Objective:To investigate the protective effects of gypenoside XVII(GP-17)against cisplatin-induced acute kidney injury and to elucidate whether its mechanism involves the activation of PINK1/Parkin-mediated mitophagy....Objective:To investigate the protective effects of gypenoside XVII(GP-17)against cisplatin-induced acute kidney injury and to elucidate whether its mechanism involves the activation of PINK1/Parkin-mediated mitophagy.Methods:Sprague-Dawley rats were randomly divided into four groups:control,cisplatin,cisplatin+GP-17,and GP-17 alone.Cisplatin was administered intraperitoneally at 20 mg/kg to induce acute kidney injury,while GP-17 was given orally at 40 mg/kg/day for 7 d.The levels of serum creatinine and blood urea nitrogen,superoxide dismutase activity,and malondialdehyde content were measured.Histopathological analysis and transmission electron microscopy were also performed to evaluate the effects of GP-17 on renal injury.Moreover,the expression of mitophagy-related proteins,including PINK1,Parkin,LC3,and p62,and the mRNA expression of inflammatory markers were determined by Western blot and quantitative RT-PCR assays.Furthermore,human renal tubular epithelial HK-2 cells were treated with cisplatin and GP-17,with or without PINK1 siRNA transfection.Cell viability,apoptosis,reactive oxygen species levels,mitochondrial membrane potential,and the protein expression associated with the PINK1/Parkin pathway were measured.Results:In rats with cisplatin-induced acute kidney injury,GP-17 significantly ameliorated cisplatin-induced elevations in serum creatinine and blood urea nitrogen,attenuated tubular damage and mitochondrial ultrastructural injury,and reduced oxidative stress by increasing superoxide dismutase activity and decreasing malondialdehyde content.GP-17 further upregulated the protein levels of PINK1,Parkin,and LC3-Ⅱ/Ⅰratio while promoting p62 degradation,indicating enhanced mitophagic flux.In HK-2 cells,GP-17(20μM)co-treatment markedly attenuated cisplatin-induced cytotoxicity,apoptosis,reactive oxygen species overproduction,and mitochondrial depolarization.However,all these protective effects of GP-17 were completely abolished upon PINK1 knockdown.Conclusions:GP-17 protects against cisplatin-induced nephrotoxicity by activating PINK1/Parkin-mediated mitophagy,which facilitates the clearance of damaged mitochondria,alleviates oxidative stress,and inhibits renal cell apoptosis.These findings identify GP-17 as a promising candidate for mitigating chemotherapy-induced acute kidney injury.展开更多
目的:探讨加味升降散通过激活线粒体自噬来改善糖尿病肾病(DKD)的作用机制。方法:选取60只7~8周龄的SPF级SD雄性大鼠,采用高糖高脂饮食联合链脲佐菌素(STZ)腹腔注射建立DKD模型,模型建立后随机分为正常组,模型组,加味升降散低、中、高...目的:探讨加味升降散通过激活线粒体自噬来改善糖尿病肾病(DKD)的作用机制。方法:选取60只7~8周龄的SPF级SD雄性大鼠,采用高糖高脂饮食联合链脲佐菌素(STZ)腹腔注射建立DKD模型,模型建立后随机分为正常组,模型组,加味升降散低、中、高剂量组(7.7、15.4、30.8 g·kg^(-1))及厄贝沙坦组(0.384 g·kg^(-1)),每组予以等体积生理盐水和相应浓度药物灌胃,连续给药28 d。检测各组大鼠的血糖、体质量、肾脏质量,通过全自动血液分析仪测定血清中肌酐(SCr)、尿素氮(BUN)含量;酶联免疫吸附测定法(ELISA)测定大鼠尿液中尿微量白蛋白(mALB)、血清中肿瘤坏死因子-α(TNF-α)、白细胞介素-1β(IL-1β)和白细胞介素-6(IL-6)的含量;苏木素-伊红(HE)、过碘酸-雪夫(PAS)染色和透射电镜法观察肾脏组织的病理变化;蛋白免疫印迹法(Western blot)测定大鼠肾脏组织线粒体自噬相关蛋白的表达;免疫荧光共定位法检测微管相关蛋白1轻链3β(LC3B)和细胞色素C氧化酶亚基Ⅳ(COXⅣ)的共表达情况。结果:模型组大鼠与正常组比较,肾重指数、血糖及24 h mALB明显升高(P<0.05,P<0.01);SCr、BUN水平均显著升高(P<0.01),血清中的TNF-α、IL-1β和IL-6水平显著上调(P<0.01);大鼠的肾脏组织显示出肾小球肥大、系膜区增宽、系膜区沉积增多、足细胞足突扁平融合,自噬小体数量减少伴随线粒体肿胀,肾小管上皮细胞出现空泡变性,肾间质伴有炎症细胞浸润;肾脏组织中自噬标志蛋白LC3B、PTEN诱导的激酶1(PINK1)、E3泛素蛋白连接酶(Parkin)蛋白表达明显降低(P<0.05,P<0.01),选择性自噬接头蛋白(p62)表达显著增加(P<0.01);免疫荧光信号强度降低、LC3B与COXⅣ的共表达降低。与模型组比较,加味升降散各剂量组和阳性药组大鼠肾重指数、血糖及24 h mALB明显下降(P<0.05,P<0.01);SCr、BUN水平明显下降(P<0.05);血清中的TNF-α、IL-1β和IL-6水平明显降低(P<0.05,P<0.01);肾脏组织肾小球肥大减轻、系膜区沉积减少、足突融合减轻,自噬小体数量增多,线粒体肿胀得到改善;加味升降散各剂量组肾脏中的LC3 B、PINK1、Parkin蛋白表达量明显增加,p62蛋白表达明显减少(P<0.05,P<0.01);免疫荧光信号强度增强,LC3B与COXⅣ的共表达增加。结论:加味升降散通过调节PINK1/Parkin信号通路,激活线粒体自噬,缓解DKD大鼠体内炎症反应,发挥对肾脏的保护作用。展开更多
Objective:Buyinqianzheng Formula(BYQZF)is clinically employed in traditional Chinese medicine to treat Parkinson's disease(PD)by improving mitochondrial dysfunction.However,the underlying mechanisms by which BYQZF...Objective:Buyinqianzheng Formula(BYQZF)is clinically employed in traditional Chinese medicine to treat Parkinson's disease(PD)by improving mitochondrial dysfunction.However,the underlying mechanisms by which BYQZF affects mitochondrial morphology remain unknown.Therefore,we observed the effects of BYQZF on mitochondria from the perspective of the PINK1/Parkin pathway.Methods:Cell survival rates were assessed by Cell Counting Kit-8 assay.Expression levels of PINK1 and Parkin mRNA were examined by qRT-PCR.Protein expression levels of PINK1,PINK1-Ser228,Parkin,Parkin-Ser65,Drp1,and Drp1-Ser637 were examined by western blotting.PINK1,Parkin,and MitoTracker?Red CMXRos(MTR)were stained by triple-labeled immunofluorescence,and observed under laser confocal microscopy.Results:Cell survival rate,mitochondrial form factor,mean length and number of mitochondrial network branches,mitochondrial activity,m RNA expression levels of PINK1 and Parkin,and protein expression levels of PINK1,Parkin,and Drp1-Ser637 were reduced after 1-methyl-4-phenylpyridinium(MPP^(+))intervention.In contrast,Pearson's correlation coefficients between PINK1 and Parkin,and between Parkin and MTR,as well as protein expression levels of PINK1-Ser228,Parkin-Ser65,and Drp1 increased significantly after MPP^(+) intervention.Treatment with BYQZF increased cell survival rate,mitochondrial form factor,mean length and number of mitochondrial network branches,mitochondrial activity,m RNA expression levels of PINK1 and Parkin,and expression of PINK1,Parkin,and Drp1-Ser637 proteins.Pearson's correlation coefficients between PINK1 and Parkin,and between Parkin and MTR,as well as protein expression levels of PINK1-Ser228,Parkin-Ser65,and Drp1 decreased after BYQZF treatment.Conclusion:These results demonstrate that BYQZF has a protective effect on mitochondrial molecular mechanisms in the PD cell model,and the mechanism is related to the PINK1/Parkin pathway.展开更多
Background:This study will be aimed at investigating the effects of Baihu Renshen decoction(BHRS)on type 2 diabetes rats and on macromolecular enzyme 1(PINK1)/E3 ubiquitin protein ligase(Parkin)pathway.Methods:The exp...Background:This study will be aimed at investigating the effects of Baihu Renshen decoction(BHRS)on type 2 diabetes rats and on macromolecular enzyme 1(PINK1)/E3 ubiquitin protein ligase(Parkin)pathway.Methods:The experiment was divided into four groups:control group,model group,metformin group and BHRS low-dose group and high-dose group.Forty male rats were selected as samples and randomly assigned to at least one test group.Finally,there are 18 rats in each group.Except for the control group,the rats within the different teams got a high-fat diet associate in nursing an intraperitoneal injection of streptozotocin to make a type 2 diabetes mellitus(T2DM)rat model.The organic chemistry and inflammatory indexes of rats in every cluster were analyzed and compared once four weeks of intragastric administration of comparable reagents to review the therapeutic impact of BHRS on T2DM.In addition,we determined the pathological changes of ductal gland tissue of T2DM rats after treatment,and compared the expression of mitochondrial phagocytosis related proteins in ductal gland tissue of rats in each group.Results:FBG,LDL-C,TC,TG,MDA,IL-1,IL-6,TNF-,and mitophagy-related proteins COXIV,P62,VDAC1,and TOM20 were elevated in the model group compared to the control group,while HDL-C,SOD,GSH-Px,and mitophagy-related proteins PINK1,Parkin,and LC3II/I were decreased(P<0.05 or P<0.01).The expressions of FBG,TC,TG,LDL-C,MDA,IL-1,IL-6,TNF-,and mitophagy-related proteins COXIV,P62,VDAC1,and TOM20 were lowered in the BHRS group,while the expressions of HOMA-,HDL-C,SOD,GSH-Px,and mitophagy-related proteins PINK1,Parkin,and LC3II/I were(P<0.05 or P<0.01).After therapy with BHRS,hematoxylin-eosin staining showed that the intensity of pancreatic acinar staining increased,and islet cells became clear boundaries that were,regularly arranged,and with reduced vacuoles reduced.Conclusion:BHRS has a clear therapeutic effect on T2DM,which may be achieved by regulating mitochondrial autophagy through the PINK1/Parkin pathway.展开更多
Spinal cord ischemia-reperfusion injury,a severe form of spinal cord damage,can lead to sensory and motor dysfunction.This injury often occurs after traumatic events,spinal cord surgeries,or thoracoabdominal aortic su...Spinal cord ischemia-reperfusion injury,a severe form of spinal cord damage,can lead to sensory and motor dysfunction.This injury often occurs after traumatic events,spinal cord surgeries,or thoracoabdominal aortic surgeries.The unpredictable nature of this condition,combined with limited treatment options,poses a significant burden on patients,their families,and society.Spinal cord ischemia-reperfusion injury leads to reduced neuronal regenerative capacity and complex pathological processes.In contrast,mitophagy is crucial for degrading damaged mitochondria,thereby supporting neuronal metabolism and energy supply.However,while moderate mitophagy can be beneficial in the context of spinal cord ischemia-reperfusion injury,excessive mitophagy may be detrimental.Therefore,this review aims to investigate the potential mechanisms and regulators of mitophagy involved in the pathological processes of spinal cord ischemia-reperfusion injury.The goal is to provide a comprehensive understanding of recent advancements in mitophagy related to spinal cord ischemia-reperfusion injury and clarify its potential clinical applications.展开更多
Osteosarcoma(OS)therapy faces many challenges,especially the poor survival rate once metastasis occurs.Therefore,it is crucial to explore new OS treatment strategies that can efficiently inhibit OS metastasis.Bioactiv...Osteosarcoma(OS)therapy faces many challenges,especially the poor survival rate once metastasis occurs.Therefore,it is crucial to explore new OS treatment strategies that can efficiently inhibit OS metastasis.Bioactive nanoparticles such as zinc oxide nanoparticles(ZnO NPs)can efficiently inhibit OS growth,however,the effect and mechanisms of them on tumor metastasis are still not clear.In this study,we firstly prepared well-dispersed ZnO NPs and proved that ZnO NPs can inhibit OS metastasis-related malignant behaviors including migration,invasion,and epithelial-mesenchymal transition(EMT).RNA-Seqs found that differentially expressed genes(DEGs)in ZnO NP-treated OS cells were enriched in wingless/integrated(Wnt)and hypoxia-inducible factor-1(HIF-1)signaling pathway.We further proved that Zn^(2+)released from ZnO NPs induced downregulation ofβ-catenin expression via HIF-1α/BNIP3/LC3B-mediated mitophagy pathway.ZnO NPs combined with ICG-001,aβ-catenin inhibitor,showed a synergistic inhibitory effect on OS lung metastasis and a longer survival time.In addition,tissue microarray(TMA)of OS patients also detected much higherβ-catenin expression which indicated the role ofβ-catenin in OS development.In summary,our current study not only proved that ZnO NPs can inhibit OS metastasis by degradingβ-catenin in HIF-1α/BNIP3/LC3B-mediated mitophagy pathway,but also provided a far-reaching potential of ZnO NPs in clinical OS treatment with metastasis.展开更多
基金supported by grants from the Health Commission of Zigong High-Level Talent Development Project(WJW-GCCRC007).
文摘Objective:To investigate the protective effects of gypenoside XVII(GP-17)against cisplatin-induced acute kidney injury and to elucidate whether its mechanism involves the activation of PINK1/Parkin-mediated mitophagy.Methods:Sprague-Dawley rats were randomly divided into four groups:control,cisplatin,cisplatin+GP-17,and GP-17 alone.Cisplatin was administered intraperitoneally at 20 mg/kg to induce acute kidney injury,while GP-17 was given orally at 40 mg/kg/day for 7 d.The levels of serum creatinine and blood urea nitrogen,superoxide dismutase activity,and malondialdehyde content were measured.Histopathological analysis and transmission electron microscopy were also performed to evaluate the effects of GP-17 on renal injury.Moreover,the expression of mitophagy-related proteins,including PINK1,Parkin,LC3,and p62,and the mRNA expression of inflammatory markers were determined by Western blot and quantitative RT-PCR assays.Furthermore,human renal tubular epithelial HK-2 cells were treated with cisplatin and GP-17,with or without PINK1 siRNA transfection.Cell viability,apoptosis,reactive oxygen species levels,mitochondrial membrane potential,and the protein expression associated with the PINK1/Parkin pathway were measured.Results:In rats with cisplatin-induced acute kidney injury,GP-17 significantly ameliorated cisplatin-induced elevations in serum creatinine and blood urea nitrogen,attenuated tubular damage and mitochondrial ultrastructural injury,and reduced oxidative stress by increasing superoxide dismutase activity and decreasing malondialdehyde content.GP-17 further upregulated the protein levels of PINK1,Parkin,and LC3-Ⅱ/Ⅰratio while promoting p62 degradation,indicating enhanced mitophagic flux.In HK-2 cells,GP-17(20μM)co-treatment markedly attenuated cisplatin-induced cytotoxicity,apoptosis,reactive oxygen species overproduction,and mitochondrial depolarization.However,all these protective effects of GP-17 were completely abolished upon PINK1 knockdown.Conclusions:GP-17 protects against cisplatin-induced nephrotoxicity by activating PINK1/Parkin-mediated mitophagy,which facilitates the clearance of damaged mitochondria,alleviates oxidative stress,and inhibits renal cell apoptosis.These findings identify GP-17 as a promising candidate for mitigating chemotherapy-induced acute kidney injury.
文摘目的:探讨加味升降散通过激活线粒体自噬来改善糖尿病肾病(DKD)的作用机制。方法:选取60只7~8周龄的SPF级SD雄性大鼠,采用高糖高脂饮食联合链脲佐菌素(STZ)腹腔注射建立DKD模型,模型建立后随机分为正常组,模型组,加味升降散低、中、高剂量组(7.7、15.4、30.8 g·kg^(-1))及厄贝沙坦组(0.384 g·kg^(-1)),每组予以等体积生理盐水和相应浓度药物灌胃,连续给药28 d。检测各组大鼠的血糖、体质量、肾脏质量,通过全自动血液分析仪测定血清中肌酐(SCr)、尿素氮(BUN)含量;酶联免疫吸附测定法(ELISA)测定大鼠尿液中尿微量白蛋白(mALB)、血清中肿瘤坏死因子-α(TNF-α)、白细胞介素-1β(IL-1β)和白细胞介素-6(IL-6)的含量;苏木素-伊红(HE)、过碘酸-雪夫(PAS)染色和透射电镜法观察肾脏组织的病理变化;蛋白免疫印迹法(Western blot)测定大鼠肾脏组织线粒体自噬相关蛋白的表达;免疫荧光共定位法检测微管相关蛋白1轻链3β(LC3B)和细胞色素C氧化酶亚基Ⅳ(COXⅣ)的共表达情况。结果:模型组大鼠与正常组比较,肾重指数、血糖及24 h mALB明显升高(P<0.05,P<0.01);SCr、BUN水平均显著升高(P<0.01),血清中的TNF-α、IL-1β和IL-6水平显著上调(P<0.01);大鼠的肾脏组织显示出肾小球肥大、系膜区增宽、系膜区沉积增多、足细胞足突扁平融合,自噬小体数量减少伴随线粒体肿胀,肾小管上皮细胞出现空泡变性,肾间质伴有炎症细胞浸润;肾脏组织中自噬标志蛋白LC3B、PTEN诱导的激酶1(PINK1)、E3泛素蛋白连接酶(Parkin)蛋白表达明显降低(P<0.05,P<0.01),选择性自噬接头蛋白(p62)表达显著增加(P<0.01);免疫荧光信号强度降低、LC3B与COXⅣ的共表达降低。与模型组比较,加味升降散各剂量组和阳性药组大鼠肾重指数、血糖及24 h mALB明显下降(P<0.05,P<0.01);SCr、BUN水平明显下降(P<0.05);血清中的TNF-α、IL-1β和IL-6水平明显降低(P<0.05,P<0.01);肾脏组织肾小球肥大减轻、系膜区沉积减少、足突融合减轻,自噬小体数量增多,线粒体肿胀得到改善;加味升降散各剂量组肾脏中的LC3 B、PINK1、Parkin蛋白表达量明显增加,p62蛋白表达明显减少(P<0.05,P<0.01);免疫荧光信号强度增强,LC3B与COXⅣ的共表达增加。结论:加味升降散通过调节PINK1/Parkin信号通路,激活线粒体自噬,缓解DKD大鼠体内炎症反应,发挥对肾脏的保护作用。
基金the National Natural Science Foundation of China(Grant Nos.81573773 and 81774110)。
文摘Objective:Buyinqianzheng Formula(BYQZF)is clinically employed in traditional Chinese medicine to treat Parkinson's disease(PD)by improving mitochondrial dysfunction.However,the underlying mechanisms by which BYQZF affects mitochondrial morphology remain unknown.Therefore,we observed the effects of BYQZF on mitochondria from the perspective of the PINK1/Parkin pathway.Methods:Cell survival rates were assessed by Cell Counting Kit-8 assay.Expression levels of PINK1 and Parkin mRNA were examined by qRT-PCR.Protein expression levels of PINK1,PINK1-Ser228,Parkin,Parkin-Ser65,Drp1,and Drp1-Ser637 were examined by western blotting.PINK1,Parkin,and MitoTracker?Red CMXRos(MTR)were stained by triple-labeled immunofluorescence,and observed under laser confocal microscopy.Results:Cell survival rate,mitochondrial form factor,mean length and number of mitochondrial network branches,mitochondrial activity,m RNA expression levels of PINK1 and Parkin,and protein expression levels of PINK1,Parkin,and Drp1-Ser637 were reduced after 1-methyl-4-phenylpyridinium(MPP^(+))intervention.In contrast,Pearson's correlation coefficients between PINK1 and Parkin,and between Parkin and MTR,as well as protein expression levels of PINK1-Ser228,Parkin-Ser65,and Drp1 increased significantly after MPP^(+) intervention.Treatment with BYQZF increased cell survival rate,mitochondrial form factor,mean length and number of mitochondrial network branches,mitochondrial activity,m RNA expression levels of PINK1 and Parkin,and expression of PINK1,Parkin,and Drp1-Ser637 proteins.Pearson's correlation coefficients between PINK1 and Parkin,and between Parkin and MTR,as well as protein expression levels of PINK1-Ser228,Parkin-Ser65,and Drp1 decreased after BYQZF treatment.Conclusion:These results demonstrate that BYQZF has a protective effect on mitochondrial molecular mechanisms in the PD cell model,and the mechanism is related to the PINK1/Parkin pathway.
基金the Construction Project of Workshop of Prestigious Chinese Physician Xiu-Hai Su(2022-75).
文摘Background:This study will be aimed at investigating the effects of Baihu Renshen decoction(BHRS)on type 2 diabetes rats and on macromolecular enzyme 1(PINK1)/E3 ubiquitin protein ligase(Parkin)pathway.Methods:The experiment was divided into four groups:control group,model group,metformin group and BHRS low-dose group and high-dose group.Forty male rats were selected as samples and randomly assigned to at least one test group.Finally,there are 18 rats in each group.Except for the control group,the rats within the different teams got a high-fat diet associate in nursing an intraperitoneal injection of streptozotocin to make a type 2 diabetes mellitus(T2DM)rat model.The organic chemistry and inflammatory indexes of rats in every cluster were analyzed and compared once four weeks of intragastric administration of comparable reagents to review the therapeutic impact of BHRS on T2DM.In addition,we determined the pathological changes of ductal gland tissue of T2DM rats after treatment,and compared the expression of mitochondrial phagocytosis related proteins in ductal gland tissue of rats in each group.Results:FBG,LDL-C,TC,TG,MDA,IL-1,IL-6,TNF-,and mitophagy-related proteins COXIV,P62,VDAC1,and TOM20 were elevated in the model group compared to the control group,while HDL-C,SOD,GSH-Px,and mitophagy-related proteins PINK1,Parkin,and LC3II/I were decreased(P<0.05 or P<0.01).The expressions of FBG,TC,TG,LDL-C,MDA,IL-1,IL-6,TNF-,and mitophagy-related proteins COXIV,P62,VDAC1,and TOM20 were lowered in the BHRS group,while the expressions of HOMA-,HDL-C,SOD,GSH-Px,and mitophagy-related proteins PINK1,Parkin,and LC3II/I were(P<0.05 or P<0.01).After therapy with BHRS,hematoxylin-eosin staining showed that the intensity of pancreatic acinar staining increased,and islet cells became clear boundaries that were,regularly arranged,and with reduced vacuoles reduced.Conclusion:BHRS has a clear therapeutic effect on T2DM,which may be achieved by regulating mitochondrial autophagy through the PINK1/Parkin pathway.
基金supported by Cuiying Scientific and Technological Innovation Program of Second Hospital of Lanzhou University,Nos.CY2023-QN-B18(to YD),2020QN-16(to YZ)the Natural Science Foundation of Gansu Province,No.22JR11RA082(to YZ)Key R&D Plan of Gansu Provincial Department of Science and Technology-Social Development Projects,No.23YFFA0043(to XK).
文摘Spinal cord ischemia-reperfusion injury,a severe form of spinal cord damage,can lead to sensory and motor dysfunction.This injury often occurs after traumatic events,spinal cord surgeries,or thoracoabdominal aortic surgeries.The unpredictable nature of this condition,combined with limited treatment options,poses a significant burden on patients,their families,and society.Spinal cord ischemia-reperfusion injury leads to reduced neuronal regenerative capacity and complex pathological processes.In contrast,mitophagy is crucial for degrading damaged mitochondria,thereby supporting neuronal metabolism and energy supply.However,while moderate mitophagy can be beneficial in the context of spinal cord ischemia-reperfusion injury,excessive mitophagy may be detrimental.Therefore,this review aims to investigate the potential mechanisms and regulators of mitophagy involved in the pathological processes of spinal cord ischemia-reperfusion injury.The goal is to provide a comprehensive understanding of recent advancements in mitophagy related to spinal cord ischemia-reperfusion injury and clarify its potential clinical applications.
基金supported in part by Beijing Natural Science Foundation(7192226,7222011)Beijing Chao-Yang Hospital Golden Seeds Foundation(CYJZ202148)+3 种基金National Key Research and Development Program(2021YFC2400500)National Natural Science Foundation of China(51903013,51973021,51932002,52173275)Beijing Hospitals Authority Youth Programme(QML20210402)the Beijing Municipal Health Commission(PXM 2020_026275_000002,BMHC-2021-6,BMHC-2019-9).
文摘Osteosarcoma(OS)therapy faces many challenges,especially the poor survival rate once metastasis occurs.Therefore,it is crucial to explore new OS treatment strategies that can efficiently inhibit OS metastasis.Bioactive nanoparticles such as zinc oxide nanoparticles(ZnO NPs)can efficiently inhibit OS growth,however,the effect and mechanisms of them on tumor metastasis are still not clear.In this study,we firstly prepared well-dispersed ZnO NPs and proved that ZnO NPs can inhibit OS metastasis-related malignant behaviors including migration,invasion,and epithelial-mesenchymal transition(EMT).RNA-Seqs found that differentially expressed genes(DEGs)in ZnO NP-treated OS cells were enriched in wingless/integrated(Wnt)and hypoxia-inducible factor-1(HIF-1)signaling pathway.We further proved that Zn^(2+)released from ZnO NPs induced downregulation ofβ-catenin expression via HIF-1α/BNIP3/LC3B-mediated mitophagy pathway.ZnO NPs combined with ICG-001,aβ-catenin inhibitor,showed a synergistic inhibitory effect on OS lung metastasis and a longer survival time.In addition,tissue microarray(TMA)of OS patients also detected much higherβ-catenin expression which indicated the role ofβ-catenin in OS development.In summary,our current study not only proved that ZnO NPs can inhibit OS metastasis by degradingβ-catenin in HIF-1α/BNIP3/LC3B-mediated mitophagy pathway,but also provided a far-reaching potential of ZnO NPs in clinical OS treatment with metastasis.
