Cannabidiol(CBD),the second most significant phytocannabinoid in the plant Cannabis sativa,which lacks potential as a drug of abuse(Viudez-Martinez et al.,2019),has gained widespread attention due to its anti-inflamma...Cannabidiol(CBD),the second most significant phytocannabinoid in the plant Cannabis sativa,which lacks potential as a drug of abuse(Viudez-Martinez et al.,2019),has gained widespread attention due to its anti-inflammatory,antioxidant,and antidepressant properties(Garci a-Gutierrez et al.,2020).Additionally,CBD exhibits neuroprotective properties,preserving neuronal viability and function by preventing or limiting cellular damage.Our team has demonstrated that CBD produces rapid antidepressant-like effects in a murine model of chronic mild stress,restoring hippocampal expression of brain-derived neurotrophic factor(BDNF).展开更多
Neuronal degeneration and inflammation are hallmark features of spinal cord injury that severely hinder functional recovery.As key regulators of the post-injury microenvironment,macrophages can promote either tissue r...Neuronal degeneration and inflammation are hallmark features of spinal cord injury that severely hinder functional recovery.As key regulators of the post-injury microenvironment,macrophages can promote either tissue repair or exacerbate damage.Among macrophage secreted factors,transforming growth factor-beta 1 has emerged as a critical mediator of pathological changes.In this study,we show the pivotal role of macrophage-derived transforming growth factor-beta 1 in driving neuronal senescence and impairing functional recovery after spinal cord injury.In a mouse spinal cord injury model,transforming growth factor-beta 1 levels were significantly increased at the injury site,accompanied by increased mothers against decapentaplegic homolog 2(SMAD2)phosphorylation and upregulation of neuronal senescence markers such as p16INK4a andβ-galactosidase activity.Treatment with LY-364947,a SMAD2 phosphorylation inhibitor,markedly reduced the number of senescent neurons,mitigated tissue degeneration,and improved motor function recovery.Additionally,macrophage depletion using clodronate liposomes lowered transforming growth factor-beta 1 levels at the injury site and attenuated neuronal senescence.These findings highlight the transforming growth factor-beta 1-SMAD2 signaling axis as a potential therapeutic target to reduce neuronal senescence and enhance functional recovery following spinal cord injury.展开更多
Among the macromolecular drug targets in neurodegenerative disorders, the neurotrophin brain-derived neurotrophic factor（BDNF） and its high-affinity tropomyosin-related kinase receptor（Trk B） present strong intere...Among the macromolecular drug targets in neurodegenerative disorders, the neurotrophin brain-derived neurotrophic factor（BDNF） and its high-affinity tropomyosin-related kinase receptor（Trk B） present strong interest for nanomedicine development aiming at neuronal and synaptic repair. Currently, BDNF is regarded as the neurotrophic factor of highest therapeutic significance. However, BDNF has delivery problems as a protein drug. The enhanced activation of the transcription factor CREB（c AMP response element-binding protein） has been evidenced to increase the BDNF gene expression and hence the production of endogenous BDNF. We assume that BDNF delivery by nanocarriers and mitochondrial protection may provide high potential for therapeutic amelioration of the neuroregenerative strategies. Beneficial therapeutic outcomes may be expected for synergistic dual or multi-drug action aiming at（i） neurotrophic protein regulation in the central and peripheral nervous systems, and（ii） diminishment of the production of reactive oxygen species（ROS） and the oxidative damage in mitochondria. Our research strategy is based on a nanoarchitectonics approach for the design of nanomedicine assemblies by hierarchical self-assembly. We explore nanoarchitectonics concepts in soft-matter nanotechnology towards preparation of biodegradable self-assembled lipid nanostructures for safe neuro-therapeutic applications of multi-target nanomedicines.展开更多
Excessive noise, ototoxic drugs, infections, autoimmune diseases, and aging can cause loss of spiral ganglion neurons, leading to permanent sensorineural hearing loss in mammals. Stem cells have been confirmed to be a...Excessive noise, ototoxic drugs, infections, autoimmune diseases, and aging can cause loss of spiral ganglion neurons, leading to permanent sensorineural hearing loss in mammals. Stem cells have been confirmed to be able to differentiate into spiral ganglion neurons. Little has been reported on adipose tissue-derived stem cells（ADSCs） for repair of injured spiral ganglion neurons. In this study, we hypothesized that transplantation of neural induced-human ADSCs（NI-h ADSCs） can repair the injured spiral ganglion neurons in guinea pigs with neomycin-induced sensorineural hearing loss. NI-h ADSCs were induced with culture medium containing basic fibroblast growth factor and forskolin and then injected to the injured cochleae. Guinea pigs that received injection of Hanks＇ balanced salt solution into the cochleae were used as controls. Hematoxylin-eosin staining showed that at 8 weeks after cell transplantation, the number of surviving spiral ganglion neurons in the cell transplantation group was significantly increased than that in the control group. Also at 8 weeks after cell transplantation, immunohistochemical staining showed that a greater number of NI-h ADSCs in the spiral ganglions were detected in the cell transplantation group than in the control group, and these NI-h ADSCs expressed neuronal markers neurofilament protein and microtubule-associated protein 2. Within 8 weeks after cell transplantation, the guinea pigs in the cell transplantation group had a gradually decreased auditory brainstem response threshold, while those in the control group had almost no response to 80 d B of clicks or pure tone burst. These findings suggest that a large amount of NI-h ADSCs migrated to the spiral ganglions, survived for a period of time, repaired the injured spiral ganglion cells, and thereby contributed to the recovery of sensorineural hearing loss in guinea pigs.展开更多
Stem cell treatments,and in particular,stem cell transplants have been identified as potential therapeutic strategies for a range of neurodegenerative and acquired conditions of the central nervous system（CNS）.Stem ...Stem cell treatments,and in particular,stem cell transplants have been identified as potential therapeutic strategies for a range of neurodegenerative and acquired conditions of the central nervous system（CNS）.Stem cell transplants are seen as a way of replacing lost neurons,or providing a cellular environment that is more permissible for axon and cell regeneration.展开更多
基金supported by Instituto de Salud CarlosⅢ,Spanish Ministry of Science and Innovation,grant number PI18/00576 to MSGG and JMRRed de Investigación en Atención Primaria de Adicciones,Instituto de Salud CarlosⅢ,Spanish Ministry of Science and Innovation,grant number RD21/0009/0008 and RD24/0003/0002+1 种基金Instituto de Investigación Sanitaria y Biomédica de Alicante(ISABIAL)to JMThe Instituto de Neurociencias is a“Centre of Excellence Severo Ochoa”(CEX2021-001165-S).
文摘Cannabidiol(CBD),the second most significant phytocannabinoid in the plant Cannabis sativa,which lacks potential as a drug of abuse(Viudez-Martinez et al.,2019),has gained widespread attention due to its anti-inflammatory,antioxidant,and antidepressant properties(Garci a-Gutierrez et al.,2020).Additionally,CBD exhibits neuroprotective properties,preserving neuronal viability and function by preventing or limiting cellular damage.Our team has demonstrated that CBD produces rapid antidepressant-like effects in a murine model of chronic mild stress,restoring hippocampal expression of brain-derived neurotrophic factor(BDNF).
基金supported by grants from Tianjin Key Medical Discipline(Specialty)Construct Project,No.TJYXZDXK-027A(to SF)National Key Research and Development Project of Stem Cell and Transformation Research,No.2019YFA0112100(to SF)+3 种基金the National Natural Science Foundation of China,Nos.81930070(to SF),82402825(to XS)Tianjin Health Science and Technology Project Key Discipline Special Project,No.hUCMSC preferred subgroup,No.TJWJ2022XK002(to SF)2022 Beijing-Tianjin-Hebei Basic Research Cooperation Project,No.22JCZXJC00050(to SF)Youth Research Incubation Fund of School of Basic Medical Sciences,Tianjin Medical University,No.023FY05(to XS).
文摘Neuronal degeneration and inflammation are hallmark features of spinal cord injury that severely hinder functional recovery.As key regulators of the post-injury microenvironment,macrophages can promote either tissue repair or exacerbate damage.Among macrophage secreted factors,transforming growth factor-beta 1 has emerged as a critical mediator of pathological changes.In this study,we show the pivotal role of macrophage-derived transforming growth factor-beta 1 in driving neuronal senescence and impairing functional recovery after spinal cord injury.In a mouse spinal cord injury model,transforming growth factor-beta 1 levels were significantly increased at the injury site,accompanied by increased mothers against decapentaplegic homolog 2(SMAD2)phosphorylation and upregulation of neuronal senescence markers such as p16INK4a andβ-galactosidase activity.Treatment with LY-364947,a SMAD2 phosphorylation inhibitor,markedly reduced the number of senescent neurons,mitigated tissue degeneration,and improved motor function recovery.Additionally,macrophage depletion using clodronate liposomes lowered transforming growth factor-beta 1 levels at the injury site and attenuated neuronal senescence.These findings highlight the transforming growth factor-beta 1-SMAD2 signaling axis as a potential therapeutic target to reduce neuronal senescence and enhance functional recovery following spinal cord injury.
基金supported by CNRSsupported by the Czech Science Foundation Grant GACR 17-00973S+1 种基金the projects ELI-Extreme Light Infrastructure–phase 2(CZ.02.1.01/0.0/0.0/15_008/0000162)ELIBIO(CZ.02.1.01/0.0/0.0/15_003/0000447)from the European Regional Development Fund
文摘Among the macromolecular drug targets in neurodegenerative disorders, the neurotrophin brain-derived neurotrophic factor（BDNF） and its high-affinity tropomyosin-related kinase receptor（Trk B） present strong interest for nanomedicine development aiming at neuronal and synaptic repair. Currently, BDNF is regarded as the neurotrophic factor of highest therapeutic significance. However, BDNF has delivery problems as a protein drug. The enhanced activation of the transcription factor CREB（c AMP response element-binding protein） has been evidenced to increase the BDNF gene expression and hence the production of endogenous BDNF. We assume that BDNF delivery by nanocarriers and mitochondrial protection may provide high potential for therapeutic amelioration of the neuroregenerative strategies. Beneficial therapeutic outcomes may be expected for synergistic dual or multi-drug action aiming at（i） neurotrophic protein regulation in the central and peripheral nervous systems, and（ii） diminishment of the production of reactive oxygen species（ROS） and the oxidative damage in mitochondria. Our research strategy is based on a nanoarchitectonics approach for the design of nanomedicine assemblies by hierarchical self-assembly. We explore nanoarchitectonics concepts in soft-matter nanotechnology towards preparation of biodegradable self-assembled lipid nanostructures for safe neuro-therapeutic applications of multi-target nanomedicines.
基金supported by Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by Ministry of Education,Science and Technology,No.2010-0025501a grant from Chonnam National University Hospital Biomedical Research Institute,No.CRI11048-1a grant from the Chonnam National University,No.2012-2894
文摘Excessive noise, ototoxic drugs, infections, autoimmune diseases, and aging can cause loss of spiral ganglion neurons, leading to permanent sensorineural hearing loss in mammals. Stem cells have been confirmed to be able to differentiate into spiral ganglion neurons. Little has been reported on adipose tissue-derived stem cells（ADSCs） for repair of injured spiral ganglion neurons. In this study, we hypothesized that transplantation of neural induced-human ADSCs（NI-h ADSCs） can repair the injured spiral ganglion neurons in guinea pigs with neomycin-induced sensorineural hearing loss. NI-h ADSCs were induced with culture medium containing basic fibroblast growth factor and forskolin and then injected to the injured cochleae. Guinea pigs that received injection of Hanks＇ balanced salt solution into the cochleae were used as controls. Hematoxylin-eosin staining showed that at 8 weeks after cell transplantation, the number of surviving spiral ganglion neurons in the cell transplantation group was significantly increased than that in the control group. Also at 8 weeks after cell transplantation, immunohistochemical staining showed that a greater number of NI-h ADSCs in the spiral ganglions were detected in the cell transplantation group than in the control group, and these NI-h ADSCs expressed neuronal markers neurofilament protein and microtubule-associated protein 2. Within 8 weeks after cell transplantation, the guinea pigs in the cell transplantation group had a gradually decreased auditory brainstem response threshold, while those in the control group had almost no response to 80 d B of clicks or pure tone burst. These findings suggest that a large amount of NI-h ADSCs migrated to the spiral ganglions, survived for a period of time, repaired the injured spiral ganglion cells, and thereby contributed to the recovery of sensorineural hearing loss in guinea pigs.
基金supported by University of Technology,Sydney Early Career Research Grant to CAG
文摘Stem cell treatments,and in particular,stem cell transplants have been identified as potential therapeutic strategies for a range of neurodegenerative and acquired conditions of the central nervous system（CNS）.Stem cell transplants are seen as a way of replacing lost neurons,or providing a cellular environment that is more permissible for axon and cell regeneration.
