Folic Acid Protects Melanocytes from Oxidative Stress via Activation of Nrf2 and Inhibition of HMGB1

Vitiligo is a cutaneous depigmentation disease due to loss of epidermal melanocytes. Accumulating evidence has indicated that oxidative stress plays a vital role in vitiligo via directly destructing melanocytes and triggering inflammatory response that ultimately undermines melanocytes. Folic acid (FA), an oxidized form of folate with high bioavailability, exhibits potent antioxidant properties and shows therapeutic potential in multiple oxidative stress-related diseases. However, whether FA safeguards melanocytes from oxidative damages remains unknown. In this study, we first found that FA relieved melanocytes from H2O2-induced abnormal growth and apoptosis. Furthermore, FA enhanced the activity of antioxidative enzymes and remarkably reduced intracellular ROS levels in melanocytes. Subsequently, FA effectively activated nuclear factor E2-related factor 2 (Nrf2) pathway, and Nrf2 knockdown blocked the protective effects of FA on H2O2-treated melanocytes. Additionally, FA inhibited the production of proinflammatory HMGB1 in melanocytes under oxidative stress. Taken together, our findings support the protective effects of FA on human melanocytes against oxidative injury via the activation of Nrf2 and the inhibition of HMGB1, thus indicating FA as a potential therapeutic agent for the treatment of vitiligo.

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Oral delivery of nanoparticle urolithin A normalizes cellular stress and improves survival in mouse model of cisplatin-induced AKI

AJP Renal Physiology ◽

10.1152/ajprenal.00346.2019 ◽

2019 ◽

Vol 317 (5) ◽

pp. F1255-F1264 ◽

Cited By ~ 4

Author(s):

Dianxiong Zou ◽

Raghu Ganugula ◽

Meenakshi Arora ◽

Mary B. Nabity ◽

David Sheikh-Hamad ◽

...

Keyword(s):

Oxidative Stress ◽

Mouse Model ◽

Oral Bioavailability ◽

Oral Delivery ◽

Therapeutic Potential ◽

Survival Rates ◽

Antioxidant Properties ◽

Kidney Injury ◽

Related Factor ◽

Urolithin A

The popular anticancer drug cisplatin causes many adverse side effects, the most serious of which is acute kidney injury (AKI). Emerging evidence from laboratory and clinical studies suggests that the AKI pathogenesis involves oxidative stress pathways; therefore, regulating such pathways may offer protection. Urolithin A (UA), a gut metabolite of the dietary tannin ellagic acid, possesses antioxidant properties and has shown promise in mouse models of AKI. However, therapeutic potential of UA is constrained by poor bioavailability. We aimed to improve oral bioavailability of UA by formulating it into biodegradable nanoparticles that use a surface-conjugated ligand targeting the gut-expressed transferrin receptor. Nanoparticle encapsulation of UA led to a sevenfold enhancement in oral bioavailability compared with native UA. Treatment with nanoparticle UA also significantly attenuated the histopathological hallmarks of cisplatin-induced AKI and reduced mortality by 63% in the mouse model. Expression analyses indicated that nanoparticle UA therapy coincided with oxidative stress mitigation and downregulation of nuclear factor erythroid 2-related factor 2- and P53-inducible genes. Additionally, normalization of miRNA (miR-192-5p and miR-140-5p) implicated in AKI, poly(ADP-ribose) polymerase 1 levels, antiapoptotic signaling, intracellular NAD+, and mitochondrial oxidative phosphorylation were observed in the treatment group. Our findings suggest that nanoparticles greatly increase the oral bioavailability of UA, leading to improved survival rates in AKI mice, in part by reducing renal oxidative and apoptotic stress.

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Blueberry Polyphenol Extracts Enhance the Intestinal Antioxidant Capacity in Weaned Rats by Modulating the Nrf2–Keap1 Signal Pathway

Frontiers in Physiology ◽

10.3389/fphys.2021.640737 ◽

2021 ◽

Vol 12 ◽

Author(s):

Fangfang Zhao ◽

Shen Yan ◽

Mengliang Tian

Keyword(s):

Oxidative Stress ◽

Antioxidant Capacity ◽

Gene Transcription ◽

Interleukin 1 ◽

Antioxidant Properties ◽

The Body ◽

Initiation Factor ◽

Standard Diet ◽

Related Factor ◽

Protective Effects

Weaning causes the generation of excessive reactive oxygen species in the body, which could lead to oxidative stress. Polyphenols, for which blueberries are an important dietary source, are known for various health benefits including antioxidant properties. Here, we sought to elucidate the effects of blueberry polyphenol extracts (BPE) on intestinal antioxidant capacity and possible underlying mechanisms in weaned rats. Ninety-six rats were assigned to two groups and fed either a standard diet or a standard diet supplemented with BPE (200 mg/kg). The results showed that BPE supplementation increased (P < 0.05) catalase and superoxide dismutase activities and decreased (P < 0.05) interleukin-1 and interferon-γ contents in the jejunum and ileum. The abundances of mammalian target of rapamycin, ribosomal p70 S6 kinase and eukaryotic initiation factor 4E-binding protein 1 mRNA were elevated in the jejunum and ileum (P < 0.05) after BPE supplementation. Additionally, BPE supplementation decreased (P < 0.05) Kelch-like ECH-associated protein 1 (Keap1) gene transcription and enhanced (P < 0.05) NF-E2-related factor 2 (Nrf2) gene transcription in the jejunum and ileum. According to our results, BPE-induced protective effects against oxidative stress appear through the promotion of the jejunal and ileal antioxidant defense system in weaned rats, which was associated with the Nrf2–Keap1 signaling pathway.

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Ameliorative effects of crocin on paraquat-induced oxidative stress in testis of adult mice: An experimental study

International Journal of Reproductive BioMedicine ◽

10.18502/ijrm.v17i10.5490 ◽

2019 ◽

Author(s):

Fahime Sadat Kamali ◽

Rasoul Shahrooz ◽

Golamreza Najafi ◽

Mazdak Razi

Keyword(s):

Oxidative Stress ◽

Antioxidant Properties ◽

B Cell Lymphoma ◽

Testicular Tissue ◽

Control Group ◽

Protective Effects ◽

Adult Mice ◽

Oxidative Damages ◽

Sham Control Group ◽

Annual Weeds

Background: Paraquat (PQ), as a pyridine compound, is widely used worldwide to control annual weeds. The oxidative stress caused by PQ can cause deleterious changes in the testicular tissue. Objective: An investigation on the protective effects of Crocin (CCN) against PQinduced oxidative damages and apoptotic indices in testicular tissue. Materials and Methods: Twenty-eight adult male albino mice (20-25 gr) were divided into four groups (n = 7/each). The control group received 0.1 ml/day of normal saline by intraperitoneal injection (IP); sham-control group received PQ 5 mg/kg/day, IP, and the experimental groups received PQ (CCN+PQ) and CCN-sole (200 mg/kg/day, IP), respectively, for 35 continuous days. At the end of the treatment period, the testes were dissected out and used for biochemical, molecular, and histological analyses. The expressions of tumor suppressor p53, B-cell lymphoma 2 (bcl-2), and caspase-3 were considered as hallmark factors of mitochondria-dependent apoptosis. Moreover, the testicular superoxide dismutase (SOD) and malondialdehyde (MDA) were evaluated as key biomarkers for oxidative stress. Results: The PQ significantly (p < 0.02, p < 0.01) diminished the spermatogenesis indices and SOD, increased MDA levels, and enhanced the apoptosis-related gene expression. However, the co-administration of CCN and PQ significantly (p < 0.01, p < 0.01, p < 0.02) ameliorated the spermatogenesis ratio, upregulated the SOD level as well as bcl-2 expression, and reduced the MDA content and apoptosis vs the PQ-sole group. Conclusion: This study showed that the antioxidant properties of CCN enable to ameliorate the PQ-induced destructive effects by upregulating the testicular structure, antioxidant and apoptotic status. Key words: Histology, Testis, Paraquat, Crocin, Mice.

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Transit and Metabolic Pathways of Quercetin in Tubular Cells: Involvement of Its Antioxidant Properties in the Kidney

Antioxidants ◽

10.3390/antiox10060909 ◽

2021 ◽

Vol 10 (6) ◽

pp. 909

Author(s):

Daniel Muñoz-Reyes ◽

Ana I. Morales ◽

Marta Prieto

Keyword(s):

Oxidative Stress ◽

Therapeutic Potential ◽

Antioxidant Properties ◽

The Body ◽

Protective Effects ◽

Metabolic Processes ◽

Intracellular Space ◽

Tubular Cells

Quercetin is a flavonoid with antioxidant, antiviral, antimicrobial, and anti-inflammatory properties. Therefore, it has been postulated as a molecule with great therapeutic potential. The renoprotective capacity of quercetin against various toxins that produce oxidative stress, in both in vivo and in vitro models, has been shown. However, it is not clear whether quercetin itself or any of its metabolites are responsible for the protective effects on the kidney. Although the pharmacokinetics of quercetin have been widely studied and the complexity of its transit throughout the body is well known, the metabolic processes that occur in the kidney are less known. Because of that, the objective of this review was to delve into the molecular and cellular events triggered by quercetin and/or its metabolites in the tubular cells, which could explain some of the protective properties of this flavonoid against oxidative stress produced by toxin administration. Thus, the following are analyzed: (1) the transit of quercetin to the kidney; (2) the uptake mechanisms of quercetin and its metabolites from plasma to the tubular cells; (3) the metabolic processes triggered in those cells, which affect the accumulation of metabolites in the intracellular space; and (4) the efflux mechanisms of these compounds and their subsequent elimination through urine. Finally, it is discussed whether those processes that are mediated in the tubular cells and that give rise to different metabolites are related to the antioxidant and renoprotective properties observed after the administration of quercetin.

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Structurally Related Edaravone Analogues: Synthesis, Antiradical, Antioxidant, and Copper-Chelating Properties

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527318666191114092007 ◽

2020 ◽

Vol 18 (10) ◽

pp. 779-790 ◽

Cited By ~ 1

Author(s):

Alexandre LeBlanc ◽

Miroslava Cuperlovic-Culf ◽

Pier Jr. Morin ◽

Mohamed Touaibia

Keyword(s):

Oxidative Stress ◽

Amyotrophic Lateral Sclerosis ◽

Therapeutic Potential ◽

Antioxidant Properties ◽

Radical Scavenging ◽

Therapeutic Options ◽

Partial Charge ◽

Associated Diseases ◽

Significant Interest ◽

Lateral Sclerosis

Background:: The current therapeutic options available to patients diagnosed with Amyotrophic Lateral Sclerosis (ALS) are limited and edaravone is a compound that has gained significant interest for its therapeutic potential in this condition. Objectives: : The current work was thus undertaken to synthesize and characterize a series of edaravone analogues. Methods: A total of 17 analogues were synthesized and characterized for their antioxidant properties, radical scavenging potential and copper-chelating capabilities. Results: Radical scavenging and copper-chelating properties were notably observed for edaravone. Analogues bearing hydrogen in position 1 and a phenyl at position 3 and a phenyl in both positions of pyrazol-5 (4H)-one displayed substantial radical scavenging, antioxidants and copper-chelating properties. High accessibility of electronegative groups combined with higher electronegativity and partial charge of the carbonyl moiety in edaravone might explain the observed difference in the activity of edaravone relative to the closely related analogues 6 and 7 bearing hydrogen at position 1 and a phenyl at position 3 (6) and a phenyl in both positions (7). Conclusion: Overall, this study reveals a subset of edaravone analogues with interesting properties. Further investigation of these compounds is foreseen in relevant models of oxidative stress-associated diseases in order to assess their therapeutic potential in such conditions.

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Protective Effects of GYY4137 on Renal Ischaemia/Reperfusion Injury through Nrf2-Mediated Antioxidant Defence

Kidney & Blood Pressure Research ◽

10.1159/000509933 ◽

2021 ◽

pp. 1-9

Author(s):

Hongmei Zhao ◽

Yun Qiu ◽

Yichen Wu ◽

Hong Sun ◽

Sumin Gao

Keyword(s):

Oxidative Stress ◽

Reperfusion Injury ◽

Nuclear Translocation ◽

Organ Damage ◽

Related Factor ◽

Protective Effects ◽

Ischaemia Reperfusion Injury ◽

Renal Ischaemia ◽

Ischaemia Reperfusion ◽

Renal Histology

Introduction/Aims: Hydrogen sulfide (H2S) is considered to be the third most important endogenous gasotransmitter in organisms. GYY4137 is a long-acting donor for H2S, a gas transmitter that has been shown to prevent multi-organ damage in animal studies. We previously reported the effect of GYY4137 on cardiac ischaemia reperfusion injury (IRI) in diabetic mice. However, the role and mechanism of GYY4137 in renal IRI are poorly understood. The aims of this study were to determine whether GYY4137 can effectively alleviate the injury induced by renal ischaemia reperfusion and to explore its possible mechanism. Methods: Mice received right nephrectomy and clipping of the left renal pedicle for 45 min. GYY4137 was administered by intraperitoneal injection for 2 consecutive days before the operation. The model of hypoxia/reoxygenation injury was established in HK-2 cells, which were pre-treated with or without GYY4137. Renal histology, function, apoptosis, and oxidative stress were measured. Western blot was used to measure the target protein after renal IRI. Results: The results indicated that GYY4137 had a clear protective effect on renal IRI as reflected by the attenuation of renal dysfunction, renal tubule injury, and apoptosis. Moreover, GYY4137 remarkably reduced renal IRI-induced oxidative stress. GYY4137 significantly elevated the nuclear translocation of nuclear factor-erythroid-2-related factor 2 (Nrf2) and the expression of antioxidant enzymes regulated by Nrf2, including SOD, HO-1, and NQO-1. Conclusions: GYY4137 alleviates ischaemia reperfusion-induced renal injury through activating the antioxidant effect mediated by Nrf2 signalling.

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Ethanol Extract of Maclura tricuspidata Fruit Protects SH-SY5Y Neuroblastoma Cells against H2O2-Induced Oxidative Damage via Inhibiting MAPK and NF-κB Signaling

International Journal of Molecular Sciences ◽

10.3390/ijms22136946 ◽

2021 ◽

Vol 22 (13) ◽

pp. 6946

Author(s):

Weishun Tian ◽

Suyoung Heo ◽

Dae-Woon Kim ◽

In-Shik Kim ◽

Dongchoon Ahn ◽

...

Keyword(s):

Oxidative Stress ◽

Free Radical ◽

Oxidative Damage ◽

Cell Damage ◽

Antioxidant Properties ◽

Radical Scavenging ◽

Biologically Active ◽

Mitogen Activated Protein Kinase ◽

Protective Effects ◽

Neuroprotective Effects

Free radical generation and oxidative stress push forward an immense influence on the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Maclura tricuspidata fruit (MT) contains many biologically active substances, including compounds with antioxidant properties. The current study aimed to investigate the neuroprotective effects of MT fruit on hydrogen peroxide (H2O2)-induced neurotoxicity in SH-SY5Y cells. SH-SY5Y cells were pretreated with MT, and cell damage was induced by H2O2. First, the chemical composition and free radical scavenging properties of MT were analyzed. MT attenuated oxidative stress-induced damage in cells based on the assessment of cell viability. The H2O2-induced toxicity caused by ROS production and lactate dehydrogenase (LDH) release was ameliorated by MT pretreatment. MT also promoted an increase in the expression of genes encoding the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT). MT pretreatment was associated with an increase in the expression of neuronal genes downregulated by H2O2. Mechanistically, MT dramatically suppressed H2O2-induced Bcl-2 downregulation, Bax upregulation, apoptotic factor caspase-3 activation, Mitogen-activated protein kinase (MAPK) (JNK, ERK, and p38), and Nuclear factor-κB (NF-κB) activation, thereby preventing H2O2-induced neurotoxicity. These results indicate that MT has protective effects against H2O2-induced oxidative damage in SH-SY5Y cells and can be used to prevent and protect against neurodegeneration.

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Protective effects of N-acetyl-cysteine in mitochondria bioenergetics, oxidative stress, dynamics and S-glutathionylation alterations in acute kidney damage induced by folic acid

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2018.11.005 ◽

2019 ◽

Vol 130 ◽

pp. 379-396 ◽

Cited By ~ 20

Author(s):

Omar Emiliano Aparicio-Trejo ◽

Laura María Reyes-Fermín ◽

Alfredo Briones-Herrera ◽

Edilia Tapia ◽

Juan Carlos León-Contreras ◽

...

Keyword(s):

Oxidative Stress ◽

Folic Acid ◽

Kidney Damage ◽

Protective Effects ◽

Acetyl Cysteine

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A Polysaccharide Purified from Morchella conica Pers. Prevents Oxidative Stress Induced by H2O2 in Human Embryonic Kidney (HEK) 293T Cells

International Journal of Molecular Sciences ◽

10.3390/ijms19124027 ◽

2018 ◽

Vol 19 (12) ◽

pp. 4027 ◽

Cited By ~ 6

Author(s):

Na Xu ◽

Yi Lu ◽

Jumin Hou ◽

Chao Liu ◽

Yonghai Sun

Keyword(s):

Oxidative Stress ◽

Antioxidant Activities ◽

Average Molecular Weight ◽

Antioxidant Properties ◽

Radical Scavenging ◽

Ultrastructural Observation ◽

Protective Effects ◽

Ferrous Ions ◽

Nuclear Condensation ◽

Morchella Conica

Morchella conica Pers. (M. conica) has been used both as a medical and edible mushroom and possesses antimicrobial properties and antioxidant activities. However, the antioxidant properties of polysaccharides purified from M. conica have not been studied. The aim of this study was to investigate the in vitro antioxidant properties of a polysaccharide NMCP-2 (neutral M. conica polysaccharides-2) purified from M. conica, as determined by radical scavenging assay and H2O2-induced oxidative stress in HEK 293T cells. Results showed that NMCP-2 with an average molecular weight of 48.3 kDa possessed a much stronger chelating ability on ferrous ions and a higher ability to scavenge radical scavenging 2,2-diphenyl-1-picrylhydrazyl (DPPH) than the other purified fraction of NMCP-1 from M. conica. Moreover, 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetra-zolium bromide (MTT) assay showed that NMCP-2 dose-dependently preserved cell viability of H2O2-induced cells. The NMCP-2 pretreated group reduced the generation of reactive oxygen species (ROS) content and increased the mitochondria membrane potential (MMP) levels. In addition, Hoechst 33342 staining revealed cells treated with NMCP-2 declined nuclear condensation. Ultrastructural observation revealed that NMCP-2 pretreatment alleviated the ruptured mitochondria when exposed to H2O2. Furthermore, western blot analysis showed that NMCP-2 prevented significant downregulation of the protein expression of Bax, cleaved caspases 3, and upregulated Bcl-2 levels. These results suggest the protective effects of NMCP-2 against H2O2-induced injury in HEK 293T cells. NMCP-2 could be used as a natural antioxidant of functional foods and natural drugs.

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Ezetimibe Attenuates Oxidative Stress and Neuroinflammation via the AMPK/Nrf2/TXNIP Pathway after MCAO in Rats

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/4717258 ◽

2020 ◽

Vol 2020 ◽

pp. 1-14 ◽

Cited By ~ 2

Author(s):

Jing Yu ◽

Wen-na Wang ◽

Nathanael Matei ◽

Xue Li ◽

Jin-wei Pang ◽

...

Keyword(s):

Oxidative Stress ◽

Ischemic Stroke ◽

Brain Infarction ◽

Neutrophil Infiltration ◽

Artery Occlusion ◽

Receptor Protein ◽

Related Factor ◽

Protective Effects ◽

Sprague Dawley ◽

Interacting Protein

Oxidative stress and neuroinflammation play essential roles in ischemic stroke-induced brain injury. Previous studies have reported that Ezetimibe (Eze) exerts antioxidative stress and anti-inflammatory properties in hepatocytes. In the present study, we investigated the effects of Eze on oxidative stress and neuroinflammation in a rat middle cerebral artery occlusion (MCAO) model. One hundred and ninety-eight male Sprague-Dawley rats were used. Animals assigned to MCAO were given either Eze or its control. To explore the downstream signaling of Eze, the following interventions were given: AMPK inhibitor dorsomorphin and nuclear factor erythroid 2-related factor 2 (Nrf2) siRNA. Intranasal administration of Eze, 1 h post-MCAO, further increased the endogenous p-AMPK expression, reducing brain infarction, neurologic deficits, neutrophil infiltration, microglia/macrophage activation, number of dihydroethidium- (DHE-) positive cells, and malonaldehyde (MDA) levels. Specifically, treatment with Eze increased the expression of p-AMPK, Nrf2, and HO-1; Romo-1, thioredoxin-interacting protein (TXNIP), NOD-like receptor protein 3 (NLRP3), Cleaved Caspase-1, and IL-1β were reduced. Dorsomorphin and Nrf2 siRNA reversed the protective effects of Eze. In summary, Eze decreases oxidative stress and subsequent neuroinflammation via activation of the AMPK/Nrf2/TXNIP pathway after MCAO in rats. Therefore, Eze may be a potential therapeutic approach for ischemic stroke patients.

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