Human dental pulp stem cell transplantation has been shown to be an effective therapeutic strategy for spinal cord injury.However,whether the human dental pulp stem cell secretome can contribute to functional recovery...Human dental pulp stem cell transplantation has been shown to be an effective therapeutic strategy for spinal cord injury.However,whether the human dental pulp stem cell secretome can contribute to functional recovery after spinal cord injury remains unclear.In the present study,we established a rat model of spinal cord injury based on impact injury from a dropped weight and then intraperitoneally injected the rats with conditioned medium from human dental pulp stem cells.We found that the conditioned medium effectively promoted the recovery of sensory and motor functions in rats with spinal cord injury,decreased expression of the microglial pyroptosis markers NLRP3,GSDMD,caspase-1,and interleukin-1β,promoted axonal and myelin regeneration,and inhibited the formation of glial scars.In addition,in a lipopolysaccharide-induced BV2 microglia model,conditioned medium from human dental pulp stem cells protected cells from pyroptosis by inhibiting the NLRP3/caspase-1/interleukin-1βpathway.These results indicate that conditioned medium from human dental pulp stem cells can reduce microglial pyroptosis by inhibiting the NLRP3/caspase-1/interleukin-1βpathway,thereby promoting the recovery of neurological function after spinal cord injury.Therefore,conditioned medium from human dental pulp stem cells may become an alternative therapy for spinal cord injury.展开更多
Neuroinflammation exacerbates secondary damage after spinal cord injury,while microglia/macrophage pyroptosis is important to neuroinflammation.Circular RNAs(circRNAs)play a role in the central nervous system.However,...Neuroinflammation exacerbates secondary damage after spinal cord injury,while microglia/macrophage pyroptosis is important to neuroinflammation.Circular RNAs(circRNAs)play a role in the central nervous system.However,the functional role and mechanism of circRNAs in regulating microglia/macrophage pyroptosis after spinal cord injury are still poorly studied.In the present study,we detected microglia/macrophage pyroptosis in a female rat model of spinal cord injury,along with upregulated levels of circ0000381 in the spinal cord.Our further experimental results suggest that circ0000381 may function as a sponge to sequester endogenous microRNA423-3p(miR-423-3p),which can increase the expression of NOD-like receptor 3(NLRP3),a pyroptosis marker.Therefore,upregulation of circ0000381 may be a compensatory change after spinal cord injury to attenuate microglia/macrophage pyroptosis.Indeed,knockdown of circ0000381 expression exacerbated microglia/macrophage pyroptosis.Collectively,our findings provide novel evidence for the upregulation of circ0000381,which may serve as a neuroprotective mechanism to attenuate microglia/macrophage pyroptosis after spinal cord injury.Accordingly,circ0000381 may be a novel therapeutic target for the treatment of spinal cord injury.展开更多
Spinal cord injury（SCI） from trauma or disease severely impairs sensory and motor function. Neurorehabilitation after SCI is a complex medical process that focuses on improving neurologic function and repairing dama...Spinal cord injury（SCI） from trauma or disease severely impairs sensory and motor function. Neurorehabilitation after SCI is a complex medical process that focuses on improving neurologic function and repairing damaged connections in the central nervous system. An increasing number of preclinical studies suggest that melatonin may be useful for the treatment of SCI. Melatonin is an indolamine that is primarily secreted by the pineal gland and known to be regulated by photoperiodicity. However, it is also a versatile hormone with antioxidative, antiapoptotic, neuroprotective, and anti-inflammatory properties. Here, we review the neuroprotective properties of melatonin and the potential mechanisms by which it might be beneficial in the treatment of SCI. We also describe therapies that combine melatonin with exercise, oxytetracycline, and dexamethasone to attenuate the secondary injury after SCI and limit potential side effects. Finally, we discuss how injury at different spinal levels may differentially affect the secretion of melatonin.展开更多
Skeletal interoception regulates bone homeostasis through the prostaglandin E2(PGE2)concentration in bone.Vertebral endplates undergo ossification and become highly porous during intervertebral disc degeneration and a...Skeletal interoception regulates bone homeostasis through the prostaglandin E2(PGE2)concentration in bone.Vertebral endplates undergo ossification and become highly porous during intervertebral disc degeneration and aging.We found that the PGE2 concentration was elevated in porous endplates to generate spinal pain.Importantly,treatment with a high-dose cyclooxygenase 2 inhibitor(celecoxib,80 mg·kg−1 per day)decreased the prostaglandin E2 concentration and attenuated spinal pain in mice with lumbar spine instability.However,this treatment impaired bone formation in porous endplates,and spinal pain recurred after discontinuing the treatment.Interestingly,low-dose celecoxib(20 mg·kg−1 per day,which is equivalent to one-quarter of the clinical maximum dosage)induced a latent inhibition of spinal pain at 3 weeks post-treatment,which persisted even after discontinuing treatment.Furthermore,when the prostaglandin E2 concentration was maintained at the physiological level with low-dose celecoxib,endplate porosity was reduced significantly,which was associated with decreased sensory nerve innervation and spinal pain.These findings suggest that low-dose celecoxib may help to maintain skeletal interoception and decrease vertebral endplate porosity,thereby reducing sensory innervation and spinal pain in mice.展开更多
The field of research on pain originating from various bone diseases is expanding rapidly, with new mechanisms and targets asserting both peripheral and central sites of action. The scope of research is broadening fro...The field of research on pain originating from various bone diseases is expanding rapidly, with new mechanisms and targets asserting both peripheral and central sites of action. The scope of research is broadening from bone biology to neuroscience,neuroendocrinology, and immunology. In particular, the roles of primary sensory neurons and non-neuronal cells in the peripheral tissues as important targets for bone pain treatment are under extensive investigation in both pre-clinical and clinical settings. An understanding of the peripheral mechanisms underlying pain conditions associated with various bone diseases will aid in the appropriate application and development of optimal strategies for not only managing bone pain symptoms but also improving bone repairing and remodeling, which potentially cures the underlying etiology for long-term functional recovery. In this review, we focus on advances in important preclinical studies of significant bone pain conditions in the past 5 years that indicated new peripheral neuronal and non-neuronal mechanisms, novel targets for potential clinical interventions, and future directions of research.展开更多
BACKGROUND Myelodysplastic syndromes(MDSs)are a group of hematological diseases caused by expansion of an abnormal clone of hematopoietic stem cells.Primary MDS is a potentially premalignant clonal disorder that may p...BACKGROUND Myelodysplastic syndromes(MDSs)are a group of hematological diseases caused by expansion of an abnormal clone of hematopoietic stem cells.Primary MDS is a potentially premalignant clonal disorder that may progress to overt acute leukemia in 25%-50%of cases.However,most of these cases evolve into acute myeloid leukemia and rarely progress to acute lymphoblastic leukemia(ALL).Thus,transformation of MDS into B-cell ALL is rare.CASE SUMMARY A 58-year-old man was admitted to the hospital for reduced blood cell counts.Based on all the test results and the World Health Organization diagnosis and classification,the patient was finally diagnosed with ring-shaped sideroblastic MDS with refractory hemocytopenia due to multilineage dysplasia.We used red blood cell transfusions and other symptomatic support treatments.After 4 years,the patient felt dizziness,fatigue,and night sweats.We improved bone marrow and peripheral blood and other related auxiliary examinations.He was eventually diagnosed with B-lineage acute lymphocytic leukemia(MDS transformation).CONCLUSION The number of peripheral blood cells,type of MDS,proportion of primitive cells in bone marrow,and number and quality of karyotypes are all closely related to the conversion of MDS to ALL.展开更多
As one of the most important contemporary art forms,film is a medium to present stories with multi-dimensional stimulation.It seems that movies and interaction design are two unrelated majors,but in fact there are man...As one of the most important contemporary art forms,film is a medium to present stories with multi-dimensional stimulation.It seems that movies and interaction design are two unrelated majors,but in fact there are many contents and forms of existence in movies which take interaction design as the design method.In other words,movies and interaction design actually have a lot in common.This paper will analyze and find the interweaving points from the perspective of interaction design and film respectively.Also through some specific interaction or film cases to further explain the relationship between the two.展开更多
In addition to restoration of bladder, bowel, and motor functions, alleviating the accompanying debilitating pain is equally important for improving the quality of life of patients with spinal cord injury(SCI). Curren...In addition to restoration of bladder, bowel, and motor functions, alleviating the accompanying debilitating pain is equally important for improving the quality of life of patients with spinal cord injury(SCI). Currently,however, the treatment of chronic pain after SCI remains a largely unmet need. Electrical spinal cord stimulation(SCS) has been used to manage a variety of chronic pain conditions that are refractory to pharmacotherapy. Yet, its efficacy, benefit profiles, and mechanisms of action in SCI pain remain elusive, due to limited research, methodological weaknesses in previous clinical studies, and a lack of mechanistic exploration of SCS for SCI pain control. We aim to review recent studies and outline the therapeutic potential of different SCS paradigms for traumatic SCI pain. We begin with an overview of its manifestations,classification, potential underlying etiology, and currentchallenges for its treatment. The clinical evidence for using SCS in SCI pain is then reviewed. Finally, future perspectives of pre-clinical research and clinical study of SCS for SCI pain treatment are discussed.展开更多
Microglia can modulate spinal nociceptive transmission.Yet,their role in spinal cord stimulation(SCS)-induced pain inhibition is unclear.Here,we examined how SCS affects microglial activation in the lumbar cord of rat...Microglia can modulate spinal nociceptive transmission.Yet,their role in spinal cord stimulation(SCS)-induced pain inhibition is unclear.Here,we examined how SCS affects microglial activation in the lumbar cord of rats with chronic constriction injury(CCI)of the sciatic nerve.Male rats received conventional SCS(50 Hz,80%motor threshold,180 min,2 sessions/day)or sham stimulation on days 18-20 post-CCI.SCS transiently attenuated the mechanical hypersensitivity in the ipsilateral hind paw and increased OX-42 immunoreactivity in the bilateral dorsal horns.SCS also upregulated the mRNAs of Ml-like markers,but not M2-like markers.Inducible NOS protein expression was increased,but brain-derived neurotrophic factor was decreased after SCS.Intrathecal minocycline(1μg-100μg),which inhibits microglial activation,dosedependently attenuated the mechanical hypersensitivity.Pretreatment with low-dose minocycline(1μg,30 min)prolonged the SCS-induced pain inhibition.These findings suggest that conventional SCS may paradoxically increase spinal M1-like microglial activity and thereby compromise its own ability to inhibit pain.展开更多
基金supported by the Research Foundation of Technology Committee of Tongzhou District,No.KJ2019CX001(to SX).
文摘Human dental pulp stem cell transplantation has been shown to be an effective therapeutic strategy for spinal cord injury.However,whether the human dental pulp stem cell secretome can contribute to functional recovery after spinal cord injury remains unclear.In the present study,we established a rat model of spinal cord injury based on impact injury from a dropped weight and then intraperitoneally injected the rats with conditioned medium from human dental pulp stem cells.We found that the conditioned medium effectively promoted the recovery of sensory and motor functions in rats with spinal cord injury,decreased expression of the microglial pyroptosis markers NLRP3,GSDMD,caspase-1,and interleukin-1β,promoted axonal and myelin regeneration,and inhibited the formation of glial scars.In addition,in a lipopolysaccharide-induced BV2 microglia model,conditioned medium from human dental pulp stem cells protected cells from pyroptosis by inhibiting the NLRP3/caspase-1/interleukin-1βpathway.These results indicate that conditioned medium from human dental pulp stem cells can reduce microglial pyroptosis by inhibiting the NLRP3/caspase-1/interleukin-1βpathway,thereby promoting the recovery of neurological function after spinal cord injury.Therefore,conditioned medium from human dental pulp stem cells may become an alternative therapy for spinal cord injury.
基金supported by the National Natural Science Foundation of China,No.81901241(to YZ)。
文摘Neuroinflammation exacerbates secondary damage after spinal cord injury,while microglia/macrophage pyroptosis is important to neuroinflammation.Circular RNAs(circRNAs)play a role in the central nervous system.However,the functional role and mechanism of circRNAs in regulating microglia/macrophage pyroptosis after spinal cord injury are still poorly studied.In the present study,we detected microglia/macrophage pyroptosis in a female rat model of spinal cord injury,along with upregulated levels of circ0000381 in the spinal cord.Our further experimental results suggest that circ0000381 may function as a sponge to sequester endogenous microRNA423-3p(miR-423-3p),which can increase the expression of NOD-like receptor 3(NLRP3),a pyroptosis marker.Therefore,upregulation of circ0000381 may be a compensatory change after spinal cord injury to attenuate microglia/macrophage pyroptosis.Indeed,knockdown of circ0000381 expression exacerbated microglia/macrophage pyroptosis.Collectively,our findings provide novel evidence for the upregulation of circ0000381,which may serve as a neuroprotective mechanism to attenuate microglia/macrophage pyroptosis after spinal cord injury.Accordingly,circ0000381 may be a novel therapeutic target for the treatment of spinal cord injury.
基金supported by the National Natural Science Foundation of China,No.81671161(to ZJL)
文摘Spinal cord injury（SCI） from trauma or disease severely impairs sensory and motor function. Neurorehabilitation after SCI is a complex medical process that focuses on improving neurologic function and repairing damaged connections in the central nervous system. An increasing number of preclinical studies suggest that melatonin may be useful for the treatment of SCI. Melatonin is an indolamine that is primarily secreted by the pineal gland and known to be regulated by photoperiodicity. However, it is also a versatile hormone with antioxidative, antiapoptotic, neuroprotective, and anti-inflammatory properties. Here, we review the neuroprotective properties of melatonin and the potential mechanisms by which it might be beneficial in the treatment of SCI. We also describe therapies that combine melatonin with exercise, oxytetracycline, and dexamethasone to attenuate the secondary injury after SCI and limit potential side effects. Finally, we discuss how injury at different spinal levels may differentially affect the secretion of melatonin.
基金supported by National Institute on Aging of the National Institutes of Health under Award Number R01 AG068997 and P01 AG066603(to X.C.).
文摘Skeletal interoception regulates bone homeostasis through the prostaglandin E2(PGE2)concentration in bone.Vertebral endplates undergo ossification and become highly porous during intervertebral disc degeneration and aging.We found that the PGE2 concentration was elevated in porous endplates to generate spinal pain.Importantly,treatment with a high-dose cyclooxygenase 2 inhibitor(celecoxib,80 mg·kg−1 per day)decreased the prostaglandin E2 concentration and attenuated spinal pain in mice with lumbar spine instability.However,this treatment impaired bone formation in porous endplates,and spinal pain recurred after discontinuing the treatment.Interestingly,low-dose celecoxib(20 mg·kg−1 per day,which is equivalent to one-quarter of the clinical maximum dosage)induced a latent inhibition of spinal pain at 3 weeks post-treatment,which persisted even after discontinuing treatment.Furthermore,when the prostaglandin E2 concentration was maintained at the physiological level with low-dose celecoxib,endplate porosity was reduced significantly,which was associated with decreased sensory nerve innervation and spinal pain.These findings suggest that low-dose celecoxib may help to maintain skeletal interoception and decrease vertebral endplate porosity,thereby reducing sensory innervation and spinal pain in mice.
文摘The field of research on pain originating from various bone diseases is expanding rapidly, with new mechanisms and targets asserting both peripheral and central sites of action. The scope of research is broadening from bone biology to neuroscience,neuroendocrinology, and immunology. In particular, the roles of primary sensory neurons and non-neuronal cells in the peripheral tissues as important targets for bone pain treatment are under extensive investigation in both pre-clinical and clinical settings. An understanding of the peripheral mechanisms underlying pain conditions associated with various bone diseases will aid in the appropriate application and development of optimal strategies for not only managing bone pain symptoms but also improving bone repairing and remodeling, which potentially cures the underlying etiology for long-term functional recovery. In this review, we focus on advances in important preclinical studies of significant bone pain conditions in the past 5 years that indicated new peripheral neuronal and non-neuronal mechanisms, novel targets for potential clinical interventions, and future directions of research.
基金Shandong Medicine and Health Science Technology Development Plan,No.2017WSA08039Jining Key Research and Development Program,No.2018SMNS008+1 种基金Doctoral Research Startup Foundation of Jining First People’s Hospital,No.2019003and TCM Technology Development Plan,No.20190744.
文摘BACKGROUND Myelodysplastic syndromes(MDSs)are a group of hematological diseases caused by expansion of an abnormal clone of hematopoietic stem cells.Primary MDS is a potentially premalignant clonal disorder that may progress to overt acute leukemia in 25%-50%of cases.However,most of these cases evolve into acute myeloid leukemia and rarely progress to acute lymphoblastic leukemia(ALL).Thus,transformation of MDS into B-cell ALL is rare.CASE SUMMARY A 58-year-old man was admitted to the hospital for reduced blood cell counts.Based on all the test results and the World Health Organization diagnosis and classification,the patient was finally diagnosed with ring-shaped sideroblastic MDS with refractory hemocytopenia due to multilineage dysplasia.We used red blood cell transfusions and other symptomatic support treatments.After 4 years,the patient felt dizziness,fatigue,and night sweats.We improved bone marrow and peripheral blood and other related auxiliary examinations.He was eventually diagnosed with B-lineage acute lymphocytic leukemia(MDS transformation).CONCLUSION The number of peripheral blood cells,type of MDS,proportion of primitive cells in bone marrow,and number and quality of karyotypes are all closely related to the conversion of MDS to ALL.
文摘As one of the most important contemporary art forms,film is a medium to present stories with multi-dimensional stimulation.It seems that movies and interaction design are two unrelated majors,but in fact there are many contents and forms of existence in movies which take interaction design as the design method.In other words,movies and interaction design actually have a lot in common.This paper will analyze and find the interweaving points from the perspective of interaction design and film respectively.Also through some specific interaction or film cases to further explain the relationship between the two.
基金supported by grants from the National Institutes of Health, Bethesda, MD (R01NS70814 and R21NS99879 to YG)
文摘In addition to restoration of bladder, bowel, and motor functions, alleviating the accompanying debilitating pain is equally important for improving the quality of life of patients with spinal cord injury(SCI). Currently,however, the treatment of chronic pain after SCI remains a largely unmet need. Electrical spinal cord stimulation(SCS) has been used to manage a variety of chronic pain conditions that are refractory to pharmacotherapy. Yet, its efficacy, benefit profiles, and mechanisms of action in SCI pain remain elusive, due to limited research, methodological weaknesses in previous clinical studies, and a lack of mechanistic exploration of SCS for SCI pain control. We aim to review recent studies and outline the therapeutic potential of different SCS paradigms for traumatic SCI pain. We begin with an overview of its manifestations,classification, potential underlying etiology, and currentchallenges for its treatment. The clinical evidence for using SCS in SCI pain is then reviewed. Finally, future perspectives of pre-clinical research and clinical study of SCS for SCI pain treatment are discussed.
基金the Neurosurgery Pain Research Institute at the Johns Hopkins University and subsidized by the National Institutes of Health(Bethesda,Maryland,USA)(NS 110598)supported by an award from the China Scholarship Council for Chinese PhD candidates to study abroad。
文摘Microglia can modulate spinal nociceptive transmission.Yet,their role in spinal cord stimulation(SCS)-induced pain inhibition is unclear.Here,we examined how SCS affects microglial activation in the lumbar cord of rats with chronic constriction injury(CCI)of the sciatic nerve.Male rats received conventional SCS(50 Hz,80%motor threshold,180 min,2 sessions/day)or sham stimulation on days 18-20 post-CCI.SCS transiently attenuated the mechanical hypersensitivity in the ipsilateral hind paw and increased OX-42 immunoreactivity in the bilateral dorsal horns.SCS also upregulated the mRNAs of Ml-like markers,but not M2-like markers.Inducible NOS protein expression was increased,but brain-derived neurotrophic factor was decreased after SCS.Intrathecal minocycline(1μg-100μg),which inhibits microglial activation,dosedependently attenuated the mechanical hypersensitivity.Pretreatment with low-dose minocycline(1μg,30 min)prolonged the SCS-induced pain inhibition.These findings suggest that conventional SCS may paradoxically increase spinal M1-like microglial activity and thereby compromise its own ability to inhibit pain.
