Endometrial cancer(EC)stands as one of the most prevalent gynecological malignancies affecting women,with its incidence and disease-related mortality steadily on the rise.Disulfiram(DSF),an FDA-approved medication pri...Endometrial cancer(EC)stands as one of the most prevalent gynecological malignancies affecting women,with its incidence and disease-related mortality steadily on the rise.Disulfiram(DSF),an FDA-approved medication primarily used for treating alcohol addiction,has exhibited promising anti-tumor properties.Studies have revealed DSF’s capacity for enhanced anti-tumor activity,particularly when combined with copper.The novel Copper-Cysteamine(CuCy)compound,Cu_(3)Cl(SR)_(2)(R--CH_(2)CH_(2)NH_(2)),showcases photodynamic effects and demonstrates significant anti-tumor potential under various conditions,including exposure to ultraviolet light,X-ray,microwave,and ultrasound.This study delves into exploring the synergistic anti-tumor effects and underlying mechanisms by utilizing copper-cysteamine in conjunction with DSF against endometrial cancer.The investigation involved comprehensive analyses encompassing in vitro experiments utilizing Ishikawa cells,in vivo studies,and transcriptomic analyses.Remarkably,the combined administration of both compounds at a low dose of 0.5μM exhibited pronounced efficacy in impeding tumor growth,inhibiting blood vessel formation,and stimulating cell apoptosis.Notably,experiments involving transplanted tumors in nude mice vividly demonstrated the significant in vivo anti-tumor effects of this combination treatment.Detailed examination through transmission electron microscopy unveiled compelling evidence of mitochondrial damage,cellular swelling,and rupture,indicative of apoptotic changes in morphology due to the combined treatment.Moreover,transcriptomic analysis unveiled substantial downregulation of mitochondrial-related genes at the molecular level,coupled with a significant hindrance in the DNA repair pathway.These findings strongly suggest that the combined application of CuCy and DSF induces mitochondrial impairment in Ishikawa cells,thereby fostering apoptosis and ultimately yielding potent anti-tumor effects.展开更多
Despite a growing body of studies demonstrating the specific antitumor effect of nano-hydroxyapatite(n-HA),the underlying mechanism remained unclear.Endoplasmic reticulum(ER)and mitochondria are two key players in int...Despite a growing body of studies demonstrating the specific antitumor effect of nano-hydroxyapatite(n-HA),the underlying mechanism remained unclear.Endoplasmic reticulum(ER)and mitochondria are two key players in intracellular Ca^(2+)homeostasis and both require Ca^(2+)to participate.Moreover,the ER–mitochondria interplay coordinates the maintenance of cellular Ca^(2+)homeostasis to prevent any negative consequences from excess of Ca^(2+),hence there needs in-depth study of n-HA effect on them.In this study,we fabricated needle-like n-HA to investigate the anti-tumor effectiveness as well as the underlying mechanisms from cellular and molecular perspectives.Data from in vitro experiments indicated that the growth and invasion of glioma cells were obviously reduced with the aid of n-HA.It is interesting to note that the expression of ER stress biomarkers(GRP78,p-IRE1,p-PERK,PERK,and ATF6)were all upregulated after n-HA treatment,along with the activation of the pro-apoptotic transcription factor CHOP,showing that ER stress produced by n-HA triggered cell apoptosis.Moreover,the increased expression level of intracellular reactive oxygen species and the mitochondrial membrane depolarization,as well as the downstream cell apoptotic signaling activation,further demonstrated the pro-apoptotic roles of n-HA induced Ca^(2+)overload through inducing mitochondria damage.The in vivo data provided additional evidence that n-HA caused ER stress and mitochondria damage in cells and effectively restrain the growth of glioma tumors.Collectively,the work showed that n-HA co-activated intracellular ER stress and mitochondria damage are critical triggers for cancer cells apoptosis,offering fresh perspectives on ER-mitochondria targeted anti-tumor therapy.展开更多
Photodynamic therapy is a highly recommended alternative treatment for solid tumors,such as cutaneous or luminal tumors,in clinical practice.However,conventional photosensitizers(PSs)often induce undesirable phototoxi...Photodynamic therapy is a highly recommended alternative treatment for solid tumors,such as cutaneous or luminal tumors,in clinical practice.However,conventional photosensitizers(PSs)often induce undesirable phototoxic effects because of their normal tissue distribution and a reduction in antitumor effects resulting from aggregation-caused quenching effects.The present study developed a novel nanoformulated aggregation-induced emission(AIE)-characteristic PS,nab-TTVPHE,which is composed of human serum albumin as a carrier and TTVPHE as a therapeutic agent,as a more effective cancer treatment with lower phototoxic effects.Notably,the reactive oxygen species generated by TTVPHE were shielded by the nanoaggregate structure,and the photodynamic activity was after nanostructure dissociation.Nab-TTVPHE was actively internalized in tumor cells via secreted protein,acidic and rich in cysteine and released to form nanoaggregates.TTVPHE accumulated in mitochondria,where it triggered mitochondrial damage under light irradiation via its photodynamic activity and induced pyroptosis via the caspase-3/gasdermin E(GSDME)signaling pathway to kill tumor cells.Therefore,this nano-formulated AIE-characteristic PS provides an innovative strategy for cancer treatment with lower phototoxic effect and the ability to boost potential antitumor immunity via GSDME-mediated pyroptosis.展开更多
As lanthanide-doped sodium yttrium flouride(NaYF_4)nanoparticles have great potential inbiomedical applications,their biosafety is important and has attracted significant attention.In the present work,three different ...As lanthanide-doped sodium yttrium flouride(NaYF_4)nanoparticles have great potential inbiomedical applications,their biosafety is important and has attracted significant attention.In the present work,three different sized NaYF_4:Eu^(3+)nanoparticles have been prepared.Liver BRL 3 A cell was used as a cell model to evaluate their biological effects.Cell viability and apoptosis assays were used to confirm the cytotoxicity induced by NaYF_4:Eu^(3+)NPs.Apart from the elevated malondialdehyde(MDA),the decrease of superoxide dismutase(SOD),glutathione peroxidase(GSH-PX)and catalase(CAT)activity indicated reactive oxygen species(ROS)generation,which were associated with oxidative damage.The decrease of mitochondrial membrane potential(MMP)value demonstrated the occurrence of mitochondria damage.Then,release of cytochrome c from mitochondria and activation of caspase-3 confirmed that NaYF_4:Eu^(3+)NPs induced apoptosis was mitochondria damage-dependent.展开更多
Mitochondria provides adenosine triphosphate for multiple vital movements to ensure tumor cell proliferation.Compared to the broadly used method of inducing DNA replication arrest to kill cancer,inducing mitochondria ...Mitochondria provides adenosine triphosphate for multiple vital movements to ensure tumor cell proliferation.Compared to the broadly used method of inducing DNA replication arrest to kill cancer,inducing mitochondria damage to cause energy shortage is quite promising as it can inhibit tumor cell bioactivities,increase intracellular accumulation of toxic drugs,eventually sensitize chemotherapy and even reverse drug resistance.Breaking the balance of glutathione(GSH)and reactive oxygen species(ROS)contents have been proven efficient in destroying mitochondria respectively.Herein,apigenin,a GSH efflux reagent,and 2-deoxy-5-fluorouridine 5-monophosphate sodium salt(FdUMP)that could induce toxic ROS were co-delivered by constructed lipid nanoparticles,noted as Lip@AF.An immune-checkpoint inhibition reagent CD276 antibody was modified onto the surface of Lip@AF with high reaction specificity(noted asαCD276-Lip@AF)to enhance the recognition of immune cells to tumor.Results showed that the redox balancewas destroyed,leading to severe injury to mitochondria and cell membrane.Furthermore,synergistic DNA/RNA replication inhibition caused by inhibiting the function of thymidylate synthase were observed.Eventually,significantly enhanced cytotoxicity was achieved by combining multiple mechanisms including ferroptosis,apoptosis and pyroptosis.In vivo,strengthen tumor growth inhibitionwas achieved byαCD276-Lip@AF with high biosafety,providing new sights in enhancing chemotherapy sensitiveness and achieving high-performance chemo-immunotherapy.展开更多
Changes in mitochondrial morphology and function play an important role in secondary damage after acute spinal cord injury. We recorded the time representation of mitochondrial morphology and function in rats with acu...Changes in mitochondrial morphology and function play an important role in secondary damage after acute spinal cord injury. We recorded the time representation of mitochondrial morphology and function in rats with acute spinal cord injury. Results showed that mitochondria had an irregular shape, and increased in size. Mitochondrial cristae were disordered and mitochondrial membrane rupture was visible at 2–24 hours after injury. Fusion protein mitofusin 1 expression gradually increased, peaked at 8 hours after injury, and then decreased to its lowest level at 24 hours. Expression of dynamin-related protein 1, amitochondrial fission protein, showed the opposite kinetics. At 2–24 hours after acute spinal cord injury, malondialdehyde content, cytochrome c levels and caspase-3 expression were increased, but glutathione content, adenosine triphosphate content, Na＋-K＋-ATPase activity and mitochondrial membrane potential were gradually reduced. Furthermore, mitochondrial morphology altered during the acute stage of spinal cord injury. Fusion was important within the first 8 hours, but fission played a key role at 24 hours. Oxidative stress was inhibited, biological productivity was diminished, and mitochondrial membrane potential and permeability were reduced in the acute stage of injury. In summary, mitochondrial apoptosis is activated when the time of spinal cord injury is prolonged.展开更多
Alzheimer’s disease is the most prevalent neurodegenerative disease affecting older adults.Primary features of Alzheimer’s disease include extra cellular aggregation of amyloid-βplaques and the accumulation of neur...Alzheimer’s disease is the most prevalent neurodegenerative disease affecting older adults.Primary features of Alzheimer’s disease include extra cellular aggregation of amyloid-βplaques and the accumulation of neurofibrillary tangles,fo rmed by tau protein,in the cells.While there are amyloid-β-ta rgeting therapies for the treatment of Alzheimer’s disease,these therapies are costly and exhibit potential negative side effects.Mounting evidence suggests significant involvement of tau protein in Alzheimer’s disease-related neurodegeneration.As an important microtubule-associated protein,tau plays an important role in maintaining the stability of neuronal microtubules and promoting axonal growth.In fact,clinical studies have shown that abnormal phosphorylation of tau protein occurs before accumulation of amyloid-βin the brain.Various therapeutic strategies targeting tau protein have begun to emerge,and are considered possible methods to prevent and treat Alzheimer’s disease.Specifically,abnormalities in post-translational modifications of the tau protein,including aberrant phosphorylation,ubiquitination,small ubiquitin-like modifier(SUMO)ylation,acetylation,and truncation,contribute to its microtubule dissociation,misfolding,and subcellular missorting.This causes mitochondrial damage,synaptic impairments,gliosis,and neuroinflammation,eventually leading to neurodegeneration and cognitive deficits.This review summarizes the recent findings on the underlying mechanisms of tau protein in the onset and progression of Alzheimer’s disease and discusses tau-targeted treatment of Alzheimer’s disease.展开更多
Development of effective treatments for neurodegenerative disorders is a clinical conundrum that has puzzled many researchers.Currently available drugs target symptomatic relief rather than suppressing,ceasing or repa...Development of effective treatments for neurodegenerative disorders is a clinical conundrum that has puzzled many researchers.Currently available drugs target symptomatic relief rather than suppressing,ceasing or repairing the devastating neural damages.For Alzheimer’s disease,two classes of procognitive compounds are approved as a treatment.展开更多
Background:B-cell receptor-associated protein 31(BCAP31)has protective effects against alveolar epithelial type lIl cells(AECll)damage by inhibiting mitochondrial injury in acute lung injury(ALI)induced by lipopolysac...Background:B-cell receptor-associated protein 31(BCAP31)has protective effects against alveolar epithelial type lIl cells(AECll)damage by inhibiting mitochondrial injury in acute lung injury(ALI)induced by lipopolysaccharide(LPS),whereas the precise mechanism is still unclear.It is known that PTEN-induced putative kinase 1(PINK1)/Parkin-mediated mitophagy can remove damaged mitochondria selectively,which may be involved in BCAP31 protection against mitochondrial injury.Methods:In the current study,ALI mice models were established by using surfactant protein C(Sftpc)-BCAP31 transgenic mice(BCAP31^(TG) mice)and AECIl-specific BCAP31 knockout mice(BCAP31^(CKO) mice)treated with LPS.Results:BCAP31 expression in lung tissue and AECll were inhibited in ALI mice.Under LPS challenge,lower level of BCAP31 was found to correlate positively with pathological injury of the lung,respiratory dysfunction,mortality rates,inflammation response,and AECll damage.Further study showed that down-regulation of BCAP31 induced decreased phosphorylation of PINK1 via reduced binding to PINK1,thereby restraining PINK1/Parkin-mediated mitophagy.Down-regulation of mitophagy promoted mitochondrial injury,as shown by the increase in mitochondrial permeability transition pore opening rate,together with enhanced mitochondrial reactive oxygen species(mROS),which were accompanied by increased cellular apoptosis and reactive oxygen species(ROS).The increased cellular ROS contributed to the inflammatory response via activation of nuclear factor kB(NF-kB).In contrast,BCAP31 overexpression promoted phosphorylation of PINK1 and PINK1/Parkin-mediated mitophagy,thus blocking the mROS/ROS/NF-kB pathway,favoring a protective condition that ultimately led to the inhibition of AECl apoptosis and inflammatory response in LPS-induced ALI.Conclusion:Ultimately,BCAP31 alleviated ALI by activating PINK1/Parkin-mediated mitophagy and blocking the mROS/ROS/NF-kB pathway in AECll.展开更多
基金supported by the National Natural Science Foundation of China(22071066)CAMS Innovation Fund for Medical Science(CIFMS,No.2018-12M-1-004)the project from department of Education,Jiangsu Province for the School of CHIPS at XJTLU(EFP10120240023).
文摘Endometrial cancer(EC)stands as one of the most prevalent gynecological malignancies affecting women,with its incidence and disease-related mortality steadily on the rise.Disulfiram(DSF),an FDA-approved medication primarily used for treating alcohol addiction,has exhibited promising anti-tumor properties.Studies have revealed DSF’s capacity for enhanced anti-tumor activity,particularly when combined with copper.The novel Copper-Cysteamine(CuCy)compound,Cu_(3)Cl(SR)_(2)(R--CH_(2)CH_(2)NH_(2)),showcases photodynamic effects and demonstrates significant anti-tumor potential under various conditions,including exposure to ultraviolet light,X-ray,microwave,and ultrasound.This study delves into exploring the synergistic anti-tumor effects and underlying mechanisms by utilizing copper-cysteamine in conjunction with DSF against endometrial cancer.The investigation involved comprehensive analyses encompassing in vitro experiments utilizing Ishikawa cells,in vivo studies,and transcriptomic analyses.Remarkably,the combined administration of both compounds at a low dose of 0.5μM exhibited pronounced efficacy in impeding tumor growth,inhibiting blood vessel formation,and stimulating cell apoptosis.Notably,experiments involving transplanted tumors in nude mice vividly demonstrated the significant in vivo anti-tumor effects of this combination treatment.Detailed examination through transmission electron microscopy unveiled compelling evidence of mitochondrial damage,cellular swelling,and rupture,indicative of apoptotic changes in morphology due to the combined treatment.Moreover,transcriptomic analysis unveiled substantial downregulation of mitochondrial-related genes at the molecular level,coupled with a significant hindrance in the DNA repair pathway.These findings strongly suggest that the combined application of CuCy and DSF induces mitochondrial impairment in Ishikawa cells,thereby fostering apoptosis and ultimately yielding potent anti-tumor effects.
基金supported by National Key Research and Development Program of China[grant number 2022YFC2409705]Sichuan Science and Technology Program[grant number 2023NSFSC0330]Chengdu Science and Technology Program[grant number 2021-YF08-00107-GX].
文摘Despite a growing body of studies demonstrating the specific antitumor effect of nano-hydroxyapatite(n-HA),the underlying mechanism remained unclear.Endoplasmic reticulum(ER)and mitochondria are two key players in intracellular Ca^(2+)homeostasis and both require Ca^(2+)to participate.Moreover,the ER–mitochondria interplay coordinates the maintenance of cellular Ca^(2+)homeostasis to prevent any negative consequences from excess of Ca^(2+),hence there needs in-depth study of n-HA effect on them.In this study,we fabricated needle-like n-HA to investigate the anti-tumor effectiveness as well as the underlying mechanisms from cellular and molecular perspectives.Data from in vitro experiments indicated that the growth and invasion of glioma cells were obviously reduced with the aid of n-HA.It is interesting to note that the expression of ER stress biomarkers(GRP78,p-IRE1,p-PERK,PERK,and ATF6)were all upregulated after n-HA treatment,along with the activation of the pro-apoptotic transcription factor CHOP,showing that ER stress produced by n-HA triggered cell apoptosis.Moreover,the increased expression level of intracellular reactive oxygen species and the mitochondrial membrane depolarization,as well as the downstream cell apoptotic signaling activation,further demonstrated the pro-apoptotic roles of n-HA induced Ca^(2+)overload through inducing mitochondria damage.The in vivo data provided additional evidence that n-HA caused ER stress and mitochondria damage in cells and effectively restrain the growth of glioma tumors.Collectively,the work showed that n-HA co-activated intracellular ER stress and mitochondria damage are critical triggers for cancer cells apoptosis,offering fresh perspectives on ER-mitochondria targeted anti-tumor therapy.
基金National Natural Science Foundation of China,Grant/Award Numbers:82172754,22175065,81972565,81874208Xinjiang Production and Construction Corps,Grant/Award Number:2023ZD023。
文摘Photodynamic therapy is a highly recommended alternative treatment for solid tumors,such as cutaneous or luminal tumors,in clinical practice.However,conventional photosensitizers(PSs)often induce undesirable phototoxic effects because of their normal tissue distribution and a reduction in antitumor effects resulting from aggregation-caused quenching effects.The present study developed a novel nanoformulated aggregation-induced emission(AIE)-characteristic PS,nab-TTVPHE,which is composed of human serum albumin as a carrier and TTVPHE as a therapeutic agent,as a more effective cancer treatment with lower phototoxic effects.Notably,the reactive oxygen species generated by TTVPHE were shielded by the nanoaggregate structure,and the photodynamic activity was after nanostructure dissociation.Nab-TTVPHE was actively internalized in tumor cells via secreted protein,acidic and rich in cysteine and released to form nanoaggregates.TTVPHE accumulated in mitochondria,where it triggered mitochondrial damage under light irradiation via its photodynamic activity and induced pyroptosis via the caspase-3/gasdermin E(GSDME)signaling pathway to kill tumor cells.Therefore,this nano-formulated AIE-characteristic PS provides an innovative strategy for cancer treatment with lower phototoxic effect and the ability to boost potential antitumor immunity via GSDME-mediated pyroptosis.
基金the Natural Science Foundation of China(21271059,31470961,21603051,21601046, 31500812)Science and Technology Research Project of Higher Education Institutions in Hebei Province(QN2015230,QN2015132)+1 种基金the Natural Science Foundation of Hebei Province(B2015201097,B2016201169)the Science and Technology Support Program of Baoding(15ZF055)
文摘As lanthanide-doped sodium yttrium flouride(NaYF_4)nanoparticles have great potential inbiomedical applications,their biosafety is important and has attracted significant attention.In the present work,three different sized NaYF_4:Eu^(3+)nanoparticles have been prepared.Liver BRL 3 A cell was used as a cell model to evaluate their biological effects.Cell viability and apoptosis assays were used to confirm the cytotoxicity induced by NaYF_4:Eu^(3+)NPs.Apart from the elevated malondialdehyde(MDA),the decrease of superoxide dismutase(SOD),glutathione peroxidase(GSH-PX)and catalase(CAT)activity indicated reactive oxygen species(ROS)generation,which were associated with oxidative damage.The decrease of mitochondrial membrane potential(MMP)value demonstrated the occurrence of mitochondria damage.Then,release of cytochrome c from mitochondria and activation of caspase-3 confirmed that NaYF_4:Eu^(3+)NPs induced apoptosis was mitochondria damage-dependent.
基金financially supported by the National Natural Science Foundation of China(82173769)Tianjin Science Foundation for Distinguished Young Scholars(24JCJQJC00050)+2 种基金Applied Basic Research Multi-Investment Foundation of Tianjin(21JCYBJC01540)the National Natural Science Foundation of China(82300336)the Science&Technology Development Fund of Tianjin Education Commission for Higher Education(2019KJ178).
文摘Mitochondria provides adenosine triphosphate for multiple vital movements to ensure tumor cell proliferation.Compared to the broadly used method of inducing DNA replication arrest to kill cancer,inducing mitochondria damage to cause energy shortage is quite promising as it can inhibit tumor cell bioactivities,increase intracellular accumulation of toxic drugs,eventually sensitize chemotherapy and even reverse drug resistance.Breaking the balance of glutathione(GSH)and reactive oxygen species(ROS)contents have been proven efficient in destroying mitochondria respectively.Herein,apigenin,a GSH efflux reagent,and 2-deoxy-5-fluorouridine 5-monophosphate sodium salt(FdUMP)that could induce toxic ROS were co-delivered by constructed lipid nanoparticles,noted as Lip@AF.An immune-checkpoint inhibition reagent CD276 antibody was modified onto the surface of Lip@AF with high reaction specificity(noted asαCD276-Lip@AF)to enhance the recognition of immune cells to tumor.Results showed that the redox balancewas destroyed,leading to severe injury to mitochondria and cell membrane.Furthermore,synergistic DNA/RNA replication inhibition caused by inhibiting the function of thymidylate synthase were observed.Eventually,significantly enhanced cytotoxicity was achieved by combining multiple mechanisms including ferroptosis,apoptosis and pyroptosis.In vivo,strengthen tumor growth inhibitionwas achieved byαCD276-Lip@AF with high biosafety,providing new sights in enhancing chemotherapy sensitiveness and achieving high-performance chemo-immunotherapy.
基金supported by the National Natural Science Foundation of China,No.81272074the Scientific Research Foundation Project for Doctors in Liaoning Province of China,No.20121094+1 种基金Aohongboze Graduate Sci-tech Innovation Foundationthe President Fund of Liaoning Medical University of China,No.2013003
文摘Changes in mitochondrial morphology and function play an important role in secondary damage after acute spinal cord injury. We recorded the time representation of mitochondrial morphology and function in rats with acute spinal cord injury. Results showed that mitochondria had an irregular shape, and increased in size. Mitochondrial cristae were disordered and mitochondrial membrane rupture was visible at 2–24 hours after injury. Fusion protein mitofusin 1 expression gradually increased, peaked at 8 hours after injury, and then decreased to its lowest level at 24 hours. Expression of dynamin-related protein 1, amitochondrial fission protein, showed the opposite kinetics. At 2–24 hours after acute spinal cord injury, malondialdehyde content, cytochrome c levels and caspase-3 expression were increased, but glutathione content, adenosine triphosphate content, Na＋-K＋-ATPase activity and mitochondrial membrane potential were gradually reduced. Furthermore, mitochondrial morphology altered during the acute stage of spinal cord injury. Fusion was important within the first 8 hours, but fission played a key role at 24 hours. Oxidative stress was inhibited, biological productivity was diminished, and mitochondrial membrane potential and permeability were reduced in the acute stage of injury. In summary, mitochondrial apoptosis is activated when the time of spinal cord injury is prolonged.
基金supported by the National Natural Science Foundation of China,No.82101493(to JY)。
文摘Alzheimer’s disease is the most prevalent neurodegenerative disease affecting older adults.Primary features of Alzheimer’s disease include extra cellular aggregation of amyloid-βplaques and the accumulation of neurofibrillary tangles,fo rmed by tau protein,in the cells.While there are amyloid-β-ta rgeting therapies for the treatment of Alzheimer’s disease,these therapies are costly and exhibit potential negative side effects.Mounting evidence suggests significant involvement of tau protein in Alzheimer’s disease-related neurodegeneration.As an important microtubule-associated protein,tau plays an important role in maintaining the stability of neuronal microtubules and promoting axonal growth.In fact,clinical studies have shown that abnormal phosphorylation of tau protein occurs before accumulation of amyloid-βin the brain.Various therapeutic strategies targeting tau protein have begun to emerge,and are considered possible methods to prevent and treat Alzheimer’s disease.Specifically,abnormalities in post-translational modifications of the tau protein,including aberrant phosphorylation,ubiquitination,small ubiquitin-like modifier(SUMO)ylation,acetylation,and truncation,contribute to its microtubule dissociation,misfolding,and subcellular missorting.This causes mitochondrial damage,synaptic impairments,gliosis,and neuroinflammation,eventually leading to neurodegeneration and cognitive deficits.This review summarizes the recent findings on the underlying mechanisms of tau protein in the onset and progression of Alzheimer’s disease and discusses tau-targeted treatment of Alzheimer’s disease.
文摘Development of effective treatments for neurodegenerative disorders is a clinical conundrum that has puzzled many researchers.Currently available drugs target symptomatic relief rather than suppressing,ceasing or repairing the devastating neural damages.For Alzheimer’s disease,two classes of procognitive compounds are approved as a treatment.
基金supported by grants from the National Natural Science Foundation of China(No.82200091,No.82341089,and No.82370083)the Beijing Natural Science Foundation(No.7232150,No.7242029,No.7242028,and No.7222166)Chinese PLA General Hospital Youth Independent Innovation Science Fund Project(No.22QNFC086).
文摘Background:B-cell receptor-associated protein 31(BCAP31)has protective effects against alveolar epithelial type lIl cells(AECll)damage by inhibiting mitochondrial injury in acute lung injury(ALI)induced by lipopolysaccharide(LPS),whereas the precise mechanism is still unclear.It is known that PTEN-induced putative kinase 1(PINK1)/Parkin-mediated mitophagy can remove damaged mitochondria selectively,which may be involved in BCAP31 protection against mitochondrial injury.Methods:In the current study,ALI mice models were established by using surfactant protein C(Sftpc)-BCAP31 transgenic mice(BCAP31^(TG) mice)and AECIl-specific BCAP31 knockout mice(BCAP31^(CKO) mice)treated with LPS.Results:BCAP31 expression in lung tissue and AECll were inhibited in ALI mice.Under LPS challenge,lower level of BCAP31 was found to correlate positively with pathological injury of the lung,respiratory dysfunction,mortality rates,inflammation response,and AECll damage.Further study showed that down-regulation of BCAP31 induced decreased phosphorylation of PINK1 via reduced binding to PINK1,thereby restraining PINK1/Parkin-mediated mitophagy.Down-regulation of mitophagy promoted mitochondrial injury,as shown by the increase in mitochondrial permeability transition pore opening rate,together with enhanced mitochondrial reactive oxygen species(mROS),which were accompanied by increased cellular apoptosis and reactive oxygen species(ROS).The increased cellular ROS contributed to the inflammatory response via activation of nuclear factor kB(NF-kB).In contrast,BCAP31 overexpression promoted phosphorylation of PINK1 and PINK1/Parkin-mediated mitophagy,thus blocking the mROS/ROS/NF-kB pathway,favoring a protective condition that ultimately led to the inhibition of AECl apoptosis and inflammatory response in LPS-induced ALI.Conclusion:Ultimately,BCAP31 alleviated ALI by activating PINK1/Parkin-mediated mitophagy and blocking the mROS/ROS/NF-kB pathway in AECll.
