The activation of the sirtuin1(SIRT1)/nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase 1(HO-1)pathway has been shown to mitigate oxidative stress-induced apoptosis and mitochondrial damage by reducing ...The activation of the sirtuin1(SIRT1)/nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase 1(HO-1)pathway has been shown to mitigate oxidative stress-induced apoptosis and mitochondrial damage by reducing reactive oxygen species(ROS)levels.Clinical trials have demonstrated that Zhongfeng Xingnao Liquid(ZFXN)ameliorates post-stroke cognitive impairment(PSCI).However,the underlying mechanism,particularly whether it involves protecting mitochondria and inhibiting apoptosis through the SIRT1/Nrf2/HO-1 pathway,remains unclear.This study employed an oxygen-glucose deprivation(OGD)cell model using SHSY5Y cells and induced PSCI in rats through modified bilateral carotid artery ligation(2VO).The effects of ZFXN on learning and memory,neuroprotective activity,mitochondrial function,oxidative stress,and the SIRT1/Nrf2/HO-1 pathway were evaluated both in vivo and in vitro.Results indicated that ZFXN significantly increased the B-cell lymphoma 2(Bcl2)/Bcl2-associated X(Bax)ratio,reduced terminal deoxynucleotidyl transferase-mediated d UTP nickend-labeling(TUNEL)+cells,and markedly improved cognition,synaptic plasticity,and neuronal function in the hippocampus and cortex.Furthermore,ZFXN exhibited potent antioxidant activity,evidenced by decreased ROS and malondialdehyde(MDA)content and increased superoxide dismutase(SOD),catalase(CAT),and glutathione(GSH)levels.ZFXN also demonstrated considerable enhancement of mitochondrial membrane potential(MMP),Tom 20 fluorescence intensity,adenosine triphosphate(ATP)and energy charge(EC)levels,and mitochondrial complexⅠandⅢactivity,thereby inhibiting mitochondrial damage.Additionally,ZFXN significantly increased SIRT1 activity and elevated SIRT1,nuclear Nrf2,and HO-1 levels.Notably,these effects were substantially counteracted when SIRT1 was suppressed by the inhibitor EX-527 in vitro.In conclusion,ZFXN alleviates PSCI by activating the SIRT1/Nrf2/HO-1 pathway and preventing mitochondrial damage.展开更多
[目的]探究缬草酸对骨折后深静脉血栓形成及Sirtuin1/NF-κB通路的影响。[方法]所有Sprague Dawley大鼠被随机分为3组(每组n=10):假手术组、模型组和缬草酸组。通过HE染色分析下腔静脉组织病理变化。通过蛋白免疫印迹分析Sirtuin1/NF-κ...[目的]探究缬草酸对骨折后深静脉血栓形成及Sirtuin1/NF-κB通路的影响。[方法]所有Sprague Dawley大鼠被随机分为3组(每组n=10):假手术组、模型组和缬草酸组。通过HE染色分析下腔静脉组织病理变化。通过蛋白免疫印迹分析Sirtuin1/NF-κB通路的变化。通过酶联免疫吸附剂测定分析炎症因子IL-6、IL-1β和TNF-α的水平。通过全自动凝血分析仪检测凝血酶原时间、活化部分凝血活酶时间、凝血酶时间。[结果]病理分析发现,缬草酸治疗后,模型组大鼠血栓染色变淡,血管再通,血管壁有少数炎症细胞。此外,缬草酸治疗后,模型组大鼠血栓重量逐渐减小(6.36±0.02 vs 11.03±0.02,P<0.05),长度逐渐缩短。此外,模型组大鼠在经过缬草酸治疗后炎症因子水平明显降低(4.67±0.08 vs 7.02±0.01;5.99±0.05 vs 11.02±0.03;5.81±0.06 vs 10.02±0.03;P<0.05),凝血酶原时间、活化部分凝血活酶时间、凝血酶时间水平明显上升。蛋白免疫印迹结果发现,与模型组相比,缬草酸组大鼠的下腔静脉组织中NF-κB p65磷酸化水平降低(0.58±0.02 vs 0.92±0.03;P<0.05),Sirtuin1水平增加(0.69±0.01 vs 0.16±0.03;P<0.05)。[结论]缬草酸能够改善下腔静脉血栓导致的病理损伤、抑制下腔静脉血栓形成,并能抑制血浆中炎症因子的水平。这一作用可能与Sirtuin1表达上调而NF-κB的抑制相关。展开更多
BACKGROUND Constipation,a highly prevalent functional gastrointestinal disorder,induces a significant burden on the quality of patients'life and is associated with substantial healthcare expenditures.Therefore,ide...BACKGROUND Constipation,a highly prevalent functional gastrointestinal disorder,induces a significant burden on the quality of patients'life and is associated with substantial healthcare expenditures.Therefore,identifying efficient therapeutic modalities for constipation is of paramount importance.Oxidative stress is a pivotal contributor to colonic dysmotility and is the underlying pathology responsible for constipation symptoms.Consequently,we postulate that hydrogen therapy,an emerging and promising intervention,can serve as a safe and efficacious treatment for constipation.AIM To determine whether hydrogen-rich water(HRW)alleviates constipation and its potential mechanism.METHODS Constipation models were established by orally loperamide to Sprague-Dawley rats.Rats freely consumed HRW,and were recorded their 24 h total stool weight,fecal water content,and charcoal propulsion rate.Fecal samples were subjected to 16S rDNA gene sequencing.Serum non-targeted metabolomic analysis,malondialdehyde,and superoxide dismutase levels were determined.Colonic tissues were stained with hematoxylin and eosin,Alcian blue-periodic acid-Schiff,reactive oxygen species(ROS)immunofluorescence,and immunohistochemistry for cell growth factor receptor kit(c-kit),PGP 9.5,sirtuin1(SIRT1),nuclear factor-erythroid-2-related factor 2(Nrf2),and heme oxygenase-1(HO-1).Quantitative real-time PCR and western blot analysis were conducted to determine the expression level of SIRT1,Nrf2 and HO-1.A rescue experiment was conducted by intraperitoneally injecting the SIRT1 inhibitor,EX527,into constipated rats.NCM460 cells were induced with H2O2 and treated with the metabolites to evaluate ROS and SIRT1 expression.RESULTS HRW alleviated constipation symptoms by improving the total amount of stool over 24 h,fecal water content,charcoal propulsion rate,thickness of the intestinal mucus layer,c-kit expression,and the number of intestinal neurons.HRW modulated intestinal microbiota imbalance and abnormalities in serum metabolism.HRW could also reduce intestinal oxidative stress through the SIRT1/Nrf2/HO-1 signaling pathway.This regulatory effect on oxidative stress was confirmed via an intraperitoneal injection of a SIRT1 inhibitor to constipated rats.The serum metabolites,β-leucine(β-Leu)and traumatic acid,were also found to attenuate H2O2-induced oxidative stress in NCM460 cells by up-regulating SIRT1.CONCLUSION HRW attenuates constipation-associated intestinal oxidative stress via SIRT1/Nrf2/HO-1 signaling pathway,modulating gut microbiota and serum metabolites.β-Leu and traumatic acid are potential metabolites that upregulate SIRT1 expression and reduce oxidative stress.展开更多
BACKGROUND The occurrence and development of acute liver failure(ALF)is closely related to a series of inflammatory reactions,such as the production of reactive oxygen species(ROS).Hypoxia inducible factor 1α(HIF-1α...BACKGROUND The occurrence and development of acute liver failure(ALF)is closely related to a series of inflammatory reactions,such as the production of reactive oxygen species(ROS).Hypoxia inducible factor 1α(HIF-1α)is a key factor that regulates oxygen homeostasis and redox,and the stability of HIF-1αis related to the ROS level regulated by Sirtuin(Sirt)family.The activation of Sirt1 will lead to a powerful antioxidant defense system and therapeutic effects in liver disease.However,little is known about the relationship between HIF-1αand Sirt1 in the process of ALF and the molecular mechanism.AIM To investigate whether HIF-1αmay be a target of Sirt1 deacetylation and what the effects on ALF are.METHODS Mice were administrated lipopolysaccharide(LPS)/D-gal and exposed to hypoxic conditions as animal model,and resveratrol was used as an activator of Sirt1.The cellular model was established with L02 cells stimulated by LPS.N-acetyl-Lcysteine was used to remove ROS,and the expression of Sirt1 was inhibited by nicotinamide.Western blotting was used to detect Sirt1 and HIF-1αactivity and related protein expression.The possible signaling pathways involved were analyzed by immunofluorescent staining,co-immunoprecipitation,dihydroethidium staining,and Western blotting.RESULTS Compared with mice stimulated with LPS alone,the expression of Sirt1 decreased,the level of HIF-1αacetylation increased in hypoxic mice,and the levels of carbonic anhydrase 9 and Bcl-2-adenovirus E1B interacting protein 3 increased significantly,which was regulated by HIF-1α,indicating an increase of HIF-1αactivity.Under hypoxia,the down-regulation of Sirt1 activated and acetylated HIF-1αin L02 cells.The inhibition of Sirt1 significantly aggravated this effect and the massive production of ROS.The regulation of ROS was partly through peroxisome proliferatoractivated receptor alpha or AMP-activated protein kinase.Resveratrol,a Sirt1 activator,effectively relieved ALF aggravated by hypoxia,the production of ROS,and cell apoptosis.It also induced the deacetylation of HIF-1αand inhibited the activity of HIF-1α.CONCLUSION Sirt1 may have a protective effect on ALF by inducing HIF-1α deacetylation to reduce ROS.展开更多
An increase in oxidative stress plays a key role in neurotoxicity induction and cell death, which leads to neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease. Cyanidin-3-glucoside (C3G) i...An increase in oxidative stress plays a key role in neurotoxicity induction and cell death, which leads to neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease. Cyanidin-3-glucoside (C3G) is a common anthocyanin and shows antioxidant activity in neuronal cells. Silent information regulator 2-related protein 1 (Sirt1) regulates antioxidant and anti-inflammatory effects. However, the effects of C3G on Sirt1 in neuronal cells remain unclear. This study evaluated the effect of C3G on Sirt1 expression and activity in human neuroblastoma (SH-SY5Y) cells. In the study, C3G increased the expression of Sirt1 and Sirt1 activity in SH-SY5Y cells. Additionally, C3G increased the expression of nuclear factor erythroid 2-related factor 2, a vital transcription factor for regulating the expression of antioxidant genes, as well as antioxidant enzymes such as superoxide dismutase and catalase. Moreover, C3G protected SH-SY5Y cells from oxidative stress. These results suggest that C3G decreased oxidative stress-induced cell injury by increasing the expression of Sirt1 and other antioxidant factors. Therefore, C3G might merit further investigation for use in attenuating the progress of neurodegenerative diseases.展开更多
After spinal cord injury,programmed cell death is common.In this context,autophagy plays a crucial role in clearing cellular debris,while necroptosis exacerbates neuroinflammation and further damages neural structures...After spinal cord injury,programmed cell death is common.In this context,autophagy plays a crucial role in clearing cellular debris,while necroptosis exacerbates neuroinflammation and further damages neural structures.The neuroprotective drug davunetide has shown substantial therapeutic effects on brain diseases,but its role in treating spinal cord injury remains unclear.Therefore,the aim of this study was to investigate the effects of davunetide on cell death after spinal cord injury.To do this,we established a mouse model of spinal cord contusion and administered davunetide intranasally daily at a dose of 0.5μg/5μL.Mouse locomotor function was assessed using footprint analysis and Basso Mouse Scale scoring,while the extent of spinal cord injury was evaluated using Masson’s trichrome staining.The expression levels of proteins related to locomotor function and spinal cord injury were analyzed by Western blotting and immunofluorescence staining,and protein-protein interactions were evaluated using immunoprecipitation techniques.Our results demonstrated that davunetide not only reduced the size of the injury area but also promoted the recovery of locomotor function after spinal cord injury.Specifically,davunetide exerted its effects by enhancing autophagy and inhibiting necroptosis.Inhibition of autophagy reversed the protective effects of davunetide on necroptosis.Further investigation revealed that davunetide acted through the SIRT1-FOXO1-TFEB signaling pathway,which is key to its therapeutic effects.These findings suggest the potential of davunetide in the treatment of spinal cord injury and provide valuable insights into the underlying mechanisms.This study offers strong scientific evidence to support the development of new therapeutic strategies for spinal cord injury.展开更多
Moutan Cortex terpene glycoside is derived from the dried root bark of Paeonia suffruticosa Andr.in the Paeoniaceae family,which holds significant value as a traditional Chinese medicine.This study investigated that M...Moutan Cortex terpene glycoside is derived from the dried root bark of Paeonia suffruticosa Andr.in the Paeoniaceae family,which holds significant value as a traditional Chinese medicine.This study investigated that Moutan Cortex terpene glycoside(MCTG)improved diabetic kidney disease(DKD)by targeting sirtuin 1(SIRT1)mediated autophagy pathway.Mechanistic insights were gained using DKD model rats and human umbilical vein endothelial cells(HUVECs)to delineate how MCTG operated in the treatment of DKD.Furthermore,network pharmacology was used to identify the primary metabolic pathways affected by MCTG,with key targets being confirmed through polymerase chain reaction(PCR),Western blot,Transmission electron microscope,immunofluorescence staining and monodansylcadaverine(MDC)staining.Finally,small interfering RNA transfection testified SIRT1 in advanced glycation end-products(AGEs)-induced HUVECs injury.MCTG effectively decreased blood glucose rise in DKD rats and reduced levels of cytokines and biochemical indicators.Network pharmacology revealed that metabolism was the main pathway of Moutan Cortex,and the main targets were verified by PCR and protein experiments.Based on these results,we found that Moutan Cortex could improve DKD and SIRT1 was a potential target.Furthermore,knockdown of SIRT1 attenuated AGEs-induced the expression of Beclin 1 and microtubule-associated protein 1 light chain 3 II/I(LC3 II/I)in HUVECs.In summary,this study demonstrated that Moutan Cortex could alleviate DKD via down-regulating SIRT1-mediated autophagy pathway.展开更多
基金supported by the Science&Technology Department of Sichuan Province(No.2019YFS0040)the Improvement Plan of“Xinglin Scholar”Scientific Research Talent,Chengdu University of Traditional Chinese Medicine(No.XKTD2022002)。
文摘The activation of the sirtuin1(SIRT1)/nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase 1(HO-1)pathway has been shown to mitigate oxidative stress-induced apoptosis and mitochondrial damage by reducing reactive oxygen species(ROS)levels.Clinical trials have demonstrated that Zhongfeng Xingnao Liquid(ZFXN)ameliorates post-stroke cognitive impairment(PSCI).However,the underlying mechanism,particularly whether it involves protecting mitochondria and inhibiting apoptosis through the SIRT1/Nrf2/HO-1 pathway,remains unclear.This study employed an oxygen-glucose deprivation(OGD)cell model using SHSY5Y cells and induced PSCI in rats through modified bilateral carotid artery ligation(2VO).The effects of ZFXN on learning and memory,neuroprotective activity,mitochondrial function,oxidative stress,and the SIRT1/Nrf2/HO-1 pathway were evaluated both in vivo and in vitro.Results indicated that ZFXN significantly increased the B-cell lymphoma 2(Bcl2)/Bcl2-associated X(Bax)ratio,reduced terminal deoxynucleotidyl transferase-mediated d UTP nickend-labeling(TUNEL)+cells,and markedly improved cognition,synaptic plasticity,and neuronal function in the hippocampus and cortex.Furthermore,ZFXN exhibited potent antioxidant activity,evidenced by decreased ROS and malondialdehyde(MDA)content and increased superoxide dismutase(SOD),catalase(CAT),and glutathione(GSH)levels.ZFXN also demonstrated considerable enhancement of mitochondrial membrane potential(MMP),Tom 20 fluorescence intensity,adenosine triphosphate(ATP)and energy charge(EC)levels,and mitochondrial complexⅠandⅢactivity,thereby inhibiting mitochondrial damage.Additionally,ZFXN significantly increased SIRT1 activity and elevated SIRT1,nuclear Nrf2,and HO-1 levels.Notably,these effects were substantially counteracted when SIRT1 was suppressed by the inhibitor EX-527 in vitro.In conclusion,ZFXN alleviates PSCI by activating the SIRT1/Nrf2/HO-1 pathway and preventing mitochondrial damage.
文摘[目的]探究缬草酸对骨折后深静脉血栓形成及Sirtuin1/NF-κB通路的影响。[方法]所有Sprague Dawley大鼠被随机分为3组(每组n=10):假手术组、模型组和缬草酸组。通过HE染色分析下腔静脉组织病理变化。通过蛋白免疫印迹分析Sirtuin1/NF-κB通路的变化。通过酶联免疫吸附剂测定分析炎症因子IL-6、IL-1β和TNF-α的水平。通过全自动凝血分析仪检测凝血酶原时间、活化部分凝血活酶时间、凝血酶时间。[结果]病理分析发现,缬草酸治疗后,模型组大鼠血栓染色变淡,血管再通,血管壁有少数炎症细胞。此外,缬草酸治疗后,模型组大鼠血栓重量逐渐减小(6.36±0.02 vs 11.03±0.02,P<0.05),长度逐渐缩短。此外,模型组大鼠在经过缬草酸治疗后炎症因子水平明显降低(4.67±0.08 vs 7.02±0.01;5.99±0.05 vs 11.02±0.03;5.81±0.06 vs 10.02±0.03;P<0.05),凝血酶原时间、活化部分凝血活酶时间、凝血酶时间水平明显上升。蛋白免疫印迹结果发现,与模型组相比,缬草酸组大鼠的下腔静脉组织中NF-κB p65磷酸化水平降低(0.58±0.02 vs 0.92±0.03;P<0.05),Sirtuin1水平增加(0.69±0.01 vs 0.16±0.03;P<0.05)。[结论]缬草酸能够改善下腔静脉血栓导致的病理损伤、抑制下腔静脉血栓形成,并能抑制血浆中炎症因子的水平。这一作用可能与Sirtuin1表达上调而NF-κB的抑制相关。
基金Supported by National Natural Science Foundation of China,No.82374449China Postdoctoral Science Foundation,No.2023M731782+1 种基金Jiangsu Funding Program for Excellent Postdoctoral Talent,No.2022ZB806Jiangsu Province Postgraduate Scientific Research and Innovation Plan,No.KYCX23_2136.
文摘BACKGROUND Constipation,a highly prevalent functional gastrointestinal disorder,induces a significant burden on the quality of patients'life and is associated with substantial healthcare expenditures.Therefore,identifying efficient therapeutic modalities for constipation is of paramount importance.Oxidative stress is a pivotal contributor to colonic dysmotility and is the underlying pathology responsible for constipation symptoms.Consequently,we postulate that hydrogen therapy,an emerging and promising intervention,can serve as a safe and efficacious treatment for constipation.AIM To determine whether hydrogen-rich water(HRW)alleviates constipation and its potential mechanism.METHODS Constipation models were established by orally loperamide to Sprague-Dawley rats.Rats freely consumed HRW,and were recorded their 24 h total stool weight,fecal water content,and charcoal propulsion rate.Fecal samples were subjected to 16S rDNA gene sequencing.Serum non-targeted metabolomic analysis,malondialdehyde,and superoxide dismutase levels were determined.Colonic tissues were stained with hematoxylin and eosin,Alcian blue-periodic acid-Schiff,reactive oxygen species(ROS)immunofluorescence,and immunohistochemistry for cell growth factor receptor kit(c-kit),PGP 9.5,sirtuin1(SIRT1),nuclear factor-erythroid-2-related factor 2(Nrf2),and heme oxygenase-1(HO-1).Quantitative real-time PCR and western blot analysis were conducted to determine the expression level of SIRT1,Nrf2 and HO-1.A rescue experiment was conducted by intraperitoneally injecting the SIRT1 inhibitor,EX527,into constipated rats.NCM460 cells were induced with H2O2 and treated with the metabolites to evaluate ROS and SIRT1 expression.RESULTS HRW alleviated constipation symptoms by improving the total amount of stool over 24 h,fecal water content,charcoal propulsion rate,thickness of the intestinal mucus layer,c-kit expression,and the number of intestinal neurons.HRW modulated intestinal microbiota imbalance and abnormalities in serum metabolism.HRW could also reduce intestinal oxidative stress through the SIRT1/Nrf2/HO-1 signaling pathway.This regulatory effect on oxidative stress was confirmed via an intraperitoneal injection of a SIRT1 inhibitor to constipated rats.The serum metabolites,β-leucine(β-Leu)and traumatic acid,were also found to attenuate H2O2-induced oxidative stress in NCM460 cells by up-regulating SIRT1.CONCLUSION HRW attenuates constipation-associated intestinal oxidative stress via SIRT1/Nrf2/HO-1 signaling pathway,modulating gut microbiota and serum metabolites.β-Leu and traumatic acid are potential metabolites that upregulate SIRT1 expression and reduce oxidative stress.
基金Supported by National Natural Science Foundation of China,No. 82070609
文摘BACKGROUND The occurrence and development of acute liver failure(ALF)is closely related to a series of inflammatory reactions,such as the production of reactive oxygen species(ROS).Hypoxia inducible factor 1α(HIF-1α)is a key factor that regulates oxygen homeostasis and redox,and the stability of HIF-1αis related to the ROS level regulated by Sirtuin(Sirt)family.The activation of Sirt1 will lead to a powerful antioxidant defense system and therapeutic effects in liver disease.However,little is known about the relationship between HIF-1αand Sirt1 in the process of ALF and the molecular mechanism.AIM To investigate whether HIF-1αmay be a target of Sirt1 deacetylation and what the effects on ALF are.METHODS Mice were administrated lipopolysaccharide(LPS)/D-gal and exposed to hypoxic conditions as animal model,and resveratrol was used as an activator of Sirt1.The cellular model was established with L02 cells stimulated by LPS.N-acetyl-Lcysteine was used to remove ROS,and the expression of Sirt1 was inhibited by nicotinamide.Western blotting was used to detect Sirt1 and HIF-1αactivity and related protein expression.The possible signaling pathways involved were analyzed by immunofluorescent staining,co-immunoprecipitation,dihydroethidium staining,and Western blotting.RESULTS Compared with mice stimulated with LPS alone,the expression of Sirt1 decreased,the level of HIF-1αacetylation increased in hypoxic mice,and the levels of carbonic anhydrase 9 and Bcl-2-adenovirus E1B interacting protein 3 increased significantly,which was regulated by HIF-1α,indicating an increase of HIF-1αactivity.Under hypoxia,the down-regulation of Sirt1 activated and acetylated HIF-1αin L02 cells.The inhibition of Sirt1 significantly aggravated this effect and the massive production of ROS.The regulation of ROS was partly through peroxisome proliferatoractivated receptor alpha or AMP-activated protein kinase.Resveratrol,a Sirt1 activator,effectively relieved ALF aggravated by hypoxia,the production of ROS,and cell apoptosis.It also induced the deacetylation of HIF-1αand inhibited the activity of HIF-1α.CONCLUSION Sirt1 may have a protective effect on ALF by inducing HIF-1α deacetylation to reduce ROS.
文摘An increase in oxidative stress plays a key role in neurotoxicity induction and cell death, which leads to neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease. Cyanidin-3-glucoside (C3G) is a common anthocyanin and shows antioxidant activity in neuronal cells. Silent information regulator 2-related protein 1 (Sirt1) regulates antioxidant and anti-inflammatory effects. However, the effects of C3G on Sirt1 in neuronal cells remain unclear. This study evaluated the effect of C3G on Sirt1 expression and activity in human neuroblastoma (SH-SY5Y) cells. In the study, C3G increased the expression of Sirt1 and Sirt1 activity in SH-SY5Y cells. Additionally, C3G increased the expression of nuclear factor erythroid 2-related factor 2, a vital transcription factor for regulating the expression of antioxidant genes, as well as antioxidant enzymes such as superoxide dismutase and catalase. Moreover, C3G protected SH-SY5Y cells from oxidative stress. These results suggest that C3G decreased oxidative stress-induced cell injury by increasing the expression of Sirt1 and other antioxidant factors. Therefore, C3G might merit further investigation for use in attenuating the progress of neurodegenerative diseases.
基金supported by the Natural Science Foundation of Zhejiang Province,No.LY21H060009(to WN)National Natural Science Foundation of China,Nos.82072192 and 82372540(to KZ)+2 种基金Medical and Health Technology Plan Project of Zhejiang Province,No.2024KY155(to KZ)Natural Science Foundation of Ningbo,No.2023J256(to KZ)Science and Technology Bureau Foundation of Wenzhou,No.Y20220211(to CW).
文摘After spinal cord injury,programmed cell death is common.In this context,autophagy plays a crucial role in clearing cellular debris,while necroptosis exacerbates neuroinflammation and further damages neural structures.The neuroprotective drug davunetide has shown substantial therapeutic effects on brain diseases,but its role in treating spinal cord injury remains unclear.Therefore,the aim of this study was to investigate the effects of davunetide on cell death after spinal cord injury.To do this,we established a mouse model of spinal cord contusion and administered davunetide intranasally daily at a dose of 0.5μg/5μL.Mouse locomotor function was assessed using footprint analysis and Basso Mouse Scale scoring,while the extent of spinal cord injury was evaluated using Masson’s trichrome staining.The expression levels of proteins related to locomotor function and spinal cord injury were analyzed by Western blotting and immunofluorescence staining,and protein-protein interactions were evaluated using immunoprecipitation techniques.Our results demonstrated that davunetide not only reduced the size of the injury area but also promoted the recovery of locomotor function after spinal cord injury.Specifically,davunetide exerted its effects by enhancing autophagy and inhibiting necroptosis.Inhibition of autophagy reversed the protective effects of davunetide on necroptosis.Further investigation revealed that davunetide acted through the SIRT1-FOXO1-TFEB signaling pathway,which is key to its therapeutic effects.These findings suggest the potential of davunetide in the treatment of spinal cord injury and provide valuable insights into the underlying mechanisms.This study offers strong scientific evidence to support the development of new therapeutic strategies for spinal cord injury.
基金supported by grants from the National Natural Science Foundation of China(82474093,81973536)Jiangsu Province“Blue and Green Project”(184080H10240)+2 种基金Graduate Research Innovation Program of Jiangsu(KYCX23_0871)the National Natural Science Foundation of the Youth Science Fund Project(81703775)Health Research Program of Wuxi Municipal Health Commission(Q202107).
文摘Moutan Cortex terpene glycoside is derived from the dried root bark of Paeonia suffruticosa Andr.in the Paeoniaceae family,which holds significant value as a traditional Chinese medicine.This study investigated that Moutan Cortex terpene glycoside(MCTG)improved diabetic kidney disease(DKD)by targeting sirtuin 1(SIRT1)mediated autophagy pathway.Mechanistic insights were gained using DKD model rats and human umbilical vein endothelial cells(HUVECs)to delineate how MCTG operated in the treatment of DKD.Furthermore,network pharmacology was used to identify the primary metabolic pathways affected by MCTG,with key targets being confirmed through polymerase chain reaction(PCR),Western blot,Transmission electron microscope,immunofluorescence staining and monodansylcadaverine(MDC)staining.Finally,small interfering RNA transfection testified SIRT1 in advanced glycation end-products(AGEs)-induced HUVECs injury.MCTG effectively decreased blood glucose rise in DKD rats and reduced levels of cytokines and biochemical indicators.Network pharmacology revealed that metabolism was the main pathway of Moutan Cortex,and the main targets were verified by PCR and protein experiments.Based on these results,we found that Moutan Cortex could improve DKD and SIRT1 was a potential target.Furthermore,knockdown of SIRT1 attenuated AGEs-induced the expression of Beclin 1 and microtubule-associated protein 1 light chain 3 II/I(LC3 II/I)in HUVECs.In summary,this study demonstrated that Moutan Cortex could alleviate DKD via down-regulating SIRT1-mediated autophagy pathway.
