目的分析桃红四物汤通过单磷酸腺苷活化蛋白激酶(AMP-activated protein kinase,AMPK)/哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)信号通路对大鼠动脉粥样硬化形成的影响及作用机制。方法选取60只清洁级雄性SD大鼠,其...目的分析桃红四物汤通过单磷酸腺苷活化蛋白激酶(AMP-activated protein kinase,AMPK)/哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)信号通路对大鼠动脉粥样硬化形成的影响及作用机制。方法选取60只清洁级雄性SD大鼠,其中10只作为空白组,其余50只采用高脂饮食喂养及动脉内膜损伤方法建立动脉粥样硬化模型,按照随机数表法分为对照组、桃红四物汤低浓度组(L组)、桃红四物汤中浓度组(M组)、桃红四物汤高浓度组(H组)。造模后第9周开始中药干预。空白组与对照组每日予蒸馏水3 mL灌胃,L、M及H组每日分别予相应剂量浓缩至3 mL灌胃。药物干预共8周。观察大鼠下肢动脉粥样硬化斑块程度、AMPK/mTOR信号通路以及血管平滑肌细胞表型转化相关的血管平滑肌激动蛋白(α-smooth muscle actin,α-SMA)、骨桥蛋白(osteopontin,OPN)的差异表达情况。结果与空白组相比,L、M及H组大鼠动脉粥样硬化明显形成,内膜下可见泡沫细胞形成,p-AMPK、OPN在L、M及H组中明显高表达,而mTOR、α-SMA的表达明显下调(P<0.05)。结论桃红四物汤可通过激活AMPK/mTOR信号通路,降低平滑肌细胞收缩表型向合成表型的转化,从而抑制平滑肌细胞的增殖,减缓动脉粥样硬化的进展。展开更多
Obesity and metabolic dysfunction-associated steatotic liver disease(MASLD)are linked to numerous chronic conditions,including cardiovascular disease,atherosclerosis,chronic kidney disease,and type II diabetes.Previou...Obesity and metabolic dysfunction-associated steatotic liver disease(MASLD)are linked to numerous chronic conditions,including cardiovascular disease,atherosclerosis,chronic kidney disease,and type II diabetes.Previous research identified the natural flavonoid diosmin,derived from Chrysanthemum morifolium,as a regulator of glucose metabolism.However,its effects on lipid metabolism and underlying mechanisms remained unexplored.The AMP-activated protein kinase(AMPK)pathway serves a critical function in glucose and lipid metabolism.The relationship between diosmin and the AMPK pathway has not been previously documented.This investigation examined diosmin's capacity to reduce lipid content through AMPK pathway activation in hepatoblastoma cell line G2(HepG2)and 3T3-L1 cells.The study revealed that diosmin inhibits lipogenesis,indicating its potential as an anti-obesity agent in obese mice.Moreover,diosmin demonstrated effective MASLD alleviation in vivo.These findings suggest that diosmin may represent a promising therapeutic candidate for treating obesity and MASLD.展开更多
Objective:To investigate effect of oleanolic acid(OA)on atherosclerosis and its related mechanisms.Methods:Human umbilical vein endothelial cells(HUVECs)were injured by oxidized low-density lipoprotein for 24 h and tr...Objective:To investigate effect of oleanolic acid(OA)on atherosclerosis and its related mechanisms.Methods:Human umbilical vein endothelial cells(HUVECs)were injured by oxidized low-density lipoprotein for 24 h and treated with OA,and the levels of cell proliferation,migration,adhesion,and apoptosis were evaluated by BrdU staining,scratch healing assay,monocyte-endothelial cell adhesion assay and flow cytometry.The mice were fed with a high-fat diet to induce an atherosclerosis model,and treated with OA by gastric gavage.The mice were divided into the control group,the model group,and the OA administration group.The blood lipid and plaque formation in mice were detected.In addition,oxidative stress and mitochondrial structure and function changes in cells and mice were evaluated by transmission electron microscopy,JC-1 fluorescent probe,and Western blotting assays.The expression levels of proteins in the AMPK/Drp1 pathway were examined through Western blot.Results:OA markedly increased cell viability and migration rate of HUVECs,and decreased the adhesion rate of THP-1 cells and the apoptosis rate.OA significantly reduced serum lipid levels,such as total cholesterol and triglyceride,in mice and inhibited plaque formation in the aorta.OA also significantly increased the content of superoxide dismutase and catalase,alleviated mitochondrial damage,such as mitochondrial swelling and mitochondrial cristae reduction,reduced the number of mitochondria,increased adenosine triphosphate content,and significantly reduced p-Drp1(Ser616)/Drp1,MFF and FIS1 levels,increased p-AMPK/AMPK levels,activated AMPK,and then regulated DRP1 activity.Conclusions:OA activates AMPK,which in turn regulates the activity of DRP1 to restore normal mitochondrial dynamics and reduce atherosclerosis.展开更多
AIM:To determine whether paeonol(Pae),a naturally occurring phenolic compound,can serve as an effective pharmacological inhibitor of posterior capsular opacification(PCO).METHODS:A rat model of cataract surgery—induc...AIM:To determine whether paeonol(Pae),a naturally occurring phenolic compound,can serve as an effective pharmacological inhibitor of posterior capsular opacification(PCO).METHODS:A rat model of cataract surgery—induced PCO was established,and Pae was administered via anterior chamber injection to evaluate its preventive effect on capsular opacification and fibrotic remodeling.Histological and immunohistochemical analyses were performed to assess epithelial-mesenchymal transition(EMT)—related changes in lens epithelial cells(LECs).Ex vivo lens capsule cultures were employed to examine the expression of Vimentin and Zonula Occludens-1(ZO-1)by immunofluorescence and immunohistochemistry.In the human LEC line SRA01/04,EMT marker expression at both mRNA and protein levels was analyzed following transforming growth factor beta 2(TGF-β2)stimulation,with Pae treatment.Western blotting and immunofluorescence were used to investigate the effect of Pae on TGF-β/Smad signaling and AMP-activated protein kinase(AMPK)activation.Molecular docking was performed to predict Pae–AMPK binding,and rescue experiments with AMPK inhibition were conducted to validate the mechanistic pathway.RESULTS:Pae significantly reduced capsular opacification and fibrotic remodeling in the rat PCO model compared with controls.In LECs,Pae markedly suppressed TGF-β2–induced EMT,evidenced by decreased expression of mesenchymal markers,such as Vimentin,Fibronectin,Collagen 1A1,α-SMA and preserved epithelial junctional protein ZO-1.Mechanistically,Pae was predicted to directly interact with the catalytic pocket of AMPK,which was experimentally confirmed by enhanced AMPK phosphorylation and nuclear translocation(P<0.05).This activation disrupted canonical TGF-β/Smad signaling,leading to suppression of EMT.Rescue experiments using AMPK inhibition abrogated the anti-EMT effect of Pae,further validating the AMPK-dependent mechanism.CONCLUSION:Pae exerts a potent inhibitory effect on PCO formation by blocking EMT of LECs through direct activation of AMPK and subsequent disruption of TGF-β/Smad signaling.展开更多
The published article titled“MicroRNA-148a Acts as a Tumor Suppressor in Osteosarcoma via Targeting Rho-Associated Coiled-Coil Kinase”has been retracted from Oncology Research,Vol.25,No.8,2017,pp.1231–1243.DOI:10.3...The published article titled“MicroRNA-148a Acts as a Tumor Suppressor in Osteosarcoma via Targeting Rho-Associated Coiled-Coil Kinase”has been retracted from Oncology Research,Vol.25,No.8,2017,pp.1231–1243.DOI:10.3727/096504017X14850134190255 URL:https://www.techscience.com/or/v25n8/56908 Following the publication,concerns have been raised about a number of figures in this article.An unexpected area of similarity was identified in terms of the cellular data,where the results from differently performed experiments were intended to have been shown,although the areas immediately surrounding this area featured comparatively different distributions of cells.In addition,the western blots in this article were presented with atypical,unusually shaped and possibly anomalous protein bands in many cases.展开更多
目的探讨血管软化丸能否通过调控腺苷酸活化蛋白激酶(AMP-activated protein kinase,AMPK)/NOD样受体热蛋白结构域相关蛋白3(NOD-like receptor thermal protein domain associated protein 3,NLRP3)通路抑制细胞焦亡改善载脂蛋白E基因...目的探讨血管软化丸能否通过调控腺苷酸活化蛋白激酶(AMP-activated protein kinase,AMPK)/NOD样受体热蛋白结构域相关蛋白3(NOD-like receptor thermal protein domain associated protein 3,NLRP3)通路抑制细胞焦亡改善载脂蛋白E基因敲除(apolipoprotein E knockout,APOE^(-/-))小鼠动脉粥样硬化(atherosclerosis,AS)。方法10只C57BL/6J小鼠作为空白对照组,60只APOE^(-/-)小鼠随机分为模型组、血管软化丸低剂量组、血管软化丸高剂量组、阿托伐他汀组、血管软化丸高剂量和AMPK抑制剂联合组、AMPK抑制剂组,给予高脂饮食饲养18周建造动脉粥样硬化小鼠模型,并于第13周给予不同方法干预,干预6周后取材,分别检测各组小鼠甘油三酯(triglyceride,TG)、总胆固醇(total cholesterol,TC)、低密度脂蛋白-胆固醇(low density lipoprotein-eholesterol,LDL-C)、高密度脂蛋白-胆固醇(high density lipoprotein-eholesterol,HDL-C)水平,HE和油红O染色观察小鼠主动脉组织病理形态学变化,Elisa测定主动脉组织白细胞介素(interleukin,IL)-1β和IL-18水平,Western Blot检测AMPK、P-AMPK、NLRP3、裂解的半胱氨酸天冬酶1(Cleaved-Caspase-1)、Gasdermin D(GSDMD)-N蛋白表达,免疫荧光检测P-AMPK、NLRP3蛋白在主动脉根部的分布情况,透射电子显微镜观察主动脉内皮超微结构改变情况。结果与对照组相比,模型组大鼠血清TG、TC、LDL-C水平显著升高,HDL-C水平显著降低(P<0.01),主动脉根部细胞排列紊乱,且脂肪空泡明显,主动脉有明显粥样斑块沉积,P-AMPK蛋白表达水平显著降低,NLRP3、Cleaved-Caspase 1、GSDMD-N蛋白表达水平及IL-1β和IL-18水平显著升高(P<0.05或P<0.01);与模型组比较,血管软化丸高低剂量组及阿托伐他汀组血脂紊乱得到改善,主动脉组织及细胞病变程度减轻,P-AMPK蛋白表达水平显著升高,NLRP3、Cleaved-Caspase 1、GSDMD-N蛋白表达水平显著降低(P<0.05或P<0.01),IL-1β和IL-18水平显著降低(P<0.05或P<0.01);与血管软化丸高剂量+AMPK抑制剂组比较,血管软化丸高剂量组焦亡相关蛋白水平显著降低(P<0.05或P<0.01),主动脉内皮细胞损伤程度减轻,而AMPK抑制剂组与之相反。结论血管软化丸可能通过调控AMPK/NLRP3通路减轻细胞焦亡发挥对动脉粥样硬化小鼠的保护作用。展开更多
目的探讨达格列净(Dapagliflozin,DAPA)是否通过腺苷酸活化蛋白激酶(AMP-activated protein kinase,AMPK)信号通路对心力衰竭(Heart failure,HF)产生治疗作用。方法本研究从GSE57338、GSE116250和GSE141910三个公开数据集中收集HF相关...目的探讨达格列净(Dapagliflozin,DAPA)是否通过腺苷酸活化蛋白激酶(AMP-activated protein kinase,AMPK)信号通路对心力衰竭(Heart failure,HF)产生治疗作用。方法本研究从GSE57338、GSE116250和GSE141910三个公开数据集中收集HF相关的基因表达数据,GSE57338基于GPL11532平台,包含177例HF患者和136例健康对照的左心室组织基因表达数据;GSE116250基于GPL16791平台,包含50例HF患者和14例健康对照的左心室组织基因表达数据;GSE141910基于GPL16791平台,包含200例HF患者和166例健康对照的左心室组织基因表达数据。对以上数据进行差异表达基因分析和富集分析。通过基因集变异分析(Gene set variation analysis,GSVA)评估AMPK信号通路在HF中的活化情况。随后,构建急性心肌梗死(Acute myocardial infarction,AMI)诱导的HF大鼠模型,并将其分为对照组、模型组和DAPA治疗组。对实验大鼠进行超声心动图检测,评估心脏功能;通过苏木精-伊红(HE)和Masson染色观察心肌组织形态变化;利用酶联免疫吸附试验(ELISA)检测脑型利钠肽(BNP)、心肌肌钙蛋白T(cTn-T)水平;通过TUNEL染色观察细胞凋亡情况;采用Western blot检测心肌组织中与AMPK信号通路相关蛋白的表达情况。结果在3个数据集中共鉴定出2677个交集基因,这些基因显著富集于磷脂酰肌醇3-激酶(PI3K)-蛋白激酶B(AKT)信号通路、神经营养因子信号通路、AMPK信号通路和雷帕霉素靶蛋白(mTOR)信号通路。对3个数据集进行GSVA评分结果显示,与健康对照相比,HF患者的AMPK信号通路显著下调(均P<0.001)。心功能超声结果显示,模型组大鼠表现出舒张和收缩功能障碍,DAPA治疗组大鼠在接受DAPA治疗后,左心室内径(LVID)、左心室收缩期内径(LVIDs)、舒张末期容积(EDV)和收缩末期容积(ESV)显著减少,射血分数(EF)和左心室缩短分数(FS)显著增加(P<0.05);模型组大鼠心肌纤维紊乱,心肌组织存在广泛的间质性出血,并有炎性细胞浸润,DAPA治疗后,大鼠心肌炎性细胞浸润程度和纤维化水平明显减少。接受DAPA治疗的HF大鼠血清中BNP和cTn-T水平、心肌细胞凋亡率均明显低于模型组(P<0.05);DAPA治疗组中磷酸化AMPK(p-AMPK)的表达显著增加(P<0.05)。结论AMPK信号通路在HF的病理过程中起重要作用,DAPA通过激活AMPK信号通路改善心肌炎症和功能损伤,显示出潜在的治疗价值。展开更多
文摘目的分析桃红四物汤通过单磷酸腺苷活化蛋白激酶(AMP-activated protein kinase,AMPK)/哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)信号通路对大鼠动脉粥样硬化形成的影响及作用机制。方法选取60只清洁级雄性SD大鼠,其中10只作为空白组,其余50只采用高脂饮食喂养及动脉内膜损伤方法建立动脉粥样硬化模型,按照随机数表法分为对照组、桃红四物汤低浓度组(L组)、桃红四物汤中浓度组(M组)、桃红四物汤高浓度组(H组)。造模后第9周开始中药干预。空白组与对照组每日予蒸馏水3 mL灌胃,L、M及H组每日分别予相应剂量浓缩至3 mL灌胃。药物干预共8周。观察大鼠下肢动脉粥样硬化斑块程度、AMPK/mTOR信号通路以及血管平滑肌细胞表型转化相关的血管平滑肌激动蛋白(α-smooth muscle actin,α-SMA)、骨桥蛋白(osteopontin,OPN)的差异表达情况。结果与空白组相比,L、M及H组大鼠动脉粥样硬化明显形成,内膜下可见泡沫细胞形成,p-AMPK、OPN在L、M及H组中明显高表达,而mTOR、α-SMA的表达明显下调(P<0.05)。结论桃红四物汤可通过激活AMPK/mTOR信号通路,降低平滑肌细胞收缩表型向合成表型的转化,从而抑制平滑肌细胞的增殖,减缓动脉粥样硬化的进展。
基金supported by the Innovation and Entrepreneurship Team Project of Jiangsu Province(No.JSSCTD202133).
文摘Obesity and metabolic dysfunction-associated steatotic liver disease(MASLD)are linked to numerous chronic conditions,including cardiovascular disease,atherosclerosis,chronic kidney disease,and type II diabetes.Previous research identified the natural flavonoid diosmin,derived from Chrysanthemum morifolium,as a regulator of glucose metabolism.However,its effects on lipid metabolism and underlying mechanisms remained unexplored.The AMP-activated protein kinase(AMPK)pathway serves a critical function in glucose and lipid metabolism.The relationship between diosmin and the AMPK pathway has not been previously documented.This investigation examined diosmin's capacity to reduce lipid content through AMPK pathway activation in hepatoblastoma cell line G2(HepG2)and 3T3-L1 cells.The study revealed that diosmin inhibits lipogenesis,indicating its potential as an anti-obesity agent in obese mice.Moreover,diosmin demonstrated effective MASLD alleviation in vivo.These findings suggest that diosmin may represent a promising therapeutic candidate for treating obesity and MASLD.
文摘Objective:To investigate effect of oleanolic acid(OA)on atherosclerosis and its related mechanisms.Methods:Human umbilical vein endothelial cells(HUVECs)were injured by oxidized low-density lipoprotein for 24 h and treated with OA,and the levels of cell proliferation,migration,adhesion,and apoptosis were evaluated by BrdU staining,scratch healing assay,monocyte-endothelial cell adhesion assay and flow cytometry.The mice were fed with a high-fat diet to induce an atherosclerosis model,and treated with OA by gastric gavage.The mice were divided into the control group,the model group,and the OA administration group.The blood lipid and plaque formation in mice were detected.In addition,oxidative stress and mitochondrial structure and function changes in cells and mice were evaluated by transmission electron microscopy,JC-1 fluorescent probe,and Western blotting assays.The expression levels of proteins in the AMPK/Drp1 pathway were examined through Western blot.Results:OA markedly increased cell viability and migration rate of HUVECs,and decreased the adhesion rate of THP-1 cells and the apoptosis rate.OA significantly reduced serum lipid levels,such as total cholesterol and triglyceride,in mice and inhibited plaque formation in the aorta.OA also significantly increased the content of superoxide dismutase and catalase,alleviated mitochondrial damage,such as mitochondrial swelling and mitochondrial cristae reduction,reduced the number of mitochondria,increased adenosine triphosphate content,and significantly reduced p-Drp1(Ser616)/Drp1,MFF and FIS1 levels,increased p-AMPK/AMPK levels,activated AMPK,and then regulated DRP1 activity.Conclusions:OA activates AMPK,which in turn regulates the activity of DRP1 to restore normal mitochondrial dynamics and reduce atherosclerosis.
基金Supported by the Projects of Medical and Health Technology Development Program in Shandong Province(No.202107021009)Shandong Provincial Traditional Chinese Medicine Science and Technology Project(No.M-2023118).
文摘AIM:To determine whether paeonol(Pae),a naturally occurring phenolic compound,can serve as an effective pharmacological inhibitor of posterior capsular opacification(PCO).METHODS:A rat model of cataract surgery—induced PCO was established,and Pae was administered via anterior chamber injection to evaluate its preventive effect on capsular opacification and fibrotic remodeling.Histological and immunohistochemical analyses were performed to assess epithelial-mesenchymal transition(EMT)—related changes in lens epithelial cells(LECs).Ex vivo lens capsule cultures were employed to examine the expression of Vimentin and Zonula Occludens-1(ZO-1)by immunofluorescence and immunohistochemistry.In the human LEC line SRA01/04,EMT marker expression at both mRNA and protein levels was analyzed following transforming growth factor beta 2(TGF-β2)stimulation,with Pae treatment.Western blotting and immunofluorescence were used to investigate the effect of Pae on TGF-β/Smad signaling and AMP-activated protein kinase(AMPK)activation.Molecular docking was performed to predict Pae–AMPK binding,and rescue experiments with AMPK inhibition were conducted to validate the mechanistic pathway.RESULTS:Pae significantly reduced capsular opacification and fibrotic remodeling in the rat PCO model compared with controls.In LECs,Pae markedly suppressed TGF-β2–induced EMT,evidenced by decreased expression of mesenchymal markers,such as Vimentin,Fibronectin,Collagen 1A1,α-SMA and preserved epithelial junctional protein ZO-1.Mechanistically,Pae was predicted to directly interact with the catalytic pocket of AMPK,which was experimentally confirmed by enhanced AMPK phosphorylation and nuclear translocation(P<0.05).This activation disrupted canonical TGF-β/Smad signaling,leading to suppression of EMT.Rescue experiments using AMPK inhibition abrogated the anti-EMT effect of Pae,further validating the AMPK-dependent mechanism.CONCLUSION:Pae exerts a potent inhibitory effect on PCO formation by blocking EMT of LECs through direct activation of AMPK and subsequent disruption of TGF-β/Smad signaling.
文摘The published article titled“MicroRNA-148a Acts as a Tumor Suppressor in Osteosarcoma via Targeting Rho-Associated Coiled-Coil Kinase”has been retracted from Oncology Research,Vol.25,No.8,2017,pp.1231–1243.DOI:10.3727/096504017X14850134190255 URL:https://www.techscience.com/or/v25n8/56908 Following the publication,concerns have been raised about a number of figures in this article.An unexpected area of similarity was identified in terms of the cellular data,where the results from differently performed experiments were intended to have been shown,although the areas immediately surrounding this area featured comparatively different distributions of cells.In addition,the western blots in this article were presented with atypical,unusually shaped and possibly anomalous protein bands in many cases.
文摘目的探讨血管软化丸能否通过调控腺苷酸活化蛋白激酶(AMP-activated protein kinase,AMPK)/NOD样受体热蛋白结构域相关蛋白3(NOD-like receptor thermal protein domain associated protein 3,NLRP3)通路抑制细胞焦亡改善载脂蛋白E基因敲除(apolipoprotein E knockout,APOE^(-/-))小鼠动脉粥样硬化(atherosclerosis,AS)。方法10只C57BL/6J小鼠作为空白对照组,60只APOE^(-/-)小鼠随机分为模型组、血管软化丸低剂量组、血管软化丸高剂量组、阿托伐他汀组、血管软化丸高剂量和AMPK抑制剂联合组、AMPK抑制剂组,给予高脂饮食饲养18周建造动脉粥样硬化小鼠模型,并于第13周给予不同方法干预,干预6周后取材,分别检测各组小鼠甘油三酯(triglyceride,TG)、总胆固醇(total cholesterol,TC)、低密度脂蛋白-胆固醇(low density lipoprotein-eholesterol,LDL-C)、高密度脂蛋白-胆固醇(high density lipoprotein-eholesterol,HDL-C)水平,HE和油红O染色观察小鼠主动脉组织病理形态学变化,Elisa测定主动脉组织白细胞介素(interleukin,IL)-1β和IL-18水平,Western Blot检测AMPK、P-AMPK、NLRP3、裂解的半胱氨酸天冬酶1(Cleaved-Caspase-1)、Gasdermin D(GSDMD)-N蛋白表达,免疫荧光检测P-AMPK、NLRP3蛋白在主动脉根部的分布情况,透射电子显微镜观察主动脉内皮超微结构改变情况。结果与对照组相比,模型组大鼠血清TG、TC、LDL-C水平显著升高,HDL-C水平显著降低(P<0.01),主动脉根部细胞排列紊乱,且脂肪空泡明显,主动脉有明显粥样斑块沉积,P-AMPK蛋白表达水平显著降低,NLRP3、Cleaved-Caspase 1、GSDMD-N蛋白表达水平及IL-1β和IL-18水平显著升高(P<0.05或P<0.01);与模型组比较,血管软化丸高低剂量组及阿托伐他汀组血脂紊乱得到改善,主动脉组织及细胞病变程度减轻,P-AMPK蛋白表达水平显著升高,NLRP3、Cleaved-Caspase 1、GSDMD-N蛋白表达水平显著降低(P<0.05或P<0.01),IL-1β和IL-18水平显著降低(P<0.05或P<0.01);与血管软化丸高剂量+AMPK抑制剂组比较,血管软化丸高剂量组焦亡相关蛋白水平显著降低(P<0.05或P<0.01),主动脉内皮细胞损伤程度减轻,而AMPK抑制剂组与之相反。结论血管软化丸可能通过调控AMPK/NLRP3通路减轻细胞焦亡发挥对动脉粥样硬化小鼠的保护作用。
文摘目的探讨达格列净(Dapagliflozin,DAPA)是否通过腺苷酸活化蛋白激酶(AMP-activated protein kinase,AMPK)信号通路对心力衰竭(Heart failure,HF)产生治疗作用。方法本研究从GSE57338、GSE116250和GSE141910三个公开数据集中收集HF相关的基因表达数据,GSE57338基于GPL11532平台,包含177例HF患者和136例健康对照的左心室组织基因表达数据;GSE116250基于GPL16791平台,包含50例HF患者和14例健康对照的左心室组织基因表达数据;GSE141910基于GPL16791平台,包含200例HF患者和166例健康对照的左心室组织基因表达数据。对以上数据进行差异表达基因分析和富集分析。通过基因集变异分析(Gene set variation analysis,GSVA)评估AMPK信号通路在HF中的活化情况。随后,构建急性心肌梗死(Acute myocardial infarction,AMI)诱导的HF大鼠模型,并将其分为对照组、模型组和DAPA治疗组。对实验大鼠进行超声心动图检测,评估心脏功能;通过苏木精-伊红(HE)和Masson染色观察心肌组织形态变化;利用酶联免疫吸附试验(ELISA)检测脑型利钠肽(BNP)、心肌肌钙蛋白T(cTn-T)水平;通过TUNEL染色观察细胞凋亡情况;采用Western blot检测心肌组织中与AMPK信号通路相关蛋白的表达情况。结果在3个数据集中共鉴定出2677个交集基因,这些基因显著富集于磷脂酰肌醇3-激酶(PI3K)-蛋白激酶B(AKT)信号通路、神经营养因子信号通路、AMPK信号通路和雷帕霉素靶蛋白(mTOR)信号通路。对3个数据集进行GSVA评分结果显示,与健康对照相比,HF患者的AMPK信号通路显著下调(均P<0.001)。心功能超声结果显示,模型组大鼠表现出舒张和收缩功能障碍,DAPA治疗组大鼠在接受DAPA治疗后,左心室内径(LVID)、左心室收缩期内径(LVIDs)、舒张末期容积(EDV)和收缩末期容积(ESV)显著减少,射血分数(EF)和左心室缩短分数(FS)显著增加(P<0.05);模型组大鼠心肌纤维紊乱,心肌组织存在广泛的间质性出血,并有炎性细胞浸润,DAPA治疗后,大鼠心肌炎性细胞浸润程度和纤维化水平明显减少。接受DAPA治疗的HF大鼠血清中BNP和cTn-T水平、心肌细胞凋亡率均明显低于模型组(P<0.05);DAPA治疗组中磷酸化AMPK(p-AMPK)的表达显著增加(P<0.05)。结论AMPK信号通路在HF的病理过程中起重要作用,DAPA通过激活AMPK信号通路改善心肌炎症和功能损伤,显示出潜在的治疗价值。
