Evidence suggests that autophagy may be a new therapeutic target for stroke, but whether acti- vation of autophagy increases or decreases the rate of neuronal death is still under debate. This review summarizes the po...Evidence suggests that autophagy may be a new therapeutic target for stroke, but whether acti- vation of autophagy increases or decreases the rate of neuronal death is still under debate. This review summarizes the potential role and possible signaling pathway of autophagy in neuronal survival after cerebral ischemia and proposes that autophagy has dual effects.展开更多
Autophagy is involved in neural cell death after cerebral ischemia. Our previous studies showed that rapamycin-induced autophagy decreased the rate of apoptosis, but the rate of apoptosis was in- creased after the aut...Autophagy is involved in neural cell death after cerebral ischemia. Our previous studies showed that rapamycin-induced autophagy decreased the rate of apoptosis, but the rate of apoptosis was in- creased after the autophagy inhibitor, 3-methyladenine, was used. In this study, a suture-occluded method was performed to generate a rat model of brain ischemia. Under a transmission electron microscope, autophagic bodies and autophagy lysosomes were markedly accumulated in neurons at 4 hours post brain ischemic injury, with their numbers gradually reducing over time. Western blotting demonstrated that protein levels of light chain 3-11 and cathepsin B were significantly in- creased within 4 hours of ischemic injury, but these levels were not persistently upregulated over time. Confocal microscopy showed that autophagy was mainly found in neurons with positive light chain 3 signal. Injection of rapamycin via tail vein promoted the occurrence of autophagy in rat brain tissue after cerebral ischemia and elevated light chain 3 and cathepsin B expression. However, in- jection of 3-methyladenine significantly diminished light chain 3-11 and cathepsin B expression. Results verified that autophagic and lysosomal activity is increased in ischemic neurons. Abnormal components in cells can be eliminated through upregulating cell autophagy or inhibiting autophagy after ischemic brain injury, resulting in a dynamic balance of substances in cells. Moreover, drugs that interfere with autophagy may be potential therapies for the treatment of brain injury.展开更多
Lumbar degenerative disc diseases cause low back pain(LBP). The maintenance of the height and stability of the intervertebral disc(IVD) space is an effective treatment for LBP. The following study evaluated the effect...Lumbar degenerative disc diseases cause low back pain(LBP). The maintenance of the height and stability of the intervertebral disc(IVD) space is an effective treatment for LBP. The following study evaluated the effects of fibroblast injection on intervertebral disc degeneration(IDD) in a preclinical setting. Compared with the IDD group, the fibroblast treatment group demonstrated effective maintenance of IVD height, reduced endplate degeneration, and improved nuclear magnetic resonance signals and overall histological structure. In doing so, fibrotic IVDs maintained the stability and biomechanics of the vertebra. This finding is in agreement with clinical findings that human nucleus pulposus(NP) fibrosis is essential for the maintenance of IVD height and mechanical properties in patients following percutaneous endoscopic lumbar discectomy(PELD). Mechanistically, we demonstrated that injected fibroblasts not only proliferated but also induced NP cells to adopt a fibrotic phenotype via the secretion of TGF-β.Finally, to better mimic human conditions, the efficacy of autologous fibroblast injection in the treatment of IDD was further examined in a nonhuman primate cynomolgus monkey model due to their capacity for upright posture. We showed that the injection of fibroblasts could maintain the IVD height and rescue IVD signals in cynomolgus monkeys. Taken together, the results of our study reveal that autologous fibroblast injection can enhance the natural process of fibrosis during acute and subacute stages of stress-induced IDD. Fibrotic IVDs can maintain the stability, biological activity, and mechanical properties of the intervertebral space, thus providing a new direction for the treatment of intervertebral space-derived lumbar degenerative diseases.展开更多
This study aimed to reconstruct a three-dimensional map of axonal mitochondria using Fiji and Neurolucida software, and to observe directly the morphology and distribution of mitochondria in axons of motor neurons in ...This study aimed to reconstruct a three-dimensional map of axonal mitochondria using Fiji and Neurolucida software, and to observe directly the morphology and distribution of mitochondria in axons of motor neurons in dorsal longitudinal flight muscles of drosophila aged 5 days and 20 days, using electron microscopy. Results indicated that there was no difference in the total area and volume of mitochondria between 5-day-old drosophila and 20-day-old drosophila in all sections, but the ratio of mitochondrial total areas to axon total areas, as well as mitochondrial density of 20-day-old drosophila, was lower than that of 5-day-old drosophila. The number of mitochondria, whose volume was less than 1 000 000 IJm3, and between 1 000 000 pm3 and 10 000 000 pm3, was higher in 20-day-old drosophila than that in 5-day-old drosophila. The number of mitochondria with a volume between 1 000 000 pm3 and 100 000 000 IJm3 was apparently higher than those with a volume less than 1 000 000 t.lm3 or larger than 100 000 000 IJm3. In addition, the number of mitochondria with a volume more than 100 000 000 tJm3 was small; however, the volume was nearly 70% of the total volume in both 5-day-old and 20-day-old drosophila. In contrast, the number of mitochondria with a volume between 1 000 000 t.Jm3 and 10 000 000 IJm3 was large, but the volume was less than 30% of the total volume. These experimental findings suggest that changes in mitochondrial morphology and number in motor neurons from the dorsal longitudinal muscle of drosophila are present during different ages.展开更多
基金supported by grants from the project of National Natural Science Foundation of China,No.31171014 and 31371065the project of Science and Technology Commission of Board of Health of Shanghai,China,No.20134125the Key Specialty(disease) Declaration of Pudong New Area’s Health System
文摘Evidence suggests that autophagy may be a new therapeutic target for stroke, but whether acti- vation of autophagy increases or decreases the rate of neuronal death is still under debate. This review summarizes the potential role and possible signaling pathway of autophagy in neuronal survival after cerebral ischemia and proposes that autophagy has dual effects.
基金supported by grants from the National Natural Science Foundation of China,No.31171014 and No.30970869the Project of Science and Technology Commission of ShanghaiCity,No.09DZ1950400+2 种基金Board of Health of Shanghai,China,No.2008086the Youth Projects of National Natural Science Foundation of China,No.31100783Youth Key Project in Shanghai College of Medicine of Fudan University,No.09-L37
文摘Autophagy is involved in neural cell death after cerebral ischemia. Our previous studies showed that rapamycin-induced autophagy decreased the rate of apoptosis, but the rate of apoptosis was in- creased after the autophagy inhibitor, 3-methyladenine, was used. In this study, a suture-occluded method was performed to generate a rat model of brain ischemia. Under a transmission electron microscope, autophagic bodies and autophagy lysosomes were markedly accumulated in neurons at 4 hours post brain ischemic injury, with their numbers gradually reducing over time. Western blotting demonstrated that protein levels of light chain 3-11 and cathepsin B were significantly in- creased within 4 hours of ischemic injury, but these levels were not persistently upregulated over time. Confocal microscopy showed that autophagy was mainly found in neurons with positive light chain 3 signal. Injection of rapamycin via tail vein promoted the occurrence of autophagy in rat brain tissue after cerebral ischemia and elevated light chain 3 and cathepsin B expression. However, in- jection of 3-methyladenine significantly diminished light chain 3-11 and cathepsin B expression. Results verified that autophagic and lysosomal activity is increased in ischemic neurons. Abnormal components in cells can be eliminated through upregulating cell autophagy or inhibiting autophagy after ischemic brain injury, resulting in a dynamic balance of substances in cells. Moreover, drugs that interfere with autophagy may be potential therapies for the treatment of brain injury.
基金supported by the National Natural Science Foundation of China (81871790) & (81572167)the Shanghai Hospital Development Center Foundation (SHDC12016110)
文摘Lumbar degenerative disc diseases cause low back pain(LBP). The maintenance of the height and stability of the intervertebral disc(IVD) space is an effective treatment for LBP. The following study evaluated the effects of fibroblast injection on intervertebral disc degeneration(IDD) in a preclinical setting. Compared with the IDD group, the fibroblast treatment group demonstrated effective maintenance of IVD height, reduced endplate degeneration, and improved nuclear magnetic resonance signals and overall histological structure. In doing so, fibrotic IVDs maintained the stability and biomechanics of the vertebra. This finding is in agreement with clinical findings that human nucleus pulposus(NP) fibrosis is essential for the maintenance of IVD height and mechanical properties in patients following percutaneous endoscopic lumbar discectomy(PELD). Mechanistically, we demonstrated that injected fibroblasts not only proliferated but also induced NP cells to adopt a fibrotic phenotype via the secretion of TGF-β.Finally, to better mimic human conditions, the efficacy of autologous fibroblast injection in the treatment of IDD was further examined in a nonhuman primate cynomolgus monkey model due to their capacity for upright posture. We showed that the injection of fibroblasts could maintain the IVD height and rescue IVD signals in cynomolgus monkeys. Taken together, the results of our study reveal that autologous fibroblast injection can enhance the natural process of fibrosis during acute and subacute stages of stress-induced IDD. Fibrotic IVDs can maintain the stability, biological activity, and mechanical properties of the intervertebral space, thus providing a new direction for the treatment of intervertebral space-derived lumbar degenerative diseases.
文摘This study aimed to reconstruct a three-dimensional map of axonal mitochondria using Fiji and Neurolucida software, and to observe directly the morphology and distribution of mitochondria in axons of motor neurons in dorsal longitudinal flight muscles of drosophila aged 5 days and 20 days, using electron microscopy. Results indicated that there was no difference in the total area and volume of mitochondria between 5-day-old drosophila and 20-day-old drosophila in all sections, but the ratio of mitochondrial total areas to axon total areas, as well as mitochondrial density of 20-day-old drosophila, was lower than that of 5-day-old drosophila. The number of mitochondria, whose volume was less than 1 000 000 IJm3, and between 1 000 000 pm3 and 10 000 000 pm3, was higher in 20-day-old drosophila than that in 5-day-old drosophila. The number of mitochondria with a volume between 1 000 000 pm3 and 100 000 000 IJm3 was apparently higher than those with a volume less than 1 000 000 t.lm3 or larger than 100 000 000 IJm3. In addition, the number of mitochondria with a volume more than 100 000 000 tJm3 was small; however, the volume was nearly 70% of the total volume in both 5-day-old and 20-day-old drosophila. In contrast, the number of mitochondria with a volume between 1 000 000 t.Jm3 and 10 000 000 IJm3 was large, but the volume was less than 30% of the total volume. These experimental findings suggest that changes in mitochondrial morphology and number in motor neurons from the dorsal longitudinal muscle of drosophila are present during different ages.