INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
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2022
·Vol. 50
·期 5
·1-14
·
IF 5.314
Weichao Sun,Wei Xie,Dixi Huang,Yinxing Cui,Jiaji Yue,Qifei He,Luoyong Jiang,Jianyi Xiong,Wei Sun,Qian Yi
Osteoarthritis (OA) is the most common degenerative disease affecting the joints, and inflammation appears to play a critical role in the initiation and progression of OA. Caffeic acid phenethyl ester (CAPE), a natural flavonoid compound, has anti‑inflammatory and antioxidant functions. However, its anti‑inflammatory effects on OA and the underlying mechanisms of action of CAPE in the treatment of OA remain elusive. Therefore, the present study investigated the anti‑inflammatory effects of CAPE on IL‑1β‑stimulated chondrocytes in vitro and surgically induced rat models of OA in vivo. In vitro, CAPE reduced the expression of inducible nitric oxide synthase and cyclooxygenase‑2 in IL‑1β‑stimulated chondrocytes, as well as the extracellular secretion of nitric oxide and prostaglandin E2 in the cell culture supernatants. In addition, CAPE attenuated the degradation of extracellular matrix by increasing the expression of aggrecan and collagen II, and decreasing the expression of MMP3, MMP13 and a disintegrin and metalloproteinase with thrombospondin motif‑5. Furthermore, CAPE attenuated NF‑κB signaling and activated the nuclear factor erythroid 2‑related factor 2/heme oxygenase‑1 signaling pathway in IL‑1β‑stimulated chondrocytes. In vivo, CAPE protected cartilage from destruction and delayed the progression of OA in rats. Taken together, the findings of the present study indicated that CAPE may be a potential therapeutic agent for the prevention or treatment of OA.
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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2023
·Vol. 24
·期 4
·3850
·
IF 5.6
Chang-Sheng Yang,Xiao-Shuang Guo,Ying-Ying Yue,Yu Wang,Xiao-Lei Jin
The survival of free fat grafts is dependent primarily on adipose-derived stem cells (ADSCs); however, ADSCs are susceptible to oxidative stress in the recipient area. Astaxanthin (Axt) is a natural xanthophyll carotenoid with potent antioxidant properties and numerous clinical applications. To date, the therapeutic potential of Axt in fat grafting has not been explored. The purpose of this study is to investigate the effects of Axt on oxidatively stressed ADSCs. An oxidative model of ADSCs was developed to simulate the host’s microenvironment. Oxidative insult decreased the protein levels of Cyclin D1, type I collagen alpha 1 (COL1A1), and type II collagen alpha 1 (COL2A1), while increasing the expression of cleaved Caspase 3 and secretion of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in ADSCs. Axt pre-treatment significantly reduced oxidative stress, increased the synthesis of an adipose extracellular matrix, alleviated inflammation, and restored the impaired adipogenic potential in the present model. Furthermore, Axt immensely activated the NF-E2-related factor 2 (Nrf2) pathway, and ML385, an inhibitor of Nrf2, could negate Axt’s protective effects. Additionally, Axt alleviated apoptosis by inhibiting bcl-2-associated X protein (BAX)/Caspase 3 signaling and improving the mitochondrial membrane potential (MMP), which could also be abolished by ML385. Our results suggest that Axt may exert its cytoprotective effect on ADSCs through the Nrf2 signaling pathway and could be therapeutic in fat grafting.Keywords:fat grafting;mesenchymal stem cell;oxidative stress;astaxanthin;Nrf2 signaling pathway;apoptosis
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Frontiers in Pharmacology
·
2022
·
IF 5.988
Wang Kaiping,Yang Linlin,Zhou Jing,Pan Xianglin,He Zihao,Liu Junxi,Zhang Yu
The alleviation of oxidative stress is considered an effective treatment for acetaminophen (APAP)-induced acute liver injury (AILI). However, it remains unknow whether the potential antioxidant Smilax china L. polysaccharide (SCLP) protects against AILI. In this study, in vitro and in vivo experiments were conducted to verify the hepatoprotective effect of SCLP against AILI and explore the potential mechanism. We found that SCLP relieved liver histopathological changes; reversed the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), malondialdehyde (MDA) and reactive oxygen species (ROS); reversed the change in liver myeloperoxidase (MPO) activity; and enhanced liver antioxidant (GSH, GSH-Px, and t-SOD) levels in APAP-treated mice, thereby significantly reducing APAP-induced liver toxicity. SCLP rescued the cell viability and alleviated oxidative stress in H2O2-treated mouse AML12 (Alpha mouse liver 12) hepatocytes. The results of the mechanistic studies showed that SCLP upregulated nuclear factor E2 related factor (Nrf2) expression, promoted Nrf2 nuclear translocation, and enhanced the ability of Nrf2 to bind antioxidant response elements (AREs). Furthermore, SCLP activated Nrf2-ARE pathway, thus upregulating the expression of oxidative stress-related proteins heme oxygenase 1(HO-1), NAD(P)H quinone dehydrogenase 1(NQO-1) and glutamic acid cysteine ligase catalytic subunit (GCLC). In conclusion, this study confirmed the close correlation between liver protection by SCLP upon exposure to APAP and activated of the Nrf2-ARE pathway. These findings suggest that SCLP is an attractive therapeutic candidate drug for the treatment of AILI.
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FASEB JOURNAL
·
2022
·Vol. 36
·期 9
·e22505
·
IF 5.834
Xia Wu,Xueliang Zhou,Songqing Lai,Jichun Liu,Jianwei Qi
The hallmark feature of Diabetes mellitus (DM) is hyperglycemia which can lead to excess production of reactive oxygen species (ROS) in the myocardium, contributing to diabetic cardiomyopathy (DCM). Nuclear factor erythroid2-related factor2 (Nrf2), a transcriptional activator, enhances its ability to resist oxidative stress by activating multiple downstream anti-oxidants, anti-inflammatory proteins, and detoxifying enzymes. However, the mechanism of Nrf2 signaling in HG-induced DCM is unclear. In this study, we used HG pretreated H9c2 cells as the experimental basis in vitro, and established a high fat-diet, streptozotocin (STZ) induced Type 2 diabetic rat model in vivo. Meanwhile, we used shRNA-Nrf2 and curcumin (CUR) (as an activator) to affect H9c2 cells, to verify the role of the Nrf2 signaling pathway in DCM. The results showed that the excessive production of ROS caused by HG, which could inhibit the activation of Nrf2-related signaling, resulting in a decrease in cell energy metabolism and an increase in cell apoptosis. Surprisingly, we found that the activation of the Nrf2 signaling pathway significantly increased cardiomyocyte viability, reduced ROS formation, increased antioxidant enzyme activity, and inhibited cardiomyocyte apoptosis. In conclusion, these findings conclusively infer that CUR activation of the Nrf2/HO-1 signaling pathway exerts myocardial protection by reducing ROS formation.
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FOOD AND CHEMICAL TOXICOLOGY
·
2022
·
IF 5.572
Zheng Cao,Jinsong Gao,Wanyue Huang,Juli Yan,Anshan Shan,Xiang Gao
Deoxynivalenol (DON) induces intestinal epithelial barrier disruption, posing a threat to the body. Curcumin (Cur) possesses pharmacological bioactivities such as antioxidant and anti-inflammatory effects that help maintain intestinal health. Here, the protective effects of Cur against DON-induced intestinal epithelial barrier disruption were explored. Cur (75 or 150 mg/kg body weight [B.W.]) alleviated DON-induced (2.4 mg/kg B.W.) inhibition of growth performance and morphological damage to intestinal epithelium in mice. Cur also significantly attenuated DON-induced intestinal epithelial barrier disruption and structural damage to the tight junctions (TJs), as assessed by ultrastructure observation, serum FITC-dextran concentrations and diamine oxidase activity. Cur mitigated the DON-induced increase in reactive oxygen species , malondialdehyde and 8-hydroxy-2′-deoxyguanosine levels; p53, cytoplasmic cytochrome c , Bax , and Bcl-2 expression; and TUNEL-positive cell rate and caspase-3 activity. It decreased the total antioxidant capacity and expression of nuclear Nrf2 and its downstream target genes. Lastly, Cur attenuated the DON-induced increase in MLCK , p-MLC, nuclear NF-κB p65 expression, and the NF-κB downstream target genes; decrease in the expression of TJs proteins (claudin-1, occludin , and zonula occludens-1 [ZO-1]); and abnormal ZO-1 distribution. Overall, Cur mitigated the DON-induced disruption of the intestinal epithelial barrier by regulating the Nrf2/p53-mediated apoptotic pathway and NF-κB/MLCK-mediated TJs pathway in mice.
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MOLECULES
·
2020
·Vol. 25
·期 20
·4789
·
IF 3.267
Xiang-rong Cheng,Wei Zhao,Wen-le Dong,Guo-wei Le
The edible and medicinal part ofInula nervosaWall. (Xiaoheiyao) is confined to its root without sufficient phytochemical and biological investigation. In this study, the secondary metabolites of root, stem, leaf, and flower ofI. nervosaWall. were visualized using Global Natural Products Social Molecular Networking (GNPS), MolNetEnhancer, XCMS(xcmsonline.scripps.edu) analysis, and `ili mapping based on high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) data to reveal their chemical differences. Among the 11 kinds of chemical repertoires annotated by MolNetEnhancer and 16 hits against the GNPS library, 10-isobutyryloxy-8,9-epoxythymol isobutyrate (1) was revealed as the most dominant and responsible marker between the roots and the other parts. Moreover, a battery of unique MS features as well as differential markers were discovered from different parts of the plant. The chemical differences contribute to the bioactivity differences, which presented in the 2,2-diphenyl-1-picryl-hydrazyl (DPPH)assay and H2O2-insulted HepG2 cells and were in significant correlations with the contents of1. real-time reverse transcription polymerase chain reaction (RT-PCR)results demonstrated thatI. nervosaWall. extracts upregulated the mRNA expression of nuclear factor E2-related factor 2(Nrf2), heme oxygenase 1(HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), manganese superoxide dismutase (MnSOD), and glutamate-cysteine ligase catalytic subunit (GCLC) actors involved in antioxidative response in H2O2-challenged HepG2 cells. These findings support the roots ofI. nervosaWall. as active parts ofXiaoheiyao, and also indicate the potential antioxidant activities of other parts.Keywords:Xiaoheiyao;GNPS molecular networking;MolNetEnhancer;XCMS online;Nrf2
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INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
·
2021
·Vol. 47
·期 4
·1-1
·
IF 4.101
Shuo Yang,Xiao-Long Huang,Jin Chen,Li-Na Mao,Xu Liu,Wen-Sheng Yuan,Xiao-Jie Wu,Guang-Wei Luo
Fine particulate matter (PM2.5) with an average aerodynamic diameter of <2.5 µm can cause severe lung injury. Oxidative stress and inflammation are considered the main outcomes of PM2.5 exposure. Curcumin is a well‑known antioxidant; however, its effect on PM2.5‑induced oxidative injury in airway epithelial cells remains unclear. In the present study, it was demonstrated that pre‑treatment with curcumin significantly reduced the PM2.5‑induced apoptosis of BEAS‑2B human bronchial epithelial cells by decreasing the level of intercellular reactive oxygen species. Western blot analysis revealed that curcumin increased the expression of nuclear factor erythroid 2‑related factor 2 (NRF2) and regulated the transcription of downstream genes, particularly those encoding antioxidant enzymes. Moreover, curcumin reduced the PM2.5‑induced expression and production of inflammatory factors, and induced the expression of the anti‑inflammatory factors, interleukin (IL)‑5 and IL‑13. Taken together, the present study demonstrates that curcumin protects BEAS‑2B cells against PM2.5‑induced oxidative damage and inflammation, and prevents cell apoptosis by increasing the activation of NRF2‑related pathways. It is thus suggested that curcumin may be a potential compound for use in the prevention of PM2.5‑induced tissue injury.
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BIOMEDICINE & PHARMACOTHERAPY
·
2021
·
IF 6.53
Yaoxing Dou,Ronglei Huang,Qiaoping Li,Yuhong Liu,Yucui Li,Hanbin Chen,Gaoxiang Ai,Jianhui Xie,Huifang Zeng,Jiannan Chen,Chaodan Luo,Ziren Su
Berberine (BBR) is a promising anti-diabetic isoquinoline alkaloid from Rhizoma coptidis, while its bioavailability was extremely low. Here, the existing form and pharmacokinetics of BBR were comparatively characterized in conventional and antibiotic-induced pseudo germ-free (PGF) rats. Furthermore, we comparatively investigated the antidiabetic effect and potential mechanism of BBR and its intestinal oxidative metabolite oxyberberine (OBB) in STZ-induced diabetic rats. Results showed that BBR and OBB existed mainly as protein-bound form in blood, while protein-bound OBB was significantly depleted in PGF rats. Treatment with OBB and BBR effectively decreased clinical symptoms of diabetic rats, reduced blood glucose level, ameliorated the pancreatic damage, and mitigated oxidative stress and inflammatory markers. However, the anti-diabetes effect of BBR was obviously compromised by antibiotics. In addition, OBB exerted superior anti-diabetes effect to BBR of the same dose, significantly up-regulated the mRNA expression of Nrf2 signaling pathway and substantially promoted the pancreatic levels of PI3K/Akt signaling pathway. In conclusion, BBR and its absorbed oxidative metabolite OBB were mainly presented and transported in the protein-bound form in vivo . The gut microbiota may play an important role in the anti-diabetes effect of BBR through transforming itself into the superior hypoglycemic metabolite OBB. OBB possessed favorable hypoglycemic and pancreatic β-cells protective effects, which may stand a huge potential to be further developed into a promising anti-diabetes candidate.
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Food & Function
·
2020
·Vol. 11
·期 6
·5156-5165
·
IF 4.171
Yu-Sheng Shi,Xiao-Xing Li,Hao-Tian Li,Yan Zhang
Liver fibrosis is a histological change that often occurs due to hepatic stellate cell (HSC) activation and excessive formation of an extracellular matrix in the liver. Pelargonidin (PEL) is a natural anthocyanidin existing in blueberries, berries, strawberries, and red radishes and has been demonstrated to possess health beneficial effects. Herein, we investigated the effect of PEL on liver fibrosis induced by CCl4 and hepatic stellate cells induced by transforming growth factor-β (TGF-β). We found that PEL administration prevented liver injury and liver fibrosis induced by CCl4 in a dose-dependent manner. Further data revealed that PEL increased liver nuclear factor E2-related factor 2 (Nrf2) and reduced liver oxidative stress and the expression levels of NLRP3, caspase-1 and IL-1β. In TGF-β-challenged HSCs (LX-2 cells), PEL effectively inhibited the LX-2 cell activation. In addition, the anti-fibrosis effects of PEL in LX-2 cells were abolished by Nrf2 knockdown. In summary, our study demonstrated that PEL ameliorated CCl4-induced liver fibrosis and HSC activation induced by TGF-β. The possible molecular mechanisms of PEL in liver fibrosis may be attributed to its suppression of ROS-NLRP3-IL-1β signaling by Nrf2 activation.
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JOURNAL OF FOOD SCIENCE
·
2020
·Vol. 85
·期 6
·1752-1763
·
IF 2.479
Shilian Zheng,Zeyuan Deng,Fang Chen,Liufeng Zheng,Yao Pan,Qian Xing,Rong Tsao,Hongyan Li
Phenolics and carotenoids coexist in fruits and vegetables and could possess interaction effects after consumption. The present study aims to elucidate the possible mechanisms of the antioxidant interactions between anthocyanins and carotenoids using petunidin and lycopene as examples in hydrogen peroxide (H 2 O 2 )-induced heart myofibroblast cell (H9c2) line model. The results revealed that petunidin and lycopene showed antioxidant effects and petunidin in a larger proportion mixed with lycopene, for example, petunidin: lycopene = 9:1 significantly protected against the loss of the cell viability (8.98 ± 1.03%) and intracellular antioxidant enzyme activities of superoxide dismutase (SOD, 27.07 ± 3.51%), catalase (CAT, 29.51 ± 6.12%), and glutathione peroxidase (GSH-Px, 20.33 ± 2.65%). Moreover, the messenger RNA (mRNA) and protein expressions of NAD(P)H quinone reductase (NQO1) and heme oxygenase (HO-1) of the nuclear factor erythrocyte 2-related factor 2 (Nrf2) signaling pathway were significantly induced in petunidin, lycopene, and synergistic combinations, suggesting that the antioxidant action was through activating the Nrf2 antioxidant response pathway. This was further validated by Nrf2 siRNA, and the results that petunidin significantly induced more of NQO1 expression and lycopene more of HO-1 suggested that the synergism may be a result of concerted actions by the two compounds on these two different target genes of the Nrf2 pathway. The two compounds also significantly increased the phosphorylation of Akt in synergistic combinations. Findings of the present study demonstrated that petunidin and lycopene exerted synergistic antioxidant effects when petunidin in a larger proportion in the combinations and contribute to the prevention of cellular redox homeostasis, which might provide a theoretical basis for phenolics and carotenoids playing beneficial effects on the cardiovascular risk. Practical Application In this study, we revealed that the combined treatments of petunidin and lycopen inhibited H 2 O 2 -induced oxidative damage in myocardial cells. Moreover, the treatments contributed to the Nrf2 pathway and the restoration of cellular redox homeostasis might provide a theoretical basis for phenolics and carotenoids playing beneficial effects on the cardiovascular risk.
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International Journal of Environmental Research and Public Health
·
2019
·Vol. 17
·期 1
·138
·
IF 2.468
Chang Liu,Yaohui Zhu,Zhenxiang Lu,Weina Guo,Bayaer Tumen,Yalan He,Chao Chen,Shanshan Hu,Kangzhi Xu,Yan Wang,Lei Li,Shenghe Li
Acute Cadmium (Cd) exposure usually induces hepatotoxicity. It is well known that oxidative stress and inflammation causes Cd-induced liver injury. However, the effect of nuclear factor erythroid 2-related factor 2 (Nrf2) in Cd-induced liver injury is not completely understood. In this study, we observed Cd-induced liver damage and the potential contribution of Nrf2, nuclear factor-κB (NF-κB), Nod-like receptor 3 (NLRP3), and mitogen-activated protein kinases (MAPKs) signaling pathways. Changes in serum transaminases and proinflammatory cytokines expression showed that Cd could induce acute hepatotoxicity. Moreover, Nrf2 and its downstream heme oxygenase 1 (HO-1) were inhibited by Cd exposure, and Kelch-like ECH-associated protein 1 (Keap1), the inhibitory protein of Nrf2, was increased. Furthermore, NF-κB, NLRP3, and MAPKs signaling pathways were all activated by Cd intoxication. In conclusion, the inhibition of Nrf2, HO-1, and the activation of NF-κB, NLRP3, and MAPKs all contribute to Cd-induced liver injury.Keywords:Cadmium;acute liver injury;Nrf2;NLRP3;NF-κB;MAPKs
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Food & Nutrition Research
·
2022
·
IF 3.221
Yue-hong Lu,Yue Hong,Tian-yang Zhang,You-xia Chen,Zhao-jun Wei,Chun-yan Gao
Background Rosmarinic acid (RA) has biological and pharmaceutical properties and shows hepatoprotective potential. However, the hepatoprotective mechanism of RA needs to be further elucidated in vivo and in vitro. Objective This study was aimed to evaluate the protective effect of RA on carbon tetrachloride (CCl 4 )-induced liver injury and elucidate the hepatoprotective mechanism of RA in vivo and in vitro. Design In vivo, the mice were orally administrated with RA (10, 20, and 40 mg/kg bw) daily for 28 consecutive days, and 1% CCl 4 (5 mL/kg bw, dissolved in peanut oil) was used to induce liver injury. In vitro, the big rat liver (BRL) hepatocytes were pretreated with RA (0.2, 0.4, and 0.8 mg/mL) for 3 h, and then the hepatocytes were treated with CC1 4 (final concentration, 14 mM) for 3 h to induce cell injury. The related indexes, including hepatic function, oxidative stress, protein expression of nuclear-factor erythroid 2-related factor 2 (Nrf2) pathway, inflammation, histopathological change, hepatocyte apoptosis, and mitochondrial membrane potential, were evaluated. Results Oral administration of RA to mice considerably decreased the CCl 4 -induced elevation of serum alanine aminotransferase (ALT), alkaline phosphatase (ALP), triacylglycerols (TG), total cholesterol (TC), total bilirubin (TBIL), hepatic reactive oxygen species (ROS), malondialdehyde (MDA), nitric oxide (NO), 8-hydroxydeoxyguanosine (8-OHdG), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8). RA also increased the levels of hepatic glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) and the protein expressions of Nrf2, quinine oxidoreductase (NQO1), and heme oxygenease-1 (HO-1). Histopathological examinations indicated that RA (20 and 40 mg/kg bw) alleviated the liver tissue injury induced by CCl 4 . Moreover, RA inhibited the hepatocyte apoptosis caused by CCl 4 based on TUNEL assay. In vitro, RA pretreatment remarkably recovered the cell viability and reduced the CCl 4 -induced elevation of AST, ALT, lactate dehydrogenase (LDH), ROS, and 8-OHdG. Immunohistochemistry staining demonstrated that pretreatment with RA markedly inhibited the expression of IL-6, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and Caspase-3 in CCl 4 -treated hepatocytes. Additionally, RA pretreatment significantly decreased the elevation of mitochondrial membrane potential in CCl 4 -treated hepatocytes. Conclusions RA exerted a protective effect against CCl 4 -induced liver injury in mice through activating Nrf2 signaling pathway, reducing antioxidant damage, suppressing inflammatory response, and inhibiting hepatocyte apoptosis. RA could attenuate BRL hepatocyte ROS production, DNA oxidative damage, inflammatory response, and apoptosis induced by CCl 4 exposure.
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