• The Korean Journal of Physiology and Pharmacology
• /
• 제25권4호
• /
• pp.321-331
• /
• 2021

Vancomycin, an antibiotic used occasionally as a last line of treatment for methicillin-resistant Staphylococcus aureus, is reportedly associated with nephrotoxicity. This study aimed at evaluating the protective effects of lutein against vancomycin-induced acute renal injury. Peroxisome proliferator-activated receptor gamma (PPARγ) and its associated role in renoprotection by lutein was also examined. Male BALB/c mice were divided into six treatment groups: control with normal saline, lutein (200 mg/kg), vancomycin (250 mg/kg), vancomycin (500 mg/kg), vancomycin (250 mg/kg) with lutein, and vancomycin (500 mg/kg) with lutein groups; they were euthanized after 7 days of treatment. Thereafter, samples of blood, urine, and kidney tissue of the mice were analyzed, followed by the determination of levels of N-acetyl-β-D-glucosaminidase (NAG) in the urine, renal creatine kinase; protein carbonyl, malondialdehyde, and caspase-3 in the kidney; and the expression of PPARγ, nuclear factor erythroid 2-related factor 2 (Nrf2), and nuclear factor-kappaB (NF-κB) in renal tissue. Results showed that the levels of protein carbonyl and malondialdehyde, and the activity of NAG, creatine kinase and caspase-3, were significantly increased in the vancomycin-treatment groups. Moreover, the levels of Nrf2 significantly decreased, while NF-κB expression increased. Lutein ameliorated these effects, and significantly increased PPARγ expression. Furthermore, it attenuated vancomycin-induced histological alterations such as, tissue necrosis and hypertrophy. Therefore, we conclude that lutein protects against vancomycin-induced renal injury by potentially upregulating PPARγ/Nrf2 expression in the renal tissues, and consequently downregulating the pathways: inflammation by NF-κB and apoptosis by caspase-3.

• BMB Reports
• /
• 제56권9호
• /
• pp.496-501
• /
• 2023

Elongation of most bones occur at the growth plate through endochondral ossification in postnatal mammals. The maturation of chondrocyte is a crucial factor in longitudinal bone growth, which is regulated by a complex network of paracrine and endocrine signaling pathways. Here, we show that a phytochemical sulfuretin can stimulate hypertrophic chondrocyte differentiation in vitro and in vivo. We found that sulfuretin stabilized nuclear factor (erythroid-derived 2)-like 2 (Nrf2), stimulated its transcriptional activity, and induced expression of its target genes. Sulfuretin treatment resulted in an increase in body length of zebrafish larvae and induced the expression of chondrocyte markers. Consistently, a clinically available Nrf2 activator, dimethyl fumarate (DMF), induced the expression of hypertrophic chondrocyte markers and increased the body length of zebrafish. Importantly, we found that chondrocyte gene expression in cell culture and skeletal growth in zebrafish stimulated by sulfuretin were significantly abrogated by Nrf2 depletion, suggesting that such stimulatory effects of sulfuretin were dependent on Nrf2, at least in part. Taken together, these data show that sulfuretin has a potential use as supporting ingredients for enhancing bone growth.

• 생명과학회지
• /
• 제33권10호
• /
• pp.776-782
• /
• 2023

Silymarin은 간 보호, 항산화, 항염, 항암 등 다양한 생리 활성을 나타내는 것으로 보고되었고, 본 연구에서는 산화 스트레스에 대한 항산화 잠재력과 그 기전을 세포 생존력 및 활성산소종 생성 분석과 Western blot 분석을 통해 RAW 264.7 세포에서 알아보고자 하였다. Silymarin은 세포 독성 없이 lipopolysaccharide(LPS)에 의해 자극된 세포 내 활성산소종을 농도 의존적으로 소거하였다. 그리고 항산화 효과를 보여주는 것으로 알려진 제2상 효소 중 하나인 heme oxygenase (HO)-1의 발현은 silymarin 처리에 의해 강하게 유도되었다. 또한 silymarin 처리는 항산화 효소의 전사인자인 nuclear factor-erythroid 2 p45-related factor (Nrf)-2의 발현을 유의미하게 유도하였고, 이는 HO-1 발현증가와 일치하였다. 세포내 산화와 환원 항상성 조절과 관련된 신호 전달물질인 mitogen activated protein kinase (MAPK)와 phosphoinositde 3-kinase (PI3K)의 인산화 정도 또한 Western blot으로 분석하였고, 그 결과 silymarin 은 p38 MAPK 인산화에 의해 HO-1 발현을 유도하는 것으로 나타났다. 그리고 tert-butyl hydroperoxide (t-BHP)를 이용하여 세포내 지질 과산화를 유도함으로써 silymarin에 의해 유도된 HO-1의 항산화 효과를 확인하였다. 그 결과 silymarin 처리에 의해 세포사멸이 유의적으로 억제되었고, p38의 선택적 저해제를 처리한 세포군에서는 t-BHP에 의해 유의적인 세포사멸이 발생하였다. 이 결과를 통해 silymarin은 Nrf-2/p38 MAPK 신호 전달 경로를 통해 HO-1의 발현을 유도하고, 이를 통해 항산화 효과를 높이는 것을 확인할 수 있었다.

• Animal Bioscience
• /
• 제34권8호
• /
• pp.1403-1414
• /
• 2021

Objective: This study explored the mechanism of the Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway under conditions of zearalenone (ZEA)-induced oxidative stress in the duodenum of post-weaning gilts. Methods: Forty post-weaning gilts were randomly allocated to four groups and fed diets supplemented with 0, 0.5, 1.0, or 1.5 mg/kg ZEA. Results: The results showed significant reductions in the activity of the antioxidant enzymes total superoxide dismutase and glutathione peroxidase and increases the malondialdehyde content with increasing concentrations of dietary ZEA. Immunohistochemical analysis supported these findings by showing a significantly increased expression of Nrf2 and glutathione peroxidase 1 (GPX1) with increasing concentrations of ZEA. The relative mRNA and protein expression of Nrf2, GPX1 increased linearly (p<0.05) and quadratically (p<0.05), which was consistent with the immunohistochemical results. The relative mRNA expression of Keap1 decreased linearly (p<0.05) and quadratically (p<0.05) in the duodenum as the ZEA concentration increased in the diet. The relative mRNA expression of modifier subunit of glutamate-cysteine ligase (GCLM) increased quadratically (p<0.05) in all ZEA treatment groups and the relative mRNA expression of quinone oxidoreductase 1 (NQO1) catalytic subunit of glutamate-cysteine ligase decreased linearly (p<0.05) and quadratically (p<0.05) in the ZEA1.0 group and ZEA1.5 group. The relative protein expression of Keap1 and GCLM decreased quadratically (p<0.05) in the duodenum as the ZEA concentration increased in the diet, respectively. The relative protein expression of NQO1 increased linearly (p<0.05) and quadratically (p<0.05) in all ZEA treatment groups in the duodenum. Conclusion: These findings suggest that ZEA regulates the expression of key factors of the Keap1-Nrf2 signaling pathway in the duodenum, which enables resistance to ZEA-induced oxidative stress. Further studies are needed to examine the effects of ZEA induced oxidative stress on other tissues and organs in post-weaning gilts.

• BMB Reports
• /
• 제45권6호
• /
• pp.348-353
• /
• 2012

L-2-Oxothiazolidine-4-carboxylic acid (OTC) is a cysteine prodrug that maintains glutathione in tissues. The present study was designed to investigate anti-fibrotic and anti-oxidative effects of OTC via modulation of nuclear factor erythroid 2-related factor 2 (Nrf2) in an in vivo thioacetamide (TAA)-induced hepatic fibrosis model. Treatment with OTC (80 or 160 mg/kg) improved serum liver function parameters and significantly ameliorated liver fibrosis. The OTC treatment groups exhibited significantly lower expression of ${\alpha}$-smooth muscle actin, transforming growth factor-${\beta}1$, and collagen ${\alpha}1$ mRNA than that in the TAA model group. Furthermore, the OTC treatment groups showed a significant decrease in hepatic malondialdehyde level compared to that in the TAA model group. Nrf2 and heme oxygenase-1 expression increased significantly in the OTC treatment groups compared with that in the TAA model group. Taken together, these results suggest that OTC restores the anti-oxidative system by upregulating Nrf2; thus, ameliorating liver injury and a fibrotic reaction.

• Journal of Ginseng Research
• /
• 제44권6호
• /
• pp.790-798
• /
• 2020

Background: Beneficial effects of Korean Red Ginseng (KRG) on polycystic ovarian syndrome (PCOS) remains unclear. Methods: We examined whether pretreatment (daily from 2 hours before PCOS induction) with KRG extract in water (KRGE; 75 and 150 mg/kg/day, p.o.) could exert a favorable effect in a dehydroepian-drosterone (DHEA)-induced PCOS rat model. Results: Pretreatment with KRGE significantly inhibited the elevation of body and ovary weights, the increase in number and size of ovarian cysts, and the elevation of serum testosterone and estradiol levels induced by DHEA. Pretreatment with KRGE also inhibited macrophage infiltration and enhanced mRNA expression levels of chemokines [interleukin (IL)-8, monocyte chemoattractant protein-1), proinflammatory cytokines (IL-1β, IL-6), and inducible nitric oxide synthase in ovaries induced by DHEA. It also prevented the reduction in mRNA expression of growth factors (epidermal growth factor, transforming growth factor-beta (EGF, TGF-β)) related to inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cell pathway and stimulation of the nuclear factor erythroid-derived 2-related factor 2 pathway. Interestingly, KRGE or representative ginsenosides (Rb1, Rg1, and Rg3(s)) inhibited the activity of inflammatory enzymes cyclooxygenase-2 and iNOS, cytosolic p-IκB, and nuclear p-nuclear factor kappa-light-chain-enhancer of activated B in lipopolysaccharide-induced RAW264.7 cells, whereas they increased nuclear factor erythroid-derived 2-related factor 2 nuclear translocation. Conclusion: These results provide that KRGE could prevent DHEA-induced PCOS via antiinflammatory and antioxidant activities. Thus, KRGE may be used in preventive and therapeutic strategies for PCOS-like symptoms.

• 한방비만학회지
• /
• 제15권2호
• /
• pp.93-103
• /
• 2015

Objectives: It was investigated the cytoprotective efficacies of isorhamnetin, a flavonoid originally derived from Hippophae rhamnoides L., against oxidative stress-induced apoptosis in C2C12 myoblasts. Methods: The effects of isorhamnetin on cell growth, apoptosis and reactive oxygen species (ROS) generation were evaluated by trypan blue dye exclusion assay, 4',6-diamidino-2-phenylindole staining and flow cytometry. The levels of apoptosis-regulatory and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway-related proteins, and caspase activities (caspase-3 and -9) were determined by Western blot analysis and colorimetric assay, respectively. Results: Our results revealed that treatment with isorhamnetin prior to hydrogen peroxide ($H_2O_2$) exposure significantly increased the C2C12 cell viability and, indicating that the exposure of C2C12 cells to isorhamnetin conferred a protective effect against oxidative stress. Isorhamnetin also effectively attenuated $H_2O_2$-induced apoptosis and ROS generation, which was associated with the restoration of the upregulation of Bax and downregulation of Bcl-2 induced by $H_2O_2$. In addition, $H_2O_2$ enhanced the activation of caspase-9 and -3, and degradation of poly (ADP-ribose)-polymerase, a typical substrate protein of activated caspase-3; however, these events were almost totally reversed by pretreatment with isorhamnetin. Moreover, isorhamnetin increased the levels of heme oxygenase-1, a potent antioxidant enzyme, associated with the induction of Nrf2. Conclusions: Our data indicated that isorhamnetin may potentially serve as an agent for the treatment and prevention of muscle disorders caused by oxidative stress.

• Fisheries and Aquatic Sciences
• /
• 제26권1호
• /
• pp.35-47
• /
• 2023

Myelophycus caespitosus, a brown alga belonging to genus Myelophycus, has been traditionally used as a food and medicinal resource in Northeastern Asia. However, few studies have been conducted on its pharmacological activity. In this study, we evaluated whether methanol extract of M. caespitosus (MEMC) could protect against oxidative damage caused by hydrogen peroxide (H₂O₂) in C2C12 murine myoblasts. Our results revealed that MEMC could suppress H₂O₂-induced growth inhibition and DNA damage while blocking the production of reactive oxygen species. In H₂O₂-treated cells, cell cycle progression was halted at the G2/M phase, accompanied by changes in expression of key cell cycle regulators. However, these effects were attenuated by MEMC. In addition, we found that MEMC protected cells from induction of apoptosis associated with mitochondrial impairment caused by H₂O₂ treatment. Furthermore, MEMC enhanced the phosphorylation of nuclear factor-erythroid-2 related factor 2 (Nrf2) and expression and activity of heme oxygenase-1 (HO-1) in H₂O₂-treaetd C2C12 myoblasts. However, such anti-apoptotic and cytoprotective effects of MEMC were greatly abolished by HO-1 inhibitor, suggesting that MEMC could increase Nrf2-mediated activity of HO-1 to protect C2C12 myoblasts from oxidative stress.

• Nutrition Research and Practice
• /
• 제11권3호
• /
• pp.206-213
• /
• 2017

BACKGROUN/OBJECTIVES: Although studies have revealed that black garlic is a potent antioxidant, its antioxidant mechanism remains unclear. The objective of this study was to determine black garlic's antioxidant activities and possible antioxidant mechanisms related to nuclear factor erythroid 2-like factor 2 (Nrf2)-Keap1 complex. METHODS/MATERIALS: After four weeks of feeding rats with a normal fat diet (NF), a high-fat diet (HF), a high-fat diet with 0.5% black garlic extract (HF+BGE 0.5), a high-fat diet with 1.0% black garlic extract (HF+BGE 1.0), or a high-fat diet with 1.5% black garlic extract (HF+BGE 1.5), plasma concentrations of glucose, insulin,homeostatic model assessment of insulin resistance (HOMA-IR) were determined. As oxidative stress indices, plasma concentrations of thiobarbituric acid reactive substances (TBARS) and 8-isoprostaglandin $F2{\alpha}$ (8-iso-PGF) were determined. To measure antioxidant capacities, plasma total antioxidant capacity (TAC) and activities of antioxidant enzymes in plasma and liver were determined. The mRNA expression levels of antioxidant related proteins such as Nrf2, NAD(P)H: quinone-oxidoreductase-1 (NQO1), heme oxygenase-1 (HO-1), glutathione reductase (GR), and glutathione S-transferase alpha 2 (GSTA2) were examined. RESULTS: Plasma glucose level, plasma insulin level, and HOMA-IR in black garlic supplemented groups were significantly (P < 0.05) lower than those in the HF group without dose-dependent effect. Plasma TBARS concentration and TAC in the HF+BGE 1.5 group were significantly decreased compared to those of the HF group. The activities of catalase and glutathione peroxidase were significantly (P < 0.05) increased in the HF+BGE 1.0 and HF+BGE 1.5 groups compared to those of the HF group. The mRNA expression levels of hepatic Nrf2, NQO1, HO-1, and GSTA2 were significantly (P < 0.05) increased in the HF with BGE groups compared to those in the HF group. CONCLUSIONS: The improvements of blood glucose homeostasis and antioxidant systems in rats fed with black garlic extract were related to mRNA expression levels of Nrf2 related genes.

• Animal Bioscience
• /
• 제34권4호
• /
• pp.652-661
• /
• 2021

Objective: Wooden breast (WB) is a novel myopathy affecting modern broiler chickens, which causes substantial economic losses in the poultry industry. The objective of this study was to evaluate the effect of WB abnormality on meat quality, redox status, as well as the expression of genes of the nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway. Methods: A total of 80 broilers (Ross 308, 42 days of age, about 2.6 kg body weight) raised at Jiujin farm (Suqian, Jiangsu, China) were used. Twelve unaffected (no detectable hardness of the breast area) and twelve WB-affected (diffuse remarkable hardness in the breast muscle) birds were selected from the commercial broiler farm according to the criteria proposed by previous studies. Results: The results indicated that WB showed histological lesions characterized by fiber degeneration and fibrosis, along with an increase of muscle fiber diameter (p<0.05). Moreover, higher pH value, lightness, yellowness, drip loss and cooking loss were observed in the WB group (p<0.05). Compared with the normal breast (NOR) group, the WB group showed higher formation of reactive oxygen species (p<0.05), increased level of oxidation products and antioxidant activities (p<0.05), accompanied with mitochondrial damages and lower mitochondrial membrane potential (p<0.05). Meanwhile, the relative mRNA expressions of Nrf2 and its downstream antioxidant genes including heme oxygenase-1, NAD(P)H qui none dehydrogenase 1, glutathione peroxidase, superoxide dismutase, and glutamate-cysteine ligase were higher than those of the NOR group (p<0.05). Conclusion: In conclusion, WB myopathy impairs meat quality by causing oxidative damages and mitochondrial dysfunction in broilers, even though the activated Nrf2/antioxidant response element pathway provides protection for the birds.