Antioxidants

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19 pages, 5643 KiB

Open AccessArticle

Anti-Neuroinflammatory Potential of a Nectandra angustifolia (Laurel Amarillo) Ethanolic Extract

by María Carla Crescitelli, Inmaculada Simon, Leandro Ferrini, Hugo Calvo, Ana M. Torres, Isabel Cabero, Mónica Macías Panedas, Maria B. Rauschemberger, Maria V. Aguirre, Juan Pablo Rodríguez, Marita Hernández and María Luisa Nieto

Antioxidants 2023, 12(2), 232; https://doi.org/10.3390/antiox12020232 - 19 Jan 2023

Cited by 1 | Viewed by 2814

Abstract

Microglia, the resident macrophage-like population in the CNS, plays an important role in the pathogenesis of many neurodegenerative disorders. Nectandra genus is known to produce different metabolites with anti-inflammatory, anti-oxidant and analgesic properties. Although the species Nectandra angustifolia is popularly used for the [...] Read more.

Microglia, the resident macrophage-like population in the CNS, plays an important role in the pathogenesis of many neurodegenerative disorders. Nectandra genus is known to produce different metabolites with anti-inflammatory, anti-oxidant and analgesic properties. Although the species Nectandra angustifolia is popularly used for the treatment of different types of inflammatory processes, its biological effects on neuroinflammation have not yet been addressed. In this study, we have investigated the role of a Nectandra angustifolia ethanolic extract (NaE) in lipopolysaccharide (LPS)-induced neuroinflammation in vitro and in vivo. In LPS-activated BV2 microglial cells, NaE significantly reduced the induced proinflammatory mediators TNF-α, IL-1β, IL-6, COX-2 and iNOS, as well as NO accumulation, while it promoted IL-10 secretion and YM-1 expression. Likewise, reduced CD14 expression levels were detected in microglial cells in the NaE+LPS group. NaE also attenuated LPS-induced ROS and lipid peroxidation build-up in BV2 cells. Mechanistically, NaE prevented NF-κB and MAPKs phosphorylation, as well as NLRP3 upregulation when added before LPS stimulation, although it did not affect the level of some proteins related to antioxidant defense such as Keap-1 and HO-1. Additionally, we observed that NaE modulated some activated microglia functions, decreasing cell migration, without affecting their phagocytic capabilities. In LPS-injected mice, NaE pre-treatment markedly suppressed the up-regulated TNF-α, IL-6 and IL-1β mRNA expression induced by LPS in brain. Our findings indicate that NaE is beneficial in preventing the neuroinflammatory response both in vivo and in vitro. NaE may regulate microglia homeostasis, not only restraining activation of LPS towards the M1 phenotype but promoting an M2 phenotype. Full article

(This article belongs to the Special Issue Phytochemicals as Modulators of Oxidative Stress-Dependent, Inflammatory Conditions)

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24 pages, 8390 KiB

Open AccessArticle

Flavonoid-Conjugated Gadolinium Complexes as Anti-Inflammatory Theranostic Agents

by Byeong Woo Yang, Sohyeon Yang, Soyeon Kim, Ah Rum Baek, Bokyung Sung, Yeoun-Hee Kim, Jung Tae Lee, Sang Yun Lee, Hee-Kyung Kim, Garam Choi, Ji-Ae Park, Sung-Wook Nam, Gang-Ho Lee and Yongmin Chang

Antioxidants 2022, 11(12), 2470; https://doi.org/10.3390/antiox11122470 - 15 Dec 2022

Cited by 2 | Viewed by 2319

Abstract

In this study, we designed, synthesized, and evaluated gadolinium compounds conjugated with flavonoids as potential theranostic agents for the treatment of inflammation. These novel theranostic agents combine a molecular imaging agent and one of three flavonoids (galangin, chrysin, and 7-hydroxyflavone) as anti-inflammatory drugs [...] Read more.

In this study, we designed, synthesized, and evaluated gadolinium compounds conjugated with flavonoids as potential theranostic agents for the treatment of inflammation. These novel theranostic agents combine a molecular imaging agent and one of three flavonoids (galangin, chrysin, and 7-hydroxyflavone) as anti-inflammatory drugs as a single integrated platform. Using these agents, MR imaging showed contrast enhancement (>10 in CNR) at inflamed sites in an animal inflammation model, and subsequent MR imaging used to monitor the therapeutic efficacy of these integrated agents revealed changes in inflamed regions. The anti-inflammatory effects of these agents were demonstrated both in vitro and in vivo. Furthermore, the antioxidant efficacy of the agents was evaluated by measuring their reactive oxygen species scavenging properties. For example, Gd-galangin at 30 μM showed a three-fold higher ROS scavenging of DPPH. Taken together, our findings provide convincing evidence to indicate that flavonoid-conjugated gadolinium compounds can be used as potentially efficient theranostic agents for the treatment of inflammation. Full article

(This article belongs to the Special Issue Phytochemicals as Modulators of Oxidative Stress-Dependent, Inflammatory Conditions)

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20 pages, 35743 KiB

Open AccessArticle

Hesperetin, a Promising Dietary Supplement for Preventing the Development of Calcific Aortic Valve Disease

by Hengli Zhao, Gaopeng Xian, Jingxin Zeng, Guoheng Zhong, Dongqi An, You Peng, Dongtu Hu, Yingwen Lin, Juncong Li, Shuwen Su, Yunshan Ning, Dingli Xu and Qingchun Zeng

Antioxidants 2022, 11(11), 2093; https://doi.org/10.3390/antiox11112093 - 24 Oct 2022

Cited by 9 | Viewed by 2587

Abstract

Background: No effective therapeutic agents for calcific aortic valve disease (CAVD) are available currently. Dietary supplementation has been proposed as a novel treatment modality for various diseases. As a flavanone, hesperetin is widely abundant in citrus fruits and has been proven to exert [...] Read more.

Background: No effective therapeutic agents for calcific aortic valve disease (CAVD) are available currently. Dietary supplementation has been proposed as a novel treatment modality for various diseases. As a flavanone, hesperetin is widely abundant in citrus fruits and has been proven to exert protective effects in multiple diseases. However, the role of hesperetin in CAVD remains unclear. Methods: Human aortic valve interstitial cells (VICs) were isolated from aortic valve leaflets. A mouse model of aortic valve stenosis was constructed by direct wire injury (DWI). Immunoblotting, immunofluorescence staining, and flow cytometry were used to investigate the roles of sirtuin 7 (Sirt7) and nuclear factor erythroid 2-related factor 2 (Nrf2) in hesperetin-mediated protective effects in VICs. Results: Hesperetin supplementation protected the mice from wire-injury-induced aortic valve stenosis; in vitro, hesperetin inhibited the lipopolysaccharide (LPS)-induced activation of NF-κB inflammatory cytokine secretion and osteogenic factors expression, reduced ROS production and apoptosis, and abrogated LPS-mediated injury to the mitochondrial membrane potential and the decline in the antioxidant levels in VICs. These benefits of hesperetin may have been obtained by activating Nrf2–ARE signaling, which corrected the dysfunctional mitochondria. Furthermore, we found that hesperetin could directly bind to Sirt7 and that the silencing of Sirt7 decreased the effects of hesperetin in VICs and potently abolished the ability of hesperetin to increase Nrf2 transcriptional activation. Conclusions: Our work demonstrates that hesperetin plays protective roles in the aortic valve through the Sirt7–Nrf2–ARE axis; thus, hesperetin might be a potential dietary supplement that could prevent the development of CAVD. Full article

(This article belongs to the Special Issue Phytochemicals as Modulators of Oxidative Stress-Dependent, Inflammatory Conditions)

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14 pages, 2384 KiB

Open AccessArticle

Garlic-Derived Metabolites Exert Antioxidant Activity, Modulate Gut Microbiota Composition and Limit Citrobacter rodentium Infection in Mice

by Ling Zhu, Audrey I. S. Andersen-Civil, Josue L. Castro-Meija, Dennis S. Nielsen, Alexandra Blanchard, John E. Olsen, Stig M. Thamsborg and Andrew R. Williams

Antioxidants 2022, 11(10), 2033; https://doi.org/10.3390/antiox11102033 - 15 Oct 2022

Cited by 4 | Viewed by 2326

Abstract

The garlic-derived compounds propyl propane thiosulfinate (PTS) and propyl propane thiosulfonate (PTSO) are metabolites with putative health benefits against intestinal inflammation that may be related to their antioxidant activity. However, the underlying mechanisms remain unclear, and whether PTS-PTSO can promote gut health by [...] Read more.

The garlic-derived compounds propyl propane thiosulfinate (PTS) and propyl propane thiosulfonate (PTSO) are metabolites with putative health benefits against intestinal inflammation that may be related to their antioxidant activity. However, the underlying mechanisms remain unclear, and whether PTS-PTSO can promote gut health by altering the microbiota and exert protection against enteric pathogens needs further investigation. Here, we explored the antioxidant activity of PTS-PTSO in murine macrophages in vitro, and in an in vivo model of bacterial infection with the bacterial pathogen Citrobacter rodentium. PTS-PTSO attenuated reactive oxygen species in lipopolysaccharide-stimulated macrophages in a nuclear factor erythroid factor 2-related factor 2 (Nrf2)-dependent manner, decreased nitric oxide levels both in macrophages in vitro and in the sera of mice fed PTS-PTSO, and had putatively beneficial effects on the commensal gut microbiota. Importantly, PTS-PTSO decreased faecal C. rodentium counts, concomitant with upregulation of Nrf2-related genes in colon tissue. Thus, PTS-PTSO mediates Nrf2-mediated antioxidant activity and modulates gut microbiota, which may protect the host against C. rodentium colonization. Our results provide further insight into how PTS-PTSO and related bioactive dietary compounds may reduce enteric infections. Full article

(This article belongs to the Special Issue Phytochemicals as Modulators of Oxidative Stress-Dependent, Inflammatory Conditions)

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20 pages, 5794 KiB

Open AccessArticle

Vaccinium bracteatum Thunb Extract Inhibits HSV-1 Infection by Regulating ER Stress and Apoptosis

by Buyun Kim, Eun-Bin Kwon, Hye Jin Yang, Wei Li, Youn-Hwan Hwang, Young Soo Kim, Malk Eun Pak, Younghoon Go and Jang-Gi Choi

Antioxidants 2022, 11(9), 1773; https://doi.org/10.3390/antiox11091773 - 8 Sep 2022

Cited by 3 | Viewed by 2462

Abstract

Herpes simplex Type 1 (HSV-1) is a neurotropic virus that infects the peripheral and central nervous system. Usually, after primary infection in epithelial cells, HSV-1 migrates retrograde to the peripheral nervous system (PNS), where it establishes a latent infection. HSV-1 can remain latent [...] Read more.

Herpes simplex Type 1 (HSV-1) is a neurotropic virus that infects the peripheral and central nervous system. Usually, after primary infection in epithelial cells, HSV-1 migrates retrograde to the peripheral nervous system (PNS), where it establishes a latent infection. HSV-1 can remain latent in the nervous system, and its reactivation in the brain can rarely cause acute HSV-1 encephalitis, often a life-threatening condition, or asymptomatic reactivations that could lead to neuronal damage and ultimately neurodegenerative disorders. Acyclovir and related nucleoside analogs have been used as therapeutic agents for HSV-1 infection, but resistance to the drug can arise, and the protective effect of HSV-1 on brain cells is limited. Therefore, there is an urgent need for research into safe and effective new antiviral agents that can protect brain cells from the damage that is caused by HSV-1 infection. Vaccinium bracteatum Thunb. (VBT) is widely distributed in Korea and China, and has pharmacological actions such as anti-inflammatory, antioxidant, and antidiabetic activity. Studies on the antiviral effect of VBT on HSV-1 infection have not been reported so far. Therefore, we sought to determine the HSV-1 antiviral effect and molecular mechanism of VBT at the cellular level. We confirmed that VBT repressed the VP16 and IE genes in both Vero and SK-N-SH cells. We also found that the generation of HSV-1 virions was inhibited by VBT treatment. VBT inhibited the activities of the HSV-1-induced endoplasmic reticulum (ER) stressors PERK, ATF4, and CHOP. We confirmed that VBT inhibited the activity of apoptosis factors by regulating the expression of death receptor (DR) after HSV-1 infection. As HSV-1 is closely associated with brain diseases, the study of the antiviral drug effects and mechanism of VBT is meaningful. Further studies using animal models of infection will also be performed to determine the potential of VBT as an antiviral agent. Full article

(This article belongs to the Special Issue Phytochemicals as Modulators of Oxidative Stress-Dependent, Inflammatory Conditions)

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13 pages, 2384 KiB

Open AccessArticle

Cynanoside F Controls Skin Inflammation by Suppressing Mitogen-Activated Protein Kinase Activation

by Mara Melissa Duarte Fleitas, Seon Sook Kim, Nam Kyoung Kim and Su Ryeon Seo

Antioxidants 2022, 11(9), 1740; https://doi.org/10.3390/antiox11091740 - 1 Sep 2022

Cited by 2 | Viewed by 2441

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disease accompanied by severe itching and dry skin. Currently, the incidence of AD due to excessive activation of immune cells by various environmental factors is increasing worldwide, and research on inflammatory response inhibitors with fewer [...] Read more.

Atopic dermatitis (AD) is a chronic inflammatory skin disease accompanied by severe itching and dry skin. Currently, the incidence of AD due to excessive activation of immune cells by various environmental factors is increasing worldwide, and research on inflammatory response inhibitors with fewer side effects is continuously needed. Cynanoside F (CF) is one of the pregnane-type compounds in the root of Cynanchum atratum, an oriental medicinal herb that has been shown to have antioxidant, antitumor, and anti-inflammatory effects. Although CF has been isolated as a component in Cynanchum atratum, the scientific role of CF has not yet been explored. In this study, we evaluated the effect of CF on AD and revealed the mechanism using in vitro and in vivo experimental models. CF significantly reduced lipopolysaccharide (LPS)-induced protein expression levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), and cyclooxygenase-2 (COX-2), which are important proinflammatory mediators in the RAW264.7 macrophage cell line. CF did not inhibit the nuclear factor-kappa B (NF-κB) signaling activated by LPS but significantly reduced the phosphorylation of mitogen-activated protein kinases (MAPKs), such as p38 MAPK, JNK, and ERK. CF consistently inhibited the activity of the activator protein-1 (AP-1) transcription factor, a downstream molecule of MAPK signaling. In addition, in an experiment using an oxazolone-induced AD mouse model, the CF-treated group showed a marked decrease in epidermal thickness, the number of infiltrated mast cells, and the amount of histamine. The mRNA levels of IL-1β, interleukin-4 (IL-4), and thymic stromal lymphopoietin (TSLP) were consistently lowered in the group treated with CF. Moreover, the phosphorylation of c-Jun and c-Fos protein levels, which are the AP-1 components, were lowered in the skin tissues of CF-treated mice. These results provide the first evidence that CF has an inhibitory effect on AD and suggest the possibility of CF being developed as a potential therapeutic agent for AD. Full article

(This article belongs to the Special Issue Phytochemicals as Modulators of Oxidative Stress-Dependent, Inflammatory Conditions)

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12 pages, 1350 KiB

Open AccessArticle

One-Year Changes in Urinary Microbial Phenolic Metabolites and the Risk of Type 2 Diabetes—A Case-Control Study

by María Marhuenda-Muñoz, Inés Domínguez-López, Emily P. Laveriano-Santos, Isabella Parilli-Moser, Cristina Razquin, Miguel Ruiz-Canela, Francisco Javier Basterra-Gortari, Dolores Corella, Jordi Salas-Salvadó, Montserrat Fitó, José Lapetra, Fernando Arós, Miquel Fiol, Lluis Serra-Majem, Xavier Pintó, Enrique Gómez-Gracia, Emilio Ros, Ramon Estruch and Rosa M. Lamuela-Raventós

Antioxidants 2022, 11(8), 1540; https://doi.org/10.3390/antiox11081540 - 8 Aug 2022

Cited by 2 | Viewed by 2444

Abstract

The intake of polyphenols has been associated with a risk reduction of type 2 diabetes. Nevertheless, to the best of our knowledge, the molecules that might be metabolically active after ingestion are only starting to be investigated regarding this metabolic disease. To investigate [...] Read more.

The intake of polyphenols has been associated with a risk reduction of type 2 diabetes. Nevertheless, to the best of our knowledge, the molecules that might be metabolically active after ingestion are only starting to be investigated regarding this metabolic disease. To investigate the association between one-year changes in urinary microbial phenolic metabolites (MPM) and the incidence of type 2 diabetes, we performed a case-control study using data and samples of the PREDIMED trial including 46 incident type 2 diabetes cases of 172 randomly selected participants. Eight urinary MPMs were quantified in urine by liquid chromatography coupled to mass spectrometry and used to assess their associations with type 2 diabetes risk by multivariable logistic regression models. Compared to participants in the lowest tertile of one-year changes in hydroxybenzoic acid glucuronide, those in the highest tertile had a significantly lowered probability of developing type 2 diabetes (OR [95% CI], 0.39 [0.23–0.64]; p < 0.001 for trend). However, when additionally adjusting for fasting plasma glucose, the statistical significance was lost. Changes in the dietary pattern can increase the concentrations of this compound, derived from many (poly)phenol-rich foods, and might be changing the gut microbial population as well, promoting the production of the metabolite. Full article

(This article belongs to the Special Issue Phytochemicals as Modulators of Oxidative Stress-Dependent, Inflammatory Conditions)

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13 pages, 3300 KiB

Open AccessArticle

Beneficial Effects of Standardized Extracts from Wastes of Red Oranges and Olive Leaves

by Ilaria Burò, Valeria Consoli, Angela Castellano, Luca Vanella and Valeria Sorrenti

Antioxidants 2022, 11(8), 1496; https://doi.org/10.3390/antiox11081496 - 30 Jul 2022

Cited by 7 | Viewed by 1957

Abstract

The awareness of the large amount of waste produced along the food chain, starting in the agricultural sector and continuing across industrial transformation to the domestic context, has in recent years also aroused strong concern amongst the public, who are ing about the [...] Read more.

The awareness of the large amount of waste produced along the food chain, starting in the agricultural sector and continuing across industrial transformation to the domestic context, has in recent years also aroused strong concern amongst the public, who are ing about the possible consequences that this could have on environmental sustainability, resource waste and human health. The aim of the present research is the recovery of substances with high added value from waste and by-products typical of the Mediterranean area, such as the residue from the industrial processing of red oranges, called pastazzo (peels, pulps and seeds), which is particularly rich in anthocyanins, flavanones and hydroxycinnamic acids, and has numerous nutraceutical properties, as well as the olive leaves coming from olive-tree pruning, which are rich in substances such as oleuropein, elenolic acid, hydroxytyrosol, tyrosol and rutin. The effect of Red Orange Extract (ROE) and Olive Leaf Extract (OLE) on HepG2 fatty storage capacity was assessed performing Oil Red O’ staining, and antioxidant properties of the extracts were evaluated following the steatosis model onset. Based on the results obtained, the preparation of natural extracts that are derived from these waste products can be useful for preventing, counteracting or delaying the onset of the complications of fatty liver disease, such as hepatic steatosis. Full article

(This article belongs to the Special Issue Phytochemicals as Modulators of Oxidative Stress-Dependent, Inflammatory Conditions)

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11 pages, 2893 KiB

Open AccessArticle

7-O-Methylluteolin Suppresses the 2,4-Dinitrochlorobenzene-Induced Nrf2/HO-1 Pathway and Atopic Dermatitis-like Lesions

by Tae-Young Kim, No-June Park, Beom-Geun Jo, Jin-Hyub Paik, Sangho Choi, Su-Nam Kim and Min Hye Yang

Antioxidants 2022, 11(7), 1344; https://doi.org/10.3390/antiox11071344 - 8 Jul 2022

Cited by 5 | Viewed by 2499

Abstract

7-O-methylluteolin (7-ML) is a flavonoid isolated from the aerial parts of Wikstroemia ganpi (W. ganpi). We describe the anti–atopic dermatitis (AD) effects of 7-ML in tert-butyl hydroperoxide (tBHP)-induced HepG2 cells and 2,4-dinitrochlorobenzene (DNCB)-induced SKH-1 hairless mice. Results demonstrated that [...] Read more.

7-O-methylluteolin (7-ML) is a flavonoid isolated from the aerial parts of Wikstroemia ganpi (W. ganpi). We describe the anti–atopic dermatitis (AD) effects of 7-ML in tert-butyl hydroperoxide (tBHP)-induced HepG2 cells and 2,4-dinitrochlorobenzene (DNCB)-induced SKH-1 hairless mice. Results demonstrated that 7-ML dose-dependently inhibited the activation of Nrf2 (nuclear factor-erythroid 2-related factor 2) in tBHP-induced HepG2 cells. 7-ML applied topically to our DNCB-induced mouse model upregulated the antioxidant protein expression (phosphorylated Nrf2 (pNrf2), Nrf2, and heme oxygenase-1 (HO-1)) in skin tissues, improved epidermal thickness, and reduced mast cell infiltration into the skin. In addition, 7-ML reduced the serum levels of immunoglobulin E (IgE) and interleukin-4 (IL-4) and improved skin barrier functions. These results suggest that 7-ML should be considered a novel antioxidant and anti-AD agent. Full article

(This article belongs to the Special Issue Phytochemicals as Modulators of Oxidative Stress-Dependent, Inflammatory Conditions)

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12 pages, 1509 KiB

Open AccessArticle

The Impact of Quercetin and Its Methylated Derivatives 3-o-Methylquercetin and Rhamnazin in Lipopolysaccharide-Induced Inflammation in Porcine Intestinal Cells

by Zita Karancsi, Dóra Kovács, Nikolett Palkovicsné Pézsa, Péter Gálfi, Ákos Jerzsele and Orsolya Farkas

Antioxidants 2022, 11(7), 1265; https://doi.org/10.3390/antiox11071265 - 27 Jun 2022

Cited by 10 | Viewed by 2455

Abstract

Oxidative stress in the small intestine can lead to inflammation and barrier malfunction. The present study describes the effect of quercetin (Q), 3-o-methylquercetin (QM), and rhamnazin (R) on cell viability, paracellular permeability, production of intracellular reactive oxygen species (ROS), extracellular hydrogen peroxide (H [...] Read more.

Oxidative stress in the small intestine can lead to inflammation and barrier malfunction. The present study describes the effect of quercetin (Q), 3-o-methylquercetin (QM), and rhamnazin (R) on cell viability, paracellular permeability, production of intracellular reactive oxygen species (ROS), extracellular hydrogen peroxide (H₂O₂), and interleukin-6 (IL-6) after challenging jejunal cells (IPEC-J2) with different types (Salmonella enterica ser. Typhimurium, Escherichia coli O111:B4, and E. coli O127:B8) of lipopolysaccharides (LPS) applied in 10 µg/mL concentration. The intracellular ROS level increased after all LPS treatments, which could be decreased by all tested flavonoid compounds in 50 µM concentration. Extracellular H₂O₂ production significantly increased after Q and R treatment (50 µM). S. Typhimurium LPS could significantly increase IL-6 production of enterocytes, which could be alleviated by Q, QM, and R (50 µM) as well. Using fluorescein isothiocyanate dextran (FD4) tracer dye, we could demonstrate that S. Typhimurium LPS significantly increased the permeability of the cell layer. The simultaneous treatments of S. Typhimurium LPS and the flavonoid compounds showed no alteration in FD4 penetration compared to untreated cells. These results highlight that Q, QM, and R are promising substances that can be used to protect intestinal epithelial cells from the deteriorating effects of oxidative stress. Full article

(This article belongs to the Special Issue Phytochemicals as Modulators of Oxidative Stress-Dependent, Inflammatory Conditions)

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18 pages, 5087 KiB

Open AccessArticle

Indicaxanthin from Opuntia ficus-indica Fruit Ameliorates Glucose Dysmetabolism and Counteracts Insulin Resistance in High-Fat-Diet-Fed Mice

by Simona Terzo, Alessandro Attanzio, Pasquale Calvi, Flavia Mulè, Luisa Tesoriere, Mario Allegra and Antonella Amato

Antioxidants 2022, 11(1), 80; https://doi.org/10.3390/antiox11010080 - 29 Dec 2021

Cited by 17 | Viewed by 2798

Abstract

Obesity-related dysmetabolic conditions are amongst the most common causes of death globally. Indicaxanthin, a bioavailable betalain pigment from Opuntia ficus-indica fruit, has been demonstrated to modulate redox-dependent signalling pathways, exerting significant anti-oxidative and anti-inflammatory effects in vitro and in vivo. In light of [...] Read more.

Obesity-related dysmetabolic conditions are amongst the most common causes of death globally. Indicaxanthin, a bioavailable betalain pigment from Opuntia ficus-indica fruit, has been demonstrated to modulate redox-dependent signalling pathways, exerting significant anti-oxidative and anti-inflammatory effects in vitro and in vivo. In light of the strict interconnections between inflammation, oxidative stress and insulin resistance (IR), a nutritionally relevant dose of indicaxanthin has been evaluated in a high-fat diet (HFD) model of obesity-related IR. To this end, biochemical and histological analysis, oxidative stress and inflammation evaluations in liver and adipose tissue were carried out. Our results showed that indicaxanthin treatment significantly reduced body weight, daily food intake and visceral fat mass. Moreover, indicaxanthin administration induced remarkable, beneficial effects on HFD-induced glucose dysmetabolism, reducing fasting glycaemia and insulinaemia, improving glucose and insulin tolerance and restoring the HOMA index to physiological values. These effects were associated with a reduction in hepatic and adipose tissue oxidative stress and inflammation. A decrease in RONS, malondialdehyde and NO levels, in TNF-α, CCL-2 and F4-80 gene expression, in p65, p-JNK, COX-2 and i-NOS protein levels, in crown-like structures and hepatic inflammatory foci was, indeed, observed. The current findings encourage further clinical studies to confirm the effectiveness of indicaxanthin to prevent and treat obesity-related dysmetabolic conditions. Full article

(This article belongs to the Special Issue Phytochemicals as Modulators of Oxidative Stress-Dependent, Inflammatory Conditions)

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19 pages, 6855 KiB

Open AccessArticle

Fisetin Inhibits NLRP3 Inflammasome by Suppressing TLR4/MD2-Mediated Mitochondrial ROS Production

by Ilandarage Menu Neelaka Molagoda, Athapaththu Mudiyanselage Gihan Kavinda Athapaththu, Yung Hyun Choi, Cheol Park, Cheng-Yung Jin, Chang-Hee Kang, Mi-Hwa Lee and Gi-Young Kim

Antioxidants 2021, 10(8), 1215; https://doi.org/10.3390/antiox10081215 - 28 Jul 2021

Cited by 22 | Viewed by 4042

Abstract

Fisetin has numerous therapeutic properties, such as anti-inflammatory, antioxidative, and anticancer effects. However, the mechanism by which fisetin inhibits NLRP3 inflammasome remains unclear. In this study, we observed that fisetin bound to TLR4 and occluded the hydrophobic pocket of MD2, which in turn [...] Read more.

Fisetin has numerous therapeutic properties, such as anti-inflammatory, antioxidative, and anticancer effects. However, the mechanism by which fisetin inhibits NLRP3 inflammasome remains unclear. In this study, we observed that fisetin bound to TLR4 and occluded the hydrophobic pocket of MD2, which in turn inhibited the binding of LPS to the TLR4/MD2 complex. This prevented the initiation of scaffold formation by the inhibition of MyD88/IRAK4 and subsequently downregulated the NF-κB signaling pathway. The result also demonstrated that fisetin downregulated the activation of the NLRP3 inflammasome induced by LPS and ATP (LPS/ATP) and the subsequent maturation of IL-1β. Fisetin also activated mitophagy and prevented the accumulation of damaged mitochondria and the excessive production of mitochondrial reactive oxygen species. The transient knockdown of p62 reversed the inhibitory activity of fisetin on the LPS/ATP-induced formation of the NLRP3 inflammasome. This indicated that fisetin induces p62-mediated mitophagy for eliminating damaged mitochondria. Recently, the existence of inflammasomes in non-mammalian species including zebrafish have been identified. Treatment of an LPS/ATP-stimulated zebrafish model with fisetin aided the recovery of the impaired heart rate, decreased the recruitment of macrophage to the brain, and gradually downregulated the expression of inflammasome-related genes. These results indicated that fisetin inhibited the TLR4/MD2-mediated activation of NLRP3 inflammasome by eliminating damaged mitochondria in a p62-dependent manner. Full article

(This article belongs to the Special Issue Phytochemicals as Modulators of Oxidative Stress-Dependent, Inflammatory Conditions)

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Review

Jump to: Research

60 pages, 9019 KiB

Open AccessReview

Neuroprotective Potentials of Flavonoids: Experimental Studies and Mechanisms of Action

by Paolo Bellavite

Antioxidants 2023, 12(2), 280; https://doi.org/10.3390/antiox12020280 - 27 Jan 2023

Cited by 47 | Viewed by 12966

Abstract

Neurological and neurodegenerative diseases, particularly those related to aging, are on the rise, but drug therapies are rarely curative. Functional disorders and the organic degeneration of nervous tissue often have complex causes, in which phenomena of oxidative stress, inflammation and cytotoxicity are intertwined. [...] Read more.

Neurological and neurodegenerative diseases, particularly those related to aging, are on the rise, but drug therapies are rarely curative. Functional disorders and the organic degeneration of nervous tissue often have complex causes, in which phenomena of oxidative stress, inflammation and cytotoxicity are intertwined. For these reasons, the search for natural substances that can slow down or counteract these pathologies has increased rapidly over the last two decades. In this paper, studies on the neuroprotective effects of flavonoids (especially the two most widely used, hesperidin and quercetin) on animal models of depression, neurotoxicity, Alzheimer’s disease (AD) and Parkinson’s disease are reviewed. The literature on these topics amounts to a few hundred publications on in vitro and in vivo models (notably in rodents) and provides us with a very detailed picture of the action mechanisms and targets of these substances. These include the decrease in enzymes that produce reactive oxygen and ferroptosis, the inhibition of mono-amine oxidases, the stimulation of the Nrf2/ARE system, the induction of brain-derived neurotrophic factor production and, in the case of AD, the prevention of amyloid-beta aggregation. The inhibition of neuroinflammatory processes has been documented as a decrease in cytokine formation (mainly TNF-alpha and IL-1beta) by microglia and astrocytes, by modulating a number of regulatory proteins such as Nf-kB and NLRP3/inflammasome. Although clinical trials on humans are still scarce, preclinical studies allow us to consider hesperidin, quercetin, and other flavonoids as very interesting and safe dietary molecules to be further investigated as complementary treatments in order to prevent neurodegenerative diseases or to moderate their deleterious effects. Full article

(This article belongs to the Special Issue Phytochemicals as Modulators of Oxidative Stress-Dependent, Inflammatory Conditions)

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36 pages, 1335 KiB

Open AccessReview

Redox Properties, Bioactivity and Health Effects of Indicaxanthin, a Bioavailable Phytochemical from Opuntia ficus indica, L.: A Critical Review of Accumulated Evidence and Perspectives

by Alessandro Attanzio, Ignazio Restivo, Marco Tutone, Luisa Tesoriere, Mario Allegra and Maria A. Livrea

Antioxidants 2022, 11(12), 2364; https://doi.org/10.3390/antiox11122364 - 29 Nov 2022

Cited by 5 | Viewed by 2463

Abstract

Phytochemicals from plant foods are considered essential to human health. Known for their role in the adaptation of plants to their environment, these compounds can induce adaptive responses in cells, many of which are directed at maintaining the redox tone. Indicaxanthin is a [...] Read more.

Phytochemicals from plant foods are considered essential to human health. Known for their role in the adaptation of plants to their environment, these compounds can induce adaptive responses in cells, many of which are directed at maintaining the redox tone. Indicaxanthin is a long-known betalain pigment found in the genus Opuntia of cactus pear and highly concentrated in the edible fruits of O. ficus indica, L. whose bioactivity has been overlooked until recently. This review summarizes studies conducted so far in vitro and in vivo, most of which have been performed in our laboratory. The chemical and physicochemical characteristics of Indicaxanthin are reflected in the molecule’s reducing properties and antioxidant effects and help explain its ability to interact with membranes, modulate redox-regulated cellular pathways, and possibly bind to protein molecules. Measurement of bioavailability in volunteers has been key to exploring its bioactivity; amounts consistent with dietary intake, or plasma concentration after dietary consumption of cactus pear fruit, have been used in experimental setups mimicking physiological or pathophysiological conditions, in cells and in animals, finally suggesting pharmacological potential and relevance of Indicaxanthin as a nutraceutical. In reporting experimental results, this review also aimed to raise questions and seek insights for further basic research and health promotion applications. Full article

(This article belongs to the Special Issue Phytochemicals as Modulators of Oxidative Stress-Dependent, Inflammatory Conditions)

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21 pages, 1387 KiB

Open AccessReview

Celastrol: A Promising Agent Fighting against Cardiovascular Diseases

by Zhexi Li, Jingyi Zhang, Xulei Duan, Guoan Zhao and Min Zhang

Antioxidants 2022, 11(8), 1597; https://doi.org/10.3390/antiox11081597 - 18 Aug 2022

Cited by 22 | Viewed by 4960

Abstract

Cardiovascular diseases (CVD) are leading causes of morbidity and mortality worldwide; therefore, seeking effective therapeutics to reduce the global burden of CVD has become increasingly urgent. Celastrol, a bioactive compound isolated from the roots of the plant Tripterygium wilfordii (TW), has been attracting [...] Read more.

Cardiovascular diseases (CVD) are leading causes of morbidity and mortality worldwide; therefore, seeking effective therapeutics to reduce the global burden of CVD has become increasingly urgent. Celastrol, a bioactive compound isolated from the roots of the plant Tripterygium wilfordii (TW), has been attracting increasing research attention in recent years, as it exerts cardiovascular treatment benefits targeting both CVD and their associated risk factors. Substantial evidence has revealed a protective role of celastrol against a broad spectrum of CVD including obesity, diabetes, atherosclerosis, cerebrovascular injury, calcific aortic valve disease and heart failure through complicated and interlinked mechanisms such as direct protection against cardiomyocyte hypertrophy and death, and indirect action on oxidation and inflammation. This review will mainly summarize the beneficial effects of celastrol against CVD, largely based on in vitro and in vivo preclinical studies, and the potential underlying mechanisms. We will also briefly discuss celastrol’s pharmacokinetic limitations, which hamper its further clinical applications, and prospective future directions. Full article

(This article belongs to the Special Issue Phytochemicals as Modulators of Oxidative Stress-Dependent, Inflammatory Conditions)

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30 pages, 1231 KiB

Open AccessReview

Green Tea Polyphenol (-)-Epigallocatechin-3-Gallate (EGCG): A Time for a New Player in the Treatment of Respiratory Diseases?

by Daniela Mokra, Jana Adamcakova and Juraj Mokry

Antioxidants 2022, 11(8), 1566; https://doi.org/10.3390/antiox11081566 - 13 Aug 2022

Cited by 50 | Viewed by 7911

Abstract

(-)-Epigallocatechin-3-gallate (EGCG) is a major polyphenol of green tea that possesses a wide variety of actions. EGCG acts as a strong antioxidant which effectively scavenges reactive oxygen species (ROS), inhibits pro-oxidant enzymes including NADPH oxidase, activates antioxidant systems including superoxide dismutase, catalase, or [...] Read more.

(-)-Epigallocatechin-3-gallate (EGCG) is a major polyphenol of green tea that possesses a wide variety of actions. EGCG acts as a strong antioxidant which effectively scavenges reactive oxygen species (ROS), inhibits pro-oxidant enzymes including NADPH oxidase, activates antioxidant systems including superoxide dismutase, catalase, or glutathione, and reduces abundant production of nitric oxide metabolites by inducible nitric oxide synthase. ECGC also exerts potent anti-inflammatory, anti-fibrotic, pro-apoptotic, anti-tumorous, and metabolic effects via modulation of a variety of intracellular signaling cascades. Based on this knowledge, the use of EGCG could be of benefit in respiratory diseases with acute or chronic inflammatory, oxidative, and fibrotizing processes in their pathogenesis. This article reviews current information on the biological effects of EGCG in those respiratory diseases or animal models in which EGCG has been administered, i.e., acute respiratory distress syndrome, respiratory infections, COVID-19, bronchial asthma, chronic obstructive pulmonary disease, lung fibrosis, silicosis, lung cancer, pulmonary hypertension, and lung embolism, and critically discusses effectiveness of EGCG administration in these respiratory disorders. For this review, articles in English language from the PubMed database were used. Full article

(This article belongs to the Special Issue Phytochemicals as Modulators of Oxidative Stress-Dependent, Inflammatory Conditions)

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34 pages, 3914 KiB

Open AccessReview

Multi-Target Effects of ß-Caryophyllene and Carnosic Acid at the Crossroads of Mitochondrial Dysfunction and Neurodegeneration: From Oxidative Stress to Microglia-Mediated Neuroinflammation

by Roberto Iorio, Giuseppe Celenza and Sabrina Petricca

Antioxidants 2022, 11(6), 1199; https://doi.org/10.3390/antiox11061199 - 18 Jun 2022

Cited by 21 | Viewed by 7061

Abstract

Inflammation and oxidative stress are interlinked and interdependent processes involved in many chronic diseases, including neurodegeneration, diabetes, cardiovascular diseases, and cancer. Therefore, targeting inflammatory pathways may represent a potential therapeutic strategy. Emerging evidence indicates that many phytochemicals extracted from edible plants have the [...] Read more.

Inflammation and oxidative stress are interlinked and interdependent processes involved in many chronic diseases, including neurodegeneration, diabetes, cardiovascular diseases, and cancer. Therefore, targeting inflammatory pathways may represent a potential therapeutic strategy. Emerging evidence indicates that many phytochemicals extracted from edible plants have the potential to ameliorate the disease phenotypes. In this scenario, ß-caryophyllene (BCP), a bicyclic sesquiterpene, and carnosic acid (CA), an ortho-diphenolic diterpene, were demonstrated to exhibit anti-inflammatory, and antioxidant activities, as well as neuroprotective and mitoprotective effects in different in vitro and in vivo models. BCP essentially promotes its effects by acting as a selective agonist and allosteric modulator of cannabinoid type-2 receptor (CB2R). CA is a pro-electrophilic compound that, in response to oxidation, is converted to its electrophilic form. This can interact and activate the Keap1/Nrf2/ARE transcription pathway, triggering the synthesis of endogenous antioxidant “phase 2” enzymes. However, given the nature of its chemical structure, CA also exhibits direct antioxidant effects. BCP and CA can readily cross the BBB and accumulate in brain regions, giving rise to neuroprotective effects by preventing mitochondrial dysfunction and inhibiting activated microglia, substantially through the activation of pro-survival signalling pathways, including regulation of apoptosis and autophagy, and molecular mechanisms related to mitochondrial quality control. Findings from different in vitro/in vivo experimental models of Parkinson’s disease and Alzheimer’s disease reported the beneficial effects of both compounds, suggesting that their use in treatments may be a promising strategy in the management of neurodegenerative diseases aimed at maintaining mitochondrial homeostasis and ameliorating glia-mediated neuroinflammation. Full article

(This article belongs to the Special Issue Phytochemicals as Modulators of Oxidative Stress-Dependent, Inflammatory Conditions)

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12 pages, 2151 KiB

Open AccessReview

Cannabis sativa L. Bioactive Compounds and Their Protective Role in Oxidative Stress and Inflammation

by Dalia M. Kopustinskiene, Ruta Masteikova, Robertas Lazauskas and Jurga Bernatoniene

Antioxidants 2022, 11(4), 660; https://doi.org/10.3390/antiox11040660 - 29 Mar 2022

Cited by 51 | Viewed by 12068

Abstract

Cannabis (Cannabis sativa L.) plants from the family Cannabidaceae have been used since ancient times, to produce fibers, oil, and for medicinal purposes. Psychoactive delta-9-tetrahydrocannabinol (THC) and nonpsychoactive cannabidiol (CBD) are the main pharmacologically active compounds of Cannabis sativa. These compounds [...] Read more.

Cannabis (Cannabis sativa L.) plants from the family Cannabidaceae have been used since ancient times, to produce fibers, oil, and for medicinal purposes. Psychoactive delta-9-tetrahydrocannabinol (THC) and nonpsychoactive cannabidiol (CBD) are the main pharmacologically active compounds of Cannabis sativa. These compounds have, for a long time, been under extensive investigation, and their potent antioxidant and inflammatory properties have been reported, although the detailed mechanisms of their actions have not been fully clarified. CB1 receptors are suggested to be responsible for the analgesic effect of THC, while CB2 receptors may account for its immunomodulatory properties. Unlike THC, CBD has a very low affinity for both CB1 and CB2 receptors, and behaves as their negative allosteric modulator. CBD activity, as a CB2 receptor inverse agonist, could be important for CBD anti-inflammatory properties. In this review, we discuss the chemical properties and bioavailability of THC and CBD, their main mechanisms of action, and their role in oxidative stress and inflammation. Full article

(This article belongs to the Special Issue Phytochemicals as Modulators of Oxidative Stress-Dependent, Inflammatory Conditions)

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