Activation Of Nrf2 Signaling Pathway Research Articles

Anti-inflammatory effects of isorhamnetin on LPS-stimulated human gingival fibroblasts by activating Nrf2 signaling pathway

Periodontitis is a highly prevalent infective and inflammatory disease with an adverse impact on systemic health. Isorhamnetin, a flavonoid mainly isolated from Hippophae fhamnoides L. fruit, has been reported to have anti-inflammatory effect. This study aimed to investigate the anti-inflammatory effects and mechanism of isorhamnetin on lipopolysaccharide (LPS)-induced inflammatory response in human gingival fibroblasts (HGFs). The production of inflammatory mediators and the expression of proteins were measured by ELISA and western blot analysis. The results demonstrated that isorhamnetin attenuated LPS-induced release of PGE2, NO, IL-6, and IL-8 in HGFs. Isorhamnetin also inhibited LPS-induced NF-κB activation. The expression of Nrf2 and HO-1 were up-regulated by treatment of isorhamnetin. Furthermore, knockdown of Nrf2 by siRNA reversed the anti-inflammatory effects of isorhamnetin. In conclusion, these results suggested that isorhamnetin inhibited LPS-induced inflammation in HGFs by activating Nrf2 signaling pathway.

Maslinic acid protects against lipopolysaccharide/d-galactosamine-induced acute liver injury in mice

Acute liver injury is a life-threatening syndrome that often caused by hepatocyte damage. In this study, we investigated the protective effects of maslinic acid (MA) on lipopolysaccharide (LPS)/d-galactosamine (D-gal)-induced acute liver injury and clarified its mechanism. Mice acute liver injury model was induced by given LPS and D-gal and MA was given intraperitoneally 1 h before LPS and D-gal. Our results showed that MA protected against liver injury by attenuating liver histopathologic changes, serum AST and ALT levels. The increased inflammatory cytokines TNF-α and IL-6 in serum and liver tissues were also inhibited by MA. The level of MDA and the activity of MPO in liver tissues were up-regulated by LPS/D-gal and dose-dependently inhibited by MA. Furthermore, MA attenuated hepatic NF-κB protein expression and increased hepatic Nrf2 and HO-1 protein expression. Taken together, MA offers a protective role against LPS/D-gal-induced liver injury through suppressing NF-κB and activating Nrf2 signaling pathways.

Effect of luteolin on ulcerative colitis in mice

Objective To investigate the effects of luteolin ondextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice. Methods Experimental acute colitis was induced by administering 3% DSS in the drinking water. 40 C57BL/6 mice were randomly divided into normal control group, DSS model group, low, medium, high-dose luteolin groups. The disease activity index (DAI), colon length, histological assessment, mRNA expressions of nuclear factor-erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), nicotinamide adenine dinucleotide phosphate (NADPH), quinone oxidoreductase 1 (NQO1), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), protein expression of Nrf2 were examined. Results Treatment with luteolin markedly attenuated the DAI compared with DSS model group (3.17±0.65, 2.03±0.40, 1.27±0.25 vs. 3.90±0.36, P=0.046, 0.000, 0.000); Administration of luteolin ameliorated colon shortening on different levels (4.27±0.75, 5.17±0.35, 5.97±0.50 vs. 3.67±0.65), medium, high-dose luteolingroups had significant difference in comparison with DSS model group (P=0.003, 0.001); Histopathological analysis showed that luteolin effectively reduced histological alterations; reverse transcriptase-polymerase chain reaction (RT-PCR) displayed that luteolin activated the expression of Nrf2 and its downstream targets, including HO-1, NQO1 compared with DSS model group (0.18±0.08, 0.16±0.13, 0.19±0.10). Luteolin also significantly (P=0.005, 0.002, 0.001; P=0.002, 0.000, 0.000); reduced the levels of TNF-α, IL-6 in comparison with DSS model group (1.59±0.47, 2.02±0.36). Western blotting shown that compared with DSS model group, luteolin significantly elevated the nuclear protein expression of Nrf2 (0.13±0.62 vs. 0.28±0.50, 0.37±0.80, 0.51±0.92; P=0.026, 0.002, 0.000). Conclusion Administration of luteolin has protective effect on experimental colitis, maybe the mechanism is activating Nrf2 signaling pathway, promoting Nrf2 into nucleus and elevating mRNA levels of its downstream targets HO-1 and NQO1, suppressing mRNA expressions of TNF-α, IL-6, thus enhancing colon antioxidant ability and regulating the oxidation/antioxidant balance. Key words: Luteolin; Ulcerative colitis; Nuclear factor-erythroid 2-related factor 2

The Association Between Oxidative Stress Alleviation via Sulforaphane-Induced Nrf2-HO-1/NQO-1 Signaling Pathway Activation and Chronic Renal Allograft Dysfunction Improvement

Background/Aims: Chronic renal allograft dysfunction (CRAD) is a leading cause of long-term renal allograft loss. Oxidative stress may account for the nonspecific interstitial fibrosis and tubular atrophy that occur in CRAD. An antioxidant intervention via Nrf2 signaling pathway activation might be a promising therapy for some kidney diseases. The present paper investigates whether there is an association between oxidative stress alleviation via sulforaphane-induced Nrf2-HO-1/NQO-1 signaling pathway activation and CRAD improvement. Methods: F344 rat kidneys were orthotopically transplanted into Lewis rat recipients to establish CRAD models. Sulforaphane was administered at 1.5 mg/kg intraperitoneally once daily. Renal function and 24-hour urinary protein were monitored for variations for 24 weeks after transplantation. After 24 weeks, renal histopathology was evaluated according to the Banff criteria after hematoxylin and eosin, Masson’s trichrome and periodic acid-Schiff stainings. Additionally, intrarenal oxidative stress was assessed by the indicators malondialdehyde, 8-isoprostane, oxidized-low density lipoprotein and 8-hydroxy-2’-deoxyguanosine, as well as the activity levels of the antioxidant enzymes total superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and γ-glutamylcysteine synthetase. Nrf2, HO-1 and NQO-1 expression levels were determined via immunohistochemical and Western blot analyses. Results: The sulforaphane-induced Nrf2-HO-1/NQO-1 signaling pathway activation, as demonstrated by immunohistochemical and Western blot analyses, delayed the progression of serum creatinine and blood urea nitrogen, particularly lowering the 24-hour urinary protein levels of CRAD. The semi-quantified histopathological changes were also alleviated. Evidence of oxidative stress alleviation, as indicated by a concurrent decrease in the indicators and sustained levels of antioxidant enzymes activity, was found in the renal allografts after sulforaphane intervention. Conclusion: Oxidative stress alleviation caused by continuous sulforaphane-induced Nrf2-HO-1/NQO-1 signaling pathway activation is associated with functional and morphological improvements of CRAD.

Uric Acid Protects against Focal Cerebral Ischemia/Reperfusion-Induced Oxidative Stress via Activating Nrf2 and Regulating Neurotrophic Factor Expression.

The aim of this study was to investigate whether uric acid (UA) might exert neuroprotection via activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and regulating neurotrophic factors in the cerebral cortices after transient focal cerebral ischemia/reperfusion (FCI/R) in rats. UA was intravenously injected through the tail vein (16 mg/kg) 30 min after the onset of reperfusion in rats subjected to middle cerebral artery occlusion for 2 h. Neurological deficit score was performed to analyze neurological function at 24 h after reperfusion. Terminal deoxynucleotidyl transferase-mediated dNTP nick end labeling (TUNEL) staining and hematoxylin and eosin (HE) staining were used to detect histological injury of the cerebral cortex. Malondialdehyde (MDA), the carbonyl groups, and 8-hydroxyl-2′-deoxyguanosine (8-OHdG) levels were employed to evaluate oxidative stress. Nrf2 and its downstream antioxidant protein, heme oxygenase- (HO-) 1,were detected by western blot. Nrf2 DNA-binding activity was observed using an ELISA-based measurement. Expressions of BDNF and NGF were analyzed by immunohistochemistry. Our results showed that UA treatment significantly suppressed FCI/R-induced oxidative stress, accompanied by attenuating neuronal damage, which subsequently decreased the infarct volume and neurological deficit. Further, the treatment of UA activated Nrf2 signaling pathway and upregulated BDNF and NGF expression levels. Interestingly, the aforementioned effects of UA were markedly inhibited by administration of brusatol, an inhibitor of Nrf2. Taken together, the antioxidant and neuroprotective effects afforded by UA treatment involved the modulation of Nrf2-mediated oxidative stress and regulation of BDNF and NGF expression levels. Thus, UA treatment could be of interest to prevent FCI/R injury.

Astragaloside IV protects blood-brain barrier integrity from LPS-induced disruption via activating Nrf2 antioxidant signaling pathway in mice

Endothelial cells of cerebral microvessels are one of the components of blood-brain-barrier (BBB), which are connected by tight junctions (TJs). BBB disruption in cerebral diseases such as ischemic stroke, Alzhemer's disease, multiple sclerosis and traumatic brain injury is implicated to exacerbate the disease progression. Astragaloside IV (ASIV) isolated from Astragalus membranaceus prevents BBB breakdown in rodents induced with cerebral edema and experimental autoimmune encephalomyelitis. However, its underlying molecular mechanism has not been elucidated yet. In present study, ASIV was found to prevent the leakage of BBB in LPS-induced mice, which was accompanied with increased zo-1 and occludin but reduced VCAM-1 in brain microvessels. Similarly, in brain endothelial cell line bEnd.3 cells, ASIV mitigated the increased permeability induced by LPS, as evidenced by increased TEER and reduced sodium fluorescein extravasation. ASIV also enhanced the expression of TJ proteins such as zo-1, occludin and claudin-5 in LPS stimulated bEnd.3 cells. Meanwhile, it inhibited the inflammatory responses and prevented the monocyte adhesion onto bEnd.3 cells upon LPS stimulation. Further study disclosed that ASIV could alleviate ROS level and activate Nrf2 antioxidant pathway in bEnd.3 cells. When Nrf2 was silenced, the protective effect of ASIV was abolished. In brain microvessels of LPS-induced mice, ASIV also enhanced the expression of Nrf2 antioxidant pathway related proteins. Collectively, our results demonstrated that ASIV protected the integrity of BBB in LPS-induced mice, the mechanism of which might be mediated via activating Nrf2 signaling pathway. The findings suggested that ASIV might be a potential neuroprotective drug acting on BBB.

Protective effects of thymol on LPS-induced acute lung injury in mice

Thymol, a naturally occurring phenol isolated from thyme, has been known to exhibit anti-inflammatory and anti-oxidative effects. The aim of this study was to determine the effect of thymol on acute lung injury (ALI) within an lipopolysaccharide (LPS)-induced mouse model. ELISA and western blotting were performed to detect the pro-inflammatory cytokines and signaling pathways. The myeloperoxidase (MPO) activity and MDA content in lung tissues, lung wet/dry (W/D) ratio and histopathological examination were detected. The results showed that thymol inhibit LPS-induced TNF-α, IL-6 and IL-1β production in BALF. Furthermore, thymol significantly reduced the MPO activity, MDA content, lung wet/dry weight ratio and histopathological changes induced by LPS. In addition, thymol inhibited LPS-induced NF-κB signaling pathway and up-regulated the expression of Nrf2 and HO-1. In conclusion, we found that thymol had anti-inflammatory and anti-oxidative effects against LPS-induced ALI and the mechanism was through suppressed NF-κB signaling pathway and activating Nrf2 signaling pathway.

Catalpol protects mice against Lipopolysaccharide/D-galactosamine-induced acute liver injury through inhibiting inflammatory and oxidative response.

The purpose of this study was to investigate the protective effect of catalpol on Lipopolysaccharide (LPS)/D-galactosamine (D-gal)-induced acute liver injury in mice. The mouse model was established by injection of LPS and D-gal. Catalpol (2.5, 5, 10 mg/kg) were pretreated intraperitoneally 1 h before LPS and D-gal. The survival rate, AST, ALT, MDA, MPO activity, hepatic tissue histology, TNF-α level, and NF-κB activation were assayed. The results revealed that catalpol dose-dependently elevated the survival rate. Furthermore, catalpol reduced the activities of AST, ALT, MDA, and MPO. The production of TNF-α was also inhibited by treatment of catalpol. In addition, catalpol inhibited LPS/D-gal-induced NF-κB activation. The expression of Nrf2 and HO-1 were up-regulated by treatment of catalpol. These results indicated that pretreatment with catalpol could attenuate LPS/D-gal-induced acute liver injury in mice and the underlying mechanism may due to the inhibition of NF-κB signaling pathway and the activation of Nrf2 signaling pathway.

Prevention effect of Ligusticum chuanxiong extraction against oxidative stress injury induced by myocardial ischemia through activation of Nrf2 signaling pathway

Ligusticum chuanxiong is one of the common traditional Chinese medicinal herbs for treating various cardiovascular and cerebrovascular diseases, and a number of previous studies have demonstrated that the extract of L. chuanxiong has strong antioxidative activity. This paper was mainly aimed to investigate the effects and possible mechanisms of L. chuanxiong extraction on oxidative stress induced by myocardial ischemia injury in rats. The rats were subcutaneously injected with isoprenaline hydrochloride to induce myocardial ischemia injury and treated for 2 weeks. Then the cardiac indexes of the rats were recorded. The concentration of malondialdehyde (MDA) and activities of serum creatine kinase (CK), lactate dehydrogenase (LDH), aspartate transaminase (AST), superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) were measured by colorimetry. Light microscope was used to observe the morphological changes of myocardium, and the protein expressions of nuclear factor E2 related factor 2 (Nrf2), quinone oxidoreductase (NQO1) and hemeoxygenase-1 (HO-1) in cardiac tissue were evaluated by Western blot. The results showed that L. chuanxiong extraction could decrease cardiac indexes and the values of CK, LDH and AST in blood serum, increase activities of serum SOD and T-AOC, reduce serum MDA concentration, improve myocardium structure after ischemia injury, and up-regulate the protein expressions of Nrf2, NQO1 and HO-1 in cardiac tissue. These findings revealed that the cardioprotective effects of L. chuanxiong extraction may be related to inhibiting oxidative stress through the activation of Nrf2 signaling pathway.

RETRACTED: Alpinumisoflavone protects against glucocorticoid-induced osteoporosis through suppressing the apoptosis of osteoblastic and osteocytic cells

The long-term use of glucocorticoids is found to cause osteoporosis. This study is designed to evaluate the protective effect of alpinumisoflavone (AIF), a naturally occurring flavonoid compound, on dexamethasone(Dex)-induced osteoporosis. We use a rat model to investigate the apoptosis of osteoblastic and osteocytic cells. The results indicate that AIF effectively protects against dexamethasone-induced osteoporosis. Moreover, AIF effectively reversed dexamethasone-induced apoptosis in osteoblastic and osteocytic cells through inhibiting ROS overproduction and regulating the Nrf2 pathway. In conclusion, the AIF activated Nrf2 signaling pathway was observed to suppress Dex-induced ROS production in osteoblastic and osteocytic cells, which may explain its anti-osteoporotic effects against dexamethasone-induced osteoporosis.

Edaravone attenuates oxidative stress induced by chronic cerebral hypoperfusion injury: role of ERK/Nrf2/HO-1 signaling pathway

ObjectivesThe potential protective effects and mechanisms of edaravone have not been well elucidated in vascular dementia (VaD) induced by chronic cerebral hypoperfusion (CCH). The aim of this study was to investigate whether edaravone could improve cognitive damage in rats induced by CCH, and whether the effects of edaravone were associated with ERK/Nrf2/HO-1 signaling pathway.MethodsCCH was induced by bilateral common carotid arteries occlusion (BCCAO). Sprague-Dawley (SD) rats were randomly divided into four groups: sham (sham-operated) group, vehicle (BCCAO + normal saline) group, edaravone3.0 group and edaravone6.0 group. The edaravone3.0 and edaravone6.0 group rats were provided 3.0 mg/kg and 6.0 mg/kg of edaravone, respectively, intraperitoneal (i.p.) injection twice daily following the first day after BCCAO. In this experiment, the spatial learning and memory were assessed using the Morris water maze. The malondialdehyde (MDA) contents and superoxide dismutase (SOD) activities in the hippocampus were measured biochemically. And, the levels of total ERK1/2 (t-ERK1/2), Phospho-ERK1/2 (p-ERK1/2), total Nrf2 (t-Nrf2), nuclear Nrf2 (n-Nrf2), and HO-1 were assessed by western blot.ResultsThe results showed that the treatment with edaravone significantly improved CCH-induced cognitive damage, and boosted endogenous antioxidants SOD activity and HO-1 level, decreased MDA contents in the hippocampus by activating Nrf2 signaling pathway which was related to ERK1/2. We also found that the neuronal morphology of the hippocampal CA1 area significantly improved and the number of Nrf2 positive cells markedly increased in the edaravone treatment groups.ConclusionOur results demonstrated a neuroprotective effect of edaravone on hippocampus against oxidative stress and cognitive deficit induced by CCH. The mechanism may be related to the enhancement of antioxidant defense system by activating ERK/Nrf2/HO-1 signaling pathway.

Dietary luteolin protects against HgCl2-induced renal injury via activation of Nrf2-mediated signaling in rat

Luteolin (Lut) belongs to the flavonoid family with various beneficial bioactivities. Here, we investigated whether Lut attenuate mercuric chloride (HgCl2)-induced renal injury in rat. We found that oral gavage administration of Lut (80mg/kg) alleviated anemia and renal histology upon HgCl2 treatment (80mg/L). Lut also significantly reduced HgCl2-induced oxidative stress and inflammatory, presenting as the reduced malondialdehyde (MDA) formation, increased glutathione (GSH) level, and inhibited activation of nuclear factor kappa B (NF-κB). Moreover, Lut protected renal cells from HgCl2-induced apoptosis, as assessed by Terminal deoxynucleotidyl transferase dUNT nick end labeling (TUNEL) assay and the protein levels of B-cell lymphoma gene 2 (Bcl-2), B-cell lymphoma-extra large (Bcl-xL), Bcl-2-associated X protein (Bax), and p53. Interestingly, Lut reduced renal mercuric accumulation in rat. Furthermore, Lut increased nuclear translocation of the nuclear factor-erythroid-2-related factor 2 (Nrf2), and subsequent protein expression of the antioxidant enzymes, heme oxygenase-1 (HO-1) and nicotinamide adenine dinucleotide phosphatase: quinone-acceptor 1 (NQO1). Our results suggest that Lut suppress HgCl2-induced renal injury via activation of Nrf2 signaling pathway.

Hepatoprotective properties of Penthorum chinense Pursh against carbon tetrachloride-induced acute liver injury in mice

BackgroundPenthorum chinense Pursh (Penthoraceae, PCP), a well-known Miao ethnomedicine, has been traditionally used to treat several liver-related diseases, such as jaundice and viral hepatitis. The aims of the present study were to evaluate the probable properties of the aqueous extract of PCP on carbon tetrachloride (CCl4)—induced acute liver injury in mice.MethodsC57BL/6 mice were orally administered an aqueous extract of PCP (5.15 and 10.3 g/kg BW) or silymarin (100 mg/kg) once daily for 1 week prior to CCl4 exposure. Silymarin serves as a positive drug to validate the effectivenes of PCP.ResultsA single dose of CCl4 exposure caused severe acute liver injury in mice, as evidenced by the elevated serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alanine phosphatase (ALP), and the increased TUNEL-positive cells in liver, which were remarkably ameliorated by the pretreatment of PCP. PCP was also found to decrease the levels of malondialdehyde (MDA), restore the glutathione (GSH) and enhance the activities of superoxide dismutase (SOD) and catalase (CAT) in the liver. In addition, the pretreatment of PCP inhibited the degradation of hepatic cytochrome P450 2E1 (CYP2E1), up-regulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its target proteins in CCl4-treated mice.ConclusionResults indicated that the pretreatment of PCP (10.3 g/kg BW) effectively protected against CCl4-induced acute liver injury, which was comparable to efficacy of silymarin (100 mg/kg). This hepatoprotective effects might be attributed to amelioration of CCl4-induced oxidative stress via activating Nrf2 signaling pathway.

Antioxidant and pro-angiogenic effects of corilagin in rat cerebral ischemia via Nrf2 activation.

The nuclear factor erythroid-2-related factor 2 (Nrf2) pathway has been considered as a potential target for neuroprotection in stroke. The aim of present study was to determine whether corilagin, a novel Nrf2 activator, can protect against ischemia-reperfusion injury and explore the underlying mechanism involved. In vivo, rats exposed to middle cerebral artery occlusion were applied to establish an ischemic stroke model. Posttreatment of corilagin significantly reduced infarct volumes and apoptotic cells as well as improved neurologic score after reperfusion, together with increased vascular density in the ischemic penumbra. Meanwhile, posttreatment with corilagin in MCAO rats significantly decreased malondialdehyde levels, restored the superoxide dismutase and glutathione activity, elevating the Nrf2, heme oxygenase-1, the vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) expression. However, consecutive intrathecal injection of short interference RNAs targeting Nrf2 at 24-h intervals 72 h before ischemia reduced the beneficial effects of corilagin. In primary cultured neurons, corilagin dose-dependently protected against oxygen and glucose deprivation-induced insult, but the protective effect of corilagin was attenuated by knockdown of Nrf2. In conclusion, these findings indicate that corilagin exerts protective effects against cerebral ischemic injury by attenuating oxidative stress and enhancing angiogenesis via activation of Nrf2 signaling pathway.

Protective roles and mechanisms of Dendrobium officinal polysaccharides on secondary liver injury in acute colitis

The purpose of this study was to investigate the protective roles and mechanisms of Dendrobium officinale polysaccharides (DOPS) on secondary liver injury in acute colitis. Firstly, the mice model of secondary liver injury in acute colitis was induced by 4% Dextran sodium sulfate (DSS). Inflammatory cell model was established by LPS-stimulated RAW264.7 cells. Then, the protective roles of DOPS were evaluated by both in vivo and in vitro experiment. The results showed that DOPS attenuated DSS-induced hepatic pathological damage, liver parameters, infiltration of macrophages, cytokines levels, MDA level and increased the antioxidant enzymes activities. In vitro, DOPS markedly inhibited inflammatory cytokines production and increased antioxidant enzymes activities. Finally, its molecular mechanisms were also observed. The results indicated that DOPS could down-regulated TNF-α signaling pathway and activated Nrf-2 signaling pathway in vivo and in vitro. These results suggested that DOPS may be an effective therapeutic reagent to attenuate secondary liver injury in acute colitis.

Effect of neoflavonoid latifolin isolated from Dalbergia odorifera on acute myocardial ischemia in rats and its mechanism of Nrf2 signaling pathway

The present study was designed to evaluate the cardioprotective effect of latifolin on pituitrin(Pit) or isoproterenol(ISO)-induced myocardial injury in rats, and further investigate its underlying mechanisms. Rats were administrated sublingually with pituitrin or subcutaneously with isoproterenol to induce acute myocardial ischemia in rats, and lead II electrocardiograph was recorded. In rats with isoproterenol, ELISA assay or colorimetric method was used to detect the content or activity of myocardial injury markers in serum, and the SOD activity and MDA content in myocardium were detected by colorimetric assay; histopathological examination was conducted by HE staining; the frozen section of myocardial tissues was used for DCFH-DA fluorescent staining to detect the content of ROS in myocardium; Western blot was used to detect the protein expression levels of Nrf2, Keap1, HO-1 and NQO1 in myocardium. Results showed that latifolin significantly inhibited ST-segment changes induced by pituitrin or isoproterenol, and increased heart rate. Further mechanism study showed that latifolin reduced cardiac troponin I(cTnI) level, aspartate transaminase(AST) and lactate dehydrogenase(LDH) activities in serum, increased myocardial superoxide dismutase(SOD) activity and reduced myocardial malondialdehyde(MDA) level, and protected myocardium with less necrosis, infiltration of inflammatory cells and fracture of myocardial fibers. Furthermore, latifolin obviously reduced ROS level in myocardium, inhibited the expression of Kelch-like ECH-associated protein-1(Keap1), increased the nuclear translocation of nuclear factor erythroid 2 related factor 2(Nrf2), and promoted the expression of Heme oxygenase-1(HO-1) and NAD(P)H quinone oxidoreductase-1 (NQO1) in myocardial tissues. Our data suggest that latifolin has a potent protective effect against pituitrin or isoproterenol-induced myocardial injury, which may be related to inhibition of oxidative stress by activating Nrf2 signaling pathway.

Eriodictyol attenuates arsenic trioxide-induced liver injury by activation of Nrf2.

Arsenic, a well-known human carcinogen, has been reported to induce hepatic oxidative stress and hepatic injury. Eriodictyol, a flavonoid found in citrus fruits, has been reported to have antioxidant effects. In this study, we aimed to investigate the protective effects of eriodictyol on arsenic trioxide (As2O3)-induced liver injury and to clarify the molecular mechanism. Male Wistar rats were administrated 3mg/kg As2O3 intravenous injection at days 1, 4, 5, and 7. Eriodictyol was given 1 h before or after As2O3 treatment. The results showed that eriodictyol prevented As2O3-induced liver reactive oxygen species (ROS) and malonaldehyde (MDA) levels. Eriodictyol abrogated As2O3-induced decrease of the antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase (CAT) activity. Eriodictyol also attenuated As2O3-induced hepatic pathological damage. In addition, eriodictyol promoted the expression of nuclear factor erythroid 2 p45 related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) up-regulated by As2O3. In conclusion, our results demonstrated that eriodictyol exhibited a protective effect on As2O3-induced liver injury and the possible mechanism is involved in activating Nrf2 signaling pathway.

Anti-Inflammatory Effects of Licochalcone A on IL-1β-Stimulated Human Osteoarthritis Chondrocytes.

Licochalcone A (Lico A), a flavonoid found in licorice root (Glycyrrhiza glabra), has been reported to have anti-inflammatory activity. In this study, we evaluated the anti-inflammatory effects of Lico A on IL-1β-stimulated human osteoarthritis chondrocytes and investigated the possible mechanism. Results demonstrated that Lico A treatment significantly inhibited PGE2 and NO production induced by IL-1β. IL-1β-induced iNOS and COX-2 expression were also inhibited by Lico A. Lico A inhibited MMP1, MMP3, and MMP13 production in IL-1β-stimulated chondrocytes. Lico A also inhibited IL-1β-induced phosphorylation of NF-κB p65 and IκBα. Meanwhile, Lico A was found to upregulate the expression of Nrf2 and HO-1. However, Nrf2 siRNA reversed the anti-inflammatory effects of Lico A. In conclusion, our results suggested that Lico A showed anti-inflammatory effects in IL-1β-stimulated chondrocytes by activating Nrf2 signaling pathway.

The involvement of Nrf2 in the protective effects of (-)-Epigallocatechin-3-gallate (EGCG) on NaAsO2-induced hepatotoxicity.

Arsenic exposure produces hepatotoxicity. The common mechanism determining its toxicity is the generation of oxidative stress. Oxidative stress induced by arsenic leads to the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. (-)-Epigallocatechin-3-gallate (EGCG) possesses a potent antioxidant capacity and exhibits extensive pharmacological activities. This study aims to evaluate effects of EGCG on arsenic-induced hepatotoxicity and activation of Nrf2 pathway. Plasma activities of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase were measured; Histological analyses were conducted to observe morphological changes; Biochemical indexes such as oxidative stress (Catalase (CAT), malonyldialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), reactive oxygen species (ROS)), Nrf2 signaling related genes (Nrf2, Nqo1, and Ho-1) were assessed. The results showed that EGCG inhibited arsenic-induced hepatic pathological damage, liver ROS level and MDA level. Arsenic decreases the antioxidant enzymes SOD, GPX, and CAT activity and the decrease was inhibited by treatment of EGCG. Furthermore, EGCG attenuated the retention of arsenic in liver tissues and improved the expressions of Nrf2 signaling related genes (Nrf2, Nqo1, and Ho-1). These findings provide evidences that EGCG may be useful for reducing hepatotoxicity associated with oxidative stress by the activation of Nrf2 signaling pathway. Our findings suggest a possible mechanism of antioxidant EGCG in preventing hepatotoxicity, which implicate that EGCG may be a potential treatment for arsenicosis therapy.

Rapamycin protects against paraquat-induced pulmonary fibrosis: Activation of Nrf2 signaling pathway

Paraquat (PQ) is a widely used herbicide indeveloping countries worldwide, and pulmonary fibrosis is one of the most typical features of PQ poisoning. The molecular mechanism of PQ toxicity especially how to treat PQ-induced pulmonary fibrosis is still largely unknown. In animal model of pulmonary fibrosis, we used HE staining, western blotting assay and Real-time PCR assay to analyze the effects of rapamycin on the PQ-induced epithelial mesenchymal transition (EMT). We found that PQ induced the pulmonary fibrosis using HE staining and Masson's staining, and up-regulated the activity of HYP and the mRNA expressions of Collagen I and III (COL-1and COL-3) in pulmonary tissues. We also found that rapamycin down-regulated the mesenchymal cell marker Vimentin and up-regulated the epithelial cell marker E-cadherin both in mRNA and protein levels compared with PQ group. And the EMT associated transcription factor Snail was decreased by rapamycin treatment compared with PQ group. And PQ decreased the Nrf2 expression both in mRNA and protein levels, and rapamycin inhibited these effects of PQ. SFN, a activator of Nrf2, could inhibit the EMT and the expression of Snail. And knockdowon of Nrf2 could abolish the inhibitory effects of rapamycin of PQ-induced EMT. In conclusion, rapamycin protects against paraquat-induced pulmonary fibrosis by activation of Nrf2 signaling pathway.