Engineered probiotics can serve as therapeutics based on their ability of produce recombinant immune-stimulating properties.In this study,we built the recombinant Bacillus subtilis WB800 expressing antimicrobial pepti...Engineered probiotics can serve as therapeutics based on their ability of produce recombinant immune-stimulating properties.In this study,we built the recombinant Bacillus subtilis WB800 expressing antimicrobial peptide KR32(WB800-KR32)using genetic engineering methods and investigated its protective effects of nuclear factor-E2-related factor 2(Nrf2)-Kelch-like ECH-associated protein 1(Keap1)pathway activation in intestinal oxidative disturbance induced by enterotoxigenic Escherichia coli(ETEC)K88 in weaned piglets.Twenty-eight weaned piglets were randomly distributed into four treatment groups with seven replicates fed with a basal diet.The feed of the control group(CON)was infused with normal sterilized saline;meanwhile,the ETEC,ETEC+WB800,and ETEC+WB800-KR32 groups were orally administered normal sterilized saline,5×10^(10)CFU(CFU:colony forming units)WB800,and 5×10^(10)CFU WB800-KR32,respectively,on Days 1-14 and all infused with ETEC K881×10^(10)CFU on Days 15-17.The results showed that pretreatment with WB800-KR32 attenuated ETEC-induced intestinal disturbance,improved the mucosal activity of antioxidant enzyme(catalase(CAT),superoxide dismutase(SOD),and glutathione peroxidase(GPx))and decreased the content of malondialdehyde(MDA).More importantly,WB800-KR32 downregulated genes involved in antioxidant defense(GPx and SOD1).Interestingly,WB800-KR32 upregulated the protein expression of Nrf2 and downregulated the protein expression of Keap1 in the ileum.WB800-KR32 markedly changed the richness estimators(Ace and Chao)of gut microbiota and increased the abundance of Eubacterium_rectale_ATCC_33656 in the feces.The results suggested that WB800-KR32 may alleviate ETEC-induced intestinal oxidative injury through the Nrf2-Keap1 pathway,providing a new perspective for WB800-KR32 as potential therapeutics to regulate intestinal oxidative disturbance in ETEC K88 infection.展开更多
Muscle atrophy can be induced by high doses or prolonged use of glucocorticoids.Kaempferol(Kae)is a naturally occurring flavonoid with a variety of biological activities and the effect of Kae on dexamethasone(Dex)indu...Muscle atrophy can be induced by high doses or prolonged use of glucocorticoids.Kaempferol(Kae)is a naturally occurring flavonoid with a variety of biological activities and the effect of Kae on dexamethasone(Dex)induced muscle atrophy in animals has not been elucidated.To explore this issue,the present experiments used a computationally assisted drug design scheme combining network pharmacology,molecular docking and in vivo experiments to investigate the mechanism of Kae against muscle atrophy.Network pharmacological analyses revealed 275 potential targets for Kae and 12294 potential targets for muscle atrophy,with a total of 228 crosstargets for Kae and muscle atrophy.GO and KEGG analyses were performed based on the protein-protein interaction(PPI)network of muscle atrophy and Kae component targets.The GO results showed that the biological processes were mainly related to the metabolic process of reactive oxygen species,and the response to oxidative stress;the cellular components were mainly focused on membrane microdomains,and membrane regions;the molecular functions mainly worked on phosphatase binding;and the KEGG pathway enrichment analyses identified the pathways of interaction between Kae and muscle atrophy.Finally,as verified by in vivo experiments,Kae may reduce the onset of muscle atrophy by activating the PI3K/AKT/m TOR/signalling pathway,inhibiting Foxo1/Foxo3 activity,and inhibiting downstream production of the ubiquitination 3 ligases Atrogin1 and Mu RF1;Kae also promotes the expression of NRF2/HO-1/KEAP1 signalling pathway,enhances muscle antioxidant capacity,inhibits the release of COX-2 and TNF-αinflammatory factors,and reduces the damage caused by oxidative stress and inflammatory factors to muscles.Therefore,there may be a synergistic effect of PI3K/AKT/m TOR and NRF2/HO-1/KEAP1 in Kae working together to prevent muscle atrophy.The binding energy and stability of Kae to potential targets were examined by molecular docking and molecular dynamics simulations,implying that Kae could be used for the prevention and treatment of muscle atrophy in patients.展开更多
Activation of spinal cord neural stem cells(NSCs)and subsequent neurogenesis holds a promising alternative for spinal cord injury(SCI)repair.Our previous study demonstrated that complement C3a,derived from reactive as...Activation of spinal cord neural stem cells(NSCs)and subsequent neurogenesis holds a promising alternative for spinal cord injury(SCI)repair.Our previous study demonstrated that complement C3a,derived from reactive astrocytes,inhibits NSC proliferation by suppressing protein aggregate clearance through the deubiquitinating enzyme ubiquitin carboxy-terminal hydrolase L1(UCHL1)-proteasome system post-SCI.However,the potential molecular mechanism by which C3a modulates NSC activation via this pathway remains unclear.Here,we revealed that C3a/C3a receptor(C3aR)signaling activated NF-κB p65,which in turn inhibited Nrf2 activity and UCHL1 expression,resulting in diminished proteasome activity and the accumulation of protein aggregates,and ultimately impaired NSC activation.Both knockdown of NF-κB p65 and Nrf2 upregulation restored UCHL1 expression and proteasome activity in vitro,promoting NSC activation by enhancing protein aggregate clearance.Mechanistically,we found that NF-κB p65 regulated Nrf2 activity through a dual mechanism:(1)promoting Keap1-dependent ubiquitination and proteasome degradation of Nrf2;(2)inhibiting protein kinase C-mediated Nrf2 phosphorylation and nuclear translocation.Using the dual-luciferase reporter assay and chromatin immunoprecipitation(ChIP)analysis,we further identified UCHL1 as a direct transcriptional target of Nrf2.Importantly,in vivo experiments using SCI mice confirmed that either C3aR blockade,NF-κB p65 knockdown,or Nrf2 overexpression could rescue SCI-induced UCHL1 downregulation.Together,this study uncovers the C3a-NF-κB p65-Nrf2-UCHL1-proteasome axis as a critical regulator of NSC activation after SCI.This may provide novel molecular targets and intervention strategies for SCI repair.展开更多
Air pollution is fourth major cause of death worldwide.Recent evidence suggests that particulate matter(PM)may affect kidneys,and the effect may be size and composition dependent.In this study,PM_(0.1),PM_(2.5),and PM...Air pollution is fourth major cause of death worldwide.Recent evidence suggests that particulate matter(PM)may affect kidneys,and the effect may be size and composition dependent.In this study,PM_(0.1),PM_(2.5),and PM_(10)were collected from ambient air and given to BALB/c male mice at 0.25 mg/m^(3) concentration in whole-body inhalation chamber for 28days(6 h/day,5 days/week)to assess their effect on kidney.Physico-chemical characterization of PM particles by SEM,ICP-MS and HPLC showed their various shapes along with the presence of metals and poly aromatic hydrocarbons(PAHs).Following PM exposure,increased serum creatinine levels were observed in animals along with dilated tubules,protein cast deposition,necrosis,immune infiltration,collagen deposition,and shrunken glomeruli in kidney.Immunofluorescence staining showed higher expressions of kidney injury molecule1(KIM-1),cystatin C,β2 microglobulin(β2M),and alpha smooth muscle actin(α-SMA)and fibronectin,suggesting renal injury and fibrosis.PM exposure also increased malondialdehyde(MDA)content and decreased superoxide dismutase 2(SOD2)activity,which in turn leads to induction of inflammation.Mechanistically,PM exposure further inhibited the nuclear factor erythroid 2-related factor 2(Nrf2)signalling and induced kelch-like ECH-associated protein 1(Keap1)and nuclear factor kappa-light-chain-enhancer of activated B(NF-κB).Interestingly,the effect of PM_(2.5)was more severe than PM_(0.1)and PM_(10),leading to higher levels of proinflammatory NF-κB and greater Nrf2 inhibition.Overall,our findings suggested that inhalation exposure to size-segregated PM can cause kidney damage and fibrosis,and PM_(2.5)showed higher toxicity than PM_(0.1)and PM_(10).展开更多
Background:Myocardial infarction(MI)remains a major global public health challenge.Although advances in reperfusion therapy have reduced acute mortality,post-infarction cardiac remodeling continues to pose a substanti...Background:Myocardial infarction(MI)remains a major global public health challenge.Although advances in reperfusion therapy have reduced acute mortality,post-infarction cardiac remodeling continues to pose a substantial threat to long-term cardiovascular health.Oxidative stress and the ensuing inflammatory response are key drivers of this pathological process,leading to cardiomyocyte death,myocardial fibrosis,and functional impairment.Among the regulatory pathways involved,the kelch-like ECH-associated protein 1(Keap1)/nuclear factor erythroid 2-related factor 2(Nrf2)axis has emerged as a critical therapeutic target for mitigating post-MI cardiac injury.Methods:A murine MI model was established by permanent ligation of the left anterior descending coronary artery.Mice received oral Tongxinbi formula(TXB)at low,medium,or high doses(9/18/36 g/kg)once daily for 28 days.Cardiac function was assessed by echocardiography;myocardial fibrosis by Masson’s trichrome;and endothelial integrity by CD31 immunofluorescence.Plasma markers of endothelial function and inflammation were quantified.In vitro,oxidative stress was induced by H2O2 in vascular endothelial cells and cardiomyocytes,followed by treatment with TXB drug-containing serum.Western blot and RT-qPCR were used to measure components of the Keap1/Nrf2 pathway;ELISA quantified oxidative stress and inflammatory indices.Conditioned-medium experiments evaluated endothelial cell–mediated paracrine protection of cardiomyocytes.Results:TXB significantly improved cardiac function and reduced myocardial fibrosis after MI,in association with preservation of microvascular structure and systemic attenuation of oxidative stress and inflammation.In vitro,TXB activated the endothelial Keap1/Nrf2 pathway,enhanced cellular antioxidant defenses,increased VEGF secretion,and,via endothelial cell-mediated paracrine signaling,alleviated cardiomyocyte injury under oxidative stress.Conclusion:TXB exerts anti-fibrotic and cardioprotective effects by activating Nrf2 signaling and engaging endothelial-mediated paracrine mechanisms,collectively mitigating oxidative stress and inflammation in the post-MI setting.展开更多
Objective:To examine the effect of shikonin against streptozotocin(STZ)-induced diabetic retinopathy in rats and elucidate the underlying mechanisms.Methods:Intraperitoneal administration of STZ(65 mg/kg)was used for ...Objective:To examine the effect of shikonin against streptozotocin(STZ)-induced diabetic retinopathy in rats and elucidate the underlying mechanisms.Methods:Intraperitoneal administration of STZ(65 mg/kg)was used for the induction of diabetic retinopathy in rats.Rats received oral administration of shikonin(10,20,and 30 mg/kg).The blood glucose level,insulin,body weight,and organ weight were estimated.Advanced glycation end products(AGEs)levels in serum and lens as well as protein carbonyl content of the lens were determined.The parameters related to oxidative stress and inflammation,and the levels of nuclear factor erythroid 2-related factor 2(Nrf2),heme oxygenase-1(HO-1),intercellular adhesion molecule-1(ICAM-1),and vascular cell adhesion molecule 1(VCAM-1)were also measured.In addition,quantitative RT-PCR was performed to determine the mRNA expressions.Results:Shikonin treatment decreased glucose level and boosted insulin level,along with an increase in body weight and improved organ weight.It also lowered O2•−,ONOO−,serum and lens AGEs,and protein carbonyl content.Furthermore,shikonin treatment significantly alleviated oxidative stress and inflammation,as evidenced by reduced malonaldehyde,nitric oxide,tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β),IL-6,cyclooxygenase-2,prostaglandin E2,protein carbonyl content,and nuclear factor kappa-B,and increased superoxide dismutase,glutathione,catalase,and glutathione peroxidase.Markedly decreased levels of ICAM-1 and VCAM-1,as well as heightened levels of Nrf2 and HO-1,were noticed after treatment with shikonin.Furthermore,the mRNA expressions of TNF-α,IL-1β,IL-6,ICAM-1,VCAM-1,RAGE,collagenⅣ,and fibronectin were significantly downregulated.Conclusions:Shikonin exhibits protective effects against STZ-induced diabetic retinopathy in rats via modulating the Nrf2/HO-1 and NF-κB signaling pathways.展开更多
基金supported by the Zhejiang Provincial Key R&D Program of China(No.2021C02008)the China Agriculture Research System of MOF and MARA(No.CARS-35)+2 种基金the National Natural Science Foundation of China(No.32022079)the Fundamental Research Funds for the Central Universities(No.2022QZJH46)the Taishan Industrial Leading Talents Project.
文摘Engineered probiotics can serve as therapeutics based on their ability of produce recombinant immune-stimulating properties.In this study,we built the recombinant Bacillus subtilis WB800 expressing antimicrobial peptide KR32(WB800-KR32)using genetic engineering methods and investigated its protective effects of nuclear factor-E2-related factor 2(Nrf2)-Kelch-like ECH-associated protein 1(Keap1)pathway activation in intestinal oxidative disturbance induced by enterotoxigenic Escherichia coli(ETEC)K88 in weaned piglets.Twenty-eight weaned piglets were randomly distributed into four treatment groups with seven replicates fed with a basal diet.The feed of the control group(CON)was infused with normal sterilized saline;meanwhile,the ETEC,ETEC+WB800,and ETEC+WB800-KR32 groups were orally administered normal sterilized saline,5×10^(10)CFU(CFU:colony forming units)WB800,and 5×10^(10)CFU WB800-KR32,respectively,on Days 1-14 and all infused with ETEC K881×10^(10)CFU on Days 15-17.The results showed that pretreatment with WB800-KR32 attenuated ETEC-induced intestinal disturbance,improved the mucosal activity of antioxidant enzyme(catalase(CAT),superoxide dismutase(SOD),and glutathione peroxidase(GPx))and decreased the content of malondialdehyde(MDA).More importantly,WB800-KR32 downregulated genes involved in antioxidant defense(GPx and SOD1).Interestingly,WB800-KR32 upregulated the protein expression of Nrf2 and downregulated the protein expression of Keap1 in the ileum.WB800-KR32 markedly changed the richness estimators(Ace and Chao)of gut microbiota and increased the abundance of Eubacterium_rectale_ATCC_33656 in the feces.The results suggested that WB800-KR32 may alleviate ETEC-induced intestinal oxidative injury through the Nrf2-Keap1 pathway,providing a new perspective for WB800-KR32 as potential therapeutics to regulate intestinal oxidative disturbance in ETEC K88 infection.
基金funded by Yunnan Youth Top-notch Talent Support Program(YNWR-QNBJ2018-173)Agricultural Joint project of Yunnan Provincial S&T Programs(202301BD070001-195)+2 种基金S&T project of Yunnan provincial finance(K212020001-01)supported by Yunnan Province Education Department’s Engineering Research Center of Eco-friendly Products from Yunnan Characteristic Edible FungiYunnan Province Yongsheng County Farmer Academician Technology service station.
文摘Muscle atrophy can be induced by high doses or prolonged use of glucocorticoids.Kaempferol(Kae)is a naturally occurring flavonoid with a variety of biological activities and the effect of Kae on dexamethasone(Dex)induced muscle atrophy in animals has not been elucidated.To explore this issue,the present experiments used a computationally assisted drug design scheme combining network pharmacology,molecular docking and in vivo experiments to investigate the mechanism of Kae against muscle atrophy.Network pharmacological analyses revealed 275 potential targets for Kae and 12294 potential targets for muscle atrophy,with a total of 228 crosstargets for Kae and muscle atrophy.GO and KEGG analyses were performed based on the protein-protein interaction(PPI)network of muscle atrophy and Kae component targets.The GO results showed that the biological processes were mainly related to the metabolic process of reactive oxygen species,and the response to oxidative stress;the cellular components were mainly focused on membrane microdomains,and membrane regions;the molecular functions mainly worked on phosphatase binding;and the KEGG pathway enrichment analyses identified the pathways of interaction between Kae and muscle atrophy.Finally,as verified by in vivo experiments,Kae may reduce the onset of muscle atrophy by activating the PI3K/AKT/m TOR/signalling pathway,inhibiting Foxo1/Foxo3 activity,and inhibiting downstream production of the ubiquitination 3 ligases Atrogin1 and Mu RF1;Kae also promotes the expression of NRF2/HO-1/KEAP1 signalling pathway,enhances muscle antioxidant capacity,inhibits the release of COX-2 and TNF-αinflammatory factors,and reduces the damage caused by oxidative stress and inflammatory factors to muscles.Therefore,there may be a synergistic effect of PI3K/AKT/m TOR and NRF2/HO-1/KEAP1 in Kae working together to prevent muscle atrophy.The binding energy and stability of Kae to potential targets were examined by molecular docking and molecular dynamics simulations,implying that Kae could be used for the prevention and treatment of muscle atrophy in patients.
基金supported by the National Natural Science Foundation of China(82071362 and 82270669)Key Project of the Regional Joint Fund of Guangdong Province(2023B1515120077)+3 种基金Basic Research Program of Shenzhen Science and Technology Innovation Commission(JCYJ20210324123001003 and JCYJ20220530144801003)Shenzhen Key Laboratory of Bone Tissue Repair and Translational Research(ZDSYS20230626091402006)the Innovation and Entrepreneurship Training Program for College Students,Sun Yat-sen University(20242150)the Leading Innovation and Entrepreneurship Team Program of Zhejiang Province,China(2023R01005).
文摘Activation of spinal cord neural stem cells(NSCs)and subsequent neurogenesis holds a promising alternative for spinal cord injury(SCI)repair.Our previous study demonstrated that complement C3a,derived from reactive astrocytes,inhibits NSC proliferation by suppressing protein aggregate clearance through the deubiquitinating enzyme ubiquitin carboxy-terminal hydrolase L1(UCHL1)-proteasome system post-SCI.However,the potential molecular mechanism by which C3a modulates NSC activation via this pathway remains unclear.Here,we revealed that C3a/C3a receptor(C3aR)signaling activated NF-κB p65,which in turn inhibited Nrf2 activity and UCHL1 expression,resulting in diminished proteasome activity and the accumulation of protein aggregates,and ultimately impaired NSC activation.Both knockdown of NF-κB p65 and Nrf2 upregulation restored UCHL1 expression and proteasome activity in vitro,promoting NSC activation by enhancing protein aggregate clearance.Mechanistically,we found that NF-κB p65 regulated Nrf2 activity through a dual mechanism:(1)promoting Keap1-dependent ubiquitination and proteasome degradation of Nrf2;(2)inhibiting protein kinase C-mediated Nrf2 phosphorylation and nuclear translocation.Using the dual-luciferase reporter assay and chromatin immunoprecipitation(ChIP)analysis,we further identified UCHL1 as a direct transcriptional target of Nrf2.Importantly,in vivo experiments using SCI mice confirmed that either C3aR blockade,NF-κB p65 knockdown,or Nrf2 overexpression could rescue SCI-induced UCHL1 downregulation.Together,this study uncovers the C3a-NF-κB p65-Nrf2-UCHL1-proteasome axis as a critical regulator of NSC activation after SCI.This may provide novel molecular targets and intervention strategies for SCI repair.
基金supported by the institutional fund MLP004 and Science and Engineering Research Board(SERB)(No.CRG/2021/002625)financial assistance from DBT-JRF,Department of Biotechnology,Gov of India,New Delhi India(DBT/2018/1111)。
文摘Air pollution is fourth major cause of death worldwide.Recent evidence suggests that particulate matter(PM)may affect kidneys,and the effect may be size and composition dependent.In this study,PM_(0.1),PM_(2.5),and PM_(10)were collected from ambient air and given to BALB/c male mice at 0.25 mg/m^(3) concentration in whole-body inhalation chamber for 28days(6 h/day,5 days/week)to assess their effect on kidney.Physico-chemical characterization of PM particles by SEM,ICP-MS and HPLC showed their various shapes along with the presence of metals and poly aromatic hydrocarbons(PAHs).Following PM exposure,increased serum creatinine levels were observed in animals along with dilated tubules,protein cast deposition,necrosis,immune infiltration,collagen deposition,and shrunken glomeruli in kidney.Immunofluorescence staining showed higher expressions of kidney injury molecule1(KIM-1),cystatin C,β2 microglobulin(β2M),and alpha smooth muscle actin(α-SMA)and fibronectin,suggesting renal injury and fibrosis.PM exposure also increased malondialdehyde(MDA)content and decreased superoxide dismutase 2(SOD2)activity,which in turn leads to induction of inflammation.Mechanistically,PM exposure further inhibited the nuclear factor erythroid 2-related factor 2(Nrf2)signalling and induced kelch-like ECH-associated protein 1(Keap1)and nuclear factor kappa-light-chain-enhancer of activated B(NF-κB).Interestingly,the effect of PM_(2.5)was more severe than PM_(0.1)and PM_(10),leading to higher levels of proinflammatory NF-κB and greater Nrf2 inhibition.Overall,our findings suggested that inhalation exposure to size-segregated PM can cause kidney damage and fibrosis,and PM_(2.5)showed higher toxicity than PM_(0.1)and PM_(10).
基金the Major Special Project of Jiangsu Administration of Traditional Chinese Medicine(Project No.ZT202116)the Key R&D Project of Jiangsu Province(Project No.BE2020727)+2 种基金the Yangzhou Science and Technology Program(Project No.YZ2021062,YZ2024143 and YZ2024194)the Third Batch of Academic Mentorship Program for Senior TCM Experts in Jiangsu Province(Project No.2019028)the 2023 Jiangsu Pharmaceutical Association–Aosaikang Hospital Pharmacy Research Project(Project No.A202333).
文摘Background:Myocardial infarction(MI)remains a major global public health challenge.Although advances in reperfusion therapy have reduced acute mortality,post-infarction cardiac remodeling continues to pose a substantial threat to long-term cardiovascular health.Oxidative stress and the ensuing inflammatory response are key drivers of this pathological process,leading to cardiomyocyte death,myocardial fibrosis,and functional impairment.Among the regulatory pathways involved,the kelch-like ECH-associated protein 1(Keap1)/nuclear factor erythroid 2-related factor 2(Nrf2)axis has emerged as a critical therapeutic target for mitigating post-MI cardiac injury.Methods:A murine MI model was established by permanent ligation of the left anterior descending coronary artery.Mice received oral Tongxinbi formula(TXB)at low,medium,or high doses(9/18/36 g/kg)once daily for 28 days.Cardiac function was assessed by echocardiography;myocardial fibrosis by Masson’s trichrome;and endothelial integrity by CD31 immunofluorescence.Plasma markers of endothelial function and inflammation were quantified.In vitro,oxidative stress was induced by H2O2 in vascular endothelial cells and cardiomyocytes,followed by treatment with TXB drug-containing serum.Western blot and RT-qPCR were used to measure components of the Keap1/Nrf2 pathway;ELISA quantified oxidative stress and inflammatory indices.Conditioned-medium experiments evaluated endothelial cell–mediated paracrine protection of cardiomyocytes.Results:TXB significantly improved cardiac function and reduced myocardial fibrosis after MI,in association with preservation of microvascular structure and systemic attenuation of oxidative stress and inflammation.In vitro,TXB activated the endothelial Keap1/Nrf2 pathway,enhanced cellular antioxidant defenses,increased VEGF secretion,and,via endothelial cell-mediated paracrine signaling,alleviated cardiomyocyte injury under oxidative stress.Conclusion:TXB exerts anti-fibrotic and cardioprotective effects by activating Nrf2 signaling and engaging endothelial-mediated paracrine mechanisms,collectively mitigating oxidative stress and inflammation in the post-MI setting.
文摘Objective:To examine the effect of shikonin against streptozotocin(STZ)-induced diabetic retinopathy in rats and elucidate the underlying mechanisms.Methods:Intraperitoneal administration of STZ(65 mg/kg)was used for the induction of diabetic retinopathy in rats.Rats received oral administration of shikonin(10,20,and 30 mg/kg).The blood glucose level,insulin,body weight,and organ weight were estimated.Advanced glycation end products(AGEs)levels in serum and lens as well as protein carbonyl content of the lens were determined.The parameters related to oxidative stress and inflammation,and the levels of nuclear factor erythroid 2-related factor 2(Nrf2),heme oxygenase-1(HO-1),intercellular adhesion molecule-1(ICAM-1),and vascular cell adhesion molecule 1(VCAM-1)were also measured.In addition,quantitative RT-PCR was performed to determine the mRNA expressions.Results:Shikonin treatment decreased glucose level and boosted insulin level,along with an increase in body weight and improved organ weight.It also lowered O2•−,ONOO−,serum and lens AGEs,and protein carbonyl content.Furthermore,shikonin treatment significantly alleviated oxidative stress and inflammation,as evidenced by reduced malonaldehyde,nitric oxide,tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β),IL-6,cyclooxygenase-2,prostaglandin E2,protein carbonyl content,and nuclear factor kappa-B,and increased superoxide dismutase,glutathione,catalase,and glutathione peroxidase.Markedly decreased levels of ICAM-1 and VCAM-1,as well as heightened levels of Nrf2 and HO-1,were noticed after treatment with shikonin.Furthermore,the mRNA expressions of TNF-α,IL-1β,IL-6,ICAM-1,VCAM-1,RAGE,collagenⅣ,and fibronectin were significantly downregulated.Conclusions:Shikonin exhibits protective effects against STZ-induced diabetic retinopathy in rats via modulating the Nrf2/HO-1 and NF-κB signaling pathways.
