Previous studies have reported upregulation of heme oxygenase-1 in different central nervous system injury models.Heme oxygenase-1 plays a critical anti-inflammatory role and is essential for regulating cellular redox...Previous studies have reported upregulation of heme oxygenase-1 in different central nervous system injury models.Heme oxygenase-1 plays a critical anti-inflammatory role and is essential for regulating cellular redox homeostasis.Metformin is a classic drug used to treat type 2 diabetes that can inhibit ferroptosis.Previous studies have shown that,when used to treat cardiovascular and digestive system diseases,metformin can also upregulate heme oxygenase-1 expression.Therefore,we hypothesized that heme oxygenase-1 plays a significant role in mediating the beneficial effects of metformin on neuronal ferroptosis after spinal cord injury.To test this,we first performed a bioinformatics analysis based on the GEO database and found that heme oxygenase-1 was upregulated in the lesion of rats with spinal cord injury.Next,we confirmed this finding in a rat model of T9 spinal cord compression injury that exhibited spinal cord nerve cell ferroptosis.Continuous intraperitoneal injection of metformin for 14 days was found to both upregulate heme oxygenase-1 expression and reduce neuronal ferroptosis in rats with spinal cord injury.Subsequently,we used a lentivirus vector to knock down heme oxygenase-1 expression in the spinal cord,and found that this significantly reduced the effect of metformin on ferroptosis after spinal cord injury.Taken together,these findings suggest that metformin inhibits neuronal ferroptosis after spinal cord injury,and that this effect is partially dependent on upregulation of heme oxygenase-1.展开更多
Interfering with the ferroptosis pathway is a new strategy for the treatment of spinal cord injury.Fibroblast growth factor 21 can inhibit ferro ptosis and promote neurofunctional recovery,while heme oxygenase-1 is a ...Interfering with the ferroptosis pathway is a new strategy for the treatment of spinal cord injury.Fibroblast growth factor 21 can inhibit ferro ptosis and promote neurofunctional recovery,while heme oxygenase-1 is a regulator of iron and reactive oxygen species homeostasis.The relationship between heme oxygenase-1and ferroptosis remains controve rsial.In this study,we used a spinal co rd injury rat model to show that the levels of fibroblast growth factor 21 in spinal co rd tissue decreased after spinal cord injury.In addition,there was a significant aggravation of ferroptosis and a rapid increase in heme oxygenase-1 expression after spinal cord injury.Furthe r,heme oxygenase-1 aggravated fe rroptosis after spinal cord injury,while fibroblast growth factor 21 inhibited fe rroptosis by downregulating heme oxygenase-1.Thus,the activation of fibroblast growth factor 21 may provide a potential treatment for spinal co rd injury.These findings could provide a new potential mechanistic explanation for fibroblast growth factor 21 in the treatment of spinal cord injury.展开更多
Opioids,such as morphine,are the most potent drugs used to treat pain.Long-term use results in high tolerance to morphine.High mobility group box-1(HMGB1) has been shown to participate in neuropathic or inflammatory p...Opioids,such as morphine,are the most potent drugs used to treat pain.Long-term use results in high tolerance to morphine.High mobility group box-1(HMGB1) has been shown to participate in neuropathic or inflammatory pain,but its role in morphine tolerance is unclear.In this study,we established rat and mouse models of morphine tolerance by intrathecal injection of morphine for 7 consecutive days.We found that morphine induced rat spinal cord neurons to release a large amount of HMGB1.HMGB1 regulated nuclear factor κB p65 phosphorylation and interleukin-1β production by increasing Toll-like receptor 4receptor expression in microglia,thereby inducing morphine tolerance.Glycyrrhizin,an HMGB1 inhibito r,markedly attenuated chronic morphine tole rance in the mouse model.Finally,compound C(adenosine 5’-monophosphate-activated protein kinase inhibitor) and zinc protoporphyrin(heme oxygenase-1 inhibitor)alleviated the morphine-induced release of HMGB1 and reduced nuclear factor κB p65 phosphorylation and interleukin-1β production in a mouse model of morphine tolerance and an SH-SY5Y cell model of morphine tole rance,and alleviated morphine tolerance in the mouse model.These findings suggest that morphine induces HMGB1 release via the adenosine 5’-monophosphate-activated protein kinase/heme oxygenase-1 signaling pathway,and that inhibiting this signaling pathway can effectively reduce morphine tole rance.展开更多
AIM:To examine whether heme oxygenase (HO)-1 overexpression would exert direct or indirect effects on Kupffer cells activation, which lead to aggravation of reperfusion injury.METHODS: Donors were pretreated with coba...AIM:To examine whether heme oxygenase (HO)-1 overexpression would exert direct or indirect effects on Kupffer cells activation, which lead to aggravation of reperfusion injury.METHODS: Donors were pretreated with cobalt protoporphyrin (CoPP) or zinc protoporphyrin (ZnPP), HO-1 inducer and antagonist, respectively. Livers were stored at 4℃ for 24 h before transplantation. Kupffer cells were isolated and cultured for 6 h after liver reperfusion.RESULTS: Postoperatively, serum transaminases were significantly lower and associated with less liver injury when donors were pretreated with CoPP, as compared with the ZnPP group. Production of the cytokines tumor necrosis factor-α and interleukin-6 generated by Kupffer cells decreased in the CoPP group. The CD14 expression levels (RT-PCR/Western blots) of Kupffer cells from CoPP-pretreated liver grafts reduced.CONCLUSION: The study suggests that the potential utility of HO-1 overexpression in preventing ischemia/reperfusion injury results from inhibition of Kupffer cells activation.展开更多
Quercetin is a widely-occurring flavonoid that protects against cancer, and improves memory and cardiovascular functions.However, whether quercetin exhibits therapeutic effects in diabetic retinopathy remains unclear....Quercetin is a widely-occurring flavonoid that protects against cancer, and improves memory and cardiovascular functions.However, whether quercetin exhibits therapeutic effects in diabetic retinopathy remains unclear.In this study, we established a rat model of streptozocininduced diabetic retinopathy.Seventy-two hours later, the rats were intraperitoneally administered 150 mg/kg quercetin for 16 successive weeks.Quercetin markedly increased the thickness of the retinal cell layer, increased the number of ganglion cells, and decreased the overexpression of the pro-inflammatory factors interleukin-1β, interleukin-18, interleukin-6 and tumor necrosis factor-α in the retinal tissue as well as the overexpression of high mobility group box-1 and the overactivation of the NLRP3 inflammasome.Furthermore, quercetin inhibited the overexpression of TLR4 and NF-κBp65, reduced the expression of the pro-angiogenic vascular endothelial growth factor and soluble intercellular adhesion molecule-1, and upregulated the neurotrophins brain-derived neurotrophic factor and nerve growth factor.Intraperitoneal injection of the heme oxygenase-1 inhibitor zinc protoporphyrin blocked the protective effect of quercetin.These findings suggest that quercetin exerts therapeutic effects in diabetic retinopathy possibly by inducing heme oxygenase-1 expression.This study was approved by the Animal Ethics Committee of China Medical University, China(approval No.2016 PS229K) on April 8, 2016.展开更多
AIM To investigate the effects of heme oxygenase-1(HO-1)-modified bone marrow mesenchymal stem cells(BMMSCs)on the microcirculation and energy metabolism of hepatic sinusoids following reduced-size liver transplantati...AIM To investigate the effects of heme oxygenase-1(HO-1)-modified bone marrow mesenchymal stem cells(BMMSCs)on the microcirculation and energy metabolism of hepatic sinusoids following reduced-size liver transplantation(RLT)in a rat model.METHODS BMMSCs were isolated and cultured in vitro using an adherent method,and then transduced with HO-1-bearing recombinant adenovirus to construct HO-1/BMMSCs.A rat acute rejection model following 50%RLT was established using a two-cuff technique.Recipients were divided into three groups based on the treatment received:normal saline(NS),BMMSCs and HO-1/BMMSCs.Liver function was examined at six time points.The levels of endothelin-1(ET-1),endothelial nitric-oxide synthase(e NOS),inducible nitric-oxide synthase(i NOS),nitric oxide(NO),and hyaluronic acid(HA)were detected using an enzyme-linked immunosorbent assay.The portal vein pressure(PVP)was detected by Power Lab ML880.The expressions of ET-1,i NOS,e NOS,and von Willebrand factor(v WF)protein in the transplanted liver were detected using immunohistochemistry and Western blotting.ATPase in the transplanted liver was detected by chemical colorimetry,and the ultrastructural changes were observed under a transmission electron microscope.RESULTS HO-1/BMMSCs could alleviate the pathological changes and rejection activity index of the transplanted liver,and improve the liver function of rats following 50%RLT,with statistically significant differences compared with those of the NS group and BMMSCs group(P<0.05).In term of the microcirculation of hepatic sinusoids:The PVP on POD7 decreased significantly in the HO-1/BMMSCs and BMMSCs groups compared with that of the NS group(P<0.01);HO-1/BMMSCs could inhibit the expressions of ET-1 and i NOS,increase the expressions of e NOS and inhibit amounts of NO production,and maintain the equilibrium of ET-1/NO(P<0.05);and HO-1/BMMSCs increased the expression of v WF in hepatic sinusoidal endothelial cells(SECs),and promoted the degradation of HA,compared with those of the NS group and BMMSCs group(P<0.05).In term of the energy metabolism of the transplanted liver,HO-1/BMMSCs repaired the damaged mitochondria,and improved the activity of mitochondrial aspartate aminotransferase(ASTm)and ATPase,compared with the other two groups(P<0.05).CONCLUSION HO-1/BMMSCs can improve the microcirculation of hepatic sinusoids significantly,and recover the energy metabolism of damaged hepatocytes in rats following RLT,thus protecting the transplanted liver.展开更多
AIM To investigate the therapeutic effect of hydrogen-rich water(HRW) on inflammatory bowel disease(IBD) and to explore the potential mechanisms involved.METHODS Male mice were randomly divided into the following four...AIM To investigate the therapeutic effect of hydrogen-rich water(HRW) on inflammatory bowel disease(IBD) and to explore the potential mechanisms involved.METHODS Male mice were randomly divided into the following four groups: control group, in which the mice received equivalent volumes of normal saline(NS) intraperitoneally(ip); dextran sulfate sodium(DSS) group, in which the mice received NS ip(5 m L/kg body weight, twice per day at 8 am and 5 pm) for 7 consecutive days after IBD modeling; DSS + HRW group, in which the mice received HRW(in the same volume as the NS treatment) for 7 consecutive days after IBD modeling; and DSS + HRW + Zn PP group, in which the mice received HRW(in the same volume as the NS treatment) and ZnP P [a heme oxygenase-1(HO-1) inhibitor, 25 mg/kg] for 7 consecutive days after IBD modeling. IBD was induced by feeding DSS to the mice, and blood and colon tissues were collected on the 7th d after IBD modeling to determine clinical symptoms, colonic inflammation and the potential mechanisms involved.RESULTS The DSS + HRW group exhibited significantly attenuated weight loss and a lower extent of disease activity index compared with the DSS group on the 7th d(P < 0.05). HRW exerted protective effects against colon shortening and colonic wall thickening in contrast to the DSS group(P < 0.05). The histological study demonstrated milder inflammation in the DSS + HRW group, which was similar to normal inflammatory levels, and the macroscopic and microcosmic damage scores were lower in this group than in the DSS group(P < 0.05). The oxidative stress parameters, including MDA and MPO in the colon, were significantly decreased in the DSS + HRW group compared with the DSS group(P < 0.05). Simultaneously, the protective indicators, superoxide dismutase and glutathione, were markedly increased with the use of HRW. Inflammatory factors were assessed, and the results showed that the DSS + HRW group exhibited significantly reduced levels of TNF-α, IL-6 and IL-1β compared with the DSS group(P < 0.05). In addition, the pivotal proteins involved in endoplasmic reticulum(ER) stress, including p-e IF2α, ATF4, XBP1 s and CHOP, were dramatically reduced after HRW treatment in contrast to the control group(P < 0.05). Furthermore, HRW treatment markedly up-regulated HO-1 expression, and the use of Zn PP obviously reversed the protective role of HRW. In the DSS + HRW + ZnP P group, colon shortening and colonic wall thickening were significantly aggravated, and the macroscopic damage scores were similar to those of the DSS + HRW group(P < 0.05). The histological study also showed more serious colonic damage that was similar to the DSS group.CONCLUSION HRW has a significant therapeutic potential in IBD by inhibiting inflammatory factors, oxidative stress and ER stress and by up-regulating HO-1 expression.展开更多
Heme oxygenase-1(HO-1) system catabolizes heme into three products:carbon monoxide,biliverdin/bilirubin and free iron.It is involved in many physiological and pathophysiological processes.A great deal of data has demo...Heme oxygenase-1(HO-1) system catabolizes heme into three products:carbon monoxide,biliverdin/bilirubin and free iron.It is involved in many physiological and pathophysiological processes.A great deal of data has demonstrated the roles of HO-1 in the formation,growth and metastasis of tumors.The interest in this system by investigators involved in gastrointestinal tumors is fairly recent,and few papers on HO-1 have touched upon this subject.This review focuses on the current understanding of the physiological significance of HO-1 induction and its possible roles in the gastrointestinal tumors studied to date.The implications for possible therapeutic manipulation of HO-1 in gastrointestinal tumors are also discussed.展开更多
BACKGROUND Sinapic acid(SA)has been shown to have various pharmacological properties such as antioxidant,antifibrotic,anti-inflammatory,and anticancer activities.Its mechanism of action is dependent upon its ability t...BACKGROUND Sinapic acid(SA)has been shown to have various pharmacological properties such as antioxidant,antifibrotic,anti-inflammatory,and anticancer activities.Its mechanism of action is dependent upon its ability to curb free radical production and protect against oxidative stress-induced tissue injuries.AIM To study the hepatoprotective effects of SA against lipopolysaccharide(LPS)/Dgalactosamine(D-GalN)-induced acute liver failure(ALF)in rats.METHODS Experimental ALF was induced with an intraperitoneal(i.p.)administration of 8μg LPS and 800 mg/kg D-GalN in normal saline.SA was administered orally once daily starting 7 d before LPS/D-GalN treatment.RESULTS Data showed that SA ameliorates acute liver dysfunction,decreases serum levels of alanine transaminase(ALT),and aspartate aminotransferase(AST),as well as malondialdehyde(MDA)and NO levels in ALF model rats.However,pretreatment with SA(20 mg/kg and 40 mg/kg)reduced nuclear factor kappalight-chain-enhancer of activated B cells(NF-κB)activation and levels of inflammatory cytokines(tumor necrosis factor-αand interleukin 6).Also,SA increased the activity of the nuclear factor erythroid-related factor 2/heme oxygenase-1(Nrf2/HO-1)signaling pathway.CONCLUSION In conclusion,SA offers significant protection against LPS/D-GalN-induced ALF in rats by upregulating Nrf2/HO-1 and downregulating NF-κB.展开更多
BACKGROUND Enterotoxigenic Bacteroides fragilis(ETBF)causes colitis and diarrhea,and is considered a candidate pathogen in inflammatory bowel diseases as well as colorectal cancers.These diseases are dependent on ETBF...BACKGROUND Enterotoxigenic Bacteroides fragilis(ETBF)causes colitis and diarrhea,and is considered a candidate pathogen in inflammatory bowel diseases as well as colorectal cancers.These diseases are dependent on ETBF-secreted toxin(BFT).Dendritic cells(DCs)play an important role in directing the nature of adaptive immune responses to bacterial infection and heme oxygenase-1(HO-1)is involved in the regulation of DC function.AIM To investigate the role of BFT in HO-1 expression in DCs.METHODS Murine DCs were generated from specific pathogen-free C57BL/6 and Nrf2−/−knockout mice.DCs were exposed to BFT,after which HO-1 expression and the related signaling factor activation were measured by quantitative RT-PCR,EMSA,fluorescent microscopy,immunoblot,and ELISA.RESULTS HO-1 expression was upregulated in DCs stimulated with BFT.Although BFT activated transcription factors such as NF-κB,AP-1,and Nrf2,activation of NF-κB and AP-1 was not involved in the induction of HO-1 expression in BFT-exposed DCs.Instead,upregulation of HO-1 expression was dependent on Nrf2 activation in DCs.Moreover,HO-1 expression via Nrf2 in DCs was regulated by mitogenactivated protein kinases such as ERK and p38.Furthermore,BFT enhanced the production of reactive oxygen species(ROS)and inhibition of ROS production resulted in a significant decrease of phospho-ERK,phospho-p38,Nrf2,and HO-1 CONCLUSION These results suggest that signaling pathways involving ROS-mediated ERK and p38 mitogen-activated protein kinases-Nrf2 activation in DCs are required for HO-1 induction during exposure to ETBF-produced BFT.展开更多
BACKGROUND Bronchopulmonary dysplasia(BPD)is not merely a chronic lung disease,but a systemic condition with multiple organs implications predominantly associated with hyperoxia exposure.Despite advances in current ma...BACKGROUND Bronchopulmonary dysplasia(BPD)is not merely a chronic lung disease,but a systemic condition with multiple organs implications predominantly associated with hyperoxia exposure.Despite advances in current management strategies,limited progress has been made in reducing the BPD-related systemic damage.Meanwhile,although the protective effects of human umbilical cord-derived mesenchymal stem cells(hUC-MSCs)or their exosomes on hyperoxia-induced lung injury have been explored by many researchers,the underlying mechanism has not been addressed in detail,and few studies have focused on the therapeutic effect on systemic multiple organ injury.AIM To investigate whether hUC-MSC intratracheal administration could attenuate hyperoxia-induced lung,heart,and kidney injuries and the underlying regulatory mechanisms.METHODS Neonatal rats were exposed to hyperoxia(80%O_(2)),treated with hUC-MSCs intratracheal(iT)or intraperitoneal(iP)on postnatal day 7,and harvested on postnatal day 21.The tissue sections of the lung,heart,and kidney were analyzed morphometrically.Protein contents of the bronchoalveolar lavage fluid(BALF),myeloper oxidase(MPO)expression,and malondialdehyde(MDA)levels were examined.Pulmonary inflammatory cytokines were measured via enzyme-linked immunosorbent assay.A comparative transcriptomic analysis of differentially expressed genes(DEGs)in lung tissue was conducted via RNA-sequencing.Subsequently,we performed reverse transcription-quantitative polymerase chain reaction and western blot analysis to explore the expression of target mRNA and proteins related to inflammatory and oxidative responses.RESULTS iT hUC-MSCs administration improved pulmonary alveolarization and angiogenesis(P<0.01,P<0.01,P<0.001,and P<0.05 for mean linear intercept,septal counts,vascular medial thickness index,and microvessel density respectively).Meanwhile,treatment with hUC-MSCs iT ameliorated right ventricular hypertrophy(for Fulton’s index,P<0.01),and relieved reduced nephrogenic zone width(P<0.01)and glomerular diameter(P<0.001)in kidneys.Among the beneficial effects,a reduction of BALF protein,MPO,and MDA was observed in hUC-MSCs groups(P<0.01,P<0.001,and P<0.05 respectively).Increased pro-inflammatory cytokines tumor necrosis factor-alpha,interleukin(IL)-1β,and IL-6 expression observed in the hyperoxia group were significantly attenuated by hUC-MSCs administration(P<0.01,P<0.001,and P<0.05 respectively).In addition,we observed an increase in anti-inflammatory cytokine IL-10 expression in rats that received hUC-MSCs iT compared with rats reared in hyperoxia(P<0.05).Transcriptomic analysis showed that the DEGs in lung tissues induced by hyperoxia were enriched in pathways related to inflammatory responses,epithelial cell proliferation,and vasculature development.hUC-MSCs administration blunted these hyperoxia-induced dysregulated genes and resulted in a shift in the gene expression pattern toward the normoxia group.hUC-MSCs increased heme oxygenase-1(HO-1),JAK2,and STAT3 expression,and their phosphorylation in the lung,heart,and kidney(P<0.05).Remarkably,no significant difference was observed between the iT and iP administration.CONCLUSION iT hUC-MSCs administration ameliorates hyperoxia-induced lung,heart,and kidney injuries by activating HO-1 expression and JAK/STAT signaling.The therapeutic benefits of local iT and iP administration are equivalent.展开更多
We found a mistake in Figure 6. Panels A (Sham group) and F (DFX group) (180degrees rotated) is same images. We have replaced the incorrect images (Panels F)with the correct Figure. This error does not change the mean...We found a mistake in Figure 6. Panels A (Sham group) and F (DFX group) (180degrees rotated) is same images. We have replaced the incorrect images (Panels F)with the correct Figure. This error does not change the meaning of the picture orthe conclusion of the manuscript. We apologize for our unintentional mistakes,which caused great inconvenience.展开更多
AIM:To investigate the efficacy and molecularmechanisms of induced heme oxygenase(HO)-1 in protecting liver from warm ischemia/reperfusion(I/R)injury.METHODS:Partial warm ischemia was produced in the left and middle h...AIM:To investigate the efficacy and molecularmechanisms of induced heme oxygenase(HO)-1 in protecting liver from warm ischemia/reperfusion(I/R)injury.METHODS:Partial warm ischemia was produced in the left and middle hepatic lobes of SD rats for 75min,followed by 6 h of reperfusion.Rats were treated with saline,cobalt protoporphyrin(Co PP)or zinc protoporphyrin(Zn PP)at 24 h prior to the ischemia insult.Blood and samples of ischemic lobes subjected to ischemia were collected at 6 h after reperfusion.Serum transaminases level,plasma lactate dehydrogenase and myeloperoxidase activity in liver were measured.Liver histological injury and inflammatory cell infiltration were evaluated by tissue section and liver immunohistochemical analysis.We used quantitative reverse transcription polymerase chain reaction to analyze liver expression of inflammatory cytokines and chemokines.The cell lysates were subjected to immunoprecipitation with anti-Toll-IL-1R-containing adaptor inducing interferon-β(TRIF)and anti-myeloid differentiation factor 88(My D88),and then the immunoprecipitates were analyzed by SDS-PAGE and immunoblotted with the indicated antibodies.RESULTS:HO-1 protected livers from I/R injury,as evidenced by diminished liver enzymes and wellpreserved tissue architecture.In comparison with Zn PP livers 6 h after surgery,Co PP treatment livers showed a significant increase inflammatory cell infiltration of lymphocytes,plasma cells,neutrophils and macrophages.The Toll-like receptor(TLR)-4 and TANK binding kinase1 protein levels of rats treated with Co PP significantly reduced in TRIF-immunoprecipitated complex,as compared with Zn PP treatment.In addition,pretreatment with Co PP reduced the expression levels of TLR2,TLR4,IL-1R-associated kinase(IRAK)-1 and tumor necrosis factor receptor-associated factor 6 in My D88-immunoprecipitated complex.The inflammatory cytokines and chemokines m RNA expression rapidly decreased inCo PP-pretreated liver,compared with the Zn PP-treated group.However,the expression of negative regulators Tollinteracting protein,suppressor of cytokine signaling-1,IRAK-M and Src homology 2 domain-containing inositol-5-phosphatase-1 in Co PP treatment rats were markedly up-regulated as compared with Zn PP-treated rats.CONCLUSION:HO-1 protects liver against I/R injury by inhibiting TLR2/TLR4-triggered My D88-and TRIFdependent signaling pathways and increasing expression of negative regulators of TLR signaling in rats.展开更多
AIM:To investigate the effects of the heme oxygenase(HO)-1/carbon monoxide system on iron deposition and portal pressure in rats with hepatic fibrosis induced by bile duct ligation(BDL).METHODS:Male Sprague-Dawley rat...AIM:To investigate the effects of the heme oxygenase(HO)-1/carbon monoxide system on iron deposition and portal pressure in rats with hepatic fibrosis induced by bile duct ligation(BDL).METHODS:Male Sprague-Dawley rats were divided randomly into a Sham group,BDL group,Fe group,deferoxamine(DFX) group,zinc protoporphyrin(ZnPP) group and cobalt protoporphyrin(CoPP) group.The levels of HO-1 were detected using different methods.The serum carboxyhemoglobin(COHb),iron,and portal vein pressure(PVP) were also quantified.The plasma and mRNA levels of hepcidin were measured.Hepatic fibrosis and its main pathway were assessed using Van Gieson's stain,hydroxyproline,transforming growth factor-β1(TGF-β1),nuclear factor-E2-related factor 2(Nrf2),matrix metalloproteinase-2(MMP-2) and tissue inhibitor of metalloproteinase-1(TIMP-1).RESULTS:Serum COHb and protein and mRNA expression levels of HO-1 and Nrf2 were increased in the BDL group compared with the Sham group and were much higher in the CoPP group.The ZnPP group showed lower expression of HO-1 and Nrf2 and lower COHb.The levels of iron and PVP were enhanced in the BDL group but were lower in the ZnPP and DFX groups and were higher in the CoPP and Fe groups.Hepcidin levels were higher,whereas superoxide dismutase levels were increased and malonaldehyde levels were decreased in the ZnPP and DFX groups.The ZnPP group also showed inhibited TGF-β1 expression and regulated TIMP-1/MMP-2 expression,as well as obviously attenuated liver fibrosis.CONCLUSION:Reducing hepatic iron deposition and CO levels by inhibiting HO-1 activity though the Nrf2/Keap pathway could be helpful in improving hepatic fibrosis and regulating PVP.展开更多
This study examined the ability of 1,2,3,4,6-penta-O-galloyl-β-D-glucose (β-PGG) to induce the expression of heme oxygenase-1 (HO-1) in the PC12 cells and its regulation in the PC12 cells.One week before treatment w...This study examined the ability of 1,2,3,4,6-penta-O-galloyl-β-D-glucose (β-PGG) to induce the expression of heme oxygenase-1 (HO-1) in the PC12 cells and its regulation in the PC12 cells.One week before treatment with the drug,nerve growth factor (NGF) was added to the cultures at a final concentration of 50 ng/mL to induce neuronal differentiation.After drug treatment,HO-1 gene transcription was analyzed by reverse transcription polymerase chain reaction (RT-PCR).Expression of HO-1 and NF-E2-related factor2 (Nrf2) and activation of extracellular signal-regulated kinase (ERK) and Akt were detected by Western blotting.The viability of the PC12 cells treated with different medicines was examined by MTT assay.The oxidative stress in the PC12 cells was evaluated qualitatively and quantitatively by DCFH-DA.The results showed that β-PGG up-regulated HO-1 expression and this increased expression provided neuroprotection against MPP+-induced oxidative injury.Moreover,β-PGG induced Nrf2 nuclear translocation,which was found to be upstream of β-PGG-induced HO-1 expression,and the activation of ERK and Akt,a pathway that is involved in β-PGG-induced Nrf2 nuclear translocation,HO-1 expression and neuroprotection.In conclusion,β-PGG up-regulates HO-1 expression by stimulating Nrf2 nuclear translocation in an ERK-and Akt-dependent manner,and HO-1 expression by β-PGG may provide the PC12 cells with an acquired antioxidant defense capacity to survive the oxidative stress.展开更多
Heme oxygenase-1(HO-1) system catalyzes heme to biologically active products:carbon monoxide,biliverdin/bilirubin and free iron.It is involved in maintaining cellular homeostasis and many physiological and pathophysio...Heme oxygenase-1(HO-1) system catalyzes heme to biologically active products:carbon monoxide,biliverdin/bilirubin and free iron.It is involved in maintaining cellular homeostasis and many physiological and pathophysiological processes.A growing body of evidence indicates that HO-1 activation may play an important protective role in acute and chronic inflammation of gastrointestinal tract.This review focuses on the current understanding of the physiological significance of HO-1 induction and its possible roles in the gastrointestinal inflammation studied to date.The ability to upregulate HO-1 by pharmacological means or using gene therapy may offer therapeutic strategies for gastrointestinal inflammation in the future.展开更多
AIM:To investigate the effect of heme oxygenase-1 (HO-1)expression on immune liver fibrosis induced by cobalt protoporphyrin(CoPP)in rats. METHODS:An immune liver fibrosis model of rat was established by administering...AIM:To investigate the effect of heme oxygenase-1 (HO-1)expression on immune liver fibrosis induced by cobalt protoporphyrin(CoPP)in rats. METHODS:An immune liver fibrosis model of rat was established by administering human serum albumin (HSA).The rats were divided into CoPP,liver fibrosis and normal control groups.Rats in the CoPP group received intraperitoneal CoPP concurrently with HSA. Expression of HO-1 protein was observed by Western blotting and immunohistochemistry.Hematoxylin and eosin(HE)staining was performed to assess fibrosis proliferation and distribution,proliferation extent of fibroblasts,and alterations in hepatocytes and inflammatory cells.TypeⅠandⅢcollagens were detected with Van Gieson’s(VG)staining and Foot’s reticular fiber staining,respectively.In addition, spindle-shaped cells existing at perisinusoidal locations beyond portal and septa areas were investigated with HE staining. RESULTS:Western blotting and immunohistochemistry showed that the expression of HO-1 protein was higher in the CoPP group than in the liver fibrosis group(P<0.05).Compared with the liver fibrosis group,the serological index of hepatic fibrosis in the CoPP group decreased significantly(P<0.05).HE,VG and Foot’s staining revealed that administration of CoPP reduced the extent of hepatic fibrosis.The levels of serological indicators and the number of spindle-shaped cells at perisinuous locations beyond the portal and septa areas were reduced in the CoPP group.Only a few inflammatory cells were seen around the portal areas and central veins in the CoPP group. CONCLUSION:Increased endogenous HO-1 may suppress liver fibrosis by protecting liver cells, inhibiting inflammatory cell infiltration and hepatic stellate cell transformation.展开更多
文摘Previous studies have reported upregulation of heme oxygenase-1 in different central nervous system injury models.Heme oxygenase-1 plays a critical anti-inflammatory role and is essential for regulating cellular redox homeostasis.Metformin is a classic drug used to treat type 2 diabetes that can inhibit ferroptosis.Previous studies have shown that,when used to treat cardiovascular and digestive system diseases,metformin can also upregulate heme oxygenase-1 expression.Therefore,we hypothesized that heme oxygenase-1 plays a significant role in mediating the beneficial effects of metformin on neuronal ferroptosis after spinal cord injury.To test this,we first performed a bioinformatics analysis based on the GEO database and found that heme oxygenase-1 was upregulated in the lesion of rats with spinal cord injury.Next,we confirmed this finding in a rat model of T9 spinal cord compression injury that exhibited spinal cord nerve cell ferroptosis.Continuous intraperitoneal injection of metformin for 14 days was found to both upregulate heme oxygenase-1 expression and reduce neuronal ferroptosis in rats with spinal cord injury.Subsequently,we used a lentivirus vector to knock down heme oxygenase-1 expression in the spinal cord,and found that this significantly reduced the effect of metformin on ferroptosis after spinal cord injury.Taken together,these findings suggest that metformin inhibits neuronal ferroptosis after spinal cord injury,and that this effect is partially dependent on upregulation of heme oxygenase-1.
基金supported by grants from Jiangsu Commission of Health,No.Z2021086(to XL)Science and Technology Program of Suzhou,Nos.SYSD2020008(to XL),SKYD2022012(to XL)+1 种基金Suzhou Municipal Health Commission,No.KJXW2020058(to XL)Science and Technology Program of Zhangjiagang,No.ZKS2018(to XL)。
文摘Interfering with the ferroptosis pathway is a new strategy for the treatment of spinal cord injury.Fibroblast growth factor 21 can inhibit ferro ptosis and promote neurofunctional recovery,while heme oxygenase-1 is a regulator of iron and reactive oxygen species homeostasis.The relationship between heme oxygenase-1and ferroptosis remains controve rsial.In this study,we used a spinal co rd injury rat model to show that the levels of fibroblast growth factor 21 in spinal co rd tissue decreased after spinal cord injury.In addition,there was a significant aggravation of ferroptosis and a rapid increase in heme oxygenase-1 expression after spinal cord injury.Furthe r,heme oxygenase-1 aggravated fe rroptosis after spinal cord injury,while fibroblast growth factor 21 inhibited fe rroptosis by downregulating heme oxygenase-1.Thus,the activation of fibroblast growth factor 21 may provide a potential treatment for spinal co rd injury.These findings could provide a new potential mechanistic explanation for fibroblast growth factor 21 in the treatment of spinal cord injury.
基金supported by the National Natural Science Foundation of ChinaNos.81971047 (to WTL) and 82073910 (to XFW)+2 种基金the Natural Science Foundation of Jiangsu Province,No.BK20191253 (to XFW)Key R&D Program (Social Development) Project of Jiangsu Province,No.BE2019 732 (to WTL)Jiangsu Province Hospital (the First Affiliated Hospital of Nanjing Medical University) Clinical Capacity Enhancement Project,No.JSPH-511B2018-8 (to YBP)。
文摘Opioids,such as morphine,are the most potent drugs used to treat pain.Long-term use results in high tolerance to morphine.High mobility group box-1(HMGB1) has been shown to participate in neuropathic or inflammatory pain,but its role in morphine tolerance is unclear.In this study,we established rat and mouse models of morphine tolerance by intrathecal injection of morphine for 7 consecutive days.We found that morphine induced rat spinal cord neurons to release a large amount of HMGB1.HMGB1 regulated nuclear factor κB p65 phosphorylation and interleukin-1β production by increasing Toll-like receptor 4receptor expression in microglia,thereby inducing morphine tolerance.Glycyrrhizin,an HMGB1 inhibito r,markedly attenuated chronic morphine tole rance in the mouse model.Finally,compound C(adenosine 5’-monophosphate-activated protein kinase inhibitor) and zinc protoporphyrin(heme oxygenase-1 inhibitor)alleviated the morphine-induced release of HMGB1 and reduced nuclear factor κB p65 phosphorylation and interleukin-1β production in a mouse model of morphine tolerance and an SH-SY5Y cell model of morphine tole rance,and alleviated morphine tolerance in the mouse model.These findings suggest that morphine induces HMGB1 release via the adenosine 5’-monophosphate-activated protein kinase/heme oxygenase-1 signaling pathway,and that inhibiting this signaling pathway can effectively reduce morphine tole rance.
基金Supported by The Natural Science Foundation of Yunnan Province,China, No.2007C137Mthe Joint Funds of Natural Science Foundation of Yunnan Province,China,No.2007C0009R
文摘AIM:To examine whether heme oxygenase (HO)-1 overexpression would exert direct or indirect effects on Kupffer cells activation, which lead to aggravation of reperfusion injury.METHODS: Donors were pretreated with cobalt protoporphyrin (CoPP) or zinc protoporphyrin (ZnPP), HO-1 inducer and antagonist, respectively. Livers were stored at 4℃ for 24 h before transplantation. Kupffer cells were isolated and cultured for 6 h after liver reperfusion.RESULTS: Postoperatively, serum transaminases were significantly lower and associated with less liver injury when donors were pretreated with CoPP, as compared with the ZnPP group. Production of the cytokines tumor necrosis factor-α and interleukin-6 generated by Kupffer cells decreased in the CoPP group. The CD14 expression levels (RT-PCR/Western blots) of Kupffer cells from CoPP-pretreated liver grafts reduced.CONCLUSION: The study suggests that the potential utility of HO-1 overexpression in preventing ischemia/reperfusion injury results from inhibition of Kupffer cells activation.
基金sponsored by the National Natural Science Foundation of China, Nos.81200718(to HWY) and 81570866(to XLC)。
文摘Quercetin is a widely-occurring flavonoid that protects against cancer, and improves memory and cardiovascular functions.However, whether quercetin exhibits therapeutic effects in diabetic retinopathy remains unclear.In this study, we established a rat model of streptozocininduced diabetic retinopathy.Seventy-two hours later, the rats were intraperitoneally administered 150 mg/kg quercetin for 16 successive weeks.Quercetin markedly increased the thickness of the retinal cell layer, increased the number of ganglion cells, and decreased the overexpression of the pro-inflammatory factors interleukin-1β, interleukin-18, interleukin-6 and tumor necrosis factor-α in the retinal tissue as well as the overexpression of high mobility group box-1 and the overactivation of the NLRP3 inflammasome.Furthermore, quercetin inhibited the overexpression of TLR4 and NF-κBp65, reduced the expression of the pro-angiogenic vascular endothelial growth factor and soluble intercellular adhesion molecule-1, and upregulated the neurotrophins brain-derived neurotrophic factor and nerve growth factor.Intraperitoneal injection of the heme oxygenase-1 inhibitor zinc protoporphyrin blocked the protective effect of quercetin.These findings suggest that quercetin exerts therapeutic effects in diabetic retinopathy possibly by inducing heme oxygenase-1 expression.This study was approved by the Animal Ethics Committee of China Medical University, China(approval No.2016 PS229K) on April 8, 2016.
基金Supported by The National Natural Science Foundation of China,No.81670574,No.81441022 and No.81270528The Natural Science Foundation of Tianjin,China,No.08JCYBJC08400,No.11JCZDJC27800,and No.12JCZDJC25200the Technology Foundation of the Health Bureau in Tianjin,China,No.2011KY11
文摘AIM To investigate the effects of heme oxygenase-1(HO-1)-modified bone marrow mesenchymal stem cells(BMMSCs)on the microcirculation and energy metabolism of hepatic sinusoids following reduced-size liver transplantation(RLT)in a rat model.METHODS BMMSCs were isolated and cultured in vitro using an adherent method,and then transduced with HO-1-bearing recombinant adenovirus to construct HO-1/BMMSCs.A rat acute rejection model following 50%RLT was established using a two-cuff technique.Recipients were divided into three groups based on the treatment received:normal saline(NS),BMMSCs and HO-1/BMMSCs.Liver function was examined at six time points.The levels of endothelin-1(ET-1),endothelial nitric-oxide synthase(e NOS),inducible nitric-oxide synthase(i NOS),nitric oxide(NO),and hyaluronic acid(HA)were detected using an enzyme-linked immunosorbent assay.The portal vein pressure(PVP)was detected by Power Lab ML880.The expressions of ET-1,i NOS,e NOS,and von Willebrand factor(v WF)protein in the transplanted liver were detected using immunohistochemistry and Western blotting.ATPase in the transplanted liver was detected by chemical colorimetry,and the ultrastructural changes were observed under a transmission electron microscope.RESULTS HO-1/BMMSCs could alleviate the pathological changes and rejection activity index of the transplanted liver,and improve the liver function of rats following 50%RLT,with statistically significant differences compared with those of the NS group and BMMSCs group(P<0.05).In term of the microcirculation of hepatic sinusoids:The PVP on POD7 decreased significantly in the HO-1/BMMSCs and BMMSCs groups compared with that of the NS group(P<0.01);HO-1/BMMSCs could inhibit the expressions of ET-1 and i NOS,increase the expressions of e NOS and inhibit amounts of NO production,and maintain the equilibrium of ET-1/NO(P<0.05);and HO-1/BMMSCs increased the expression of v WF in hepatic sinusoidal endothelial cells(SECs),and promoted the degradation of HA,compared with those of the NS group and BMMSCs group(P<0.05).In term of the energy metabolism of the transplanted liver,HO-1/BMMSCs repaired the damaged mitochondria,and improved the activity of mitochondrial aspartate aminotransferase(ASTm)and ATPase,compared with the other two groups(P<0.05).CONCLUSION HO-1/BMMSCs can improve the microcirculation of hepatic sinusoids significantly,and recover the energy metabolism of damaged hepatocytes in rats following RLT,thus protecting the transplanted liver.
基金Supported by the Project of Innovative Research Team for Key Science and Technology in Shaanxi Province,No.2013KCJ-23the Fundamental Research Funds for the Central Universities,No.1191320114the National Natural Science Foundation of China,No.81601672
文摘AIM To investigate the therapeutic effect of hydrogen-rich water(HRW) on inflammatory bowel disease(IBD) and to explore the potential mechanisms involved.METHODS Male mice were randomly divided into the following four groups: control group, in which the mice received equivalent volumes of normal saline(NS) intraperitoneally(ip); dextran sulfate sodium(DSS) group, in which the mice received NS ip(5 m L/kg body weight, twice per day at 8 am and 5 pm) for 7 consecutive days after IBD modeling; DSS + HRW group, in which the mice received HRW(in the same volume as the NS treatment) for 7 consecutive days after IBD modeling; and DSS + HRW + Zn PP group, in which the mice received HRW(in the same volume as the NS treatment) and ZnP P [a heme oxygenase-1(HO-1) inhibitor, 25 mg/kg] for 7 consecutive days after IBD modeling. IBD was induced by feeding DSS to the mice, and blood and colon tissues were collected on the 7th d after IBD modeling to determine clinical symptoms, colonic inflammation and the potential mechanisms involved.RESULTS The DSS + HRW group exhibited significantly attenuated weight loss and a lower extent of disease activity index compared with the DSS group on the 7th d(P < 0.05). HRW exerted protective effects against colon shortening and colonic wall thickening in contrast to the DSS group(P < 0.05). The histological study demonstrated milder inflammation in the DSS + HRW group, which was similar to normal inflammatory levels, and the macroscopic and microcosmic damage scores were lower in this group than in the DSS group(P < 0.05). The oxidative stress parameters, including MDA and MPO in the colon, were significantly decreased in the DSS + HRW group compared with the DSS group(P < 0.05). Simultaneously, the protective indicators, superoxide dismutase and glutathione, were markedly increased with the use of HRW. Inflammatory factors were assessed, and the results showed that the DSS + HRW group exhibited significantly reduced levels of TNF-α, IL-6 and IL-1β compared with the DSS group(P < 0.05). In addition, the pivotal proteins involved in endoplasmic reticulum(ER) stress, including p-e IF2α, ATF4, XBP1 s and CHOP, were dramatically reduced after HRW treatment in contrast to the control group(P < 0.05). Furthermore, HRW treatment markedly up-regulated HO-1 expression, and the use of Zn PP obviously reversed the protective role of HRW. In the DSS + HRW + ZnP P group, colon shortening and colonic wall thickening were significantly aggravated, and the macroscopic damage scores were similar to those of the DSS + HRW group(P < 0.05). The histological study also showed more serious colonic damage that was similar to the DSS group.CONCLUSION HRW has a significant therapeutic potential in IBD by inhibiting inflammatory factors, oxidative stress and ER stress and by up-regulating HO-1 expression.
文摘Heme oxygenase-1(HO-1) system catabolizes heme into three products:carbon monoxide,biliverdin/bilirubin and free iron.It is involved in many physiological and pathophysiological processes.A great deal of data has demonstrated the roles of HO-1 in the formation,growth and metastasis of tumors.The interest in this system by investigators involved in gastrointestinal tumors is fairly recent,and few papers on HO-1 have touched upon this subject.This review focuses on the current understanding of the physiological significance of HO-1 induction and its possible roles in the gastrointestinal tumors studied to date.The implications for possible therapeutic manipulation of HO-1 in gastrointestinal tumors are also discussed.
基金Deanship of Scientific Research at King Saud University,No.RG-1439-083.
文摘BACKGROUND Sinapic acid(SA)has been shown to have various pharmacological properties such as antioxidant,antifibrotic,anti-inflammatory,and anticancer activities.Its mechanism of action is dependent upon its ability to curb free radical production and protect against oxidative stress-induced tissue injuries.AIM To study the hepatoprotective effects of SA against lipopolysaccharide(LPS)/Dgalactosamine(D-GalN)-induced acute liver failure(ALF)in rats.METHODS Experimental ALF was induced with an intraperitoneal(i.p.)administration of 8μg LPS and 800 mg/kg D-GalN in normal saline.SA was administered orally once daily starting 7 d before LPS/D-GalN treatment.RESULTS Data showed that SA ameliorates acute liver dysfunction,decreases serum levels of alanine transaminase(ALT),and aspartate aminotransferase(AST),as well as malondialdehyde(MDA)and NO levels in ALF model rats.However,pretreatment with SA(20 mg/kg and 40 mg/kg)reduced nuclear factor kappalight-chain-enhancer of activated B cells(NF-κB)activation and levels of inflammatory cytokines(tumor necrosis factor-αand interleukin 6).Also,SA increased the activity of the nuclear factor erythroid-related factor 2/heme oxygenase-1(Nrf2/HO-1)signaling pathway.CONCLUSION In conclusion,SA offers significant protection against LPS/D-GalN-induced ALF in rats by upregulating Nrf2/HO-1 and downregulating NF-κB.
基金Supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education,Science and Technology,South Korea,No.NRF-2018R1D1A1B07043350
文摘BACKGROUND Enterotoxigenic Bacteroides fragilis(ETBF)causes colitis and diarrhea,and is considered a candidate pathogen in inflammatory bowel diseases as well as colorectal cancers.These diseases are dependent on ETBF-secreted toxin(BFT).Dendritic cells(DCs)play an important role in directing the nature of adaptive immune responses to bacterial infection and heme oxygenase-1(HO-1)is involved in the regulation of DC function.AIM To investigate the role of BFT in HO-1 expression in DCs.METHODS Murine DCs were generated from specific pathogen-free C57BL/6 and Nrf2−/−knockout mice.DCs were exposed to BFT,after which HO-1 expression and the related signaling factor activation were measured by quantitative RT-PCR,EMSA,fluorescent microscopy,immunoblot,and ELISA.RESULTS HO-1 expression was upregulated in DCs stimulated with BFT.Although BFT activated transcription factors such as NF-κB,AP-1,and Nrf2,activation of NF-κB and AP-1 was not involved in the induction of HO-1 expression in BFT-exposed DCs.Instead,upregulation of HO-1 expression was dependent on Nrf2 activation in DCs.Moreover,HO-1 expression via Nrf2 in DCs was regulated by mitogenactivated protein kinases such as ERK and p38.Furthermore,BFT enhanced the production of reactive oxygen species(ROS)and inhibition of ROS production resulted in a significant decrease of phospho-ERK,phospho-p38,Nrf2,and HO-1 CONCLUSION These results suggest that signaling pathways involving ROS-mediated ERK and p38 mitogen-activated protein kinases-Nrf2 activation in DCs are required for HO-1 induction during exposure to ETBF-produced BFT.
基金Supported by Rongxiang Regenerative Medicine Foundation of Shandong University, No. 2019SDRX-18Clinical Practical New Technology Development Found of Qilu Hospital of Shandong University, No. KYC 2019-0057+1 种基金Clinical Research Center of Shandong University, No. 2020SDUCRCA010Natural Science Foundation of Shandong Province, No. ZR2020MH063
文摘BACKGROUND Bronchopulmonary dysplasia(BPD)is not merely a chronic lung disease,but a systemic condition with multiple organs implications predominantly associated with hyperoxia exposure.Despite advances in current management strategies,limited progress has been made in reducing the BPD-related systemic damage.Meanwhile,although the protective effects of human umbilical cord-derived mesenchymal stem cells(hUC-MSCs)or their exosomes on hyperoxia-induced lung injury have been explored by many researchers,the underlying mechanism has not been addressed in detail,and few studies have focused on the therapeutic effect on systemic multiple organ injury.AIM To investigate whether hUC-MSC intratracheal administration could attenuate hyperoxia-induced lung,heart,and kidney injuries and the underlying regulatory mechanisms.METHODS Neonatal rats were exposed to hyperoxia(80%O_(2)),treated with hUC-MSCs intratracheal(iT)or intraperitoneal(iP)on postnatal day 7,and harvested on postnatal day 21.The tissue sections of the lung,heart,and kidney were analyzed morphometrically.Protein contents of the bronchoalveolar lavage fluid(BALF),myeloper oxidase(MPO)expression,and malondialdehyde(MDA)levels were examined.Pulmonary inflammatory cytokines were measured via enzyme-linked immunosorbent assay.A comparative transcriptomic analysis of differentially expressed genes(DEGs)in lung tissue was conducted via RNA-sequencing.Subsequently,we performed reverse transcription-quantitative polymerase chain reaction and western blot analysis to explore the expression of target mRNA and proteins related to inflammatory and oxidative responses.RESULTS iT hUC-MSCs administration improved pulmonary alveolarization and angiogenesis(P<0.01,P<0.01,P<0.001,and P<0.05 for mean linear intercept,septal counts,vascular medial thickness index,and microvessel density respectively).Meanwhile,treatment with hUC-MSCs iT ameliorated right ventricular hypertrophy(for Fulton’s index,P<0.01),and relieved reduced nephrogenic zone width(P<0.01)and glomerular diameter(P<0.001)in kidneys.Among the beneficial effects,a reduction of BALF protein,MPO,and MDA was observed in hUC-MSCs groups(P<0.01,P<0.001,and P<0.05 respectively).Increased pro-inflammatory cytokines tumor necrosis factor-alpha,interleukin(IL)-1β,and IL-6 expression observed in the hyperoxia group were significantly attenuated by hUC-MSCs administration(P<0.01,P<0.001,and P<0.05 respectively).In addition,we observed an increase in anti-inflammatory cytokine IL-10 expression in rats that received hUC-MSCs iT compared with rats reared in hyperoxia(P<0.05).Transcriptomic analysis showed that the DEGs in lung tissues induced by hyperoxia were enriched in pathways related to inflammatory responses,epithelial cell proliferation,and vasculature development.hUC-MSCs administration blunted these hyperoxia-induced dysregulated genes and resulted in a shift in the gene expression pattern toward the normoxia group.hUC-MSCs increased heme oxygenase-1(HO-1),JAK2,and STAT3 expression,and their phosphorylation in the lung,heart,and kidney(P<0.05).Remarkably,no significant difference was observed between the iT and iP administration.CONCLUSION iT hUC-MSCs administration ameliorates hyperoxia-induced lung,heart,and kidney injuries by activating HO-1 expression and JAK/STAT signaling.The therapeutic benefits of local iT and iP administration are equivalent.
文摘We found a mistake in Figure 6. Panels A (Sham group) and F (DFX group) (180degrees rotated) is same images. We have replaced the incorrect images (Panels F)with the correct Figure. This error does not change the meaning of the picture orthe conclusion of the manuscript. We apologize for our unintentional mistakes,which caused great inconvenience.
基金Supported by National Natural Science Foundation of China,No.81360079Yunnan Provincial Science and Technology Department and Kunming Medical University Collaborative Fund,No.2013FB142
文摘AIM:To investigate the efficacy and molecularmechanisms of induced heme oxygenase(HO)-1 in protecting liver from warm ischemia/reperfusion(I/R)injury.METHODS:Partial warm ischemia was produced in the left and middle hepatic lobes of SD rats for 75min,followed by 6 h of reperfusion.Rats were treated with saline,cobalt protoporphyrin(Co PP)or zinc protoporphyrin(Zn PP)at 24 h prior to the ischemia insult.Blood and samples of ischemic lobes subjected to ischemia were collected at 6 h after reperfusion.Serum transaminases level,plasma lactate dehydrogenase and myeloperoxidase activity in liver were measured.Liver histological injury and inflammatory cell infiltration were evaluated by tissue section and liver immunohistochemical analysis.We used quantitative reverse transcription polymerase chain reaction to analyze liver expression of inflammatory cytokines and chemokines.The cell lysates were subjected to immunoprecipitation with anti-Toll-IL-1R-containing adaptor inducing interferon-β(TRIF)and anti-myeloid differentiation factor 88(My D88),and then the immunoprecipitates were analyzed by SDS-PAGE and immunoblotted with the indicated antibodies.RESULTS:HO-1 protected livers from I/R injury,as evidenced by diminished liver enzymes and wellpreserved tissue architecture.In comparison with Zn PP livers 6 h after surgery,Co PP treatment livers showed a significant increase inflammatory cell infiltration of lymphocytes,plasma cells,neutrophils and macrophages.The Toll-like receptor(TLR)-4 and TANK binding kinase1 protein levels of rats treated with Co PP significantly reduced in TRIF-immunoprecipitated complex,as compared with Zn PP treatment.In addition,pretreatment with Co PP reduced the expression levels of TLR2,TLR4,IL-1R-associated kinase(IRAK)-1 and tumor necrosis factor receptor-associated factor 6 in My D88-immunoprecipitated complex.The inflammatory cytokines and chemokines m RNA expression rapidly decreased inCo PP-pretreated liver,compared with the Zn PP-treated group.However,the expression of negative regulators Tollinteracting protein,suppressor of cytokine signaling-1,IRAK-M and Src homology 2 domain-containing inositol-5-phosphatase-1 in Co PP treatment rats were markedly up-regulated as compared with Zn PP-treated rats.CONCLUSION:HO-1 protects liver against I/R injury by inhibiting TLR2/TLR4-triggered My D88-and TRIFdependent signaling pathways and increasing expression of negative regulators of TLR signaling in rats.
基金Supported by Grants from the National Natural Science Foun-dation of China,No. 30970886The Science and Technology Project of Dalian,No. 2010E15SF179the Initial Doctoral funding of Liaoning Province,No. 20121110
文摘AIM:To investigate the effects of the heme oxygenase(HO)-1/carbon monoxide system on iron deposition and portal pressure in rats with hepatic fibrosis induced by bile duct ligation(BDL).METHODS:Male Sprague-Dawley rats were divided randomly into a Sham group,BDL group,Fe group,deferoxamine(DFX) group,zinc protoporphyrin(ZnPP) group and cobalt protoporphyrin(CoPP) group.The levels of HO-1 were detected using different methods.The serum carboxyhemoglobin(COHb),iron,and portal vein pressure(PVP) were also quantified.The plasma and mRNA levels of hepcidin were measured.Hepatic fibrosis and its main pathway were assessed using Van Gieson's stain,hydroxyproline,transforming growth factor-β1(TGF-β1),nuclear factor-E2-related factor 2(Nrf2),matrix metalloproteinase-2(MMP-2) and tissue inhibitor of metalloproteinase-1(TIMP-1).RESULTS:Serum COHb and protein and mRNA expression levels of HO-1 and Nrf2 were increased in the BDL group compared with the Sham group and were much higher in the CoPP group.The ZnPP group showed lower expression of HO-1 and Nrf2 and lower COHb.The levels of iron and PVP were enhanced in the BDL group but were lower in the ZnPP and DFX groups and were higher in the CoPP and Fe groups.Hepcidin levels were higher,whereas superoxide dismutase levels were increased and malonaldehyde levels were decreased in the ZnPP and DFX groups.The ZnPP group also showed inhibited TGF-β1 expression and regulated TIMP-1/MMP-2 expression,as well as obviously attenuated liver fibrosis.CONCLUSION:Reducing hepatic iron deposition and CO levels by inhibiting HO-1 activity though the Nrf2/Keap pathway could be helpful in improving hepatic fibrosis and regulating PVP.
基金supported by National 11th Five-Year Plan Research Foundation of China (No.2006BAI01A14)
文摘This study examined the ability of 1,2,3,4,6-penta-O-galloyl-β-D-glucose (β-PGG) to induce the expression of heme oxygenase-1 (HO-1) in the PC12 cells and its regulation in the PC12 cells.One week before treatment with the drug,nerve growth factor (NGF) was added to the cultures at a final concentration of 50 ng/mL to induce neuronal differentiation.After drug treatment,HO-1 gene transcription was analyzed by reverse transcription polymerase chain reaction (RT-PCR).Expression of HO-1 and NF-E2-related factor2 (Nrf2) and activation of extracellular signal-regulated kinase (ERK) and Akt were detected by Western blotting.The viability of the PC12 cells treated with different medicines was examined by MTT assay.The oxidative stress in the PC12 cells was evaluated qualitatively and quantitatively by DCFH-DA.The results showed that β-PGG up-regulated HO-1 expression and this increased expression provided neuroprotection against MPP+-induced oxidative injury.Moreover,β-PGG induced Nrf2 nuclear translocation,which was found to be upstream of β-PGG-induced HO-1 expression,and the activation of ERK and Akt,a pathway that is involved in β-PGG-induced Nrf2 nuclear translocation,HO-1 expression and neuroprotection.In conclusion,β-PGG up-regulates HO-1 expression by stimulating Nrf2 nuclear translocation in an ERK-and Akt-dependent manner,and HO-1 expression by β-PGG may provide the PC12 cells with an acquired antioxidant defense capacity to survive the oxidative stress.
基金Supported by National Natural Science Foundation of China,No. 81071697Research Project of Health Bureau of Guangzhou City,No. 201102A213005 and 2010A30Research Project of Education Bureau of Guangzhou City,No. 10A192
文摘Heme oxygenase-1(HO-1) system catalyzes heme to biologically active products:carbon monoxide,biliverdin/bilirubin and free iron.It is involved in maintaining cellular homeostasis and many physiological and pathophysiological processes.A growing body of evidence indicates that HO-1 activation may play an important protective role in acute and chronic inflammation of gastrointestinal tract.This review focuses on the current understanding of the physiological significance of HO-1 induction and its possible roles in the gastrointestinal inflammation studied to date.The ability to upregulate HO-1 by pharmacological means or using gene therapy may offer therapeutic strategies for gastrointestinal inflammation in the future.
基金Supported by The National Natural Science Foundation of China,2005-30570515The Educational Department Project of Liaoning Province,2004-F063+2 种基金The Natural Science Fund Projects of Liaoning Province,2006-1058Science and Technology Project of DaLian City,2002-B3NS137The Project Sponsored by the Scientific Research Foundation for Returned Overseas Chinese Scholars,State Education Ministry,2005-546
文摘AIM:To investigate the effect of heme oxygenase-1 (HO-1)expression on immune liver fibrosis induced by cobalt protoporphyrin(CoPP)in rats. METHODS:An immune liver fibrosis model of rat was established by administering human serum albumin (HSA).The rats were divided into CoPP,liver fibrosis and normal control groups.Rats in the CoPP group received intraperitoneal CoPP concurrently with HSA. Expression of HO-1 protein was observed by Western blotting and immunohistochemistry.Hematoxylin and eosin(HE)staining was performed to assess fibrosis proliferation and distribution,proliferation extent of fibroblasts,and alterations in hepatocytes and inflammatory cells.TypeⅠandⅢcollagens were detected with Van Gieson’s(VG)staining and Foot’s reticular fiber staining,respectively.In addition, spindle-shaped cells existing at perisinusoidal locations beyond portal and septa areas were investigated with HE staining. RESULTS:Western blotting and immunohistochemistry showed that the expression of HO-1 protein was higher in the CoPP group than in the liver fibrosis group(P<0.05).Compared with the liver fibrosis group,the serological index of hepatic fibrosis in the CoPP group decreased significantly(P<0.05).HE,VG and Foot’s staining revealed that administration of CoPP reduced the extent of hepatic fibrosis.The levels of serological indicators and the number of spindle-shaped cells at perisinuous locations beyond the portal and septa areas were reduced in the CoPP group.Only a few inflammatory cells were seen around the portal areas and central veins in the CoPP group. CONCLUSION:Increased endogenous HO-1 may suppress liver fibrosis by protecting liver cells, inhibiting inflammatory cell infiltration and hepatic stellate cell transformation.
