Age-related eye diseases,including cataract,glaucoma,diabetic retinopathy(DR),and age-related macular degeneration(AMD),are the leading causes of vision loss in the world.Several studies have shown that the occurrence...Age-related eye diseases,including cataract,glaucoma,diabetic retinopathy(DR),and age-related macular degeneration(AMD),are the leading causes of vision loss in the world.Several studies have shown that the occurrence and development of these diseases have an important relationship with oxidative stress in the eye.The Keap1-Nrf2-ARE pathway is a classical pathway that resists oxidative stress and inflammation in the body.This pathway is also active in the development of age-related eye diseases.A variety of drugs have been shown to treat agerelated eye diseases through the Keap1-Nrf2-ARE(Kelch-like ECH-Associating protein 1-nuclear factor erythroid 2 related factor 2-antioxidant response element)pathway.This review describes the role of oxidative stress in the development of age-related eye diseases,the function and regulation of the Keap1-Nrf2-ARE pathway,and the therapeutic effects of drugs associated with this pathway on age-related eye diseases.展开更多
Many degenerative or pathological processes, such as aging, cancer and coronary heart disease, are related to reactive oxygen species (ROS) and radical-mediated reactions. We examined the effectiveness of aged garlic ...Many degenerative or pathological processes, such as aging, cancer and coronary heart disease, are related to reactive oxygen species (ROS) and radical-mediated reactions. We examined the effectiveness of aged garlic extract (AGE), a garlic preparation rich in water-soluble cysteinyl moieties, for protection of cells from ROS produced by 6-hydroxy-dopamine (6-OHDA) using human neuroblastoma SH-SY5Y cells. Concomitant treatment of cells with AGE (2 and 4 mg/ml) showed the dose-dependent protective effect on the cell death induced by 6-OHDA. In addition, the AGE treatment significantly suppressed the increase of ROS generation by 6-OHDA. Furthermore, the protective effect of AGE was accompanied by activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway and the increase of mRNAs of heme oxygenase-1 and NAD(P)H quinone oxidoreductase 1. These two enzymes are important in the cellular antioxidant system. These results indicated that AGE protected cells from ROS damage by not only capturing ROS directly but also activating the cellular antioxidant system by stimulating antioxidant gene expression via the Nrf2-ARE pathway. The present study suggested that AGE may be useful for prevention and treatment of cell damage caused by ROS.展开更多
Background:Epidemiological studies have confirmed that longer exposure to insecticides like cypermethrin(CYP)significantly increases the risk of male reproductive toxicity.Crocus sativus L.has been recognized due to i...Background:Epidemiological studies have confirmed that longer exposure to insecticides like cypermethrin(CYP)significantly increases the risk of male reproductive toxicity.Crocus sativus L.has been recognized due to its therapeutic properties,but its exact role and molecular mechanisms in treatment of reproductive dysfunction remain unclear.Methods:During this study,36 rats were randomly divided into six groups(n=6):control,CYP-induced(60 mg/kg),standard(leuprolide 3 mg/kg)and three treatment groups receiving aqueous,ethanolic,and oil extracts(50 mg/kg or 20 mL/kg)for post-toxicity induction.Results:The finding represented that exposure of CYP significantly increased oxidative stress,disrupted testicular architecture,and markedly reduced testosterone levels(P<0.05).Importantly,Crocus sativus L.treatment alleviated these changes by increasing the expression of Nrf2(nuclear factor erythroid 2-related factor 2),restoring the activity of antioxidant enzymes,and enhancing testicular histomorphology.Surprisingly,molecular docking established a high binding affinity of Crocus sativus L.phytoconstituents such as gallic acid,cinnamic acid and quercetin to the Nrf2-Keap1 complex.It is worth noting that,Crocus sativus L.exhibited a high level of protection against reproductive toxicity caused by CYP in male rats,which was mediated by the activation of Nrf2 pathway,reduction of oxidative damage,and favorable ADMET characteristics.Conclusion:Notably,this research provides a more valid,safe,and effective method of developing new drugs for reproductive disorders,however,further investigation is needed to support the research findings and implement it in clinical practice.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
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
Aging is an inevitable biological phenomenon that involves a multitude of physiological alterations.Dietary interventions are being considered as potential strategies for delaying age-related dysfunction.Unsaponifiabl...Aging is an inevitable biological phenomenon that involves a multitude of physiological alterations.Dietary interventions are being considered as potential strategies for delaying age-related dysfunction.Unsaponifiable matter(USM),a composition of highly active ingredients found in walnut oil,has demonstrated antioxidant effects.This study aims to explore the neuroprotective effects of USM on d-galactose-treated C57BL/6 mice and elucidate its underlying mechanism,which was validated in PC12 cells treated with d-galactose.The results of behavioral tests demonstrated that USM significantly improved cognitive deficits associated with aging.The morphological analysis demonstrated that USM effectively alleviated hippocampal neuronal damage,synaptic impairment,and mitochondrial dysfunction induced by d-galactose.Furthermore,USM significantly increases the antioxidant enzymes activity while reducing the malondialdehyde and reactive oxygen species levels.The results suggest that USM can mitigate age-related symptoms caused by d-galactose by activating the nuclear factor erythroid-2-related factor 2 signaling pathway,which enhances the expression of antioxidant enzymes,restore redox balance,and improves synaptic and mitochondrial functions.This has a positive on improving cognition and memory disorders in elderly mice.展开更多
Alcohol abuse leads to alcoholic liver disease and no effective therapy is currently available.Wuzhi Tablet(WZ), a preparation of extract from Schisandra sphenanthera that is a traditional hepatoprotective herb, exert...Alcohol abuse leads to alcoholic liver disease and no effective therapy is currently available.Wuzhi Tablet(WZ), a preparation of extract from Schisandra sphenanthera that is a traditional hepatoprotective herb, exerted a significant protective effect against acetaminophen-induced liver injury in our recent studies, but whether WZ can alleviate alcohol-induced toxicity remains unclear. This study aimed to investigate the contribution of WZ to alcohol-induced liver injury by using chronic-binge and acute models of alcohol feeding. The activities of ALT and AST in serum were assessed as well as the level of GSH and the activity of SOD in the liver. The expression of CYP2E1 and proteins in the NRF2-ARE signaling pathway including NRF2, GCLC, GCLM, HO-1 were measured, and the effect of WZ on NRF2 transcriptional activity was determined. We found that both models resulted in liver steatosis accompanied by increased transaminase activities, but that liver injury was significantly attenuated by WZ. WZ administration also inhibited CYP2E1 expression induced by alcohol, and elevated the level of GSH and the activity of SOD in the liver. Moreover, the NRF2-ARE signaling pathway was activated by WZ andthe target genes were all upregulated. Furthermore, WZ significantly activated NRF2 transcriptional activity. Collectively, our study demonstrates that WZ protected against alcohol-induced liver injury by reducing oxidative stress and improving antioxidant defense, possibly by activating the NRF2-ARE pathway.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 National Natural Science Foundation of China(No.81970801No.81670859)+1 种基金Natural Science Foundation of Hunan Province(No.2019JJ40001)Key Project of Changsha Science and Technology Bureau(No.kh1801229)。
文摘Age-related eye diseases,including cataract,glaucoma,diabetic retinopathy(DR),and age-related macular degeneration(AMD),are the leading causes of vision loss in the world.Several studies have shown that the occurrence and development of these diseases have an important relationship with oxidative stress in the eye.The Keap1-Nrf2-ARE pathway is a classical pathway that resists oxidative stress and inflammation in the body.This pathway is also active in the development of age-related eye diseases.A variety of drugs have been shown to treat agerelated eye diseases through the Keap1-Nrf2-ARE(Kelch-like ECH-Associating protein 1-nuclear factor erythroid 2 related factor 2-antioxidant response element)pathway.This review describes the role of oxidative stress in the development of age-related eye diseases,the function and regulation of the Keap1-Nrf2-ARE pathway,and the therapeutic effects of drugs associated with this pathway on age-related eye diseases.
文摘Many degenerative or pathological processes, such as aging, cancer and coronary heart disease, are related to reactive oxygen species (ROS) and radical-mediated reactions. We examined the effectiveness of aged garlic extract (AGE), a garlic preparation rich in water-soluble cysteinyl moieties, for protection of cells from ROS produced by 6-hydroxy-dopamine (6-OHDA) using human neuroblastoma SH-SY5Y cells. Concomitant treatment of cells with AGE (2 and 4 mg/ml) showed the dose-dependent protective effect on the cell death induced by 6-OHDA. In addition, the AGE treatment significantly suppressed the increase of ROS generation by 6-OHDA. Furthermore, the protective effect of AGE was accompanied by activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway and the increase of mRNAs of heme oxygenase-1 and NAD(P)H quinone oxidoreductase 1. These two enzymes are important in the cellular antioxidant system. These results indicated that AGE protected cells from ROS damage by not only capturing ROS directly but also activating the cellular antioxidant system by stimulating antioxidant gene expression via the Nrf2-ARE pathway. The present study suggested that AGE may be useful for prevention and treatment of cell damage caused by ROS.
文摘Background:Epidemiological studies have confirmed that longer exposure to insecticides like cypermethrin(CYP)significantly increases the risk of male reproductive toxicity.Crocus sativus L.has been recognized due to its therapeutic properties,but its exact role and molecular mechanisms in treatment of reproductive dysfunction remain unclear.Methods:During this study,36 rats were randomly divided into six groups(n=6):control,CYP-induced(60 mg/kg),standard(leuprolide 3 mg/kg)and three treatment groups receiving aqueous,ethanolic,and oil extracts(50 mg/kg or 20 mL/kg)for post-toxicity induction.Results:The finding represented that exposure of CYP significantly increased oxidative stress,disrupted testicular architecture,and markedly reduced testosterone levels(P<0.05).Importantly,Crocus sativus L.treatment alleviated these changes by increasing the expression of Nrf2(nuclear factor erythroid 2-related factor 2),restoring the activity of antioxidant enzymes,and enhancing testicular histomorphology.Surprisingly,molecular docking established a high binding affinity of Crocus sativus L.phytoconstituents such as gallic acid,cinnamic acid and quercetin to the Nrf2-Keap1 complex.It is worth noting that,Crocus sativus L.exhibited a high level of protection against reproductive toxicity caused by CYP in male rats,which was mediated by the activation of Nrf2 pathway,reduction of oxidative damage,and favorable ADMET characteristics.Conclusion:Notably,this research provides a more valid,safe,and effective method of developing new drugs for reproductive disorders,however,further investigation is needed to support the research findings and implement it in clinical practice.
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.
基金supported by the National Key Research and Development Program(2022YFD1600402)Hebei Provincial Major Science and Technology Achievement Transformation Project(21287101Z)Hebei Provincial Innovation and Entrepreneurship Team Project(215A7102D)。
文摘Aging is an inevitable biological phenomenon that involves a multitude of physiological alterations.Dietary interventions are being considered as potential strategies for delaying age-related dysfunction.Unsaponifiable matter(USM),a composition of highly active ingredients found in walnut oil,has demonstrated antioxidant effects.This study aims to explore the neuroprotective effects of USM on d-galactose-treated C57BL/6 mice and elucidate its underlying mechanism,which was validated in PC12 cells treated with d-galactose.The results of behavioral tests demonstrated that USM significantly improved cognitive deficits associated with aging.The morphological analysis demonstrated that USM effectively alleviated hippocampal neuronal damage,synaptic impairment,and mitochondrial dysfunction induced by d-galactose.Furthermore,USM significantly increases the antioxidant enzymes activity while reducing the malondialdehyde and reactive oxygen species levels.The results suggest that USM can mitigate age-related symptoms caused by d-galactose by activating the nuclear factor erythroid-2-related factor 2 signaling pathway,which enhances the expression of antioxidant enzymes,restore redox balance,and improves synaptic and mitochondrial functions.This has a positive on improving cognition and memory disorders in elderly mice.
基金supported by the National Natural Science Foundation of China (Grant Nos. 81373470, 81573489, 81522047 and 81402998)the Natural Science Foundation of Guangdong Province (No. 2015A030313124)
文摘Alcohol abuse leads to alcoholic liver disease and no effective therapy is currently available.Wuzhi Tablet(WZ), a preparation of extract from Schisandra sphenanthera that is a traditional hepatoprotective herb, exerted a significant protective effect against acetaminophen-induced liver injury in our recent studies, but whether WZ can alleviate alcohol-induced toxicity remains unclear. This study aimed to investigate the contribution of WZ to alcohol-induced liver injury by using chronic-binge and acute models of alcohol feeding. The activities of ALT and AST in serum were assessed as well as the level of GSH and the activity of SOD in the liver. The expression of CYP2E1 and proteins in the NRF2-ARE signaling pathway including NRF2, GCLC, GCLM, HO-1 were measured, and the effect of WZ on NRF2 transcriptional activity was determined. We found that both models resulted in liver steatosis accompanied by increased transaminase activities, but that liver injury was significantly attenuated by WZ. WZ administration also inhibited CYP2E1 expression induced by alcohol, and elevated the level of GSH and the activity of SOD in the liver. Moreover, the NRF2-ARE signaling pathway was activated by WZ andthe target genes were all upregulated. Furthermore, WZ significantly activated NRF2 transcriptional activity. Collectively, our study demonstrates that WZ protected against alcohol-induced liver injury by reducing oxidative stress and improving antioxidant defense, possibly by activating the NRF2-ARE pathway.
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.
