Alzheimer'sdisease(AD)isaprogressive neurodegenerative disorder characterized by cognitive impairment and distinct neuropathological features,including amyloid-βplaques,neurofibrillary tangles,and reactive astrog...Alzheimer'sdisease(AD)isaprogressive neurodegenerative disorder characterized by cognitive impairment and distinct neuropathological features,including amyloid-βplaques,neurofibrillary tangles,and reactive astrogliosis.Developing effective diagnostic,preventative,and therapeutic strategies for AD necessitates the establishment of animal models that accurately recapitulate the pathophysiological processes of the disease.Existing transgenic mouse models have significantly contributed to understanding AD pathology but often fail to replicate the complexity of human AD.Additionally,these models are limited in their ability to elucidate the interplay among amyloid-βplaques,neurofibrillary tangles,and reactive astrogliosis due to the absence of spatially and temporally specific genetic manipulation.In this study,we introduce a novel AD mouse model(APP/PS1-TauP301L-Adeno mice)designed to rapidly induce pathological symptoms and enhance understanding of AD mechanisms.Neurofibrillary tangles and severe reactive astrogliosis were induced by injecting AAVDJ-EF1a-hTauP301L-EGFP and Adeno-GFAP-GFP viruses into the hippocampi of 5-month-old APP/PS1 mice.Three months post-injection,these mice exhibited pronounced astrogliosis,substantial amyloid-βplaque accumulation,extensiveneurofibrillarytangles,accelerated neuronal loss,elevated astrocytic GABA levels,and significant spatial memory deficits.Notably,these pathological features were less severe in AAVTauP301L-expressing APP/PS1 mice without augmented reactive astrogliosis.These findings indicate an exacerbating role of severe reactive astrogliosis in amyloid-βplaque and neurofibrillary tangle-associated pathology.The APP/PS1-TauP301L-Adeno mouse model provides a valuable tool for advancing therapeutic research aimed at mitigating the progression of AD.展开更多
Excessive osteoclastogenesis-mediated osteoporosis has been recognized as a global health concern.Candidate compounds derived from medicinal plants or functional foods are promising to treat osteoporosis due to their ...Excessive osteoclastogenesis-mediated osteoporosis has been recognized as a global health concern.Candidate compounds derived from medicinal plants or functional foods are promising to treat osteoporosis due to their high safety and efficiency.(−)-Epigallocatechin-3-gallate(EGCG)is the most abundant and biologically active polyphenol in green tea.It can inhibit osteoclastogenesis in vitro by blocking receptor activator of nuclear factor(NF)-κB(RANK)signaling pathways.This study used the ovariectomized(OVX)mouse model to estimate the therapeutic effect of EGCG on osteoporosis and verified the molecular mechanism in vivo.The results revealed that EGCG significantly inhibited the OVX-induced body weight gain.Moreover,no adverse effects were observed on blood glucose,histomorphological features,weights,as well as indices of liver and kidney in OVX mice.EGCG could significantly ameliorate bone loss in OVX mice by inhibiting osteoclastogenesis.This effect was evidenced by the reduced number of osteoclasts and the increased trabecular bone area in the femurs.Moreover,EGCG inhibited the activities of c-telopeptide of type I collagen(CTX-I)and tartrate-resistant acid phosphatase 5b(TRACP-5b)and strengthened bone gla protein(BGP)and procollagen I N-terminal peptide(PINP)activities in OVX mice.Mechanistically,EGCG significantly downregulated the expression of osteoclastogenesis-related marker genes and proteins,including nuclear factor of activated T cells,cytoplasmic 1(NFATc1),c-Fos,tartrate-resistant acid phosphatase(TRAP),c-Src,and cathepsin K.In addition,the phosphorylation levels of p65,c-Jun N-terminal kinase(JNK),extracellular signal-regulated kinase 1/2(ERK1/2),p38,and protein kinase B(AKT)were significantly suppressed in OVX mice.It was found that EGCG could alleviate OVX-induced bone loss in mice by suppressing osteoclastogenesis by blocking the NF-κB,mitogen-activated protein kinase(MAPK),and AKT signaling pathways.EGCG has the potential to prevent and treat osteoclast-related diseases such as osteoporosis.展开更多
Five new coumarin amide derivatives were synthesized with coupling reagent,the structures of which were characterized by IR,1H NMR,13C NMR,MS and element analysis.Their spectral properties were studied in dichlorometh...Five new coumarin amide derivatives were synthesized with coupling reagent,the structures of which were characterized by IR,1H NMR,13C NMR,MS and element analysis.Their spectral properties were studied in dichloromethane,in N,N-dimethylformamide（DMF） and in solid state.Solvent polarity has less influence on the UV-Vis maximum absorption at about 430 nm.The maximum emission wavelengths change from 464 nm to 474 nm in dichloromethane,from 476 nm to 482 nm in DMF and from 521 nm to 548 nm in solid state,respectively.The fluorescence intensities of compounds 8 and 9 were extremely strong in solvents or in solid state.Compounds 8 and 9 exhibited high fluorescenct quantumn yields in solution compared to compounds 4 ＂7.The fluorescence lifetimes of all the compounds in solvents were measured.展开更多
As serotoninergic transmission plays a crucial role in higher brain function in mammals, the disturbance of this system will likely have significant effects on emotion and cognition. Previous studies have reported tha...As serotoninergic transmission plays a crucial role in higher brain function in mammals, the disturbance of this system will likely have significant effects on emotion and cognition. Previous studies have reported that chronic treatment with Specific Serotonin Reuptake Inhibitors (SSRIs) during both late pregnancy and lactation was associated with abnormal behavior in adult rats. These data imply that disturbances in serotoninergic transmission during neurodevelopment may have negative effects on both the structure and function of the resultant adult brain. Therefore, the effect of a single exposure to an SSRI or a tricyclic antidepressant that preferentially inhibits serotonin reuptake during the pre-weaning period was examined in adult mice. An oral infusion of paroxetine (70 mg/kg), fluvoxamine (250 mg/kg), clomipramine (180 mg/kg), or saline was administered on postnatal day 14. Starting at 11 weeks of age, mice were assessed using a comprehensive behavioral test battery. Mice treated with paroxetine demonstrated altered behavior on the open field and hole-board tasks;those treated with fluvoxamine had behavioral changes on the light-dark box, hole-board, and sucrose preference tasks, while alteration in forced swimming and cued fear behavior were noted in mice treated with clomipramine. These results suggest that even a single administration of an antidepressant could have profound effects on behavior in adulthood, although the effects might differ dependent on the specific drug that was administered.展开更多
A<sub>2</sub>FeCoO<sub>6-δ</sub> (A = Ca or Sr) is synthesized by the solid-state synthesis method and their specific heat capacities are evaluated at 40˚C using a heat flow meter. The effect ...A<sub>2</sub>FeCoO<sub>6-δ</sub> (A = Ca or Sr) is synthesized by the solid-state synthesis method and their specific heat capacities are evaluated at 40˚C using a heat flow meter. The effect of the A-cation size on the specific heat capacity of these compounds is observed. The specific heat capacity of Sr<sub>2</sub>FeCoO<sub>6-δ</sub> is found to be the highest, and that of Ca<sub>2</sub>FeCoO<sub>6-δ</sub> is the lowest while CaSrFeCoO<sub>6-δ</sub> shows the intermediate value. The specific heat capacity decreases with the decrease of the average A-site ionic radius, demonstrating the relationship between heat capacity and A-site ionic radius. The relationship between specific heat capacity and molar mass is also confirmed as the δ value decreases or molar mass increases from Ca<sub>2</sub>FeCoO<sub>6-δ</sub> to CaSrFeCoO<sub>6-δ</sub> to Sr<sub>2</sub>FeCoO<sub>6-δ</sub>.展开更多
Glassy electrolytes could be a potential candidate for all-solid-state batteries that are considered new-generation energy storage devices. As glasses are one of the potential fast ion-conducting electrolytes, progres...Glassy electrolytes could be a potential candidate for all-solid-state batteries that are considered new-generation energy storage devices. As glasses are one of the potential fast ion-conducting electrolytes, progressive advances in glassy electrolytes have been undergoing to get commercial attention. However, the challenges offered by ionic conductivity at room temperature (10<sup>−5</sup> - 10<sup>−3</sup> S∙cm<sup>−1</sup>) in comparison to those of organic liquid electrolytes (10<sup>−2</sup> S∙cm<sup>−1</sup>) hindered the applicability of such electrolytes. To enhance the research development on ionic conductivity, the overall picture of the ionic conductivity of glassy electrolytes is reviewed in this article with a focus on alkali oxide and sulfide glasses. We portray here the techniques applied for alkali ion conductivity enhancement, such as methods of glass preparation, host optimization, doping, and salt addition for enhancing alkali ionic conductivity in the glasses.展开更多
Neuroregeneration and remyelination rarely occur in the adult mammalian brain and spinal cord following central nervous system(CNS)injury.The glial scar has been proposed as a major contributor to this failure in the ...Neuroregeneration and remyelination rarely occur in the adult mammalian brain and spinal cord following central nervous system(CNS)injury.The glial scar has been proposed as a major contributor to this failure in the regenerative process.However,its underlying molecular and cellular mechanisms remain unclear.Here,we report that monoamine oxidase B(MAOB)-dependent excessiveγ-aminobutyric acid(GABA)release from reactive astrocytes suppresses the CNS repair system by reducing brain‒derived neurotrophic factor(BDNF)and tropomyosin receptor kinase B(TrkB)expression in severe spinal cord injury(SCI)animal models.Genetic deletion of MAOB in a mouse SCI model promotes both functional and tissue recovery.Notably,the selective MAOB inhibitor,KDS2010,facilitates recovery and regeneration by disinhibiting the BDNF-TrkB axis in a rat SCI model.Its dose-dependent effects were further validated in a monkey SCI model.Moreover,KDS2010 demonstrated a tolerable safety profile and doseproportional pharmacokinetics in healthy humans during a phase 1 clinical trial.This pathway therefore represents a pivotal target for overcoming the intrinsic barriers to CNS repair after injury.Our findings identify the astrocytic MAOB‒GABA axis as a crucial molecular and cellular brake on the CNS repair system following SCI and highlight the translational potential of KDS2010 as a promising therapeutic candidate for SCI treatment.展开更多
Abstinence from prolonged psychostimulant use prompts stimulant withdrawal syndrome.Molecular adaptations within the dorsal striatum have been considered the main hallmark of stimulant abstinence. Here we explored str...Abstinence from prolonged psychostimulant use prompts stimulant withdrawal syndrome.Molecular adaptations within the dorsal striatum have been considered the main hallmark of stimulant abstinence. Here we explored striatal miRNA-target interaction and its impact on circulating miRNA marker as well as behavioral dysfunctions in methamphetamine(MA) abstinence. We conducted miRNA sequencing and profiling in the nonhuman primate model of MA abstinence, followed by miRNA qPCR,LC-MS/MS proteomics, immunoassays, and behavior tests in mice. In nonhuman primates, MA abstinence triggered a lasting upregulation of miR-137 in the dorsal striatum but a simultaneous downregulation of circulating miR-137. In mice, aberrant increase in striatal miR-137-dependent inhibition of SYNCRIP essentially mediated the MA abstinence-induced reduction of circulating miR-137. Pathway modeling through experimental deduction illustrated that the MA abstinence-mediated downregulation of circulating miR-137 was caused by reduction of SYNCRIP-dependent miRNA sorting into the exosomes in the dorsal striatum. Furthermore, diminished SYNCRIP in the dorsal striatum was necessary for MA abstinence-induced behavioral bias towards egocentric spatial learning. Taken together, our data revealed circulating miR-137 as a potential blood-based marker that could reflect MA abstinence-dependent changes in striatal miR-137/SYNCRIP axis, and striatal SYNCRIP as a potential therapeutic target for striatum-associated cognitive dysfunction by MA withdrawal syndrome.展开更多
基金supported by the National Research Foundation of Korea (NRF)funded by the Ministry of Science,ICT&Future Planning (2022R1A2C2006229,2022R1A6A3A01086868)Korea Dementia Research Project through the Korea Dementia Research Center (KDRC)funded by the Ministry of Health&Welfare and Ministry of Science and ICT,Republic of Korea (RS-2024-00345328)KIST Institutional Grant (2E32851)。
文摘Alzheimer'sdisease(AD)isaprogressive neurodegenerative disorder characterized by cognitive impairment and distinct neuropathological features,including amyloid-βplaques,neurofibrillary tangles,and reactive astrogliosis.Developing effective diagnostic,preventative,and therapeutic strategies for AD necessitates the establishment of animal models that accurately recapitulate the pathophysiological processes of the disease.Existing transgenic mouse models have significantly contributed to understanding AD pathology but often fail to replicate the complexity of human AD.Additionally,these models are limited in their ability to elucidate the interplay among amyloid-βplaques,neurofibrillary tangles,and reactive astrogliosis due to the absence of spatially and temporally specific genetic manipulation.In this study,we introduce a novel AD mouse model(APP/PS1-TauP301L-Adeno mice)designed to rapidly induce pathological symptoms and enhance understanding of AD mechanisms.Neurofibrillary tangles and severe reactive astrogliosis were induced by injecting AAVDJ-EF1a-hTauP301L-EGFP and Adeno-GFAP-GFP viruses into the hippocampi of 5-month-old APP/PS1 mice.Three months post-injection,these mice exhibited pronounced astrogliosis,substantial amyloid-βplaque accumulation,extensiveneurofibrillarytangles,accelerated neuronal loss,elevated astrocytic GABA levels,and significant spatial memory deficits.Notably,these pathological features were less severe in AAVTauP301L-expressing APP/PS1 mice without augmented reactive astrogliosis.These findings indicate an exacerbating role of severe reactive astrogliosis in amyloid-βplaque and neurofibrillary tangle-associated pathology.The APP/PS1-TauP301L-Adeno mouse model provides a valuable tool for advancing therapeutic research aimed at mitigating the progression of AD.
基金supported by grants from the National Natural Science Foundation of China(82404638)the Xingdian Talent Plan of Yunnan Province(XDYC-QNRC-2023-0427,XDYC-YLXZ 2022-0025)the Natural Science Foundation of Yunnan Province(202101BD070001-034,202101BD070001-049,202201AT070267,202201AU070183).
文摘Excessive osteoclastogenesis-mediated osteoporosis has been recognized as a global health concern.Candidate compounds derived from medicinal plants or functional foods are promising to treat osteoporosis due to their high safety and efficiency.(−)-Epigallocatechin-3-gallate(EGCG)is the most abundant and biologically active polyphenol in green tea.It can inhibit osteoclastogenesis in vitro by blocking receptor activator of nuclear factor(NF)-κB(RANK)signaling pathways.This study used the ovariectomized(OVX)mouse model to estimate the therapeutic effect of EGCG on osteoporosis and verified the molecular mechanism in vivo.The results revealed that EGCG significantly inhibited the OVX-induced body weight gain.Moreover,no adverse effects were observed on blood glucose,histomorphological features,weights,as well as indices of liver and kidney in OVX mice.EGCG could significantly ameliorate bone loss in OVX mice by inhibiting osteoclastogenesis.This effect was evidenced by the reduced number of osteoclasts and the increased trabecular bone area in the femurs.Moreover,EGCG inhibited the activities of c-telopeptide of type I collagen(CTX-I)and tartrate-resistant acid phosphatase 5b(TRACP-5b)and strengthened bone gla protein(BGP)and procollagen I N-terminal peptide(PINP)activities in OVX mice.Mechanistically,EGCG significantly downregulated the expression of osteoclastogenesis-related marker genes and proteins,including nuclear factor of activated T cells,cytoplasmic 1(NFATc1),c-Fos,tartrate-resistant acid phosphatase(TRAP),c-Src,and cathepsin K.In addition,the phosphorylation levels of p65,c-Jun N-terminal kinase(JNK),extracellular signal-regulated kinase 1/2(ERK1/2),p38,and protein kinase B(AKT)were significantly suppressed in OVX mice.It was found that EGCG could alleviate OVX-induced bone loss in mice by suppressing osteoclastogenesis by blocking the NF-κB,mitogen-activated protein kinase(MAPK),and AKT signaling pathways.EGCG has the potential to prevent and treat osteoclast-related diseases such as osteoporosis.
基金Supported by the Science & Research Program of Guangdong Province,China(No.C80017)
文摘Five new coumarin amide derivatives were synthesized with coupling reagent,the structures of which were characterized by IR,1H NMR,13C NMR,MS and element analysis.Their spectral properties were studied in dichloromethane,in N,N-dimethylformamide（DMF） and in solid state.Solvent polarity has less influence on the UV-Vis maximum absorption at about 430 nm.The maximum emission wavelengths change from 464 nm to 474 nm in dichloromethane,from 476 nm to 482 nm in DMF and from 521 nm to 548 nm in solid state,respectively.The fluorescence intensities of compounds 8 and 9 were extremely strong in solvents or in solid state.Compounds 8 and 9 exhibited high fluorescenct quantumn yields in solution compared to compounds 4 ＂7.The fluorescence lifetimes of all the compounds in solvents were measured.
文摘As serotoninergic transmission plays a crucial role in higher brain function in mammals, the disturbance of this system will likely have significant effects on emotion and cognition. Previous studies have reported that chronic treatment with Specific Serotonin Reuptake Inhibitors (SSRIs) during both late pregnancy and lactation was associated with abnormal behavior in adult rats. These data imply that disturbances in serotoninergic transmission during neurodevelopment may have negative effects on both the structure and function of the resultant adult brain. Therefore, the effect of a single exposure to an SSRI or a tricyclic antidepressant that preferentially inhibits serotonin reuptake during the pre-weaning period was examined in adult mice. An oral infusion of paroxetine (70 mg/kg), fluvoxamine (250 mg/kg), clomipramine (180 mg/kg), or saline was administered on postnatal day 14. Starting at 11 weeks of age, mice were assessed using a comprehensive behavioral test battery. Mice treated with paroxetine demonstrated altered behavior on the open field and hole-board tasks;those treated with fluvoxamine had behavioral changes on the light-dark box, hole-board, and sucrose preference tasks, while alteration in forced swimming and cued fear behavior were noted in mice treated with clomipramine. These results suggest that even a single administration of an antidepressant could have profound effects on behavior in adulthood, although the effects might differ dependent on the specific drug that was administered.
文摘A<sub>2</sub>FeCoO<sub>6-δ</sub> (A = Ca or Sr) is synthesized by the solid-state synthesis method and their specific heat capacities are evaluated at 40˚C using a heat flow meter. The effect of the A-cation size on the specific heat capacity of these compounds is observed. The specific heat capacity of Sr<sub>2</sub>FeCoO<sub>6-δ</sub> is found to be the highest, and that of Ca<sub>2</sub>FeCoO<sub>6-δ</sub> is the lowest while CaSrFeCoO<sub>6-δ</sub> shows the intermediate value. The specific heat capacity decreases with the decrease of the average A-site ionic radius, demonstrating the relationship between heat capacity and A-site ionic radius. The relationship between specific heat capacity and molar mass is also confirmed as the δ value decreases or molar mass increases from Ca<sub>2</sub>FeCoO<sub>6-δ</sub> to CaSrFeCoO<sub>6-δ</sub> to Sr<sub>2</sub>FeCoO<sub>6-δ</sub>.
文摘Glassy electrolytes could be a potential candidate for all-solid-state batteries that are considered new-generation energy storage devices. As glasses are one of the potential fast ion-conducting electrolytes, progressive advances in glassy electrolytes have been undergoing to get commercial attention. However, the challenges offered by ionic conductivity at room temperature (10<sup>−5</sup> - 10<sup>−3</sup> S∙cm<sup>−1</sup>) in comparison to those of organic liquid electrolytes (10<sup>−2</sup> S∙cm<sup>−1</sup>) hindered the applicability of such electrolytes. To enhance the research development on ionic conductivity, the overall picture of the ionic conductivity of glassy electrolytes is reviewed in this article with a focus on alkali oxide and sulfide glasses. We portray here the techniques applied for alkali ion conductivity enhancement, such as methods of glass preparation, host optimization, doping, and salt addition for enhancing alkali ionic conductivity in the glasses.
基金supported by a faculty research grant from Yonsei University College of Medicine(6-2018-0161)the National Research Foundation of Korea(NRF)grant funded by the Korea government(MSIT)(RS-2024-00341308)+1 种基金the Center for Cognition and Sociality from Institute for Basic Science(IBS)(IBS-R001-D2)and NeuroBiogen Co.,LTD.
文摘Neuroregeneration and remyelination rarely occur in the adult mammalian brain and spinal cord following central nervous system(CNS)injury.The glial scar has been proposed as a major contributor to this failure in the regenerative process.However,its underlying molecular and cellular mechanisms remain unclear.Here,we report that monoamine oxidase B(MAOB)-dependent excessiveγ-aminobutyric acid(GABA)release from reactive astrocytes suppresses the CNS repair system by reducing brain‒derived neurotrophic factor(BDNF)and tropomyosin receptor kinase B(TrkB)expression in severe spinal cord injury(SCI)animal models.Genetic deletion of MAOB in a mouse SCI model promotes both functional and tissue recovery.Notably,the selective MAOB inhibitor,KDS2010,facilitates recovery and regeneration by disinhibiting the BDNF-TrkB axis in a rat SCI model.Its dose-dependent effects were further validated in a monkey SCI model.Moreover,KDS2010 demonstrated a tolerable safety profile and doseproportional pharmacokinetics in healthy humans during a phase 1 clinical trial.This pathway therefore represents a pivotal target for overcoming the intrinsic barriers to CNS repair after injury.Our findings identify the astrocytic MAOB‒GABA axis as a crucial molecular and cellular brake on the CNS repair system following SCI and highlight the translational potential of KDS2010 as a promising therapeutic candidate for SCI treatment.
基金funded by Korea Institute of Science and Technology Intramural Funding (2E26640,2E30952Republic of Korea)+7 种基金National Research Council of Science & Technology (NST) grant by Korean government (MSIP) (CRC-15-04-KISTRepublic of Korea)Center for Women In Science,Engineering,and Technology (WISET) grant by Korean government (WISET2020-525Republic of Korea)National Research Foundation of Korea (2017R1A2B2003993,2020R1A2C2004610Republic of Korea)UST Young Scientist Research Program through Korea University of Science and Technology (UST) (2017YS03Republic of Korea)。
文摘Abstinence from prolonged psychostimulant use prompts stimulant withdrawal syndrome.Molecular adaptations within the dorsal striatum have been considered the main hallmark of stimulant abstinence. Here we explored striatal miRNA-target interaction and its impact on circulating miRNA marker as well as behavioral dysfunctions in methamphetamine(MA) abstinence. We conducted miRNA sequencing and profiling in the nonhuman primate model of MA abstinence, followed by miRNA qPCR,LC-MS/MS proteomics, immunoassays, and behavior tests in mice. In nonhuman primates, MA abstinence triggered a lasting upregulation of miR-137 in the dorsal striatum but a simultaneous downregulation of circulating miR-137. In mice, aberrant increase in striatal miR-137-dependent inhibition of SYNCRIP essentially mediated the MA abstinence-induced reduction of circulating miR-137. Pathway modeling through experimental deduction illustrated that the MA abstinence-mediated downregulation of circulating miR-137 was caused by reduction of SYNCRIP-dependent miRNA sorting into the exosomes in the dorsal striatum. Furthermore, diminished SYNCRIP in the dorsal striatum was necessary for MA abstinence-induced behavioral bias towards egocentric spatial learning. Taken together, our data revealed circulating miR-137 as a potential blood-based marker that could reflect MA abstinence-dependent changes in striatal miR-137/SYNCRIP axis, and striatal SYNCRIP as a potential therapeutic target for striatum-associated cognitive dysfunction by MA withdrawal syndrome.
