Background Previous studies have shown that oncosis in malignant tumors might be related to cellular energy supply. The aim of this study was to detect oncosis in human esophageal squamous cell carcinoma （ESCC）, and...Background Previous studies have shown that oncosis in malignant tumors might be related to cellular energy supply. The aim of this study was to detect oncosis in human esophageal squamous cell carcinoma （ESCC）, and to investigate its relationship with apoptosis and microvessel density （MVD）. Methods ESCC specimens were obtained from 30 patients with ESCC after surgery. Transmission electron microscopy TUNEL, and immunohistochemistry were used to detect oncosis, apoptosis, and MVD. The relation of oncosis to apoptosis and MVD was analyzed by ANOVA, t test, and q test using SPSS 10.0. Results Transmission electron microscopy revealed both oncosis and apoptosis in the ECSS tissues. About 10% of the TUNEL-positive cells, which were considered apoptotic cells, showed the characteristics of oncosis. In the areas, where oncotic cells accumulated, apoptotic cells were rare; contrarily, where apoptotic cells gathered, oncotic cells were sparse. Compared with the tissues with a high MVD, the number of oncotic cells was increased and that of apoptotic cells was decreased in the tissues with a low MVD. Conclusions Cellular oncosis can be detected in human ESCC tissues. The distribution of oncotic cells presents a close relationship with cellular apoptosis and MVD. Oncosis might be induced by poor blood supply.展开更多
Background:Multiple mitochondrial dysfunction syndromes(MMDS)are rare mitochondrial diseases caused by mutation of mitochondrial iron–sulfur cluster synthesis proteins.This study established a rat model simulating MM...Background:Multiple mitochondrial dysfunction syndromes(MMDS)are rare mitochondrial diseases caused by mutation of mitochondrial iron–sulfur cluster synthesis proteins.This study established a rat model simulating MMDS5 disease in the nervous system to investigate its pathological features and neuronal death.Methods:We generated neuron-specific Isca1 knockout rat(Isca1 flox/flox-NeuN-Cre)using CRISPR-Cas9 technology.The brain structure changes of CKO rats were studied with MRI,and the behavior abnormalities were analyzed through gait analysis and open field tests,Y maze tests and food maze tests.The pathological changes of neurons were analyzed through H&E staining,Nissl staining,and Golgi staining.Mitochondrial damage was assessed by TEM,western blot and ATP assay,and the morphology of neurons was assessed by WGA immunofluorescence to detect the death of neurons.Results:This study established the disease model of MMDS5 in the nervous system for the first time,and found that after Isca1 loss,the rats suffered from developmental retardation,epilepsy,memory impairment,massive neuronal death,reduced number of Nissl bodies and dendritic spines,mitochondrial fragmentation,cristae fracture,reduced content of respiratory chain complex protein,and reduced production of ATP.Isca1 knockout caused neuronal oncosis.Conclusions:This rat model can be used to study the pathogenesis of MMDS.In addition,compared with human MMDS5,the rat model can survive up to 8 weeks of age,effectively extending the window of clinical treatment research,and can be used for the treatment of neurological symptoms in other mitochondrial diseases.展开更多
The influence mechanism of the nano-apatite on the human hepatocellular carcinoma in vitro was investigated. Using the homogeneous precipitation method, the nano-apatite was synthesized at room temperature, and it was...The influence mechanism of the nano-apatite on the human hepatocellular carcinoma in vitro was investigated. Using the homogeneous precipitation method, the nano-apatite was synthesized at room temperature, and it was characterized with transmission electron microscopy (TEM) and the Zataplus. The influence on the expression of the c-myc and p53 gene in the human hepatocellular carcinoma cell lines were tested with the TEM and hybridization in situ. The TEM and the Zataplus analyses show that the nano-apatite is distributed homogenously in size and needle-shaped sizes, which ranges from 67.5 nm to 88.3 nm. It is found that the nano-apatitet increases the volume of the human hepatocellular carcinoma cells, makes extensive cytoplasmic vacuolization, the mitochondria swelling, chromatin in nucleus dispersed partially and condensed around the nuclear membranes.The interspace in nuclear membranes were separated and even the cytoplasm dissolved. It is also found that the expression of the c-myc gene is inhibited, but the p53 is enhanced. The experimental results demonstrate that the nano-apatite enables the oncosis of the human hepatocellular carcinoma cells by down-regulation of the expression of the c-myc and up-regulation of the expression of the p53 in vitro.展开更多
Poly （ADP-ribose） polymerase-I （PARP-1） plays as a double edged sword in cerebral ischemia-reperfusion, hinging on its effect on the intracellular energy storage and injury severity, and the prognosis has relation...Poly （ADP-ribose） polymerase-I （PARP-1） plays as a double edged sword in cerebral ischemia-reperfusion, hinging on its effect on the intracellular energy storage and injury severity, and the prognosis has relationship with intervention timing. During ischemia injury, apoptosis and oncosis are the two main cell death pathway sin the ischemic core. The participation of astrocytes in ische- mia-reperfusion induced cell death has triggered more and more attention. Here, we examined the pro- tective effects and intervention timing of the PARP-1 inhibitor PJ34, by using a mixed oxygen-glucose deprivation/reperfusion （OGDR） model of primary rat astrocytes in vitro, which could mimic the ische- mia-reperfusion damage in the ＂ischemic core＂. Meanwhile, cell death pathways of various P J34 treated astrocytes were also investigated. Our results showed that P J34 incubation （10 μmol/L） did not affect release of lactate dehydrogenase （LDH） from astrocytes and cell viability or survival 1 h after OGDR. Interestingly, after 3 or 5 h OGDR, P J34 significantly reduced LDH release and percentage of PI-positive cells and increased cell viability, and simultaneously increased the caspase-dependent apop- totic rate. The intervention timing study demonstrated that an earlier and longer P J34 intervention dur- ing reperfusion was associated with more apparent protective effects. In conclusion, earlier and longer PJ34 intervention provides remarkable protective effects for astrocytes in the ＂ischaemic core＂ mainly by reducing oncosis of the astrocytes, especially following serious OGDR damage.展开更多
OBJECTIVE To reveal the biological effects and effective dosage in radiotherapy model which applies high single-dose irradiation by animal experiment. METHODS We inoculated subcutaneouly human pancreatic carcinoma cel...OBJECTIVE To reveal the biological effects and effective dosage in radiotherapy model which applies high single-dose irradiation by animal experiment. METHODS We inoculated subcutaneouly human pancreatic carcinoma cell line （MIA PaCa-2） in the lateral of the right lower extremity of the athymic mouse to grow transplantation tumor. While the median diameter of transplantation tumor reached 10 mm approximately, the animals were randomly divided into 7 groups （6 animals per group） and irradiation by different dose in one fixed with consciousness for fraction （0, 2, 5, 10, 17, 25, 35 Gy）. All were kept on to be bred for observation of the change in gross tumor volume, calculation of delayed growth time and delayed growth curve. RESULTS With increased dose per fraction, cutaneous reaction on the neoplasma surface of the animal, which was mainly moist yellow effusion was more and more severe. When dosage is less than 10 Gy, all animals showed similar effects, that＇s the delayed tumor growth was not obvious. Tumors receiving more than 10 Gy in one fraction showed very good biological effect and the delayed tumor growth was obviously related to dosage. The difference in delayed tumor growth between the 2 groups was statistically significant. The delayed tumor growth time in 10, 17, 25 Gy group was respectively 3 weeks, 6 weeks and more. CONCLUSION The biological effect of the model which applies high single-dose irradiation （more than 10 Gy in one fraction） was very good. The effect of delayed tumor growth was obviously related to the dosage after transplantation tumor was radiated. Because of its higher dose per fraction and biological effects, the model of high single-dose irradiation can get better clinical effects.展开更多
Ferroptosis is a recently identified iron-dependent form of nonapoptotic cell death characterized by reactive oxygen species(ROS) generation and lipid peroxidation.Here,we report a novel iron-dependent form of ferropt...Ferroptosis is a recently identified iron-dependent form of nonapoptotic cell death characterized by reactive oxygen species(ROS) generation and lipid peroxidation.Here,we report a novel iron-dependent form of ferroptosis induced by labile iron and investigate the mechanism underlying this process.We find that labile iron-induced ferroptosis is distinct from canonical ferroptosis and is linked to the mitochondrial pathway.Specifically,the mitochondrial calcium uniporter mediates the ferroptosis induced by labile iron.Interestingly,cells undergoing labile iron-induced ferroptosis exhibit cytoplasmic features of oncosis and nuclear features of apoptosis.Furthermore,labile iron-induced ferroptosis involves a unique set of genes.Finally,labile ironinduced ferroptosis was observed in liver subjected to acute iron overload in vivo.Our study reveals a novel form of ferroptosis that may be implicated in diseases caused by acute injury.展开更多
Globally,ischemic stroke causes millions of deaths per year.The outcomes of ischemic stroke are largely determined by the amount of ischemia-related and reperfusion-related neuronal death in the infarct region.In the ...Globally,ischemic stroke causes millions of deaths per year.The outcomes of ischemic stroke are largely determined by the amount of ischemia-related and reperfusion-related neuronal death in the infarct region.In the infarct region,cell injuries follow either the regulated pathway involving precise signaling cascades,such as apoptosis and autophagy,or the nonregulated pathway,which is uncontrolled by any molecularly defined effector mechanisms such as necrosis.However,numerous studies have recently found that a certain type of necrosis can be regulated and potentially modified by drugs and is nonapoptotic;this type of necrosis is referred to as regulated necrosis.Depending on the signaling pathway,various elements of regulated necrosis contribute to the development of ischemic stroke,such as necroptosis,pyroptosis,ferroptosis,pathanatos,mitochondrial permeability transition pore-mediated necrosis and oncosis.In this review,we aim to summarize the underlying molecular mechanisms of regulated necrosis in ischemic stroke and explore the crosstalk and interplay among the diverse types of regulated necrosis.We believe that targeting these regulated necrosis pathways both pharmacologically and genetically in ischemiainduced neuronal death and protection could be an efficient strategy to increase neuronal survival and regeneration in ischemic stroke.展开更多
基金This study was supported by a grant from the Outstanding Youth Scientific Foundation of He'nan Province(No.0312002300)
文摘Background Previous studies have shown that oncosis in malignant tumors might be related to cellular energy supply. The aim of this study was to detect oncosis in human esophageal squamous cell carcinoma （ESCC）, and to investigate its relationship with apoptosis and microvessel density （MVD）. Methods ESCC specimens were obtained from 30 patients with ESCC after surgery. Transmission electron microscopy TUNEL, and immunohistochemistry were used to detect oncosis, apoptosis, and MVD. The relation of oncosis to apoptosis and MVD was analyzed by ANOVA, t test, and q test using SPSS 10.0. Results Transmission electron microscopy revealed both oncosis and apoptosis in the ECSS tissues. About 10% of the TUNEL-positive cells, which were considered apoptotic cells, showed the characteristics of oncosis. In the areas, where oncotic cells accumulated, apoptotic cells were rare; contrarily, where apoptotic cells gathered, oncotic cells were sparse. Compared with the tissues with a high MVD, the number of oncotic cells was increased and that of apoptotic cells was decreased in the tissues with a low MVD. Conclusions Cellular oncosis can be detected in human ESCC tissues. The distribution of oncotic cells presents a close relationship with cellular apoptosis and MVD. Oncosis might be induced by poor blood supply.
基金CAMS Innovation Fund for Medical Sciences CIFMSGrant/Award Number:2021-I2M-1-034+3 种基金National Key Research and Development Program of ChinaGrant/Award Number:2022YFF0710702National Natural Science Foundation of ChinaGrant/Award Number:31970508。
文摘Background:Multiple mitochondrial dysfunction syndromes(MMDS)are rare mitochondrial diseases caused by mutation of mitochondrial iron–sulfur cluster synthesis proteins.This study established a rat model simulating MMDS5 disease in the nervous system to investigate its pathological features and neuronal death.Methods:We generated neuron-specific Isca1 knockout rat(Isca1 flox/flox-NeuN-Cre)using CRISPR-Cas9 technology.The brain structure changes of CKO rats were studied with MRI,and the behavior abnormalities were analyzed through gait analysis and open field tests,Y maze tests and food maze tests.The pathological changes of neurons were analyzed through H&E staining,Nissl staining,and Golgi staining.Mitochondrial damage was assessed by TEM,western blot and ATP assay,and the morphology of neurons was assessed by WGA immunofluorescence to detect the death of neurons.Results:This study established the disease model of MMDS5 in the nervous system for the first time,and found that after Isca1 loss,the rats suffered from developmental retardation,epilepsy,memory impairment,massive neuronal death,reduced number of Nissl bodies and dendritic spines,mitochondrial fragmentation,cristae fracture,reduced content of respiratory chain complex protein,and reduced production of ATP.Isca1 knockout caused neuronal oncosis.Conclusions:This rat model can be used to study the pathogenesis of MMDS.In addition,compared with human MMDS5,the rat model can survive up to 8 weeks of age,effectively extending the window of clinical treatment research,and can be used for the treatment of neurological symptoms in other mitochondrial diseases.
文摘The influence mechanism of the nano-apatite on the human hepatocellular carcinoma in vitro was investigated. Using the homogeneous precipitation method, the nano-apatite was synthesized at room temperature, and it was characterized with transmission electron microscopy (TEM) and the Zataplus. The influence on the expression of the c-myc and p53 gene in the human hepatocellular carcinoma cell lines were tested with the TEM and hybridization in situ. The TEM and the Zataplus analyses show that the nano-apatite is distributed homogenously in size and needle-shaped sizes, which ranges from 67.5 nm to 88.3 nm. It is found that the nano-apatitet increases the volume of the human hepatocellular carcinoma cells, makes extensive cytoplasmic vacuolization, the mitochondria swelling, chromatin in nucleus dispersed partially and condensed around the nuclear membranes.The interspace in nuclear membranes were separated and even the cytoplasm dissolved. It is also found that the expression of the c-myc gene is inhibited, but the p53 is enhanced. The experimental results demonstrate that the nano-apatite enables the oncosis of the human hepatocellular carcinoma cells by down-regulation of the expression of the c-myc and up-regulation of the expression of the p53 in vitro.
基金supported by the National Natural Science Foundation of China(No.30971024)
文摘Poly （ADP-ribose） polymerase-I （PARP-1） plays as a double edged sword in cerebral ischemia-reperfusion, hinging on its effect on the intracellular energy storage and injury severity, and the prognosis has relationship with intervention timing. During ischemia injury, apoptosis and oncosis are the two main cell death pathway sin the ischemic core. The participation of astrocytes in ische- mia-reperfusion induced cell death has triggered more and more attention. Here, we examined the pro- tective effects and intervention timing of the PARP-1 inhibitor PJ34, by using a mixed oxygen-glucose deprivation/reperfusion （OGDR） model of primary rat astrocytes in vitro, which could mimic the ische- mia-reperfusion damage in the ＂ischemic core＂. Meanwhile, cell death pathways of various P J34 treated astrocytes were also investigated. Our results showed that P J34 incubation （10 μmol/L） did not affect release of lactate dehydrogenase （LDH） from astrocytes and cell viability or survival 1 h after OGDR. Interestingly, after 3 or 5 h OGDR, P J34 significantly reduced LDH release and percentage of PI-positive cells and increased cell viability, and simultaneously increased the caspase-dependent apop- totic rate. The intervention timing study demonstrated that an earlier and longer P J34 intervention dur- ing reperfusion was associated with more apparent protective effects. In conclusion, earlier and longer PJ34 intervention provides remarkable protective effects for astrocytes in the ＂ischaemic core＂ mainly by reducing oncosis of the astrocytes, especially following serious OGDR damage.
文摘OBJECTIVE To reveal the biological effects and effective dosage in radiotherapy model which applies high single-dose irradiation by animal experiment. METHODS We inoculated subcutaneouly human pancreatic carcinoma cell line （MIA PaCa-2） in the lateral of the right lower extremity of the athymic mouse to grow transplantation tumor. While the median diameter of transplantation tumor reached 10 mm approximately, the animals were randomly divided into 7 groups （6 animals per group） and irradiation by different dose in one fixed with consciousness for fraction （0, 2, 5, 10, 17, 25, 35 Gy）. All were kept on to be bred for observation of the change in gross tumor volume, calculation of delayed growth time and delayed growth curve. RESULTS With increased dose per fraction, cutaneous reaction on the neoplasma surface of the animal, which was mainly moist yellow effusion was more and more severe. When dosage is less than 10 Gy, all animals showed similar effects, that＇s the delayed tumor growth was not obvious. Tumors receiving more than 10 Gy in one fraction showed very good biological effect and the delayed tumor growth was obviously related to dosage. The difference in delayed tumor growth between the 2 groups was statistically significant. The delayed tumor growth time in 10, 17, 25 Gy group was respectively 3 weeks, 6 weeks and more. CONCLUSION The biological effect of the model which applies high single-dose irradiation （more than 10 Gy in one fraction） was very good. The effect of delayed tumor growth was obviously related to the dosage after transplantation tumor was radiated. Because of its higher dose per fraction and biological effects, the model of high single-dose irradiation can get better clinical effects.
基金supported by the Beijing Natural Science Foundation (7202034)the National Natural Science Foundation of China (82170614)。
文摘Ferroptosis is a recently identified iron-dependent form of nonapoptotic cell death characterized by reactive oxygen species(ROS) generation and lipid peroxidation.Here,we report a novel iron-dependent form of ferroptosis induced by labile iron and investigate the mechanism underlying this process.We find that labile iron-induced ferroptosis is distinct from canonical ferroptosis and is linked to the mitochondrial pathway.Specifically,the mitochondrial calcium uniporter mediates the ferroptosis induced by labile iron.Interestingly,cells undergoing labile iron-induced ferroptosis exhibit cytoplasmic features of oncosis and nuclear features of apoptosis.Furthermore,labile iron-induced ferroptosis involves a unique set of genes.Finally,labile ironinduced ferroptosis was observed in liver subjected to acute iron overload in vivo.Our study reveals a novel form of ferroptosis that may be implicated in diseases caused by acute injury.
基金supported by the National Key Research and Development Program of China(No.2020YFC2008304)Natural Science Foundation of Henan Province(No.222300420350)+3 种基金National Natural Science Foundation of China(No.82204389),Medical Science and Technique Foundation of Henan Province(No.LHGJ20200310,SBGJ202102145)Foundation of Henan Educational Committee(No.21A310027,No.21A350014)National Natural Science Young Scientists Foundation of China(No.82200796)China Postdoctoral Science Foundation(No.2022M722901).
文摘Globally,ischemic stroke causes millions of deaths per year.The outcomes of ischemic stroke are largely determined by the amount of ischemia-related and reperfusion-related neuronal death in the infarct region.In the infarct region,cell injuries follow either the regulated pathway involving precise signaling cascades,such as apoptosis and autophagy,or the nonregulated pathway,which is uncontrolled by any molecularly defined effector mechanisms such as necrosis.However,numerous studies have recently found that a certain type of necrosis can be regulated and potentially modified by drugs and is nonapoptotic;this type of necrosis is referred to as regulated necrosis.Depending on the signaling pathway,various elements of regulated necrosis contribute to the development of ischemic stroke,such as necroptosis,pyroptosis,ferroptosis,pathanatos,mitochondrial permeability transition pore-mediated necrosis and oncosis.In this review,we aim to summarize the underlying molecular mechanisms of regulated necrosis in ischemic stroke and explore the crosstalk and interplay among the diverse types of regulated necrosis.We believe that targeting these regulated necrosis pathways both pharmacologically and genetically in ischemiainduced neuronal death and protection could be an efficient strategy to increase neuronal survival and regeneration in ischemic stroke.
