Antioxidants

26 pages, 2729 KiB

Open AccessReview

Seaweed-Derived Proteins and Peptides: Promising Marine Bioactives

by Javier Echave, Paz Otero, Paula Garcia-Oliveira, Paulo E. S. Munekata, Mirian Pateiro, Jose M. Lorenzo, Jesus Simal-Gandara and Miguel A. Prieto

Antioxidants 2022, 11(1), 176; https://doi.org/10.3390/antiox11010176 - 17 Jan 2022

Cited by 69 | Viewed by 8229

Abstract

Seaweeds are a typical food of East-Asian cuisine, to which are alleged several beneficial health effects have been attributed. Their availability and their nutritional and chemical composition have favored the increase in its consumption worldwide, as well as a focus of research due [...] Read more.

Seaweeds are a typical food of East-Asian cuisine, to which are alleged several beneficial health effects have been attributed. Their availability and their nutritional and chemical composition have favored the increase in its consumption worldwide, as well as a focus of research due to their bioactive properties. In this regard, seaweed proteins are nutritionally valuable and comprise several specific enzymes, glycoproteins, cell wall-attached proteins, red algae phycobiliproteins, lectins, peptides, or mycosporine-like amino acids. This great extent of molecules has been reported to exert significant antioxidant, antimicrobial, anti-inflammatory, antihypertensive, antidiabetic, or antitumoral properties. Hence, knowledge on algae proteins and derived compounds have gained special interest for the potential nutraceutical, cosmetic or pharmaceutical industries based on these bioactivities. Although several molecular mechanisms of action on how these proteins and peptides exert biological activities have been described, many gaps in knowledge still need to be filled. Updating the current knowledge related to seaweed proteins and peptides is of interest to further asses their potential health benefits. This review addresses the characteristics of seaweed protein and protein-derived molecules, their natural occurrence, their studied bioactive properties, and their described potential mechanisms of action. Full article

(This article belongs to the Special Issue From the Green Extraction of Food Waste and By-Products to the Structure-Activity Relationships of Natural Antioxidants)

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Chemical structure of the chromophore group of R-phycoerythrin, some relevant mycosporine-like amino acids, and bioactive peptides isolated from seaweed protein hydrolysates. Peptide sequences and source are presented in Table 3. Full article ">Figure 2
Schematic representation of seaweed protein hydrolysis into peptides. The hydrolyzation process usually involves the action of proteases and the adjustment of reaction parameters. Among the peptides produced by protein hydrolyzation, some display bioactive properties. Full article ">Figure 3
Summary of reported mechanisms of action of several SPs and BAPs. Their location with respect to the bilayer membrane represents that these effects are inducted inside, outside the cell, or on the cell surface. Abbreviations: PBPs: phycobiliproteins; MAAs: mycosporine-like amino acids; BAPs: bioactive peptides; ROS: reactive oxygen species; IL-1β: interleukin-1β; TNF-α: tumor necrosis factor- α; COX-2: cyclooxygenase-2; iNOS: inducible nitric oxide synthase; NF-κB: nuclear factor- κB; DPP-IV: dipeptidyl peptidase-IV; GLP-1: glucagon-like peptide-1; ACE: angiotensin I-converter enzyme. Full article ">Figure 4
Potential applications of seaweed proteins, bioactive peptides, and Mycosporine-like amino acids considering their described bioactivities. Several properties of these molecules may be applied to diverse fields and industries in different formulations. Full article ">

22 pages, 4115 KiB

Open AccessArticle

Acremonium terricola Culture’s Dose–Response Effects on Lactational Performance, Antioxidant Capacity, and Ruminal Characteristics in Holstein Dairy Cows

by Fanlin Kong, Yijia Zhang, Shuo Wang, Zan Cao, Yanfang Liu, Zixiao Zhang, Wei Wang, Na Lu and Shengli Li

Antioxidants 2022, 11(1), 175; https://doi.org/10.3390/antiox11010175 - 17 Jan 2022

Cited by 16 | Viewed by 4327

Abstract

Acremonium terricola culture (ATC) has similar bioactive constituents to Cordyceps and is known for its nutrient and pharmacological value, indicating the potential of ATC as a new feed additive in dairy cow feeding. The primary aim of this experiment was to investigate the [...] Read more.

Acremonium terricola culture (ATC) has similar bioactive constituents to Cordyceps and is known for its nutrient and pharmacological value, indicating the potential of ATC as a new feed additive in dairy cow feeding. The primary aim of this experiment was to investigate the effects of increasing amounts of ATC in diets on milk performance, antioxidant capacity, and rumen fermentation, and the secondary aim was to evaluate the potential effects of high doses of ATC. A total of 60 multiparous Holstein cows (110 ± 21 days in milk; 2.53 ± 0.82 parity) were assigned into 15 blocks and randomly assigned to one of four groups: 0, 30, 60, or 300 g/d of ATC per cow for 97 days. Data were analyzed using repeated measures in the Mixed procedure. Dry-matter intake was not changed (p > 0.05), while energy-corrected milk and fat-corrected milk yields increased linearly and quadratically, and somatic cell count in milk decreased linearly and quadratically (p < 0.05). The lactation efficiency and the yields of milk fat and protein increased linearly (p < 0.05). On day 90, serum catalase level, total oxidative capacity, glutathione peroxidase, immunoglobulin A, and immunoglobulin M concentrations were significantly higher in the 60 and 300 g/d groups than in the 0 g/d group (p < 0.05). ATC addition showed linear effects on total volatile fatty acid (VFA), acetate, branched VFA concentrations, and rumen pH (p < 0.05). Supplementing 60 and 300 g/d ATC significantly affected the bacterial composition (p < 0.05). The relative abundance of Christensenellaceae_R–7_group and Lachnospiraceae_NK3A20_group were significantly increased by 60 g/d supplementation, and the relative abundance of Erysipelotrichaceae_UCG_002, Acetitomaculum, Olsenella, and Syntrophococcus were significantly increased by 300 g/d supplementation (p < 0.05). ATC was effective in enhancing rumen fermentation and reducing somatic cell count in milk, thereby improving milk yield. The optimized dose of ATC was 60 g/d for lactating cows, and there were no risks associated with high doses of ATC. Full article

(This article belongs to the Special Issue Antioxidants in Animal Feed)

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16 pages, 35887 KiB

Open AccessArticle

Near-Infrared Light-Triggered Generation of Reactive Oxygen Species and Induction of Local Hyperthermia from Indocyanine Green Encapsulated Mesoporous Silica-Coated Graphene Oxide for Colorectal Cancer Therapy

by Hyung Woo Choi, Jae Hyun Lim, Chan Woo Kim, Eunmi Lee, Jin-Moo Kim, Kiyuk Chang and Bong Geun Chung

Antioxidants 2022, 11(1), 174; https://doi.org/10.3390/antiox11010174 - 17 Jan 2022

Cited by 16 | Viewed by 3506

Abstract

Near-infrared (NIR) light-mediated photothermal therapy (PTT) and photodynamic therapy (PDT) have widely been used for cancer treatment applications. However, a number of limitations (e.g., low NIR absorption capacity of photothermal agents, insufficient loading efficiency of photosensitive molecules) have hindered the widespread use of [...] Read more.

Near-infrared (NIR) light-mediated photothermal therapy (PTT) and photodynamic therapy (PDT) have widely been used for cancer treatment applications. However, a number of limitations (e.g., low NIR absorption capacity of photothermal agents, insufficient loading efficiency of photosensitive molecules) have hindered the widespread use of NIR-mediated cancer therapy. Therefore, we developed a mesoporous silica-coated reduced graphene oxide (rGO) nanocomposite that could provide a high encapsulation rate of indocyanine green (ICG) and enhance PTT/PDT efficiency in vitro and in vivo. The ICG-encapsulated nanocomposite not only enhances the photothermal effect but also generates a large number of tumor toxic reactive oxygen species (ROS). By conjugation of polyethylene glycol (PEG) with folic acid (FA) as a tumor targeting moiety, we confirmed that ICG-encapsulated mesoporous silica (MS)-coated rGO nanocomposite (ICG@MS-rGO-FA) exhibited high colloidal stability and intracellular uptake in folate receptor-expressing CT-26 colorectal cancer cells. Upon NIR laser irradiation, this ICG@MS-rGO-FA nanocomposite induced the apoptosis of only CT-26 cells via enhanced PTT and PDT effects without any damage to normal cells. Furthermore, the ICG@MS-rGO-FA nanocomposite revealed satisfactory tumor targeting and biocompatibility in CT-26 tumor-bearing mice, thereby enhancing the therapeutic effects of PTT and PDT in vivo. Therefore, this tumor-targeted ICG@MS-rGO-FA nanocomposite shows a great potential for phototherapy applications. Full article

(This article belongs to the Section ROS, RNS and RSS)

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15 pages, 1970 KiB

Open AccessArticle

Combined Treatment with Herbal Medicine and Drug Ameliorates Inflammation and Metabolic Abnormalities in the Liver of an Amyotrophic Lateral Sclerosis Mouse Model

by Hee Ra Park and Eun Jin Yang

Antioxidants 2022, 11(1), 173; https://doi.org/10.3390/antiox11010173 - 17 Jan 2022

Cited by 7 | Viewed by 2900

Abstract

To date, no effective drugs exist for amyotrophic lateral sclerosis (ALS), although riluzole (RZ) and edaravone have been approved for treatment. We previously reported that Bojungikgi-tang (BJIGT) improved motor activity through anti-inflammatory effects in the muscle and spinal cord of hSOD1^G93A mice. [...] Read more.

To date, no effective drugs exist for amyotrophic lateral sclerosis (ALS), although riluzole (RZ) and edaravone have been approved for treatment. We previously reported that Bojungikgi-tang (BJIGT) improved motor activity through anti-inflammatory effects in the muscle and spinal cord of hSOD1^G93A mice. Therefore, whether combined treatment with BJIGT and RZ synergistically affects liver function in hSOD1^G93A mice was investigated. Two-month-old male hSOD1^G93A mice were treated with BJIGT (1 mg/g) and RZ (8 μg/g) administered orally for 5 weeks. Drug metabolism and liver function tests of serum and liver homogenates were conducted. mRNA expression levels of cytochrome P450 (CYP) isozymes, inflammatory cytokines, metabolic factors, and mitochondrial oxidative phosphorylation (OXPHOS) subunits were examined using qPCR and Western blotting. Combined administration of BJIGT and RZ did not alter mRNA expression levels of drug-metabolism-related isozymes (CYP1A2 and CYP3A4) but significantly decreased the activity of liver-function-related enzymes (AST, ALT, ALP, and LDH). Increased expression of inflammatory cytokines (IL-1β, TNF-α, and IL-6) and of intracellular stress-related proteins (Bax, AMPKα, JNK, and p38) was reduced by the combined treatment in hSOD1^G93A mice compared to that in control mice. Combined administration reduced the mRNA expression of metabolism-related factors and the expression of OXPHOS subunits. Elevated ATP levels and mitochondrial-fusion-associated protein were decreased after co-administration. Co-administration of BJIGT and RZ did not cause liver damage or toxicity but rather restored liver function in hSOD1^G93A mice. This suggests that this combination can be considered a candidate therapeutic agent for ALS. Full article

(This article belongs to the Special Issue Oxidative Stress and Mitochondrial Dysfunction in Disease)

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20 pages, 1057 KiB

Open AccessReview

Arterial Hypertension—Oxidative Stress and Inflammation

by Julia Krzemińska, Magdalena Wronka, Ewelina Młynarska, Beata Franczyk and Jacek Rysz

Antioxidants 2022, 11(1), 172; https://doi.org/10.3390/antiox11010172 - 17 Jan 2022

Cited by 67 | Viewed by 5609

Abstract

Arterial hypertension (AH) is a major cause of cardiovascular diseases (CVD), leading to dysfunction of many organs, including the heart, blood vessels and kidneys. AH is a multifactorial disease. It has been suggested that the development of each factor is influenced by oxidative [...] Read more.

Arterial hypertension (AH) is a major cause of cardiovascular diseases (CVD), leading to dysfunction of many organs, including the heart, blood vessels and kidneys. AH is a multifactorial disease. It has been suggested that the development of each factor is influenced by oxidative stress, which is characterized by a disturbed oxidant-antioxidant balance. Excessive production of reactive oxygen species (ROS) and an impaired antioxidant system promote the development of endothelial dysfunction (ED), inflammation and increased vascular contractility, resulting in remodeling of cardiovascular (CV) tissue. The hope for restoring the proper functioning of the vessels is placed on antioxidants, and pharmacological strategies are still being sought to reverse the harmful effects of free radicals. In our review, we focused on the correlation of AH with oxidative stress and inflammation, which are influenced by many factors, such as diet, supplementation and pharmacotherapy. Studies show that the addition of a single dietary component may have a beneficial effect on blood pressure (BP) values; however, the relationship between the antioxidant/anti-inflammatory properties of individual dietary components and the hypotensive effect is not clear. Moreover, AH pharmacotherapy alleviates the increased oxidative stress, which may help prevent organ damage. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation in Cardiovascular Diseases II)

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Correlation between oxidative stress, inflammation and hypertension. Full article ">Figure 2
Comparison of plasma levels of NOx (μmol/L) at baseline and at year 5 in the enalapril and zofenopril groups. Newly diagnosed hypertensive patients (SBP > 160 mm Hg and/or DBP > 95 mm Hg) participated in the study. They were randomly assigned to receive enalapril (20 mg/d, n = 24) or zofenopril (30 mg/d, n = 24). Exclusion factors were additional risk factors for coronary artery disease or a history of ischemic events, as well as prior or concurrent therapy with ACE-I, antiplatelet agents or anticoagulants [<a href="#B37-antioxidants-11-00172" class="html-bibr">37</a>]. Full article ">Figure 3
Comparison of plasma levels of ADMA (μmol/L) at baseline and at year 5 in the enalapril and zofenopril groups. Newly diagnosed hypertensive patients (SBP > 160 mm Hg and/or DBP > 95 mm Hg) participated in the study. They were randomly assigned to receive enalapril (20 mg/d, n = 24) or zofenopril (30 mg/d, n = 24). Exclusion factors were additional risk factors for coronary artery disease or a history of ischemic events, as well as prior or concurrent therapy with ACE-I, antiplatelet agents or anticoagulants [<a href="#B37-antioxidants-11-00172" class="html-bibr">37</a>]. Full article ">Figure 4
The beneficial effects of the discussed drugs and specific nutrients. Full article ">

13 pages, 3673 KiB

Open AccessArticle

Inhibitory Effects of 6,8-Diprenylorobol on Endometriosis Progression in Humans by Disrupting Calcium Homeostasis and Mitochondrial Function

by Jisoo Song, Gwonhwa Song, Sunwoo Park and Whasun Lim

Antioxidants 2022, 11(1), 171; https://doi.org/10.3390/antiox11010171 - 17 Jan 2022

Cited by 17 | Viewed by 3050

Abstract

6,8-Diprenylorobol is a flavonoid compound extracted from Cudrania tricuspidata. It has various biological functions, such as inhibiting melanin synthesis and inducting cell death in cancerous cells. In addition, Cudrania tricuspidata is known to be effective in female diseases, and previous studies have [...] Read more.

6,8-Diprenylorobol is a flavonoid compound extracted from Cudrania tricuspidata. It has various biological functions, such as inhibiting melanin synthesis and inducting cell death in cancerous cells. In addition, Cudrania tricuspidata is known to be effective in female diseases, and previous studies have shown anticancer effects in cervical cancer, a female reproductive disease. Outside of that, Cudrania tricuspidata has various physiological effects. However, the effect of 6,8-diprenylorobol is not well known in other benign and chronic diseases, even in endometriosis, which commonly arises in the female reproductive tract. In the present study, we determined the inhibitory effects of 6,8-diprenylorobol on the growth of endometriosis VK2/E6E7 and End1/E6E7 cells. Results indicated that 6,8-diprenylorobol suppressed cellular proliferation and increased the disruption of the cell cycle, mitochondrial membrane potential (MMP), generation of reactive oxygen species, and Ca²⁺ homeostasis in both endometriosis cells. However, the proliferation of normal stromal cells isolated from endometrial tissue was not altered by 6,8-diprenylorobol. The change in Ca²⁺ levels was estimated in fluo-4- or rhod-2-stained VK2/E6E7 and End1/E6E7 cells after the treatment of the intracellular calcium regulators 2-aminoethoxydiphenyl borate (2-APB) and ruthenium red (RUR) with 6,8-diprenylorobol. A combination of 6,8-diprenylorobol with each regulator decreased the calcium accumulation in endometriosis cells. Furthermore, Western blot analysis indicated that 6,8-diprenylorobol inactivated AKT pathways, whereas it activated P38 MAPK pathways. In addition, 6,8-diprenylorobol decreased mitochondrial respiration, leading to the reduction in ATP production in VK2/E6E7 and End1/E6E7 cells. Collectively, our results suggested that 6,8-diprenylorobol might be a potential therapeutic agent or adjuvant therapy for the management of endometriosis. Full article

(This article belongs to the Special Issue Mitochondria Biology in Reproductive Function)

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18 pages, 994 KiB

Open AccessReview

Neuroprotection and Disease Modification by Astrocytes and Microglia in Parkinson Disease

by Shinichi Takahashi and Kyoko Mashima

Antioxidants 2022, 11(1), 170; https://doi.org/10.3390/antiox11010170 - 17 Jan 2022

Cited by 36 | Viewed by 6541

Abstract

Oxidative stress and neuroinflammation are common bases for disease onset and progression in many neurodegenerative diseases. In Parkinson disease, which is characterized by the degeneration of dopaminergic neurons resulting in dopamine depletion, the pathogenesis differs between hereditary and solitary disease forms and is [...] Read more.

Oxidative stress and neuroinflammation are common bases for disease onset and progression in many neurodegenerative diseases. In Parkinson disease, which is characterized by the degeneration of dopaminergic neurons resulting in dopamine depletion, the pathogenesis differs between hereditary and solitary disease forms and is often unclear. In addition to the pathogenicity of alpha-synuclein as a pathological disease marker, the involvement of dopamine itself and its interactions with glial cells (astrocyte or microglia) have attracted attention. Pacemaking activity, which is a hallmark of dopaminergic neurons, is essential for the homeostatic maintenance of adequate dopamine concentrations in the synaptic cleft, but it imposes a burden on mitochondrial oxidative glucose metabolism, leading to reactive oxygen species production. Astrocytes provide endogenous neuroprotection to the brain by producing and releasing antioxidants in response to oxidative stress. Additionally, the protective function of astrocytes can be modified by microglia. Some types of microglia themselves are thought to exacerbate Parkinson disease by releasing pro-inflammatory factors (M1 microglia). Although these inflammatory microglia may further trigger the inflammatory conversion of astrocytes, microglia may induce astrocytic neuroprotective effects (A2 astrocytes) simultaneously. Interestingly, both astrocytes and microglia express dopamine receptors, which are upregulated in the presence of neuroinflammation. The anti-inflammatory effects of dopamine receptor stimulation are also attracting attention because the functions of astrocytes and microglia are greatly affected by both dopamine depletion and therapeutic dopamine replacement in Parkinson disease. In this review article, we will focus on the antioxidative and anti-inflammatory effects of astrocytes and their synergism with microglia and dopamine. Full article

(This article belongs to the Special Issue Antioxidants and Anti-inflammatory Effects in Neurodegenerative Diseases)

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18 pages, 1825 KiB

Open AccessReview

Hydropersulfides (RSSH) and Nitric Oxide (NO) Signaling: Possible Effects on S-Nitrosothiols (RS-NO)

by Jon M. Fukuto, Cristina Perez-Ternero, Jessica Zarenkiewicz, Joseph Lin, Adrian J. Hobbs and John P. Toscano

Antioxidants 2022, 11(1), 169; https://doi.org/10.3390/antiox11010169 - 16 Jan 2022

Cited by 12 | Viewed by 3046

Abstract

S-Nitrosothiol (RS-NO) formation in proteins and peptides have been implicated as factors in the etiology of many diseases and as possible regulators of thiol protein function. They have also been proposed as possible storage forms of nitric oxide (NO). However, despite their proposed [...] Read more.

S-Nitrosothiol (RS-NO) formation in proteins and peptides have been implicated as factors in the etiology of many diseases and as possible regulators of thiol protein function. They have also been proposed as possible storage forms of nitric oxide (NO). However, despite their proposed functions/roles, there appears to be little consensus regarding the physiological mechanisms of RS-NO formation and degradation. Hydropersulfides (RSSH) have recently been discovered as endogenously generated species with unique reactivity. One important reaction of RSSH is with RS-NO, which leads to the degradation of RS-NO as well as the release of NO. Thus, it can be speculated that RSSH can be a factor in the regulation of steady-state RS-NO levels, and therefore may be important in RS-NO (patho)physiology. Moreover, RSSH-mediated NO release from RS-NO may be a possible mechanism allowing RS-NO to serve as a storage form of NO. Full article

(This article belongs to the Special Issue Straddling Physiology and Pathology: A Radical Control of Signal Transduction Pathways)

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Possible pathways for the formation of RS-NO from RSH and NO. [O] denotes a one-electron oxidation. Full article ">Figure 2
Possible mechanism for the Trx/Grx-mediated denitrozation of a protein RS-NO. [H] represents known biological pathways for RSSR reduction to the corresponding RSH. Full article ">Figure 3
RS-NO resonance forms that favor attack at either sulfur or nitrogen. Full article ">Figure 4
The reaction of RSSH with R’SNO to give NO and, after biological reduction ([H]), RSH and H2S. Full article ">Figure 5
Currently proposed mechanisms for RS-NO degradation. (a) S-thiolation and the generation of HNO, (b) transnitrosation, transfer of ‘NO+’ with no generation of NO, (c) CuI-mediated reaction with formation of NO and RSH (not likely to be of general relevance based on current literature), (d) photochemical cleavage of the RS-NO bond with formation of NO and highly oxidizing RS·(not of general relevance except maybe in specific situations (e.g., skin)), (e) RSSH-mediated destruction of RS-NO with formation of NO and unreactive RSS· (which dimerizes to RSSSSR, which can be reduced to RSH), (f) Trx or Grx-mediated reduction of RS-NO to RSH and ultimately to HNO, not NO, (g) dehydrogenase-mediated conversion of RS-NO to a variety of possible products without generation of NO, primarily relevant only to GS-NO. Full article ">

20 pages, 1557 KiB

Open AccessArticle

Protection against Neurological Symptoms by Consuming Corn Silk Water Extract in Artery-Occluded Gerbils with Reducing Oxidative Stress, Inflammation, and Post-Stroke Hyperglycemia through the Gut-Brain Axis

by Jin Ah Ryuk, Byoung Seob Ko, Na Rang Moon and Sunmin Park

Antioxidants 2022, 11(1), 168; https://doi.org/10.3390/antiox11010168 - 16 Jan 2022

Cited by 17 | Viewed by 4413

Abstract

Corn silk (Stigma maydis), rich in flavonoids, is traditionally used to treat edema, depression, and hyperglycemia and may alleviate ischemic stroke symptoms in Chinese medicine. This study examined whether corn silk water extract (CSW) could alleviate ischemic stroke symptoms and post-stroke [...] Read more.

Corn silk (Stigma maydis), rich in flavonoids, is traditionally used to treat edema, depression, and hyperglycemia and may alleviate ischemic stroke symptoms in Chinese medicine. This study examined whether corn silk water extract (CSW) could alleviate ischemic stroke symptoms and post-stroke hyperglycemia in Mongolian gerbils with transient cerebral ischemia and reperfusion (I/R). After being given 0.05% (I/R-LCSW) and 0.2% (I/R-HCSW), 0.02% aspirin (I/R-aspirin), and cellulose (I/R-control) in their 40 energy% fat diets for three weeks, the gerbils underwent an artery occlusion for eight minutes and reperfusion. They took the assigned diet for an additional three weeks. Sham-operated gerbils without artery occlusion had the same diet as Sham-control. CSW intake reduced neuronal cell death in gerbils with I/R and dose-dependently improved the neurological symptoms, including drooped eyes, crouched posture, flexor reflex, and walking patterns. CSW intake also alleviated the short-term memory and spontaneous alteration and grip strength compared to the I/R-control group. The protection against ischemic stroke symptoms was associated with the reduced tumor necrosis factor-α, interleukin-1β, superoxide, and lipid peroxide levels, promoting superoxide dismutase activity in the hippocampus in the CSW groups, compared to the I/R-control. The blood flow measured by Doppler was improved with CSW compared to the I/R-control. Furthermore, CSW intake prevented the post-stroke hyperglycemia related to decreasing pancreatic β-cell mass as much as the Sham-control, and it was related to protection against β-cell apoptosis, restoring the β-cell mass similar to the Sham-control. CSW intake elevated the relative abundance of Lactobacillus, Bifidobacterium, Allobaculum, and Akkermansia compared to the I/R-control. Picrust2 analysis showed that CSW increased the propionate and butyrate metabolism and the starch and glucose metabolism but reduced lipopolysaccharide biosynthesis compared to the I/R-control. In conclusion, CSW intake protects against neuronal cell death and post-hyperglycemia by reducing oxidative stress and inflammation and increasing blood flow and the β-cell mass. The alleviation was associated with promoting the gut-brain axis by changing the gut microbiome community. Full article

(This article belongs to the Special Issue Dietary Antioxidants against Neurodegenerative Diseases)

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Experimental design. Full article ">Figure 2
Brain cell death and memory loss after ischemic stroke. Gerbils that underwent the transient forebrain ischemia by carotid artery occlusion for 8 min and reperfusion were randomly divided into four groups, as follows: (1) 0.2% cellulose (I/R-control), (2) 0.02% aspirin (I/R-aspirin), (3) 0.05% freeze-dried corn silk water extract (I/R-LCSW), and (4) 0.2% CSW (I/R-HCSW) in a high-fat diet. Sham-operated gerbils without artery occlusion had the same diet as Sham-control. At the end of the experiment, the percentage of cresyl-violet-positive cells in the hippocampal CA1 region was quantified by densitometry in the cresyl violet staining. Dots and bars represent means ± SD (n = 10). a–d Different letters on the bars indicate significant differences in the means of the designated groups by Tukey’s test at p < 0.05. Full article ">Figure 3
Neurological severity scores. Gerbils that underwent the transient ischemic attack by carotid artery occlusion for 8 min and reperfusion were randomly divided into four groups, as follows: (1) 0.2% cellulose (I/R-control), (2) 0.02% aspirin (I/R-aspirin), (3) 0.05% freeze-dried corn silk water extract (I/R-LCSW), and (4) 0.2% CSW (I/R-HCSW) in a high-fat diet. Sham-operated gerbils without artery occlusion had the same diet as Sham-control. The neurological symptoms, including drooping eyelid, crouched posture, and hair bristling (A); flexor reflex, walking patterns, and force to grip the bar (B), were shown at the third week after inducing ischemic stroke attack. Bars represent means ± SD (n = 10). a–e Different letters on the bars indicate significant differences in the means of the designated groups by Tukey’s test at p < 0.05. Full article ">Figure 4
Oral glucose tolerance test (OGTT) and intraperitoneal insulin tolerance test (IPITT). Gerbils that underwent the transient forebrain ischemia by carotid artery occlusion for 8 min and reperfusion were randomly divided into four groups, as follows: (1) 0.2% cellulose (I/R-control), (2) 0.02% aspirin (I/R-aspirin), (3) 0.05% freeze-dried corn silk water extract (I/R-LCSW), and (4) 0.2% CSW (I/R-HCSW) in a high-fat diet. Sham-operated gerbils without artery occlusion had the same diet as Sham-control. After overnight fasting, gerbils had an OGTT with 2 g glucose/kg body weight. The changes of serum glucose levels during 120 min (A) and area under the curve (AUC) of serum glucose concentrations (B) in the first part (0–40 min) and the second part (40–120 min) during OGTT. Serum insulin concentrations were also measured during OGTT (C). The next day gerbils underwent an IPITT with 1 IU insulin/kg body weight after 6 h food deprivation. The area under the curve (AUC) of serum glucose in the first part (0–30 min) and the second part (30–90 min) during the IPITT (D). Bars and dots represent means ± SD (n = 10). * Significantly different among the groups at p < 0.05. a–c Different letters on the bars indicate significant differences in the means of the designated groups by Tukey’s test at p < 0.05. Full article ">Figure 4 Cont.
Oral glucose tolerance test (OGTT) and intraperitoneal insulin tolerance test (IPITT). Gerbils that underwent the transient forebrain ischemia by carotid artery occlusion for 8 min and reperfusion were randomly divided into four groups, as follows: (1) 0.2% cellulose (I/R-control), (2) 0.02% aspirin (I/R-aspirin), (3) 0.05% freeze-dried corn silk water extract (I/R-LCSW), and (4) 0.2% CSW (I/R-HCSW) in a high-fat diet. Sham-operated gerbils without artery occlusion had the same diet as Sham-control. After overnight fasting, gerbils had an OGTT with 2 g glucose/kg body weight. The changes of serum glucose levels during 120 min (A) and area under the curve (AUC) of serum glucose concentrations (B) in the first part (0–40 min) and the second part (40–120 min) during OGTT. Serum insulin concentrations were also measured during OGTT (C). The next day gerbils underwent an IPITT with 1 IU insulin/kg body weight after 6 h food deprivation. The area under the curve (AUC) of serum glucose in the first part (0–30 min) and the second part (30–90 min) during the IPITT (D). Bars and dots represent means ± SD (n = 10). * Significantly different among the groups at p < 0.05. a–c Different letters on the bars indicate significant differences in the means of the designated groups by Tukey’s test at p < 0.05. Full article ">Figure 5
The profiles of gut microbiomes. Gerbils that underwent the transient ischemic attack by carotid artery occlusion for 8 min and reperfusion were randomly divided into four groups, as follows: (1) 0.2% cellulose (I/R-control), (2) 0.02% aspirin (I/R-aspirin), (3) 0.05% freeze-dried corn silk water extract (I/R-LCSW), and (4) 0.2% CSW (I/R-HCSW) in a high-fat diet. Sham-operated gerbils without artery occlusion had the same diet as Sham-control. At the end of the experimental period, feces from the cecum were collected, and the bacterial DNA was analyzed. The β-diversity was analyzed by the principal coordinate analysis (PCoA) of the fecal bacterial community (A), and the relative abundance of bacteria at the genus level (B) was calculated. Bars represent means ± SD (n = 10). Full article ">Figure 5 Cont.
The profiles of gut microbiomes. Gerbils that underwent the transient ischemic attack by carotid artery occlusion for 8 min and reperfusion were randomly divided into four groups, as follows: (1) 0.2% cellulose (I/R-control), (2) 0.02% aspirin (I/R-aspirin), (3) 0.05% freeze-dried corn silk water extract (I/R-LCSW), and (4) 0.2% CSW (I/R-HCSW) in a high-fat diet. Sham-operated gerbils without artery occlusion had the same diet as Sham-control. At the end of the experimental period, feces from the cecum were collected, and the bacterial DNA was analyzed. The β-diversity was analyzed by the principal coordinate analysis (PCoA) of the fecal bacterial community (A), and the relative abundance of bacteria at the genus level (B) was calculated. Bars represent means ± SD (n = 10). Full article ">

17 pages, 885 KiB

Open AccessReview

Antioxidant Paradox in Male Infertility: ‘A Blind Eye’ on Inflammation

by Sulagna Dutta, Pallav Sengupta, Shubhadeep Roychoudhury, Srikumar Chakravarthi, Chee Woon Wang and Petr Slama

Antioxidants 2022, 11(1), 167; https://doi.org/10.3390/antiox11010167 - 16 Jan 2022

Cited by 27 | Viewed by 4769

Abstract

The pathophysiology of male infertility involves various interlinked endogenous pathways. About 50% of the cases of infertility in men are idiopathic, and oxidative stress (OS) reportedly serves as a central mechanism in impairing male fertility parameters. The endogenous antioxidant system operates to conserve [...] Read more.

The pathophysiology of male infertility involves various interlinked endogenous pathways. About 50% of the cases of infertility in men are idiopathic, and oxidative stress (OS) reportedly serves as a central mechanism in impairing male fertility parameters. The endogenous antioxidant system operates to conserve the seminal redox homeostasis required for normal male reproduction. OS strikes when a generation of seminal reactive oxygen species (ROS) overwhelms endogenous antioxidant capacity. Thus, antioxidant treatment finds remarkable relevance in the case of idiopathic male infertility or subfertility. However, due to lack of proper detection of OS in male infertility, use of antioxidant(s) in some cases may be arbitrary or lead to overuse and induction of ‘reductive stress’. Moreover, inflammation is closely linked to OS and may establish a vicious loop that is capable of disruption to male reproductive tissues. The result is exaggeration of cellular damage and disruption of male reproductive tissues. Therefore, limitations of antioxidant therapy in treating male infertility are the failure in the selection of specific treatments targeting inflammation and OS simultaneously, two of the core mechanisms of male infertility. The present review aims to elucidate the antioxidant paradox in male infertility treatment, from the viewpoints of both induction of reductive stress as well as overlooking the inflammatory consequences. Full article

(This article belongs to the Special Issue Paradoxical Oxidative Therapies in Chronic Oxidative Stress Diseases)

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20 pages, 4950 KiB

Open AccessArticle

Multitarget Antioxidant NO-Donor Organic Nitrates: A Novel Approach to Overcome Nitrates Tolerance, an Ex Vivo Study

by Elisabetta Marini, Marta Giorgis, Marta Leporati, Barbara Rolando, Konstantin Chegaev, Loretta Lazzarato, Massimo Bertinaria, Marco Vincenti and Antonella Di Stilo

Antioxidants 2022, 11(1), 166; https://doi.org/10.3390/antiox11010166 - 16 Jan 2022

Cited by 6 | Viewed by 2657

Abstract

Chronic use of glyceryl trinitrate (GTN) is limited by serious side effects, such as tolerance and endothelial dysfunction of coronary and resistance arteries. Although GTN is used as a drug since more than 130 years, the mechanisms of the vasodilatory effects and of [...] Read more.

Chronic use of glyceryl trinitrate (GTN) is limited by serious side effects, such as tolerance and endothelial dysfunction of coronary and resistance arteries. Although GTN is used as a drug since more than 130 years, the mechanisms of the vasodilatory effects and of tolerance development to organic nitrates are still incompletely elucidated. New synthesized organic nitrates with and without antioxidant properties were characterized for their ex vivo tolerance profile, in order to investigate the oxidative stress hypothesis of nitrate tolerance. The organic nitrates studied showed different vasodilation and tolerance profiles, probably due to the ability or inability of the compounds to interact with the aldehyde dehydrogenase-2 enzyme (ALDH-2) involved in bioactivation. Furthermore, nitrooxy derivatives endowed with antioxidant properties did not determine the onset of tolerance, even if bioactivated by ALDH-2. The results of this study could be further evidence of the involvement of ALDH-2 in the development of nitrate tolerance. Moreover, the behavior of organic nitrates with antioxidant properties supports the hypothesis of the involvement of ROS in inactivating ALDH-2. Full article

(This article belongs to the Special Issue NO-Donors with Antioxidant Activities)

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24 pages, 947 KiB

Open AccessEditor’s ChoiceReview

Therapeutic Strategies Targeting Mitochondrial Calcium Signaling: A New Hope for Neurological Diseases?

by Laura R. Rodríguez, Tamara Lapeña-Luzón, Noelia Benetó, Vicent Beltran-Beltran, Federico V. Pallardó, Pilar Gonzalez-Cabo and Juan Antonio Navarro

Antioxidants 2022, 11(1), 165; https://doi.org/10.3390/antiox11010165 - 15 Jan 2022

Cited by 27 | Viewed by 5027

Abstract

Calcium (Ca²⁺) is a versatile secondary messenger involved in the regulation of a plethora of different signaling pathways for cell maintenance. Specifically, intracellular Ca²⁺ homeostasis is mainly regulated by the endoplasmic reticulum and the mitochondria, whose Ca²⁺ exchange is [...] Read more.

Calcium (Ca²⁺) is a versatile secondary messenger involved in the regulation of a plethora of different signaling pathways for cell maintenance. Specifically, intracellular Ca²⁺ homeostasis is mainly regulated by the endoplasmic reticulum and the mitochondria, whose Ca²⁺ exchange is mediated by appositions, termed endoplasmic reticulum–mitochondria-associated membranes (MAMs), formed by proteins resident in both compartments. These tethers are essential to manage the mitochondrial Ca²⁺ influx that regulates the mitochondrial function of bioenergetics, mitochondrial dynamics, cell death, and oxidative stress. However, alterations of these pathways lead to the development of multiple human diseases, including neurological disorders, such as amyotrophic lateral sclerosis, Friedreich’s ataxia, and Charcot–Marie–Tooth. A common hallmark in these disorders is mitochondrial dysfunction, associated with abnormal mitochondrial Ca²⁺ handling that contributes to neurodegeneration. In this work, we highlight the importance of Ca²⁺ signaling in mitochondria and how the mechanism of communication in MAMs is pivotal for mitochondrial maintenance and cell homeostasis. Lately, we outstand potential targets located in MAMs by addressing different therapeutic strategies focused on restoring mitochondrial Ca²⁺ uptake as an emergent approach for neurological diseases. Full article

(This article belongs to the Special Issue Oxidative Stress, Calcium Dysregulation, and Mitochondrial Dysfunction in Human Diseases)

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Schematic representation showing the effects of mitochondrial Ca2+ uptake promoters. The ER is the main Ca2+ storage in the cell and Ca2+ exchange between the ER and the mitochondria requires the formation of tethers composed by proteins of both compartments. Sig-1R resides in the ER membrane, in a dormant, Ca2+-dependent state. Upon activation by agonists, Sig-1R dissociates from BiP/GRP78 and reallocates within the ER membrane, interacting with IP3R and chaperoning the protein complex that transfers Ca2+ to the mitochondria. This complex formed by IP3R-GRP75-VDAC ensures a rapid Ca2+ flux to the mitochondrial intermembrane space, which triggers MCU opening and Ca2+ to cross the mitochondrial inner membrane. Several models of neurological disorders such as ALS, CMT and FRDA have exhibited alterations in mitochondrial Ca2+ buffering by defective appositions between the two organelles. Both Sig-1R agonists and MCU enhancers promote Ca2+ exchange between the ER and the mitochondria, exerting beneficial effects in different models of neurological diseases. On the one hand, Sig-1R agonists (pridopidine, SA4503, Blacarmesine, PRE-084, and fluvoxamine) have been demonstrated to exert neuroprotective effects, improving mitochondrial dysfunction, preventing cells from apoptosis, activating the antioxidant response, ameliorating ER stress, and improving axonal defects. On the other hand, the MCU enhancer, Kaempferol, has helped to improve mitochondrial dysfunction, activate the oxidative stress response, modulate autophagy, regulate ER stress, and prevent cells from apoptosis. This figure has been created using Creative Commons resources from Servier Medical Art [<a href="#B99-antioxidants-11-00165" class="html-bibr">99</a>]. ALS: amyotrophic lateral sclerosis; Bip/GRP78: binding immunoglobulin protein/glucose-regulated protein 78; CMT: Charcot–Marie–Tooth; ER: endoplasmic reticulum; FRDA: Friedreich’s ataxia; GRP75: glucose-regulated protein 75; IP3R: inositol 1,4,5-trisphosphate receptor; MCU: mitochondrial calcium uniporter; Sig-1R: sigma non-opioid intracellular receptor 1; VDAC: voltage-dependent anion channel. Full article ">

20 pages, 3231 KiB

Open AccessArticle

The Trypanosoma brucei-Derived Ketoacids, Indole Pyruvate and Hydroxyphenylpyruvate, Induce HO-1 Expression and Suppress Inflammatory Responses in Human Dendritic Cells

by Hannah K. Fitzgerald, Sinead A. O’Rourke, Eva Desmond, Nuno G. B. Neto, Michael G. Monaghan, Miriam Tosetto, Jayne Doherty, Elizabeth J. Ryan, Glen A. Doherty, Derek P. Nolan, Jean M. Fletcher and Aisling Dunne

Antioxidants 2022, 11(1), 164; https://doi.org/10.3390/antiox11010164 - 15 Jan 2022

Cited by 6 | Viewed by 3683

Abstract

The extracellular parasite and causative agent of African sleeping sickness Trypanosoma brucei (T. brucei) has evolved a number of strategies to avoid immune detection in the host. One recently described mechanism involves the conversion of host-derived amino acids to aromatic ketoacids, [...] Read more.

The extracellular parasite and causative agent of African sleeping sickness Trypanosoma brucei (T. brucei) has evolved a number of strategies to avoid immune detection in the host. One recently described mechanism involves the conversion of host-derived amino acids to aromatic ketoacids, which are detected at relatively high concentrations in the bloodstream of infected individuals. These ketoacids have been shown to directly suppress inflammatory responses in murine immune cells, as well as acting as potent inducers of the stress response enzyme, heme oxygenase 1 (HO-1), which has proven anti-inflammatory properties. The aim of this study was to investigate the immunomodulatory properties of the T. brucei-derived ketoacids in primary human immune cells and further examine their potential as a therapy for inflammatory diseases. We report that the T. brucei-derived ketoacids, indole pyruvate (IP) and hydroxyphenylpyruvate (HPP), induce HO-1 expression through Nrf2 activation in human dendritic cells (DC). They also limit DC maturation and suppress the production of pro-inflammatory cytokines, which, in turn, leads to a reduced capacity to differentiate adaptive CD4⁺ T cells. Furthermore, the ketoacids are capable of modulating DC cellular metabolism and suppressing the inflammatory profile of cells isolated from patients with inflammatory bowel disease. This study therefore not only provides further evidence of the immune-evasion mechanisms employed by T. brucei, but also supports further exploration of this new class of HO-1 inducers as potential therapeutics for the treatment of inflammatory conditions. Full article

(This article belongs to the Special Issue Heme Oxygenase (HO)-1 as an Immunoregulator in Health and Disease)

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Graphical abstract

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Hydroxyphenylpyruvate (HPP) and indole pyruvate (IP) upregulate HO-1 in primary human dendritic cells (DC). (A) Primary human DC were left untreated (UT) or incubated with HPP or IP (250–1000 μM) for 24 h. HO-1 expression was detected by western blot. Densitometry results shown are mean ± SEM of the relative expression of HO-1: β-actin from five healthy donors. (B) DC were left UT or incubated with HPP or IP at 1000 μM for 3, 6, or 24 h. HO-1 expression was detected by western blot. Densitometry results shown are mean ± SEM of the relative expression of HO-1: β-actin from seven healthy donors. (C) Primary human DC were left UT or incubated with HPP or IP at 1000 μM, or carnosol or curcumin (both 10 μM), for 1 h. Total antioxidant capacity of the cells was determined and expressed as an equivalent concentration of Trolox (μM). Pooled data showing the mean (±SEM) from five healthy donors. Repeated measures one-way ANOVA, with Dunnett’s multiple comparisons post hoc test, was used to determine statistical significance by comparing means of treatment groups against the mean of the control group (** p < 0.01, * p < 0.05). ImageLab (Bio-Rad) software was used to perform densitometric analysis. Full article ">Figure 2
HPP and IP induce HO-1 through Nrf2 activation. (A) Primary human DC were left untreated (UT) or incubated with HPP or IP at 1000 μM for 6 or 24 h. Nrf2 expression was measured by western blot. Densitometry results shown are mean ± SEM of the relative expression of Nrf2: β-actin from five healthy donors. (B) Primary human DC were left UT or incubated with HPP or IP at 1000 µM for 24 h. mRNA expression of the Nrf2-dependent genes, NQO-1 and GSR, were measured by RT-PCR. Results show mean (±SEM) for six healthy donors. (C) Primary human DC were pre-treated either with or without the Nrf2 inhibitor ML385 (10 μM) for 1 h, prior to incubation with HPP or IP at 1000 μM for 24 h. HO-1 expression was measured by western blot. Densitometry results shown are mean ± SEM of the relative expression of HO-1: β-actin from five healthy donors. (A) One-way ANOVA, with Dunnett’s multiple comparisons post hoc test, was used to determine statistical significance. (B) Two-way ANOVA, with Šídák’s multiple comparisons post hoc test, was used to determine statistical significance. (C) One-way ANOVA, with Šídák’s multiple comparisons post hoc test, was used to determine statistical significance (**** p < 0.0001, *** p < 0.001, ** p < 0.01, * p < 0.05). ImageLab (Bio-Rad) software was used to perform densitometric analysis. Full article ">Figure 3
HPP and IP reduce the production of pro-inflammatory cytokines in LPS-stimulated human DC. Primary human DC were left untreated (UT) or incubated with IP (A,C,E,G,I) or HPP (B,D,F,H,J) (500–1000 µM) for 6 h prior to stimulation with LPS (100 ng/mL) for 24 h. Cell supernatants were assessed for TNF, IL-6, IL-23, IL-12p70, and IL-10 secretion by ELISA. Pooled data depict mean (±SEM) cytokine concentrations for four to seven healthy donors (means of three technical replicates per donor). Repeated measures one-way ANOVA, with Dunnett’s multiple comparisons post hoc test, was used to determine statistical significance, by comparing means of treatment groups against the mean of the control group (** p < 0.01, * p < 0.05). Full article ">Figure 4
HPP treatment reduces DC maturation and subsequent CD4+ T cell activation. Primary human DC were left untreated (UT) or incubated with HPP (500–1000 μM) for 6 h prior to stimulation with LPS (100 ng/mL) for 24 h. (A) Cells were stained for CD40, CD80, CD86, and CD83 and analysed by flow cytometry. Histograms showing the expression of maturation markers for HPP-treated, LPS-stimulated DC compared to unstimulated cells or LPS stimulation alone from one representative experiment. Pooled data showing the mean (±SEM) MFI for each marker expressed as a percentage of control (LPS stimulation alone) from six to seven healthy donors. (B) DC were incubated with FITC-conjugated DQ-Ovalbumin (DQ-Ova; 500 ng/mL) for 20 min and were immediately acquired by flow cytometry. Dot plots depicting DQ-Ova uptake from one representative experiment. Pooled data showing the mean (±SEM) DQ-Ova uptake as a percentage of total cells from nine healthy donors. (C) DC were pre-treated with HPP prior to stimulation with LPS, and subsequently cultured with CD4+ T cells for five days. Dot plots depicting ki67 expression (as a measure of proliferation) and IFNγ expression from one representative experiment. Pooled data showing the mean (±SEM) of ki67+ and IFNγ+ cells as a percentage of CD3+CD8− cells from four healthy donors. (D) Cell supernatants were assessed for IL-10 secretion by ELISA. Pooled data depict mean (±SEM) cytokine concentrations for four healthy donors (means of three technical replicates per donor). Repeated measures one-way ANOVA, with Dunnett’s multiple comparisons post hoc test, was used to determine statistical significance by comparing means of treatment groups against the mean of the control group (*** p < 0.001, ** p < 0.01, * p < 0.05). Full article ">Figure 5
HPP and IP modulate metabolic reprogramming in LPS-stimulated DC. Primary human DC were pre-treated with either HPP or IP at 1000 μM for 6 h before stimulation with LPS (100 ng/mL) for 12 h. The extracellular acidification rate (ECAR) and the oxygen consumption rate (OCR) were measured using a Seahorse XFe96 analyser before and after the injections of oligomycin (1 mM), FCCP (1 mM), antimycin A (500 nM) and rotenone (500 nM), and 2-DG (25 mM). Bioenergetic profiles from one representative experiment depicting (A) ECAR and (E) OCR measurements over time. Pooled data (N = 6) depicts the calculated mean (±SEM) of (B) basal glycolytic rate, (C) max glycolytic rate, (D) glycolytic reserve, (F) basal respiratory rate, (G) max respiratory rate, and (H) respiratory reserve for each treatment group. (I) HK2 expression was measured by western blot. Densitometry results shown are mean ± SEM of the relative expression of HK2: β-actin from five to seven healthy donors. (J) FLIM images of DC measuring intracellular NADH. Pooled data (N = 4) depicts the mean (±SEM) of the ratio of bound:free NADH, represented by the τ average. Repeated measures one-way ANOVA, with Dunnett’s multiple comparisons post hoc test, was used to determine statistical significance by comparing means of treatment groups against the mean of the control group (** p < 0.01, * p < 0.05). ImageLab (Bio-Rad) software was used to perform densitometric analysis. Full article ">Figure 6
HPP and IP modulate autophagy-related proteins. (A) Primary human DC were left untreated (UT) or incubated with IP or HPP at 1000 µM for 15 min. Phosphorylation of AMPK was measured by western blot. Densitometry results shown are mean ± SEM of the relative expression of p-AMPK: β-actin from four healthy donors. (B,C) Primary human DC were left UT or incubated with IP or HPP at 1000 µM for 6, 12, or 24 h. Expression of (B) p62 and (C) LC3 were measured by western blot. Densitometry results shown are mean ± SEM of the relative expression of (B) p62: β-actin from five healthy donors and (C) LC3 II: β-actin from six healthy donors. (A) Statistical significance was determined using a Paired t-test. (B,C) Statistical significance was determined by repeated measures one-way ANOVA with Dunnett’s multiple comparisons post hoc test to compare means of treatment groups to the control group (*** p < 0.001, ** p < 0.01, * p < 0.05). ImageLab (Bio-Rad) software was used to perform densitometric analysis. Full article ">Figure 7
HPP and IP reduce proliferation and cytokine expression in ex vivo stimulated PBMC from patients with Inflammatory Bowel Disease. PBMC isolated from IBD patients were treated with (A,C) HPP or (B,D) IP (250 µM–1000 µM) for 6 h prior to stimulation with anti-CD3 for 12 h. After 18 h, culture media was replaced with fresh media and cells were incubated for a further 4 days with anti-CD3 stimulation. Supernatants were removed for analysis of cytokine concentration by ELISA. (A,B) Proliferation and cytokine production by CD3+CD8− cells was analysed by flow cytometry. Pooled data (N = 14) depicting the mean ± SEM of ki67 (as a measure of proliferation), IFNγ, and IL-17 in CD3+CD8− T cells. (C,D) Cell supernatants were assessed for concentrations of IL-10, IFNγ, and IL-17 by ELISA. Pooled data depicts mean (±SEM) cytokine concentrations for six IBD patients (means of three technical replicates per donor). Statistical significance was determined by repeated measures one-way ANOVA with Dunnett’s multiple comparisons post hoc test to compare means of treatment groups to the control group (*** p < 0.001, ** p < 0.01, * p < 0.05). Full article ">

21 pages, 4962 KiB

Open AccessEditor’s ChoiceReview

Peroxide-Mediated Oxygenation of Organic Compounds by Fungal Peroxygenases

by Martin Hofrichter, Harald Kellner, Robert Herzog, Alexander Karich, Jan Kiebist, Katrin Scheibner and René Ullrich

Antioxidants 2022, 11(1), 163; https://doi.org/10.3390/antiox11010163 - 14 Jan 2022

Cited by 49 | Viewed by 6544

Abstract

Unspecific peroxygenases (UPOs), whose sequences can be found in the genomes of thousands of filamentous fungi, many yeasts and certain fungus-like protists, are fascinating biocatalysts that transfer peroxide-borne oxygen (from H₂O₂ or R-OOH) with high efficiency to a wide range [...] Read more.

Unspecific peroxygenases (UPOs), whose sequences can be found in the genomes of thousands of filamentous fungi, many yeasts and certain fungus-like protists, are fascinating biocatalysts that transfer peroxide-borne oxygen (from H₂O₂ or R-OOH) with high efficiency to a wide range of organic substrates, including less or unactivated carbons and heteroatoms. A twice-proline-flanked cysteine (PCP motif) typically ligates the heme that forms the heart of the active site of UPOs and enables various types of relevant oxygenation reactions (hydroxylation, epoxidation, subsequent dealkylations, deacylation, or aromatization) together with less specific one-electron oxidations (e.g., phenoxy radical formation). In consequence, the substrate portfolio of a UPO enzyme always combines prototypical monooxygenase and peroxidase activities. Here, we briefly review nearly 20 years of peroxygenase research, considering basic mechanistic, molecular, phylogenetic, and biotechnological aspects. Full article

(This article belongs to the Special Issue Dream Peroxygenases)

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14 pages, 3184 KiB

Open AccessArticle

Potential Implications of Rimonabant on Age-Related Oxidative Stress and Inflammation

by Renáta Szabó, Zsuzsanna Szabó, Denise Börzsei, Alexandra Hoffmann, Zelma Nadin Lesi, Patrícia Pálszabó, Andrea Pálszabó, Szabolcs Dvorácskó, Rudolf Gesztelyi, Krisztina Kupai, Dániel Priksz, Béla Juhász, Anita Altmayer, Csaba Varga and Anikó Pósa

Antioxidants 2022, 11(1), 162; https://doi.org/10.3390/antiox11010162 - 14 Jan 2022

Cited by 7 | Viewed by 2878

Abstract

Over the last decades, growing interest has turned to preventive and therapeutic approaches for achieving successful aging. Oxidative stress and inflammation are fundamental features of cardiovascular diseases; therefore, potential targets of them can improve cardiac outcomes. Our study aimed to examine the involvement [...] Read more.

Over the last decades, growing interest has turned to preventive and therapeutic approaches for achieving successful aging. Oxidative stress and inflammation are fundamental features of cardiovascular diseases; therefore, potential targets of them can improve cardiac outcomes. Our study aimed to examine the involvement of the endocannabinoid system, especially the CB1 receptor blockade, on inflammatory and oxidant/antioxidant processes. Twenty-month-old female and male Wistar rats were divided into rimonabant-treated and aging control (untreated) groups. Rimonabant, a selective CB1 receptor antagonist, was administered at the dose of 1 mg/kg/day intraperitoneally for 2 weeks. Cardiac amounts of ROS, the antioxidant glutathione and superoxide dismutase (SOD), and the activity and concentration of the heme oxygenase (HO) enzyme were detected. Among inflammatory parameters, nuclear factor-kappa B (NF-?B), tumor necrosis factor-alpha (TNF-?), and myeloperoxidase (MPO) enzyme activity were measured. Two weeks of low dose rimonabant treatment significantly reduced the cardiac ROS via boosting of the antioxidant defense mechanisms as regards the HO system, and the SOD and glutathione content. Consistently, the age-related inflammatory response was alleviated. Rimonabant-treated animals showed significantly decreased NF-?B, TNF-?, and MPO levels. Our findings prove the beneficial involvement of CB1 receptor blocker rimonabant on inflammatory and oxidative damages to the aging heart. Full article

(This article belongs to the Special Issue Oxidative Stress in Chronic and Age-Related Diseases)

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15 pages, 825 KiB

Open AccessArticle

On the Role of the Carboxyl Group to the Protective Effect of o-dihydroxybenzoic Acids to Saccharomyces cerevisiae Cells upon Induced Oxidative Stress

by Nikolaos Nenadis, Efi Samara and Fani Th. Mantzouridou

Antioxidants 2022, 11(1), 161; https://doi.org/10.3390/antiox11010161 - 14 Jan 2022

Cited by 7 | Viewed by 3085

Abstract

In the present work, the role of the carboxyl group of o-dihydroxybenzoic acids (pyrocatechuic, 2,3-diOH-BA and protocatechuic, 3,4-diOH-BA) on the protection against induced oxidative stress in Saccharomyces cerevisiae was examined. Catechol (3,4-diOH-B) was included for comparison. Cell survival, antioxidant enzyme activities, and [...] Read more.

In the present work, the role of the carboxyl group of o-dihydroxybenzoic acids (pyrocatechuic, 2,3-diOH-BA and protocatechuic, 3,4-diOH-BA) on the protection against induced oxidative stress in Saccharomyces cerevisiae was examined. Catechol (3,4-diOH-B) was included for comparison. Cell survival, antioxidant enzyme activities, and TBARS level were used to evaluate the efficiency upon the stress induced by H₂O₂ or cumene hydroperoxide. Theoretical calculation of atomic charge values, dipole moment, and a set of indices relevant to the redox properties of the compounds was also carried out in the liquid phase (water). Irrespective of the oxidant used, 2,3-diOH-BA required by far the lowest concentration (3–5 μM) to facilitate cell survival. The two acids did not activate catalase but reduced superoxide dismutase activity (3,4-diOH-BA>2,3-diOH-BA). TBARS assay showed an antioxidant effect only when H₂O₂ was used; equal activity for the two acids and inferior to that of 3,4-diOH B. Overall, theoretical and experimental findings suggest that the 2,3-diOH-BA high activity should be governed by metal chelation. In the case of 3,4-diOH BA, radical scavenging increases, and chelation capacity decreases. The lack of carboxyl moiety (3,4-diOH B) improves to radical scavenging, interaction with lipophilic free radicals, and antioxidant enzymes. The present study adds to our knowledge of the antioxidant mechanism of dietary phenols in biological systems. Full article

(This article belongs to the Section Natural and Synthetic Antioxidants)

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Figure 1
Effect of the tested phenolic compounds on survival rates of S. cerevisiae BY4741 cells treated with H2O2 (5 mM). Black bar means untreated cells, gray bar means cells treated only with H2O2, and white bars mean cells treated with H2O2 + 2,3-diOH-BA (A), 3,4-diOH-BA (B), and 3,4-diOH-B (C). Data represent the mean values ± SD of at least three independent experiments. Different lowercase letters above the bars indicate a statistically significant difference at p < 0.05. Full article ">Figure 1 Cont.
Effect of the tested phenolic compounds on survival rates of S. cerevisiae BY4741 cells treated with H2O2 (5 mM). Black bar means untreated cells, gray bar means cells treated only with H2O2, and white bars mean cells treated with H2O2 + 2,3-diOH-BA (A), 3,4-diOH-BA (B), and 3,4-diOH-B (C). Data represent the mean values ± SD of at least three independent experiments. Different lowercase letters above the bars indicate a statistically significant difference at p < 0.05. Full article ">Figure 2
Effect of the tested phenolic compounds on survival rates of S. cerevisiae BY4741 cells treated with CumOOH (150 µM). Black bar means untreated cells, gray bar means cells treated only with CumOOH and white bars mean cells treated with CumOOH +2,3-diOH-BA (A), 3,4-diOH-BA (B), and 3,4-diOH-B (C). Data represent the mean values ± SD of at least three independent experiments. Different lowercase letters above the bars indicate a statistically significant difference at p < 0.05. Full article ">

8 pages, 1228 KiB

Open AccessArticle

Protective Effects of Transient Glucose Exposure in Adult C. elegans

by Katharina Murillo, Azat Samigullin, Per M. Humpert, Thomas Fleming, Kübra Özer, Andrea Schlotterer, Hans-Peter Hammes and Michael Morcos

Antioxidants 2022, 11(1), 160; https://doi.org/10.3390/antiox11010160 - 14 Jan 2022

Cited by 3 | Viewed by 3213

Abstract

C. elegans are used to study molecular pathways, linking high glucose levels (HG) to diabetic complications. Persistent exposure of C. elegans to a HG environment induces the mitochondrial formation of reactive oxygen species (ROS) and advanced glycation endproducts (AGEs), leading to neuronal damage [...] Read more.

C. elegans are used to study molecular pathways, linking high glucose levels (HG) to diabetic complications. Persistent exposure of C. elegans to a HG environment induces the mitochondrial formation of reactive oxygen species (ROS) and advanced glycation endproducts (AGEs), leading to neuronal damage and decreased lifespan. Studies suggest that transient high glucose exposure (TGE) exerts different effects than persistent exposure. Thus, the effects of TGE on ROS, AGE-formation and life span were studied in C. elegans. Four-day TGE (400 mM) as compared to controls (0mM) showed a persistent increase of ROS (4-days 286 ± 40 RLUs vs. control 187 ± 23 RLUs) without increased formation of AGEs. TGE increased body motility (1-day 0.14 ± 0.02; 4-days 0.15 ± 0.01; 6-days 0.16 ± 0.02 vs. control 0.10 ± 0.02 in mm/s), and bending angle (1-day 17.7 ± 1.55; 3-days 18.7 ± 1.39; 6-days 20.3 ± 0.61 vs. control 15.3 ± 1.63 in degree/s) as signs of neuronal damage. Lifespan was increased by 27% (21 ± 2.4 days) after one-day TGE, 34% (22 ± 1.2 days) after four-days TGE, and 26% (21 ± 1.4 days) after six-days TGE vs. control (16 ± 1.3 days). These experiments suggest that TGE in C. elegans has positive effects on life span and neuronal function, associated with mildly increased ROS-formation. From the perspective of metabolic memory, hormetic effects outweighed the detrimental effects of a HG environment. Full article

(This article belongs to the Special Issue Oxidative Stress, Endoplasmic Reticulum and Mitochondrial Stress and Senescence)

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GFP-reporter for glutathione-S-transferase 4 expression after exposure to transient high glucose over indicated time-periods (day one, two, three, or four) and subsequent conduction of the experiment without TGE exposure for the same time period (measurement after a total of two, four, six, and eight days) to assess the persisting gst-4 exposure. In each experimental group the mean and standard deviation of three individual experiments is displayed with * p < 0.05. Full article ">Figure 2
AGEs (a) argpyrimidine (AP), (b) fructosyllysine (FL), and (c) methylglyoxal-hydroimidazolone-1 (MG-H1), were not significantly increased on day 12 after initial TGE over 1, 4 or 6 days. In each experimental group the mean and standard deviation of three individual experiments is displayed. Full article ">Figure 3
Whole body motility (a) and bending angle average (b) at the end of the experiment (12 days) after TGE over one, four, and six days. In each experimental group the mean and standard deviation of four individual experiments is displayed with * p < 0.05, ** p < 0.01, *** p < 0.001. Full article ">Figure 4
Survival rate of C. elegans after one, four, and six days of TGE. Full article ">

14 pages, 1658 KiB

Open AccessArticle

Redox-Regulation of α-Globin in Vascular Physiology

by Laurent Kiger, Julia Keith, Abdullah Freiwan, Alfonso G. Fernandez, Heather Tillman, Brant E. Isakson, Mitchell J. Weiss and Christophe Lechauve

Antioxidants 2022, 11(1), 159; https://doi.org/10.3390/antiox11010159 - 14 Jan 2022

Cited by 8 | Viewed by 2706

Abstract

Interest in the structure, function, and evolutionary relations of circulating and intracellular globins dates back more than 60 years to the first determination of the three-dimensional structure of these proteins. Non-erythrocytic globins have been implicated in circulatory control through reactions that couple nitric [...] Read more.

Interest in the structure, function, and evolutionary relations of circulating and intracellular globins dates back more than 60 years to the first determination of the three-dimensional structure of these proteins. Non-erythrocytic globins have been implicated in circulatory control through reactions that couple nitric oxide (NO) signaling with cellular oxygen availability and redox status. Small artery endothelial cells (ECs) express free α-globin, which causes vasoconstriction by degrading NO. This reaction converts reduced (Fe²⁺) α-globin to the oxidized (Fe³⁺) form, which is unstable, cytotoxic, and unable to degrade NO. Therefore, (Fe³⁺) α-globin must be stabilized and recycled to (Fe²⁺) α-globin to reinitiate the catalytic cycle. The molecular chaperone α-hemoglobin-stabilizing protein (AHSP) binds (Fe³⁺) α-globin to inhibit its degradation and facilitate its reduction. The mechanisms that reduce (Fe³⁺) α-globin in ECs are unknown, although endothelial nitric oxide synthase (eNOS) and cytochrome b₅ reductase (CyB5R3) with cytochrome b₅ type A (CyB5a) can reduce (Fe³⁺) α-globin in solution. Here, we examine the expression and cellular localization of eNOS, CyB5a, and CyB5R3 in mouse arterial ECs and show that α-globin can be reduced by either of two independent redox systems, CyB5R3/CyB5a and eNOS. Together, our findings provide new insights into the regulation of blood vessel contractility. Full article

(This article belongs to the Special Issue NO Role in Evolution: Significance and Signaling)

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α-Globin and redox systems are co-expressed in small arteries. (A) mRNA levels in the thoracodorsal artery (TDA) and mesenteric arteries. The bar chart shows data from three or four 6-month-old mice. (B,C) Indirect immunofluorescence multiplexing staining for α-globin, endothelial nitric oxide synthase (eNOS), CyB5a, CyB5b, and CyB5R3 (white arrows) in TDA (B) and mesenteric artery (C) preparations. The dashed line across the internal elastic lamina demarcates the ECs and VSMCs. Merges represent the overlap of “α-globin+DAPI” with other staining based on the black arrow upstream. DAPI-stained nuclei are shown in blue, in combination with differential interference contrast. Scale bars are equivalent to 10 μm and 20 μm (for the higher magnification). Full article ">Figure 2
eNOS reduction. (A) Spectra for full-length Fe3+ eNOS (black line), after the addition of NADPH (red line) or with sodium dithionite (cyan line), under anaerobic conditions. The red spectrum is simulated as a combination of 40% ferric and 60% ferrous eNOS. The insert shows the differential spectrum for the oxygenase domain redox transition of the full-length eNOS after addition of NADPH, which also involves flavin reduction in the reductase domain (485 nm, black arrow). (B) eNOS reduction kinetics in the presence of cofactors and L-arginine after mixing NADPH under anaerobic conditions. The dashed lines represent the exponential rise fit with the associated determination coefficient (R2). Full article ">Figure 3
α-Globin reduction by eNOS. (A) α-Globin–AHSP reduction kinetics after mixing with eNOS pre-incubated under anaerobic conditions in the presence of NADPH (as presented in <a href="#antioxidants-11-00159-f002" class="html-fig">Figure 2</a>A). The chosen detection wavelength of 410 nm is close to the isosbestic point of the eNOS redox transition (as presented in <a href="#antioxidants-11-00159-f002" class="html-fig">Figure 2</a>B). The dashed line represents the exponential decay fit with the associated determination coefficient (R2). The insert shows the transition spectrum of the oxidized (black line) and reduced (red line) α-globin. (B) The second derivative of the eNOS/NADPH and α-globin–AHSP mixture after the completion of globin reduction under anaerobic conditions with CO. The (Fe3+) α-globin–AHSP second derivative is centered at 414 nm, which is characteristic of bis-histidyl hexacoordination (black solid line). After reduction, the (Fe2+) α-globin–CO is revealed with the minima of its second derivative centered at 419 nm, whereas the (Fe2+) eNOS–CO is revealed with the minima centered at 445 nm (orange line). Upon the addition of dithionite, the amplitude of the (Fe2+) eNOS–CO second derivative increases almost two-fold (purple dashed line) by comparison with that of (Fe2+) α-globin–CO, which does not change (orange line). This underlines the fact that (Fe3+) α-globin–AHSP is fully reduced by eNOS after a few tens of seconds, whereas eNOS is only partially reduced by approximately 50%. All reaction were performed at 25 °C. Full article ">Figure 4
Model for regulation of NO metabolism by α-globin in the myoendothelial junction (MEJ) of vascular endothelial cells. After translation, newly formed apo–α-globin subunits bind to their partner subunit, AHSP, or, to a lesser extent, eNOS. AHSP can bind to both reduced (Fe2+) and oxidized (Fe3+) α-globin. In the reduced complex, the heme group is coordinated with the bound O2. O2 (Fe2+) α-globin interacts with eNOS and degrades NO via dioxygenation or binds AHSP and rapidly becomes oxidized. The oxidized α-globin is catalytically inert, and it is this function of AHSP that protects cells from oxidative damage. However, the specific binding of α-globin by AHSP or eNOS prevents α-globin from precipitating, allowing more time for α-globin to be reduced by eNOS directly or by the CyB5R3/CyB5 system and become functional. Full article ">

14 pages, 1810 KiB

Open AccessArticle

PEG35 and Glutathione Improve Mitochondrial Function and Reduce Oxidative Stress in Cold Fatty Liver Graft Preservation

by Raquel G. Bardallo, Idoia Company-Marin, Emma Folch-Puy, Joan Roselló-Catafau, Arnau Panisello-Rosello and Teresa Carbonell

Antioxidants 2022, 11(1), 158; https://doi.org/10.3390/antiox11010158 - 14 Jan 2022

Cited by 19 | Viewed by 3373

Abstract

The need to meet the demand for transplants entails the use of steatotic livers, more vulnerable to ischemia-reperfusion (IR) injury. Therefore, finding the optimal composition of static cold storage (SCS) preservation solutions is crucial. Given that ROS regulation is a therapeutic strategy for [...] Read more.

The need to meet the demand for transplants entails the use of steatotic livers, more vulnerable to ischemia-reperfusion (IR) injury. Therefore, finding the optimal composition of static cold storage (SCS) preservation solutions is crucial. Given that ROS regulation is a therapeutic strategy for liver IR injury, we have added increasing concentrations of PEG35 and glutathione (GSH) to the preservation solutions (IGL-1 and IGL-2) and evaluated the possible protection against energy depletion and oxidative stress. Fatty livers from obese Zücker rats were isolated and randomly distributed in the control (Sham) preserved (24 h at 4 °C) in IGL-0 (without PEG35 and 3 mmol/L GSH), IGL-1 (1 g/L PEG35, and 3 mmol/L GSH), and IGL-2 (5 g/L PEG35 and 9 mmol/L GSH). Energy metabolites (ATP and succinate) and the expression of mitochondrial oxidative phosphorylation complexes (OXPHOS) were determined. Mitochondrial carrier uncoupling protein 2 (UCP2), PTEN-induced kinase 1 (PINK1), nuclear factor-erythroid 2 related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and the inflammasome (NLRP3) expressions were analyzed. As biomarkers of oxidative stress, protein oxidation (AOPP) and carbonylation (DNP derivatives), and lipid peroxidation (malondialdehyde (MDA)–thiobarbituric acid (TBA) adducts) were measured. In addition, the reduced and oxidized glutathione (GSH and GSSG) and enzymatic (Cu–Zn superoxide dismutase (SOD), CAT, GSH S-T, GSH-Px, and GSH-R) antioxidant capacities were determined. Our results showed that the cold preservation of fatty liver graft depleted ATP, accumulated succinate and increased oxidative stress. In contrast, the preservation with IGL-2 solution maintained ATP production, decreased succinate levels and increased OXPHOS complexes I and II, UCP2, and PINK-1 expression, therefore maintaining mitochondrial integrity. IGL-2 also protected against oxidative stress by increasing Nrf2 and HO-1 expression and GSH levels. Therefore, the presence of PEG35 in storage solutions may be a valuable option as an antioxidant agent for organ preservation in clinical transplantation. Full article

(This article belongs to the Special Issue Antioxidant Agents for the Prevention and Therapy of Oxidative Stress in Hepatic Diseases)

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17 pages, 910 KiB

Open AccessReview

The Interconnected Mechanisms of Oxidative Stress and Neuroinflammation in Epilepsy

by Anna L. M. Parsons, Eboni M. V. Bucknor, Enrico Castroflorio, Tânia R. Soares, Peter L. Oliver and Daniel Rial

Antioxidants 2022, 11(1), 157; https://doi.org/10.3390/antiox11010157 - 14 Jan 2022

Cited by 58 | Viewed by 6925

Abstract

One of the most important characteristics of the brain compared to other organs is its elevated metabolic demand. Consequently, neurons consume high quantities of oxygen, generating significant amounts of reactive oxygen species (ROS) as a by-product. These potentially toxic molecules cause oxidative stress [...] Read more.

One of the most important characteristics of the brain compared to other organs is its elevated metabolic demand. Consequently, neurons consume high quantities of oxygen, generating significant amounts of reactive oxygen species (ROS) as a by-product. These potentially toxic molecules cause oxidative stress (OS) and are associated with many disorders of the nervous system, where pathological processes such as aberrant protein oxidation can ultimately lead to cellular dysfunction and death. Epilepsy, characterized by a long-term predisposition to epileptic seizures, is one of the most common of the neurological disorders associated with OS. Evidence shows that increased neuronal excitability—the hallmark of epilepsy—is accompanied by neuroinflammation and an excessive production of ROS; together, these factors are likely key features of seizure initiation and propagation. This review discusses the role of OS in epilepsy, its connection to neuroinflammation and the impact on synaptic function. Considering that the pharmacological treatment options for epilepsy are limited by the heterogeneity of these disorders, we also introduce the latest advances in anti-epileptic drugs (AEDs) and how they interact with OS. We conclude that OS is intertwined with numerous physiological and molecular mechanisms in epilepsy, although a causal relationship is yet to be established. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurons)

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22 pages, 4485 KiB

Open AccessEditor’s ChoiceArticle

by Razia Sultana Mohammad, Mustafa F. Lokhandwala and Anees A. Banday

Antioxidants 2022, 11(1), 156; https://doi.org/10.3390/antiox11010156 - 14 Jan 2022

Cited by 23 | Viewed by 3647

Abstract

Age is one of the major risk factors for the development of chronic pathologies, including kidney diseases. Oxidative stress and mitochondrial dysfunction play a pathogenic role in aging kidney disease. Transcription factor NRF2, a master regulator of redox homeostasis, is altered during aging, [...] Read more.

Age is one of the major risk factors for the development of chronic pathologies, including kidney diseases. Oxidative stress and mitochondrial dysfunction play a pathogenic role in aging kidney disease. Transcription factor NRF2, a master regulator of redox homeostasis, is altered during aging, but the exact implications of altered NRF2 signaling on age-related renal mitochondrial impairment are not yet clear. Herein, we investigated the role of sulforaphane, a well-known NRF2 activator, on age-related mitochondrial and kidney dysfunction. Young (2–4 month) and aged (20–24 month) male Fischer 344 rats were treated with sulforaphane (15 mg/kg body wt/day) in drinking water for four weeks. We observed significant impairment in renal cortical mitochondrial function along with perturbed redox homeostasis, decreased kidney function and marked impairment in NRF2 signaling in aged Fischer 344 rats. Sulforaphane significantly improved mitochondrial function and ameliorated kidney injury by increasing cortical NRF2 expression and activity and decreasing protein expression of KEAP1, an NRF2 repressor. Sulforaphane treatment did not affect the renal NRF2 expression or activity and mitochondrial function in young rats. Taken together, our results provide novel insights into the protective role of the NRF2 pathway in kidneys during aging and highlight the therapeutic potential of sulforaphane in mitigating kidney dysfunction in elders. Full article

(This article belongs to the Special Issue NRF2 in Health and Diseases)

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17 pages, 2896 KiB

Open AccessArticle

Fermentation with Tea Residues Enhances Antioxidant Activities and Polyphenol Contents in Kombucha Beverages

by Dan-Dan Zhou, Adila Saimaiti, Min Luo, Si-Yu Huang, Ruo-Gu Xiong, Ao Shang, Ren-You Gan and Hua-Bin Li

Antioxidants 2022, 11(1), 155; https://doi.org/10.3390/antiox11010155 - 14 Jan 2022

Cited by 53 | Viewed by 7199

Abstract

Kombucha is a popular beverage with various bioactivities (such as antioxidant activity), which can be attributed to its abundant bioactive compounds, especially polyphenols. Kombucha is conventionally prepared by fermentation of a sugared black tea infusion without tea residue. In this study, the effects [...] Read more.

Kombucha is a popular beverage with various bioactivities (such as antioxidant activity), which can be attributed to its abundant bioactive compounds, especially polyphenols. Kombucha is conventionally prepared by fermentation of a sugared black tea infusion without tea residue. In this study, the effects of black tea residue and green tea residue on kombucha were studied, and its antioxidant activities, total phenolic contents, as well as concentrations of polyphenols at different fermentation stages were evaluated using ferric-reducing antioxidant power, Trolox equivalent antioxidant capacity, Folin-Ciocalteu method and high-performance liquid chromatography with a photodiode array detector. The results showed that fermentation with tea residue could markedly increase antioxidant activities (maximum 3.25 times) as well as polyphenolic concentrations (5.68 times) of kombucha. In addition, green tea residue showed a stronger effect than black tea residue. Overall, it is interesting to find that fermentation with tea residues could be a better strategy to produce polyphenol-rich kombucha beverages. Full article

(This article belongs to the Special Issue Antioxidants and Bioactive Compounds in Fermented Foods)

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12 pages, 875 KiB

Open AccessArticle

GlyNAC (Glycine and N-Acetylcysteine) Supplementation Improves Impaired Mitochondrial Fuel Oxidation and Lowers Insulin Resistance in Patients with Type 2 Diabetes: Results of a Pilot Study

by Rajagopal V. Sekhar

Antioxidants 2022, 11(1), 154; https://doi.org/10.3390/antiox11010154 - 13 Jan 2022

Cited by 26 | Viewed by 11459

Abstract

Patients with type 2 diabetes (T2D) are known to have mitochondrial dysfunction and increased insulin resistance (IR), but the underlying mechanisms are not well understood. We reported previously that (a) adequacy of the antioxidant glutathione (GSH) is necessary for optimal mitochondrial fatty-acid oxidation [...] Read more.

Patients with type 2 diabetes (T2D) are known to have mitochondrial dysfunction and increased insulin resistance (IR), but the underlying mechanisms are not well understood. We reported previously that (a) adequacy of the antioxidant glutathione (GSH) is necessary for optimal mitochondrial fatty-acid oxidation (MFO); (b) supplementing the GSH precursors glycine and N-acetylcysteine (GlyNAC) in mice corrected GSH deficiency, reversed impaired MFO, and lowered oxidative stress (OxS) and IR; and (c) supplementing GlyNAC in patients with T2D improved GSH synthesis and concentrations, and lowered OxS. However, the effect of GlyNAC on MFO, MGO (mitochondrial glucose oxidation), IR and plasma FFA (free-fatty acid) concentrations in humans with T2D remains unknown. This manuscript reports the effect of supplementing GlyNAC for 14-days on MFO, MGO, IR and FFA in 10 adults with T2D and 10 unsupplemented non-diabetic controls. Fasted T2D participants had 36% lower MFO (p < 0.001), 106% higher MGO (p < 0.01), 425% higher IR (p < 0.001) and 76% higher plasma FFA (p < 0.05). GlyNAC supplementation significantly improved fasted MFO by 30% (p < 0.001), lowered MGO by 47% (p < 0.01), decreased IR by 22% (p < 0.01) and lowered FFA by 25% (p < 0.01). These results provide proof-of-concept that GlyNAC supplementation could improve mitochondrial dysfunction and IR in patients with T2D, and warrant additional research. Full article

(This article belongs to the Special Issue Antioxidants in Human Health and Disease)

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20 pages, 932 KiB

Open AccessReview

Chemical Stability of Ascorbic Acid Integrated into Commercial Products: A Review on Bioactivity and Delivery Technology

by Xin Yin, Kaiwen Chen, Hao Cheng, Xing Chen, Shuai Feng, Yuanda Song and Li Liang

Antioxidants 2022, 11(1), 153; https://doi.org/10.3390/antiox11010153 - 13 Jan 2022

Cited by 140 | Viewed by 26658

Abstract

The L-enantiomer of ascorbic acid is commonly known as vitamin C. It is an indispensable nutrient and plays a key role in retaining the physiological process of humans and animals. L-gulonolactone oxidase, the key enzyme for the de novo synthesis of ascorbic acid, [...] Read more.

The L-enantiomer of ascorbic acid is commonly known as vitamin C. It is an indispensable nutrient and plays a key role in retaining the physiological process of humans and animals. L-gulonolactone oxidase, the key enzyme for the de novo synthesis of ascorbic acid, is lacking in some mammals including humans. The functionality of ascorbic acid has prompted the development of foods fortified with this vitamin. As a natural antioxidant, it is expected to protect the sensory and nutritional characteristics of the food. It is thus important to know the degradation of ascorbic acid in the food matrix and its interaction with coexisting components. The biggest challenge in the utilization of ascorbic acid is maintaining its stability and improving its delivery to the active site. The review also includes the current strategies for stabilizing ascorbic acid and the commercial applications of ascorbic acid. Full article

(This article belongs to the Special Issue Characterization and Encapsulation of Natural Antioxidants: Interaction, Protection and Delivery)

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13 pages, 287 KiB

Open AccessArticle

Genetic Polymorphisms of MnSOD Modify the Impacts of Environmental Melamine on Oxidative Stress and Early Kidney Injury in Calcium Urolithiasis Patients

by Chia-Chu Liu, Chia-Fang Wu, Yung-Chin Lee, Tsung-Yi Huang, Shih-Ting Huang, Hsun-Shuan Wang, Jhen-Hao Jhan, Shu-Pin Huang, Ching-Chia Li, Yung-Shun Juan, Tusty-Jiuan Hsieh, Yi-Chun Tsai, Chu-Chih Chen and Ming-Tsang Wu

Antioxidants 2022, 11(1), 152; https://doi.org/10.3390/antiox11010152 - 13 Jan 2022

Cited by 4 | Viewed by 2819

Abstract

Environmental melamine exposure increases the risks of oxidative stress and early kidney injury. Manganese superoxide dismutase (MnSOD), glutathione peroxidase, and catalase can protect the kidneys against oxidative stress and maintain normal function. We evaluated whether their single-nucleotide polymorphisms (SNPs) could modify melamine’s effects. [...] Read more.

Environmental melamine exposure increases the risks of oxidative stress and early kidney injury. Manganese superoxide dismutase (MnSOD), glutathione peroxidase, and catalase can protect the kidneys against oxidative stress and maintain normal function. We evaluated whether their single-nucleotide polymorphisms (SNPs) could modify melamine’s effects. A total of 302 patients diagnosed with calcium urolithiasis were enrolled. All patients provided one-spot overnight urine samples to measure their melamine levels, urinary biomarkers of oxidative stress and renal tubular injury. Median values were used to dichotomize levels into high and low. Subjects carrying the T allele of rs4880 and high melamine levels had 3.60 times greater risk of high malondialdehyde levels than those carrying the C allele of rs4880 and low melamine levels after adjustment. Subjects carrying the G allele of rs5746136 and high melamine levels had 1.73 times greater risk of high N-Acetyl-β-d-glucosaminidase levels than those carrying the A allele of rs5746136 and low melamine levels. In conclusion, the SNPs of MnSOD, rs4880 and rs5746136, influence the risk of oxidative stress and renal tubular injury, respectively, in calcium urolithiasis patients. In the context of high urinary melamine levels, their effects on oxidative stress and renal tubular injury were further increased. Full article

(This article belongs to the Special Issue Oxidative Stress in Human Toxicology)

11 pages, 1322 KiB

Open AccessArticle

The Role of H₂O₂-Scavenging Enzymes (Ascorbate Peroxidase and Catalase) in the Tolerance of Lemna minor to Antibiotics: Implications for Phytoremediation

by Marcelo Pedrosa Gomes, Rafael Shinji Akiyama Kitamura, Raizza Zorman Marques, Marcello Locatelli Barbato and Marcel Zámocký

Antioxidants 2022, 11(1), 151; https://doi.org/10.3390/antiox11010151 - 13 Jan 2022

Cited by 33 | Viewed by 6069

Abstract

We investigated the individual and combined contributions of two distinct heme proteins namely, ascorbate peroxidase (APX) and catalase (CAT) on the tolerance of Lemna minor plants to antibiotics. For our investigation, we used specific inhibitors of these two H₂O₂-scavenging [...] Read more.

We investigated the individual and combined contributions of two distinct heme proteins namely, ascorbate peroxidase (APX) and catalase (CAT) on the tolerance of Lemna minor plants to antibiotics. For our investigation, we used specific inhibitors of these two H₂O₂-scavenging enzymes (p-aminophenol, 3-amino,1,2,4-triazole, and salicylic acid). APX activity was central for the tolerance of this aquatic plant to amoxicillin (AMX), whereas CAT activity was important for avoiding oxidative damage when exposed to ciprofloxacin (CIP). Both monitored enzymes had important roles in the tolerance of Lemna minor to erythromycin (ERY). The use of molecular kinetic approaches to detect and increase APX and/or CAT scavenging activities could enhance tolerance, and, therefore, improve the use of L. minor plants to reclaim antibiotics from water bodies. Full article

(This article belongs to the Special Issue The Role of Peroxidases and Catalases in Photosynthetic and Non–photosynthetic Eukaryotes)

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Effects of increasing concentrations of p-aminophenol (p-AI), 3-amino,1,2,4-triazole (3-AT), and salicylic acid (SA) on superoxide dismutase (SOD) (A–C), ascorbate peroxidase (APX) (D–F), and catalase (CAT) (G–I) activities in L. minor plants after exposure for seven days. Bars represent the means ± SD of four replicates. Different letters indicate significant differences (p > 0.05) using the post hoc Tukey test. Full article ">Figure 2
Fresh weight (A–C) and quantum yields of photosystem II (FV/FM; D–F) in L. minor plants exposed to isolated or combined concentrations of antibiotics and antioxidant-enzyme inhibitors for seven days. Bars represent the means ± SD of four replicates. Different letters indicate significant differences (p > 0.05) using the post hoc Tukey test. CON = control; AMX = 2 µg amoxicillin L−1; ERY = 1.7 µg erythromycin L−1; CIP = 1.05 mg ciprofloxacin L−1; p-AI = 5 mM p-aminophenol; 3-AT = 200 mM 3-amino,1,2,4-triazole; and SA = 1000 µM salicylic acid. Full article ">Figure 3
Hydrogen peroxide (H2O2; A–C) and malondialdehyde (MDA; D–F) concentrations and ascorbate peroxidase (APX; G–I) and catalase (CAT; J–L) activities in L. minor plants exposed to isolated or combined concentrations of antibiotics and antioxidant-enzyme inhibitors for seven days. Bars represent the means ± SD of four replicates. Different letters indicate significant differences (p > 0.05) using the post hoc Tukey test. CON = control; AMX = 2 µg amoxicillin L−1; ERY = 1.7 µg erythromycin L−1; CIP = 1.05 mg ciprofloxacin L−1; p-AI = 5 mM p-aminophenol; 3-AT = 200 mM 3-amino,1,2,4-triazole; and SA = 1000 µM salicylic acid. Full article ">

28 pages, 1730 KiB

Open AccessReview

Can Polyphenols Inhibit Ferroptosis?

by Marija Lesjak, Nataša Simin and Surjit K. S. Srai

Antioxidants 2022, 11(1), 150; https://doi.org/10.3390/antiox11010150 - 12 Jan 2022

Cited by 21 | Viewed by 4785

Abstract

Polyphenols, a diverse group of naturally occurring molecules commonly found in higher plants, have been heavily investigated over the last two decades due to their potent biological activities—among which the most important are their antioxidant, antimicrobial, anticancer, anti-inflammatory and neuroprotective activities. A common [...] Read more.

Polyphenols, a diverse group of naturally occurring molecules commonly found in higher plants, have been heavily investigated over the last two decades due to their potent biological activities—among which the most important are their antioxidant, antimicrobial, anticancer, anti-inflammatory and neuroprotective activities. A common route of polyphenol intake in humans is through the diet. Since they are subjected to excessive metabolism in vivo it has been questioned whether their much-proven in vitro bioactivity could be translated to in vivo systems. Ferroptosis is a newly introduced, iron-dependent, regulated mode of oxidative cell death, characterized by increased lipid peroxidation and the accumulation of toxic lipid peroxides, which are considered to be toxic reactive oxygen species. There is a growing body of evidence that ferroptosis is involved in the development of almost all chronic diseases. Thus, ferroptosis is considered a new therapeutic target for offsetting many diseases, and researchers are putting great expectations on this field of research and medicine. The aim of this review is to critically analyse the potential of polyphenols to modulate ferroptosis and whether they can be considered promising compounds for the alleviation of chronic conditions. Full article

(This article belongs to the Special Issue Dietary Bioactives and Their Metabolites as Modulators of Oxidative Stress and Inflammation)

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29 pages, 1496 KiB

Open AccessReview

Nrf2 in the Field of Dentistry with Special Attention to NLRP3

by Lisa Schieffer, Claudia Manzl, Christoph Schatz, Johannes Haybaeck and Adriano Crismani

Antioxidants 2022, 11(1), 149; https://doi.org/10.3390/antiox11010149 - 12 Jan 2022

Cited by 12 | Viewed by 4285

Abstract

The aim of this review article was to summarize the functional implications of the nuclear factor E2-related factor or nuclear factor (erythroid-derived 2)-like 2 (Nrf2), with special attention to the NACHT (nucleotide-binding oligomerization), LRR (leucine-rich repeat), and PYD (pyrin domain) domains-containing protein 3 [...] Read more.

The aim of this review article was to summarize the functional implications of the nuclear factor E2-related factor or nuclear factor (erythroid-derived 2)-like 2 (Nrf2), with special attention to the NACHT (nucleotide-binding oligomerization), LRR (leucine-rich repeat), and PYD (pyrin domain) domains-containing protein 3 (NLRP3) inflammasome in the field of dentistry. NLRP3 plays a crucial role in the progression of inflammatory and adaptive immune responses throughout the body. It is already known that this inflammasome is a key regulator of several systemic diseases. The initiation and activation of NLRP3 starts with the oral microbiome and its association with the pathogenesis and progression of several oral diseases, including periodontitis, periapical periodontitis, and oral squamous cell carcinoma (OSCC). The possible role of the inflammasome in oral disease conditions may involve the aberrant regulation of various response mechanisms, not only in the mouth but in the whole body. Understanding the cellular and molecular biology of the NLRP3 inflammasome and its relationship to Nrf2 is necessary for the rationale when suggesting it as a potential therapeutic target for treatment and prevention of oral inflammatory and immunological disorders. In this review, we highlighted the current knowledge about NLRP3, its likely role in the pathogenesis of various inflammatory oral processes, and its crosstalk with Nrf2, which might offer future possibilities for disease prevention and targeted therapy in the field of dentistry and oral health. Full article

(This article belongs to the Special Issue NRF2 in Health and Diseases)

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19 pages, 3322 KiB

Open AccessArticle

Dietary Vitamin A Improved the Flesh Quality of Grass Carp (Ctenopharyngodon idella) in Relation to the Enhanced Antioxidant Capacity through Nrf2/Keap 1a Signaling Pathway

by Pei Wu, Li Zhang, Weidan Jiang, Yang Liu, Jun Jiang, Shengyao Kuang, Shuwei Li, Ling Tang, Wuneng Tang, Xiaoqiu Zhou and Lin Feng

Antioxidants 2022, 11(1), 148; https://doi.org/10.3390/antiox11010148 - 12 Jan 2022

Cited by 26 | Viewed by 3488

Abstract

Fish is an important animal-source food for humans. However, the oxidative stress-induced by intensive aquaculture usually causes deterioration of fish meat quality. The nutritional way has been considered to be a useful method for improving fish flesh quality. This study using the same [...] Read more.

Fish is an important animal-source food for humans. However, the oxidative stress-induced by intensive aquaculture usually causes deterioration of fish meat quality. The nutritional way has been considered to be a useful method for improving fish flesh quality. This study using the same growth experiment as our previous study was conducted to investigate whether vitamin A could improve flesh quality by enhancing antioxidative ability via Nrf2/Keap1 signaling in fish muscle. Six diets with different levels of vitamin A were fed to grass carp (Ctenopharyngodon idella) (262.02 ± 0.45 g) for 10 weeks. Dietary vitamin A significantly improved flesh sensory appeal and nutritional value, as evident by higher pH_24h value, water-holding capacity, shear force, contents of protein, lipid, four indispensable amino acids (lysine, methionine, threonine, and arginine) and total polyunsaturated fatty acid in the muscle. Furthermore, dietary vitamin A reduced oxidative damage, as evident by decreased levels of muscle reactive oxygen species, malondialdehyde, and protein carbonyl, enhanced activities of antioxidative enzyme (catalase, copper/zinc superoxide dismutase (CuZnSOD), MnSOD, glutathione peroxidase, and glutathione reductase), as well as increased content of glutathione, which was probably in relation to the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. These findings demonstrated that dietary vitamin A improved flesh quality probably by enhancing antioxidant ability through Nrf2/Keap 1a signaling in fish. Full article

(This article belongs to the Special Issue Antioxidants in Animal Feed)

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The histology of on-growing grass carp muscle (H&E 100×): (A) The vitamin A-deficient group. Arrowhead showed the rupture in muscle fiber. (B) The group with vitamin A at 606.8 IU/kg. (C) The group with vitamin A at 1209 IU/kg. (D) The group with vitamin A at 1798 IU/kg. (E) The group with vitamin A at 2805 IU/kg. (F) The group with vitamin A at 3796 IU/kg. Full article ">Figure 2
Effects of dietary vitamin A on contents of ROS (A), MDA and PC (B) in muscle of on-growing grass carp. Data are means ± SEM of three replicate groups, two fish for each replicate (n = 3). a,b,c,d within a column, means without a common lowercase superscript differ (p < 0.05). p-values underlined with a solid line indicate a linear and quadratic response to dietary vitamin A levels. SEM = standard error of the mean; L = linear; Q = quadratic; ROS = reactive oxygen species, %DCF florescence; MDA = malondialdehyde, nmol/mg prot; PC = protein carbonyl, nmol/mg prot. Full article ">Figure 3
Effects of dietary vitamin A on relative mRNA levels of antioxidant enzymes genes in muscle of on-growing grass carp. Data are means ± SEM of three replicate groups, two fish for each replicate (n = 3). a, b, c within a column, means without a common lowercase superscript differ (p < 0.05). p-values underlined with a solid line indicate a linear and quadratic response to dietary vitamin A levels. SEM = standard error of the mean; L = linear; Q = quadratic; CuZnSOD = copper/zinc superoxide dismutase; MnSOD = manganese superoxide dismutase; CAT = catalase; GPx1a = glutathione peroxidase 1a; GPx1b = glutathione peroxidase 1b; GPx4a = glutathione peroxidase 4a; GPx4b = glutathione peroxidase 4b; GSTr = glutathione-S-transferase r; GSTp1 = glutathione-S-transferase p1; GSTp2 = glutathione-S-transferase p2; GR = glutathione reductase. Full article ">Figure 4
Effects of dietary vitamin A on relative mRNA levels of Nrf2, keap1a, and keap1b (A); total and nuclear levels of Nrf2 protein (B) in muscle of on-growing grass carp. Data are means ± SEM of three replicate groups, two fish for each replicate (n = 3). a,b,c,d within a column, means without a common lowercase superscript differ (p < 0.05). p-values underlined with a solid line indicate a linear and quadratic response to dietary vitamin A levels. SEM = standard error of the mean; L = linear; Q = quadratic; Nrf2 = nuclear factor erythroid 2-related factor 2; Keap1a = Kelch-like ECH-associated protein 1a; Keap1b = Kelch-like ECH-associated protein 1b. Full article ">Figure 5
Effects of dietary vitamin A on relative mRNA levels of TOR and S6K1 (A), total and phosphorylation levels of TOR protein (B) in muscle of on-growing grass carp. Data are means ± SEM of three replicate groups, two fish for each replicate (n = 3). a,b,c,d within a column, means without a common lowercase superscript differ (p < 0.05). p-values underlined with a solid line indicate a linear and quadratic response to dietary vitamin A levels. SEM = standard error of the mean; L = linear; Q = quadratic; TOR = target of rapamycin; S6K1 = ribosomal protein s6 kinase polypeptide 1. Full article ">Figure 6
The dietary vitamin A requirements for on-growing grass carp based on muscle shear force (A) and contents of reactive oxygen species (ROS, (B)). Full article ">

9 pages, 1115 KiB

Open AccessArticle

Sodium Thiosulfate Improves Hypertension in Rats with Adenine-Induced Chronic Kidney Disease

by Chien-Ning Hsu, Chih-Yao Hou, Guo-Ping Chang-Chien, Sufan Lin, Hung-Wei Yang and You-Lin Tain

Antioxidants 2022, 11(1), 147; https://doi.org/10.3390/antiox11010147 - 11 Jan 2022

Cited by 12 | Viewed by 2856

Abstract

Hypertension is highly prevalent in chronic kidney disease (CKD). Hydrogen sulfide (H₂S) is an endogenously produced gasotransmitter with vasodilator properties. We, hence, investigated whether oral administration of sodium thiosulfate (STS), a clinically applicable H₂S-based therapy, can exert a protective [...] Read more.

Hypertension is highly prevalent in chronic kidney disease (CKD). Hydrogen sulfide (H₂S) is an endogenously produced gasotransmitter with vasodilator properties. We, hence, investigated whether oral administration of sodium thiosulfate (STS), a clinically applicable H₂S-based therapy, can exert a protective effect against hypertension in an adenine-induced CKD rat model. Eight-week-old male Sprague–Dawley rats were fed with 0.5% adenine chow for 3 weeks to induce CKD. After 1 week, the rats were divided into two groups: one without and one with STS (2 g/kg body weight/day) in drinking water for 2 weeks. Treatment with STS lowered systolic and diastolic blood pressure by 7 and 9 mm Hg, respectively. Renal H₂S-generating enzyme expression was inhibited by CKD, while STS therapy increased plasma levels of H₂S and thiosulfate. Additionally, restoration of nitric oxide bioavailability and rebalance of the renin–angiotensin system may contribute to the protective effects of STS. Our data suggest that the oral administration of STS improves hypertension in an adenine-induced CKD model, which brings us closer to the clinical translation of H₂S-targeting therapy in CKD-induced hypertension. Full article

(This article belongs to the Special Issue Role of Hydrogen Sulfide in Health and Disease)

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Figure 1

Figure 1
Effects of sodium thiosulfate (STS) on the (A) plasma H2S level, (B) plasma thiosulfate level, and (C) renal mRNA expression of H2S-generating enzymes. All the results represent the mean ± the standard errors of eight animals in each group. Data are analyzed by one-way ANOVA followed by Tukey’s post hoc test. * p < 0.05 versus control g; * p < 0.05 vs. ND; # p < 0.05 CKD. Full article ">Figure 2
Effects of sodium thiosulfate (STS) on H2S-generating enzymes in the kidneys. (A) Representative Western blots show cystathionine β-synthase (CBS, ~61 kDa), cystathionine γ-lyase (CSE, ~45 kDa), and 3-mercaptopyruvate sulfurtransferase (3MST, ~52 kDa) bands. The relative abundance of renal cortical (B) CBS, (C) CSE, and (D) 3MST was quantified. All the results represent the mean ± the standard errors of eight animals in each group. Data are analyzed by one-way ANOVA followed by Tukey’s post hoc test. * p < 0.05 vs. ND. Full article ">Figure 3
Effects of sodium thiosulfate (STS) on the renin–angiotensin system. All the results represent the mean ± the standard errors of eight animals in each group. Data are analyzed by one-way ANOVA followed by Tukey’s post hoc test. * p < 0.05 vs. ND; # p < 0.05 vs. CKD. Full article ">

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