a showed high activity in the melanoma and ovarian cancer cell lines, with LD₅₀ values below 9.2 µM. Interestingly, in the AChEI test, compound 14a showed almost identical inhibitory activity to galantamine along with a 3-fold higher in vitro BBB permeation (Pe = 36.92 × 10⁻⁶ cm/s). Molecular dynamics simulations of the aspirin derivatives (14a and 14b) confirm the importance of the allylic group instead of the propargyl one. Altogether, it is concluded that some of these newly synthesized Se-derivatives, such as 14a, might become very promising candidates to treat both cancer and AD. Full article

(This article belongs to the Special Issue From Nature to Synthetic Small Molecule Antioxidants: New Candidates in Drug Discovery)

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13 pages, 2154 KiB

Open AccessArticle

YPL-001 Shows Various Beneficial Effects against Cigarette Smoke Extract-Induced Emphysema Formation: Anti-Inflammatory, Anti-Oxidative, and Anti-Apoptotic Effects

by Kyoung-Hee Lee, Jisu Woo, Jiyeon Kim, Chang-Hoon Lee and Chul-Gyu Yoo

Antioxidants 2023, 12(1), 15; https://doi.org/10.3390/antiox12010015 - 22 Dec 2022

Cited by 4 | Viewed by 2005

Abstract

Inflammation, oxidative stress, and apoptosis are thought to be important causes of chronic obstructive pulmonary disease (COPD). We investigated the effect of YPL-001 (under phase 2a study, ClinicalTrials.gov identifier NCT02272634), a drug derived from Pseudolysimachion rotundum var. subintegrum, on cigarette smoke extract [...] Read more.

Inflammation, oxidative stress, and apoptosis are thought to be important causes of chronic obstructive pulmonary disease (COPD). We investigated the effect of YPL-001 (under phase 2a study, ClinicalTrials.gov identifier NCT02272634), a drug derived from Pseudolysimachion rotundum var. subintegrum, on cigarette smoke extract (CSE)-induced inflammation, the anti-oxidative pathway, and apoptosis in human lung epithelial cells and on CSE-induced emphysema in mice. YPL-001 suppressed CSE-induced expression of IL8 mRNA and protein. This was due to the reduction in NF-κB transcriptional activity by YPL-001, which resulted from the blockade of acetylation of the NF-κB subunit p65 (Lys310). Histone deacetylases (HDACs) prevent gene transcription by condensing the DNA structure and affecting NF-κB nuclear binding. YPL-001 alone increased HDAC2 activity and enhanced CSE-induced activation of HDAC2. YPL-001-induced suppression of NF-κB transcriptional activity might be caused by increased HDAC2 activity. YPL-001 increased nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression via both degradation of its inhibitory protein, Kelch-like ECH-associated protein 1, and an increase in de novo protein synthesis. YPL-001 increased the DNA binding activity of Nrf2. Consequently, YPL-001 upregulated the expression of Nrf2-targeted anti-oxidant genes such as NAD(P)H quinone dehydrogenase 1 and heme oxygenase 1. Moreover, YPL-001 significantly suppressed CSE-induced apoptotic cell death. In vivo study showed that CSE-induced emphysematous changes, neutrophilic inflammation, protein leakage into bronchoalveolar space, and lung cell apoptosis in mice were suppressed by YPL-001 treatment. Taken together, these results suggest that YPL-001 is a good therapeutic candidate for the treatment of COPD by blocking inflammation and apoptosis and activating the anti-oxidative pathway. Full article

(This article belongs to the Special Issue From Nature to Synthetic Small Molecule Antioxidants: New Candidates in Drug Discovery)

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22 pages, 5291 KiB

Open AccessArticle

Effects of Synthetic Short Cationic Antimicrobial Peptides on the Catalytic Activity of Myeloperoxidase, Reducing Its Oxidative Capacity

by Tatyana V. Vakhrusheva, Alexey V. Sokolov, Grigoriy D. Moroz, Valeria A. Kostevich, Nikolay P. Gorbunov, Igor P. Smirnov, Ekaterina N. Grafskaia, Ivan A. Latsis, Oleg M. Panasenko and Vassili N. Lazarev

Antioxidants 2022, 11(12), 2419; https://doi.org/10.3390/antiox11122419 - 7 Dec 2022

Cited by 3 | Viewed by 2241

Abstract

Cationic antimicrobial peptides (CAMPs) have gained attention as promising antimicrobial therapeutics causing lower or no bacterial resistance. Considerable achievements have been made in designing new CAMPs that are highly active as antimicrobials. However, there is a lack of research on their interaction with [...] Read more.

Cationic antimicrobial peptides (CAMPs) have gained attention as promising antimicrobial therapeutics causing lower or no bacterial resistance. Considerable achievements have been made in designing new CAMPs that are highly active as antimicrobials. However, there is a lack of research on their interaction with biologically important proteins. This study focused on CAMPs’ effects on myeloperoxidase (MPO), an enzyme which is microbicidal and concomitantly damaging to host biomolecules and cells due to its ability to produce reactive oxygen and halogen species (ROS/RHS). Four CAMPs designed by us were employed. MPO catalytic activity was assessed by an absorbance spectra analysis and by measuring enzymatic activity using Amplex Red- and Celestine Blue B-based assays. The peptide Hm-AMP2 accelerated MPO turnover. Pept_1545 and Hm-AMP8 inhibited both the MPO chlorinating and peroxidase activities, with components of different inhibition types. Hm-AMP8 was a stronger inhibitor. Its K_i towards H₂O₂ and Cl^– was 0.3–0.4 μM vs. 11–20 μM for pept_1545. Peptide tyrosine and cysteine residues were involved in the mechanisms of the observed effects. The results propose a possible dual role of CAMPs as both antimicrobial agents and agents that downregulate MPO activation, and suggest CAMPs as prototypes for the development of antioxidant compounds to prevent MPO-mediated ROS/RHS overproduction. Full article

(This article belongs to the Special Issue From Nature to Synthetic Small Molecule Antioxidants: New Candidates in Drug Discovery)

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14 pages, 6305 KiB

Open AccessArticle

ROS-Responsive and pH-Sensitive Aminothiols Dual-Prodrug for Radiation Enteritis

by Yuanfang Chen, Yuwei Yang, Haikang Tang, Ziqi Zhang, Xiaoliang Zhou and Wenqing Xu

Antioxidants 2022, 11(11), 2145; https://doi.org/10.3390/antiox11112145 - 29 Oct 2022

Cited by 3 | Viewed by 2297

Abstract

Radiation exposure can immediately trigger a burst of reactive oxygen species (ROS), which can induce severe cell death and long-term tissue damage. Therefore, instantaneous release of sufficient radioprotective drugs is vital to neutralize those accumulated ROS in IR-exposed areas. To achieve this goal, [...] Read more.

Radiation exposure can immediately trigger a burst of reactive oxygen species (ROS), which can induce severe cell death and long-term tissue damage. Therefore, instantaneous release of sufficient radioprotective drugs is vital to neutralize those accumulated ROS in IR-exposed areas. To achieve this goal, we designed, synthesized, and evaluated a novel oral ROS-responsive radioprotective compound (M1) with high biocompatibility and efficient ROS-scavenging ability to act as a promising oral drug for radiation protection. The compound is stably present in acidic environments and is hydrolyzed in the intestine to form active molecules rich in thiols. M1 can significantly remove cellular ROS and reduce DNA damage induced by γ-ray radiation. An in vivo experiment showed that oral administration of M1 effectively alleviates acute radiation-induced intestinal injury. Immunohistochemical staining showed that M1 improved cell proliferation, reduced cell apoptosis, and enhanced the epithelial integrity of intestinal crypts. This study provides a promising oral ROS-sensitive agent for acute intestinal radiation syndrome. Full article

(This article belongs to the Special Issue From Nature to Synthetic Small Molecule Antioxidants: New Candidates in Drug Discovery)

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25 pages, 13530 KiB

Open AccessArticle

Design, Synthesis and Evaluation of Novel 1,4-Disubstituted Piperazine-2,5-dione Derivatives as Antioxidants against H₂O₂-Induced Oxidative Injury via the IL-6/Nrf2 Loop Pathway

by Liang Xiong, Hongshan Wu, Ting Zhong, Fang Luo, Qing Li, Mei Li and Yanhua Fan

Antioxidants 2022, 11(10), 2014; https://doi.org/10.3390/antiox11102014 - 12 Oct 2022

Cited by 2 | Viewed by 2022

Abstract

Excessive reactive oxygen species (ROS) production leads to oxidative stress in cells, impairing the function of mitochondria and finally inducing cell apoptosis. Considering the essential role of oxidative stress in the pathogenesis of various neurodegenerative diseases and psychiatric disorders, the discovery of novel [...] Read more.

Excessive reactive oxygen species (ROS) production leads to oxidative stress in cells, impairing the function of mitochondria and finally inducing cell apoptosis. Considering the essential role of oxidative stress in the pathogenesis of various neurodegenerative diseases and psychiatric disorders, the discovery of novel antioxidants has attracted increasing attention. Herein, a series of novel 1,4-disubstituted piperazine-2,5-dione derivatives were designed, synthesized and evaluated for their antioxidative activity. The results of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay indicated that none of the tested compounds showed significant toxicity to SH-SY5Y cells at concentrations up to 80 μM. Cell counting via flow cytometry revealed that most of the tested compounds could effectively protect SH-SY5Y cells from H₂O₂-induced oxidative damage at 20 μM. Among these compounds, compound 9r exhibited the best antioxidative activity. Further mechanistic investigation indicated that 9r decreased ROS production and stabilized the mitochondrial membrane potential to restrain cell apoptosis, and promoted cell survival via an IL-6/Nrf2 positive-feedback loop. These results suggested the potential of compound 9r as a novel antioxidative candidate for the treatment of diseases caused by oxidative stress. Full article

(This article belongs to the Special Issue From Nature to Synthetic Small Molecule Antioxidants: New Candidates in Drug Discovery)

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18 pages, 4670 KiB

Open AccessArticle

Novel Cinnamaldehyde Derivatives Inhibit Peripheral Nerve Degeneration by Targeting Schwann Cells

by Yoo Lim Chun, Ki-Hoon Park, Badvel Pallavi, Won-Joon Eom, Chan Park, Youngbuhm Huh, Yeonjoo Lee, Jimin Lee, Sang Hoon Kim, Seung Geun Yeo, Hyung-Joo Chung, Byeong-Seon Kim, Na Young Jeong and Junyang Jung

Antioxidants 2022, 11(10), 1846; https://doi.org/10.3390/antiox11101846 - 20 Sep 2022

Cited by 3 | Viewed by 2821

Abstract

Peripheral nerve degeneration (PND) is a preparative process for peripheral nerve regeneration and is regulated by Schwann cells, a unique glial cell in the peripheral nervous system. Dysregulated PND induces irreversible peripheral neurodegenerative diseases (e.g., diabetic peripheral neuropathy). To develop novel synthetic drugs [...] Read more.

Peripheral nerve degeneration (PND) is a preparative process for peripheral nerve regeneration and is regulated by Schwann cells, a unique glial cell in the peripheral nervous system. Dysregulated PND induces irreversible peripheral neurodegenerative diseases (e.g., diabetic peripheral neuropathy). To develop novel synthetic drugs for these diseases, we synthesized a set of new cinnamaldehyde (CAH) derivatives and evaluated their activities in vitro, ex vivo, and in vivo. The 12 CAH derivatives had phenyl or naphthyl groups with different substitution patterns on either side of the α,β-unsaturated ketone. Among them, 3f, which had a naphthaldehyde group, was the most potent at inhibiting PND in vitro, ex vivo, and in vivo. To assess their interactions with transient receptor potential cation channel subfamily A member 1 (TRPA1) as a target of CAH, molecular docking studies were performed. Hydrophobic interactions had the highest binding affinity. To evaluate the underlying pharmacological mechanism, we performed bioinformatics analysis of the effect of 3f on PND based on coding genes and miRNAs regulated by CAH, suggesting that 3f affects oxidative stress in Schwann cells. The results show 3f to be a potential lead compound for the development of novel synthetic drugs for the treatment of peripheral neurodegenerative diseases. Full article

(This article belongs to the Special Issue From Nature to Synthetic Small Molecule Antioxidants: New Candidates in Drug Discovery)

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15 pages, 3032 KiB

Open AccessArticle

The Application of the Neuroprotective and Potential Antioxidant Effect of Ergotamine Mediated by Targeting N-Methyl-D-Aspartate Receptors

by Shinhui Lee, Sanung Eom, Khoa V. A. Nguyen, Jiwon Lee, Youngseo Park, Hye Duck Yeom and Junho H. Lee

Antioxidants 2022, 11(8), 1471; https://doi.org/10.3390/antiox11081471 - 28 Jul 2022

Cited by 3 | Viewed by 2403

Abstract

(1) Background: The N-methyl-D-aspartate receptors (NMDARs) mediate fast excitatory currents leading to depolarization. Postsynaptic NMDARs are ionotropic glutamate receptors that mediate excitatory glutamate or glycine signaling in the CNS and play a primary role in long-term potentiation, which is a major form of [...] Read more.

(1) Background: The N-methyl-D-aspartate receptors (NMDARs) mediate fast excitatory currents leading to depolarization. Postsynaptic NMDARs are ionotropic glutamate receptors that mediate excitatory glutamate or glycine signaling in the CNS and play a primary role in long-term potentiation, which is a major form of use-dependent synaptic plasticity. The overstimulation of NMDARs mediates excessive Ca²⁺ influx to postsynaptic neurons and facilitates more production of ROS, which induces neuronal apoptosis. (2) Methods: To confirm the induced inward currents by the coapplication of glutamate and ergotamine on NMDARs, a two-electrode voltage clamp (TEVC) was conducted. The ergotamine-mediated inhibitory effects of NR1a/NR2A subunits were explored among four different kinds of recombinant NMDA subunits. In silico docking modeling was performed to confirm the main binding site of ergotamine. (3) Results: The ergotamine-mediated inhibitory effect on the NR1a/NR2A subunits has concentration-dependent, reversible, and voltage-independent properties. The major binding sites were V169 of the NR1a subunit and N466 of the NR2A subunit. (4) Conclusion: Ergotamine effectively inhibited NR1a/NR2A subunit among the subtypes of NMDAR. This inhibition effect can prevent excessive Ca²⁺ influx, which prevents neuronal death. Full article

(This article belongs to the Special Issue From Nature to Synthetic Small Molecule Antioxidants: New Candidates in Drug Discovery)

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15 pages, 1668 KiB

Open AccessArticle

Enzymatic Biosynthesis of Simple Phenolic Glycosides as Potential Anti-Melanogenic Antioxidants

by Hogwuan Jung, JaeWook Oh, Younghae Kwon, Woongshin Kang, Minsuk Seo, Yurin Seol and Je Won Park

Antioxidants 2022, 11(7), 1396; https://doi.org/10.3390/antiox11071396 - 19 Jul 2022

Cited by 2 | Viewed by 2186

Abstract

Simple phenolics (SPs) and their glycosides have recently gained much attention as functional skin-care resources for their anti-melanogenic and antioxidant activities. Enzymatic glycosylation of SP aglycone make it feasible to create SP glycosides with updated bioactive potentials. Herein, a glycosyltransferase (GT)-encoding gene was [...] Read more.

Simple phenolics (SPs) and their glycosides have recently gained much attention as functional skin-care resources for their anti-melanogenic and antioxidant activities. Enzymatic glycosylation of SP aglycone make it feasible to create SP glycosides with updated bioactive potentials. Herein, a glycosyltransferase (GT)-encoding gene was cloned from the fosmid libraries of Streptomyces tenjimariensis ATCC 31603 using GT-specific degenerate PCR followed by in silico analyses. The recombinant StSPGT was able to flexibly catalyze the transfer of two glycosyl moieties towards two SP acceptors, (hydroxyphenyl-2-propanol [HPP2] and hydroxyphenyl-3-propanol [HPP3]), generating stereospecific α-anomeric glycosides as follows: HPP2-O-α-glucoside, HPP2-O-α-2″-deoxyglucoside, HPP3-O-α-glucoside and HPP3-O-α-2″-deoxyglucoside. This enzyme seems not only to prefer UDP-glucose and HPP2 as a favorable glycosyl donor and acceptor, respectively but also differentiates the positional difference of the hydroxyl function as acceptor catalytic sites. Paired in vitro and in vivo antioxidant assays represented SPs and their corresponding glycosides as convincing antioxidants in a time- and concentration-dependent manner by scavenging DPPH radicals and intracellular ROS. Even compared to the conventional agents, HPP2 and glycoside analogs displayed improved tyrosinase inhibitory activity in vitro and still suppressed in vivo melanogenesis. Both HPP2 glycosides are further likely to exert the best inhibitory activity against elastase, eventually highlighting these glycosides with enhanced anti-melanogenic and antioxidant activities as promising anti-wrinkle hits. Full article

(This article belongs to the Special Issue From Nature to Synthetic Small Molecule Antioxidants: New Candidates in Drug Discovery)

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34 pages, 5573 KiB

Open AccessArticle

An In-Depth Study on the Metabolite Profile and Biological Properties of Primula auriculata Extracts: A Fascinating Sparkle on the Way from Nature to Functional Applications

by Inci Kurt-Celep, Dimitrina Zheleva-Dimitrova, Reneta Gevrenova, Abdullahi Ibrahim Uba, Gokhan Zengin, Evren Yıldıztugay, Carene Marie Nancy Picot-Allain, José Manuel Lorenzo, Mohamad Fawzi Mahomoodally and Domenico Montesano

Antioxidants 2022, 11(7), 1377; https://doi.org/10.3390/antiox11071377 - 15 Jul 2022

Cited by 15 | Viewed by 3086

Abstract

The biological activity of the aerial part and rhizomes of Primula auriculata were assessed for the first time. The biological activities (antioxidant properties, enzyme inhibition, and AGE inhibition) as well as the phenolic and flavonoid contents of the ethyl acetate, ethanol, hydro-ethanol and [...] Read more.

The biological activity of the aerial part and rhizomes of Primula auriculata were assessed for the first time. The biological activities (antioxidant properties, enzyme inhibition, and AGE inhibition) as well as the phenolic and flavonoid contents of the ethyl acetate, ethanol, hydro-ethanol and water extracts of P. auriculata aerial parts and rhizomes were determined. Cell viability assays and gelatin zymography were also performed for MMP-2/-9 to determine the molecular mechanisms of action. The gene expression for MMPs was described with RT-PCR. The levels of various proteins, including phospho-Nf-κB, BCL-2, BAX, p-53, and cyclin D1 as well as RAGE were measured using Western blot analysis. The hydro-ethanol extract of the aerial part possessed the highest phenolic (56.81 mg GAE/g) and flavonoid (63.92 mg RE/g) contents. In-depth profiling of the specialized metabolites by ultra-high-performance liquid chromatography—high-resolution mass spectrometry (UHPLC-HRMS) allowed for the identification and annotation of 65 compounds, including phenolic acids and glycosides, flavones, flavonols, chalcones, dihydrochalcones, and saponins. The hydro-ethanol extract of the aerial parts (132.65, 180.87, 172.46, and 108.37 mg TE/g, for the DPPH, ABTS, CUPRAC, and FRAP assays, respectively) and the ethanol extract of the rhizomes (415.06, 638.30, 477.77, and 301.02 mg TE/g, for the DPPH, ABTS, CUPRAC, and FRAP assays, respectively) exhibited the highest free radical scavenging and reducing activities. The ethanol and hydro-ethanol extracts of both the P. auriculata aerial part and rhizomes exhibited higher inhibitory activity against acetylcholinesterase, while the hydro-ethanol extracts (1.16 mmol ACAE/g, for both the aerial part and rhizomes extracts) were more active in the inhibition of α-glucosidase. After the treatment of an HT-29 colorectal cancer cell line with the extracts, the apoptosis mechanism was initiated, the integrity of the ECM was remodeled, and cell proliferation was also taken under control. In this way, Primula extracts were shown to be potential drug sources in the treatment of colorectal cancer. They were also detected as natural MMP inhibitors. The findings presented in the present study appraise the bioactivity of P. auriculata, an understudied species. Additional assessment is required to evaluate the cytotoxicity of P. auriculata as well as its activity in ex vivo systems. Full article

(This article belongs to the Special Issue From Nature to Synthetic Small Molecule Antioxidants: New Candidates in Drug Discovery)

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Review

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14 pages, 1232 KiB

Open AccessReview

Targeting Triple-Negative Breast Cancer by the Phytopolyphenol Carnosol: ROS-Dependent Mechanisms

by Halima Alsamri, Yusra Al Dhaheri and Rabah Iratni

Antioxidants 2023, 12(7), 1349; https://doi.org/10.3390/antiox12071349 - 27 Jun 2023

Cited by 7 | Viewed by 2544

Abstract

Triple-negative breast cancer (TNBC), which lacks the expression of the three hormone receptors (i.e., estrogen receptor, progesterone receptor, and human epidermal growth factor receptor), is characterized by a high proliferative index, high invasiveness, poor prognosis, early relapse, and a tendency to be present [...] Read more.

Triple-negative breast cancer (TNBC), which lacks the expression of the three hormone receptors (i.e., estrogen receptor, progesterone receptor, and human epidermal growth factor receptor), is characterized by a high proliferative index, high invasiveness, poor prognosis, early relapse, and a tendency to be present in advanced stages. These characteristics rank TNBC among the most aggressive and lethal forms of breast cancer. The lack of the three receptors renders conventional hormonal therapy ineffective against TNBC. Moreover, there are no clinically approved therapies that specifically target TNBC, and the currently used chemotherapeutic agents, such as cisplatin, taxanes, and other platinum compounds, have a limited clinical effect and develop chemoresistance over time. Phytochemicals have shown efficacy against several types of cancer, including TNBC, by targeting several pathways involved in cancer development and progression. In this review, we focus on one phytochemical carnosol, a natural polyphenolic terpenoid with strong anti-TNBC effects and its ROS-dependent molecular mechanisms of action. We discuss how carnosol targets key pathways and proteins regulating the cell cycle, growth, epigenetic regulators, invasion, and metastasis of TNBC. This review identifies carnosol as a potential novel targeting protein degradation molecule. Full article

(This article belongs to the Special Issue From Nature to Synthetic Small Molecule Antioxidants: New Candidates in Drug Discovery)

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27 pages, 1789 KiB

Open AccessReview

Relevant Membrane Transport Proteins as Possible Gatekeepers for Effective Pharmacological Ascorbate Treatment in Cancer

by Christian Leischner, Luigi Marongiu, Alban Piotrowsky, Heike Niessner, Sascha Venturelli, Markus Burkard and Olga Renner

Antioxidants 2023, 12(4), 916; https://doi.org/10.3390/antiox12040916 - 12 Apr 2023

Cited by 1 | Viewed by 2160

Abstract

Despite the increasing number of newly diagnosed malignancies worldwide, therapeutic options for some tumor diseases are unfortunately still limited. Interestingly, preclinical but also some clinical data suggest that the administration of pharmacological ascorbate seems to respond well, especially in some aggressively growing tumor [...] Read more.

Despite the increasing number of newly diagnosed malignancies worldwide, therapeutic options for some tumor diseases are unfortunately still limited. Interestingly, preclinical but also some clinical data suggest that the administration of pharmacological ascorbate seems to respond well, especially in some aggressively growing tumor entities. The membrane transport and channel proteins are highly relevant for the use of pharmacological ascorbate in cancer therapy and are involved in the transfer of active substances such as ascorbate, hydrogen peroxide, and iron that predominantly must enter malignant cells to induce antiproliferative effects and especially ferroptosis. In this review, the relevant conveying proteins from cellular surfaces are presented as an integral part of the efficacy of pharmacological ascorbate, considering the already known genetic and functional features in tumor tissues. Accordingly, candidates for diagnostic markers and therapeutic targets are mentioned. Full article

(This article belongs to the Special Issue From Nature to Synthetic Small Molecule Antioxidants: New Candidates in Drug Discovery)

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19 pages, 2377 KiB

Open AccessReview

Molecular Hydrogen: From Molecular Effects to Stem Cells Management and Tissue Regeneration

by Mikhail Yu. Artamonov, Andrew K. Martusevich, Felix A. Pyatakovich, Inessa A. Minenko, Sergei V. Dlin and Tyler W. LeBaron

Antioxidants 2023, 12(3), 636; https://doi.org/10.3390/antiox12030636 - 3 Mar 2023

Cited by 17 | Viewed by 8539

Abstract

It is known that molecular hydrogen is a relatively stable, ubiquitous gas that is a minor component of the atmosphere. At the same time, in recent decades molecular hydrogen has been shown to have diverse biological effects. By the end of 2022, more [...] Read more.

It is known that molecular hydrogen is a relatively stable, ubiquitous gas that is a minor component of the atmosphere. At the same time, in recent decades molecular hydrogen has been shown to have diverse biological effects. By the end of 2022, more than 2000 articles have been published in the field of hydrogen medicine, many of which are original studies. Despite the existence of several review articles on the biology of molecular hydrogen, many aspects of the research direction remain unsystematic. Therefore, the purpose of this review was to systematize ideas about the nature, characteristics, and mechanisms of the influence of molecular hydrogen on various types of cells, including stem cells. The historical aspects of the discovery of the biological activity of molecular hydrogen are presented. The ways of administering molecular hydrogen into the body are described. The molecular, cellular, tissue, and systemic effects of hydrogen are also reviewed. Specifically, the effect of hydrogen on various types of cells, including stem cells, is addressed. The existing literature indicates that the molecular and cellular effects of hydrogen qualify it to be a potentially effective agent in regenerative medicine. Full article

(This article belongs to the Special Issue From Nature to Synthetic Small Molecule Antioxidants: New Candidates in Drug Discovery)

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18 pages, 876 KiB

Open AccessReview

Novel Insights into the Role of the Antioxidants in Prostate Pathology

by Vittoria Rago and Silvia Di Agostino

Antioxidants 2023, 12(2), 289; https://doi.org/10.3390/antiox12020289 - 27 Jan 2023

Cited by 7 | Viewed by 2995

Abstract

To date, it is known that antioxidants protect cells from damage caused by oxidative stress and associated with pathological conditions. Several studies have established that inflammation is a state that anticipates the neoplastic transformation of the prostate. Although many experimental and clinical data [...] Read more.

To date, it is known that antioxidants protect cells from damage caused by oxidative stress and associated with pathological conditions. Several studies have established that inflammation is a state that anticipates the neoplastic transformation of the prostate. Although many experimental and clinical data have indicated the efficacy of antioxidants in preventing this form of cancer, the discrepant results, especially from recent large-scale randomized clinical trials, make it difficult to establish a real role for antioxidants in prostate tumor. Despite these concerns, clinical efficacy and safety data show that some antioxidants still hold promise for prostate cancer chemoprevention. Although more studies are needed, in this review, we briefly describe the most common antioxidants that have shown benefits in preclinical and clinical settings, focusing our attention on synthesizing the advances made so far in prostate cancer chemoprevention using antioxidants as interesting molecules for the challenges of future therapies. Full article

(This article belongs to the Special Issue From Nature to Synthetic Small Molecule Antioxidants: New Candidates in Drug Discovery)

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18 pages, 949 KiB

Open AccessReview

Thermogenic Adipose Redox Mechanisms: Potential Targets for Metabolic Disease Therapies

by Ashley K. Putman, G. Andres Contreras and Emilio P. Mottillo

Antioxidants 2023, 12(1), 196; https://doi.org/10.3390/antiox12010196 - 14 Jan 2023

Cited by 4 | Viewed by 2809

Abstract

Metabolic diseases, such as diabetes and non-alcoholic fatty liver disease (NAFLD), have several negative health outcomes on affected humans. Dysregulated energy metabolism is a key component underlying the pathophysiology of these conditions. Adipose tissue is a fundamental regulator of energy homeostasis that utilizes [...] Read more.

Metabolic diseases, such as diabetes and non-alcoholic fatty liver disease (NAFLD), have several negative health outcomes on affected humans. Dysregulated energy metabolism is a key component underlying the pathophysiology of these conditions. Adipose tissue is a fundamental regulator of energy homeostasis that utilizes several redox reactions to carry out the metabolism. Brown and beige adipose tissues, in particular, perform highly oxidative reactions during non-shivering thermogenesis to dissipate energy as heat. The appropriate regulation of energy metabolism then requires coordinated antioxidant mechanisms to counterbalance the oxidation reactions. Indeed, non-shivering thermogenesis activation can cause striking changes in concentrations of both oxidants and antioxidants in order to adapt to various oxidative environments. Current therapeutic options for metabolic diseases either translate poorly from rodent models to humans (in part due to the challenges of creating a physiologically relevant rodent model) or tend to have numerous side effects, necessitating novel therapies. As increased brown adipose tissue activity results in enhanced energy expenditure and is associated with beneficial effects on metabolic health, such as decreased obesity, it has gathered great interest as a modulator of metabolic disease. One potential reason for the beneficial health effects may be that although non-shivering thermogenesis is enormously oxidative, it is also associated with decreased oxidant formation after its activation. However, targeting its redox mechanisms specifically to alter metabolic disease remains an underexplored area. Therefore, this review will discuss the role of adipose tissue in energy homeostasis, non-shivering thermogenesis in adults, and redox mechanisms that may serve as novel therapeutic targets of metabolic disease. Full article

(This article belongs to the Special Issue From Nature to Synthetic Small Molecule Antioxidants: New Candidates in Drug Discovery)

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15 pages, 5407 KiB

Open AccessReview

Anticancer Effect of Pomegranate Peel Polyphenols against Cervical Cancer

by Sandra Lucía Teniente, Adriana Carolina Flores-Gallegos, Sandra Cecilia Esparza-González, Lizeth Guadalupe Campos-Múzquiz, Sendar Daniel Nery-Flores and Raul Rodríguez-Herrera

Antioxidants 2023, 12(1), 127; https://doi.org/10.3390/antiox12010127 - 5 Jan 2023

Cited by 30 | Viewed by 5405

Abstract

Polyphenols are a broad group of bioactive phytochemicals with powerful antioxidant, anti-inflammatory, immunomodulatory, and antiviral activities. Numerous studies have demonstrated that polyphenol extracts obtained from natural sources can be used for the prevention and treatment of cancer. Pomegranate peel extract is an excellent [...] Read more.

Polyphenols are a broad group of bioactive phytochemicals with powerful antioxidant, anti-inflammatory, immunomodulatory, and antiviral activities. Numerous studies have demonstrated that polyphenol extracts obtained from natural sources can be used for the prevention and treatment of cancer. Pomegranate peel extract is an excellent source of polyphenols, such as punicalagin, punicalin, ellagic acid, and caffeic acid, among others. These phenolic compounds have antineoplastic activity in in vitro models of cervical cancer through the regulation of cellular redox balance, induction of apoptosis, cell cycle arrest, and modulation of different signaling pathways. The current review summarizes recent data from scientific reports that address the anticancer activity of the predominant polyphenol compounds present in PPE and their different mechanisms of action in cervical cancer models. Full article

(This article belongs to the Special Issue From Nature to Synthetic Small Molecule Antioxidants: New Candidates in Drug Discovery)

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