scholarly journals Antagonizing Effects of Clematis apiifolia DC. Extract against Benzo[a]pyrene-Induced Damage to Human Keratinocytes

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Seung Eun Lee ◽  
See-Hyoung Park ◽  
Ju Ah Yoo ◽  
Kitae Kwon ◽  
Ji Woong Kim ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Human Keratinocytes ◽  
Antioxidant Response ◽  
Luciferase Reporter ◽  
Heme Oxygenase 1 ◽  
Protective Effects ◽  
Cytochrome P450 1A1 ◽  
Independent Manner ◽  
Reporter Activity ◽  
Aryl Hydrocarbon

Background. Benzo[a]pyrene (B[a]P), a polycyclic aromatic hydrocarbon present in the atmosphere, has cytotoxic and carcinogenic effects. There have been no reports to demonstrate involvement of Clematis apiifolia DC. extract (CAE) in B[a]P-induced effects. This study was conducted to investigate the effect of CAE on B[a]P-induced effects and to elucidate its mechanism of action in HaCaT human keratinocytes. CAE inhibited aryl hydrocarbon receptor (AhR) signaling by decreasing both XRE reporter activity and expression of cytochrome P450 1A1 (CYP1A1) induced by B[a]P treatment in HaCaT cells. We also found that B[a]P-induced nuclear translocation of AhR and production of reactive oxygen species (ROS) and proinflammatory cytokines were attenuated by CAE treatment. CAE treatment suppressed B[a]P-induced phosphorylation of Src (Tyr416). In addition, dasatinib, a Src inhibitor, also inhibited B[a]P-induced nuclear translocation of AhR, similar to CAE treatment. In addition, CAE activated antioxidant response element (ARE) signaling by increasing ARE luciferase reporter activity and expression of ARE-dependent genes such as nuclear factor (erythroid-derived 2)-like 2 (Nrf2), NAD(P)H dehydrogenase [quinone] 1 (NQO1), and heme oxygenase-1 (HO-1). Nuclear translocation of Nrf2 by CAE was demonstrated by Western blot analysis and immunocytochemistry. The effects of CAE on ARE signaling were attenuated by knockdown of the Nrf2 gene. Inhibition of AhR signaling and activation of antioxidant activity by CAE operated in a reciprocally independent manner as evidenced by AhR and Nrf2 siRNA experiments. These findings indicate that CAE exerts protective effects against B[a]P by inhibiting AhR signaling and activating Nrf2-mediated signaling, suggesting its potential in protection from harmful B[a]P-containing pollutants.

scholarly journals Protective Effects of Maclurin against Benzo[a]pyrene via Aryl Hydrocarbon Receptor and Nuclear Factor Erythroid 2-Related Factor 2 Targeting

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1189
Author(s):  
Jangsoon Kim ◽  
See-Hyoung Park ◽  
Seyoung Yang ◽  
Sae Woong Oh ◽  
Kitae Kwon ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Nuclear Translocation ◽  
Radical Scavenging ◽  
Luciferase Reporter ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Nuclear Factor ◽  
Response Element ◽  
Reporter Activity ◽  
Aryl Hydrocarbon

Benzo[a]pyrene (B[a]P), a polycyclic aromatic hydrocarbon formed during the incomplete combustion of organic matter, has harmful effects. Therefore, much research is ongoing to develop agents that can mitigate the effects of B[a]P. The aim of this study was to examine the effect of maclurin, one component of the branches of Morus alba L., on the B[a]P-induced effects in HaCaT cells, a human keratinocyte cell line. Maclurin treatment inhibited aryl hydrocarbon receptor (AHR) signaling as evidenced by reduced xenobiotic response element (XRE) reporter activity, decreased expression of cytochrome P450 1A1 (CYP1A1), and reduced nuclear translocation of AHR. The B[a]P-induced dissociation of AHR from AHR-interacting protein (AIP) was suppressed by maclurin. Maclurin also inhibited the production of intracellular reactive oxygen species (ROS) induced by B[a]P. In addition, the antioxidant property of maclurin itself was demonstrated by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. Furthermore, maclurin activated antioxidant response element (ARE) signaling through enhancement of ARE luciferase reporter activity and the expression of ARE-dependent genes including nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase-1 (HO-1). Nrf2 activation and its nuclear translocation were promoted by maclurin through p38 MAPK activation. These data indicate that maclurin had antagonistic activity against B[a]P effects through activation of Nrf2-mediated signaling and inhibition of AHR signaling and, suggesting its potential in protecting from harmful B[a]P-containing pollutants.

scholarly journals (−)-Loliolide Isolated from Sargassum horneri Protects against Fine Dust-Induced Oxidative Stress in Human Keratinocytes

Antioxidants ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 474
Author(s):  
Mawalle Kankanamge Hasitha Madhawa Dias ◽  
Dissanayaka Mudiyanselage Dinesh Madusanka ◽  
Eui Jeong Han ◽  
Min Ju Kim ◽  
You-Jin Jeon ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nuclear Translocation ◽  
Human Keratinocytes ◽  
Sargassum Horneri ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Protective Effects ◽  
Fine Dust ◽  
Apoptosis Pathway ◽  
Sustainable Solutions

The emergence of fine dust (FD) among air pollutants has taken a toll during the past few decades, and it has provided both controversy and a platform for open conversation amongst world powers for finding sustainable solutions and effective treatments for health issues. The present study emphasizes the protective effects of (–)-loliolide (HTT) isolated from Sargassum horneri against FD-induced oxidative stress in human HaCaT keratinocytes. The purification of (–)-loliolide was carried out by centrifugal partition chromatography. HTT did not show any cytotoxicity, and it further illustrated the potential to increase cell viability by reducing the reactive oxygen species (ROS) production in FD-stimulated keratinocytes. Furthermore, HTT suppressed FD-stimulated DNA damage and the formation of apoptotic bodies, and it reduced the population of cells in the sub-G1 apoptosis phase. FD-induced apoptosis was advancing through the mitochondria-mediated apoptosis pathway. The cytoprotective effects of the HTT against FD-stimulated oxidative damage is mediated through squaring the nuclear factor E2-related factor 2 (Nrf2)-mediated heme oxygenase-1 (HO-1) pathway, dose-dependently increasing HO-1 and NAD(P)H dehydrogenase (quinone) 1 (NQO1) levels in the cytosol while concomitantly improving the nuclear translocation of Nrf2. Future studies could implement the protective functionality of HTT in producing pharmaceuticals that utilize natural products and benefit the diseased.

scholarly journals Synergistic Protection by Isoquercitrin and Quercetin against Glutamate-Induced Oxidative Cell Death in HT22 Cells via Activating Nrf2 and HO-1 Signaling Pathway: Neuroprotective Principles and Mechanisms of Dendropanax morbifera Leaves

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 554
Author(s):  
Hye-Jin Park ◽  
Ha-Neul Kim ◽  
Chul Young Kim ◽  
Min-Duk Seo ◽  
Seung-Hoon Baek
Keyword(s):  
Cell Death ◽  
Nuclear Translocation ◽  
Interaction Analysis ◽  
Cell Model ◽  
Antioxidant Compounds ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Protective Effects ◽  
Ht22 Cells ◽  
Dendropanax Morbifera

Dendropanax morbifera leaves (DML) have long been used as traditional medicine to treat diverse symptoms in Korea. Ethyl acetate-soluble extracts of DML (DMLE) rescued HT22 mouse hippocampal neuronal cells from glutamate (Glu)-induced oxidative cell death; however, the protective compounds and mechanisms remain unknown. Here, we aimed to identify the neuroprotective ingredients and mechanisms of DMLE in the Glu-HT22 cell model. Five antioxidant compounds were isolated from DMLE and characterized as chlorogenic acid, hyperoside, isoquercitrin, quercetin, and rutin by spectroscopic methods. Isoquercitrin and quercetin significantly inhibited Glu-induced oxidative cell death by restoring intracellular reactive oxygen species (ROS) levels and mitochondrial superoxide generation, Ca2+ dysregulation, mitochondrial dysfunction, and nuclear translocation of apoptosis-inducing factor. These two compounds significantly increased the expression levels of nuclear factor erythroid-2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) in the presence or absence of Glu treatment. Combinatorial treatment of the five compounds based on the equivalent concentrations in DMLE showed that significant protection was found only in the cells cotreated with isoquercitrin and quercetin, both of whom showed prominent synergism, as assessed by drug–drug interaction analysis. These findings suggest that isoquercitrin and quercetin are the active principles representing the protective effects of DMLE, and these effects were mediated by the Nrf2/HO-1 pathway.

Regulation of heme oxygenase-1 expression by demethoxy curcuminoids through Nrf2 by a PI3-kinase/Akt-mediated pathway in mouse β-cells

2007 ◽  
Vol 293 (3) ◽  
pp. E645-E655 ◽  
Author(s):  
Subbiah Pugazhenthi ◽  
Leonid Akhov ◽  
Gopalan Selvaraj ◽  
Maorong Wang ◽  
Jawed Alam
Keyword(s):  
Signaling Pathways ◽  
Heme Oxygenase ◽  
Nuclear Translocation ◽  
Regulatory Subunit ◽  
Luciferase Reporter ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Mrna Levels ◽  
Phase 2 ◽  
Β Cells

Curcumin (diferuloylmethane), a component of turmeric, has been shown to have therapeutic properties. Induction of phase 2 detoxifying enzymes is a potential mechanism through which some of the actions of curcumin could proceed. Heme oxygenase-1 (HO-1), an antioxidant phase 2 enzyme, has been reported to have cytoprotective effects in pancreatic β-cells. Curcumin on further purification yields demethoxy curcumin (DMC) and bisdemethoxy curcumin (BDMC). The objective of the present study was to determine the mechanism by which these purified curcuminoids induce HO-1 in MIN6 cells, a mouse β-cell line. Demethoxy curcuminoids induced HO-1 promoter linked to the luciferase reporter gene more effectively than curcumin. The induction was dependent on the presence of antioxidant response element (ARE) sites containing enhancer regions (E1 and E2) in HO-1 promoter and nuclear translocation of nuclear factor-E2-related factor (Nrf2), the transcription factor that binds to ARE. Curcuminoids stimulated multiple signaling pathways that are known to induce HO-1. Inhibition of specific signaling pathways with pharmacological inhibitors and cotransfection experiments suggested the involvement of phosphotidylinositol 3-kinase and Akt. Real-time quantitative RT-PCR analysis showed significant elevation in the mRNA levels of HO-1 and two other phase 2 enzymes, the regulatory subunit of glutamyl cysteine ligase, which is needed for the synthesis of glutathione, and NAD(P)H:quinone oxidoreductase, which detoxifies quinones. DMC and BDMC induced the expression of HO-1 and translocated Nrf2 to nucleus in β-cells of mouse islets. Our observations suggest that demethoxy curcuminoids could be used to induce a cellular defense mechanism in β-cells under conditions of stress as seen in diabetes.

scholarly journals Overexpression of NRF1-742 or NRF1-772 Reduces Arsenic-Induced Cytotoxicity and Apoptosis in Human HaCaT Keratinocytes

2020 ◽  
Vol 21 (6) ◽  
pp. 2014
Author(s):  
Shuai Wang ◽  
Hao Cheng ◽  
Linlin Wang ◽  
Rui Zhao ◽  
Dawei Guan
Keyword(s):  
Leucine Zipper ◽  
Nuclear Translocation ◽  
Inorganic Arsenic ◽  
Human Keratinocytes ◽  
Antioxidant Response ◽  
Bzip Transcription Factor ◽  
Nuclear Factor ◽  
Hacat Keratinocytes ◽  
Protein Levels ◽  
Antioxidant Protein

Increasing evidence indicates that human exposure to inorganic arsenic causes cutaneous diseases and skin cancers. Nuclear factor erythroid 2-like 1 (NRF1) belongs to the cap “n” collar (CNC) basic-region leucine zipper (bZIP) transcription factor family and regulates antioxidant response element (ARE) genes. The human NRF1 gene is transcribed into multiple isoforms, which contain 584, 616, 742, 761, or 772 amino acids. We previously demonstrated that the long isoforms of NRF1 (i.e., NRF1-742, NRF1-761 and NRF1-772) are involved in the protection of human keratinocytes from acute arsenic cytotoxicity by enhancing the cellular antioxidant response. The aim of the current study was to investigate the roles of NRF1-742 and NRF1-772 in the arsenic-induced antioxidant response and cytotoxicity. We found that overexpression of NRF1-742 or NRF1-772 in human HaCaT keratinocytes decreased susceptibility to arsenic-induced apoptosis and cytotoxicity. In addition, we characterized the different protein bands observed for NRF1-742 and NRF1-772 by western blotting. The posttranslational modifications and nuclear translocation of these isoforms differed and were partially affected by arsenic exposure. Antioxidant protein levels were increased in the NRF1-742 and NRF1-772-overexpressing cell lines. The upregulation of antioxidant protein levels was partly due to the translation of nuclear factor erythroid 2-like 2 (NRF2) and its increased nuclear transport. Overall, overexpression of NRF1-742 and NRF1-772 protected HaCaT cells from arsenic-induced cytotoxicity, mainly through translational modifications and the promotion of antioxidant gene expression.

scholarly journals Induction of HO-1 by Mevastatin Mediated via a Nox/ROS-Dependent c-Src/PDGFRα/PI3K/Akt/Nrf2/ARE Cascade Suppresses TNF-α-Induced Lung Inflammation

2020 ◽  
Vol 9 (1) ◽  
pp. 226 ◽  
Author(s):  
Chih-Chung Lin ◽  
Wei-Ning Lin ◽  
Rou-Ling Cho ◽  
Chien-Chung Yang ◽  
Yi-Cheng Yeh ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
Growth Factor Receptor ◽  
Antioxidant Response ◽  
Alveolar Epithelial Cells ◽  
Intercellular Adhesion Molecule ◽  
Ros Generation ◽  
Heme Oxygenase 1 ◽  
Tnf Α

Background: Mevastatin (MVS), a 3-hydroxy-3-methylglutaryl coenzyme, a reductase (HMG-CoA) inhibitor, has anti-inflammatory effects potentially via up-regulation of heme oxygenase-1 (HO-1). However, the mechanisms underlying MVS-induced HO-1 expression remain largely unknown in human pulmonary alveolar epithelial cells (HPAEpiCs). Methods: HO-1 and intercellular adhesion molecule (ICAM)-1 expression were determined using real-time PCR, Western blotting, and promoter reporter analyses. The signaling components were investigated using pharmacological inhibitors or specific small interfering RNA (siRNA)s. Interaction between Nrf2 and the antioxidant response element (ARE) binding site for the HO-1 promoter was determined by chromatin immunoprecipitation (ChIP) assay. Results: Upregulation of HO-1 by MVS attenuated the tumor necrosis factor (TNF)-α-stimulated ICAM-1 expression associated with THP-1 adhesion to HPAEpiCs. These inhibitory effects of HO-1 were reversed by tin protoporphyrin (SnPP)IX or by transfection with HO-1 siRNA. MVS-induced HO-1 expression was mediated via NADPH oxidase (Nox)-derived reactive oxygen species (ROS) generation. Activation of Nox2/ROS further stimulated the phosphorylation of p47phox, proto-oncogene tyrosine-protein kinase (c-Src), platelet-derived growth factor receptor (PDFGR)α, protein kinase B (Akt), and Nrf2, which were inhibited by siRNAs. Pretreatment with pharmacological inhibitors, including diphenyleneiodonium (DPI), apocynin (APO), N-acetyl-L-cysteine (NAC), PP1, AG1296, or LY294002, reduced the MVS-activated Nrf2 nuclear-translocation binding to the ARE on the HO-1 promoter. Conclusions: MVS-induced HO-1 is, at least in part, mediated through a p47phox/Nox2/ROS-dependent activation of c-Src/PDGFRα/PI3K/Akt-regulated Nrf2/ARE axis and suppresses the TNF-α-mediated inflammatory responses in HPAEpiCs.

scholarly journals CYP2J2-Derived EETs Attenuated Angiotensin II-Induced Adventitial Remodeling via Reduced Inflammatory Response

2016 ◽  
Vol 39 (2) ◽  
pp. 721-739 ◽  
Author(s):  
Chi Zhou ◽  
Jin Huang ◽  
Junxiong Chen ◽  
Jinsheng Lai ◽  
Fasheng Zhu ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Gene Delivery ◽  
Signaling Pathways ◽  
Nuclear Translocation ◽  
Wall Thickening ◽  
Protective Effects ◽  
Ang Ii ◽  
Independent Manner ◽  
Stat3 Phosphorylation ◽  
Arachidonic Acids

Background: Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acids (AA) to form epoxyeicosatrienoic acids (EETs), which exert beneficial roles in the treatment of cardiovascular diseases, but little is known about its role on adventitial remodeling. Methods: We used C57BL/6J mice in vivo and primary rat adventitial fibroblasts (AFs) in vitro treated with Angiotensin II to investigate the effects of CYP2J2 gene delivery and exogenous EETs administration on adventitial remodeling. Results: CYP/sEH system was found to exist in human adventitia, and involved in adventitial remodeling process. Exogenous EETs administration significantly inhibited Ang II-induced AFs activation, characterized by differentiation, proliferation, migration, and collagen synthesis. These protective effects were partially reversed by PPARγ antagonist GW9662 pretreatment or SOCS3 siRNA transfection. EETs suppressed Ang II-induced IκBα phosphorylation, subsequent NF-κB nuclear translocation via PPARγ dependent signaling pathway in AFs. Additionally, EETs reduced Ang II-induced JAK2, STAT3 phosphorylation and subsequent phosphor-STAT3 nuclear translocation, which were mediated by SOCS3 induction but independent of PPARγ activation. Furthermore, rAAV-CYP2J2 gene delivery reduced vessel wall thickening, AFs differentiation, proliferation and collagen deposition in aortic adventitia induced by Ang II infusion, which were mediated by NF-κB and SOCS3/JAK/STAT signaling pathways in blood pressure dependent and independent manner, respectively. Conclusion: We concluded that CYP2J2 overexpression attenuated Ang II-induced adventitial remodeling via PPARγ-dependent NF-κB and PPARγ-independent SOCS3/JAK/STAT inflammatory signaling pathways.

scholarly journals Hyperoxia-induced NF-κB activation occurs via a maturationally sensitive atypical pathway

2009 ◽  
Vol 296 (3) ◽  
pp. L296-L306 ◽  
Author(s):  
Clyde J. Wright ◽  
Tiangang Zhuang ◽  
Ping La ◽  
Guang Yang ◽  
Phyllis A. Dennery
Keyword(s):  
Nuclear Translocation ◽  
Fetal Lung ◽  
Dominant Negative ◽  
Lung Fibroblasts ◽  
Luciferase Reporter ◽  
Normal Lung ◽  
Adult Lung ◽  
Fetal Cells ◽  
Reporter Activity ◽  
Tnf Α

NF-κB activation is exaggerated in neonatal organisms after oxidant and inflammatory insults, but the reason for this and the downstream effects are unclear. We hypothesized that specific phosphorylation patterns of IκBα could account for differences in NF-κB activation in hyperoxia-exposed fetal and adult lung fibroblasts. After exposure to hyperoxia (>95% O2), nuclear NF-κB binding increased in fetal, but not adult, lung fibroblasts. Unique to fetal cells, phosphorylation of IκBα on tyrosine 42, rather than serine 32/36 as seen in TNF-α-exposed cells, preceded NF-κB nuclear translocation. In fetal cells stably transfected with an NF-κB-driven luciferase reporter, hyperoxia significantly suppressed reporter activity, in contrast to increased reporter activity after TNF-α incubation. Targeted gene profiling analysis showed that hyperoxia resulted in decreased expression of multiple genes, including proapoptotic factors. Transfection with a dominant-negative IκBα (Y42F), which cannot be phosphorylated on tyrosine 42, resulted in upregulation of multiple proapoptotic genes. In support of this finding, caspase-3 activity and DNA laddering were specifically increased in fetal lung fibroblasts expressing Y42F after exposure to hyperoxia. These data demonstrate a unique pathway of NF-κB activation in fetal lung fibroblasts after exposure to hyperoxia, whereby these cells are protected against apoptosis. Activation of this pathway in fetal cells may prevent the normal pattern of fibroblast apoptosis necessary for normal lung development, resulting in aberrant lung morphology in vivo.

scholarly journals Microdose Lithium Protects against Pancreatic Islet Destruction and Renal Impairment in Streptozotocin-Elicited Diabetes

Antioxidants ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 138
Author(s):  
Jiahui Zhang ◽  
Fnu Anshul ◽  
Deepak K. Malhotra ◽  
Juan Jaume ◽  
Lance D. Dworkin ◽  
...  
Keyword(s):  
Protective Effect ◽  
Pancreatic Islet ◽  
Nuclear Translocation ◽  
Glycogen Synthase ◽  
Kidney Injury ◽  
Body Weight Loss ◽  
Antioxidant Response ◽  
Heme Oxygenase 1 ◽  
Β Cells ◽  
Selective Blockade

Psychiatric use of lithium has been associated with hypoglycemic effects, but its effect on type 1 diabetes mellitus (T1D) is unknown. In streptozotocin (STZ) induced murine models of T1D, microdose lithium therapy improved hyperglycemia, attenuated body weight loss and prevented early signs of diabetic kidney injury. This beneficial effect was associated with preservation of pancreatic islet histology and β-cell production of insulin as well as mitigated oxidative damage of islets. Mechanistically, lithium in islets cells induced inhibitory phosphorylation of glycogen synthase kinase 3β (GSK3β), the major molecular target of lithium that has been recently implicated in non-canonical regulation of Nrf2 activity. In turn, Nrf2 antioxidant response was potentiated in islets, marked by nuclear translocation of Nrf2 and augmented expression of its target antioxidant enzyme heme oxygenase 1 (HO-1). Conversely, cotreatment with trigonelline, a selective blockade of Nrf2, offset the lithium enhanced Nrf2 antioxidant response in islets, blunted the protective effect of lithium on pancreatic islets and β-cells, and abolished the hypoglycemic activity of lithium in STZ-injured mice. Collectively, our findings suggest that microdose lithium confers a protective effect on islet β-cells via targeting the GSK3β-regulated Nrf2 antioxidant response and thereby ameliorates T1D and its related kidney impairment.

scholarly journals Protective Effect of Pomegranate on Oxidative Stress and Inflammatory Response Induced by 5-Fluorouracil in Human Keratinocytes

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 203
Author(s):  
Shara Francesca Rapa ◽  
Giorgia Magliocca ◽  
Giacomo Pepe ◽  
Giuseppina Amodio ◽  
Giuseppina Autore ◽  
...  
Keyword(s):  
Side Effects ◽  
Inflammatory Response ◽  
Wound Repair ◽  
Nuclear Translocation ◽  
Antineoplastic Agent ◽  
Human Keratinocytes ◽  
Heme Oxygenase 1 ◽  
Experimental Conditions ◽  
Skin Reactions ◽  
Inflammatory State

5-Fluorouracil (5-FU) is a pyrimidine analogue used as an antineoplastic agent to treat multiple solid tumors. Despite its use and efficacy, it also has important side effects in healthy cells, including skin reactions, related to its pro-oxidant and pro-inflammatory potential. Although there are numerous remedies for chemotherapy-induced skin reactions, the efficacy of these treatments remains limited. In this study we focused on the effects of pomegranate (Punica granatum L.) juice extract (PPJE) on the oxidative and inflammatory state in 5-FU-treated human skin keratinocytes (HaCaT). The obtained results showed that PPJE significantly inhibited reactive oxygen species release and increased the cellular antioxidant response, as indicated by the increased expression of cytoprotective enzymes, such as heme oxygenase-1 and NAD(P)H dehydrogenase [quinone] 1. In these experimental conditions, PPJE also inhibited nitrotyrosine formation and 5-FU-induced inflammatory response, as indicated by the reduced cytokine level release. Moreover, PPJE inhibited nuclear translocation of p65-NF-κB, a key factor regulating the inflammatory response. In 5-FU-treated HaCaT cells PPJE also inhibited apoptosis and promoted wound repair. These results suggest a potential use of PPJE as an adjuvant in the treatment of the oxidative and inflammatory state that characterizes chemotherapy-induced skin side effects.

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