All retinoids, which can be natural and synthetic, are chemically related to vitamin A. Both natural and synthetic retinoids use specific nuclear receptors such as retinoic acid receptors and retinoid X receptors to a...All retinoids, which can be natural and synthetic, are chemically related to vitamin A. Both natural and synthetic retinoids use specific nuclear receptors such as retinoic acid receptors and retinoid X receptors to activate specific signaling pathways in the cells. Retinoic acid signaling is extremely important in the central nervous system. Impairment of retinoic acid signaling pathways causes severe pathological processes in the central nervous system, especially in the adult brain. Retinoids have major roles in neural patterning, differentiation, axon outgrowth in normal development, and function of the brain. Impaired retinoic acid signaling results in neuroinflammation, oxidative stress, mitochondrial malfunction, and neurodegeneration leading to progressive Alzheimer’s disease, which is pathologically characterized by extra-neuronal accumulation of amyloid plaques(aggregated amyloid-beta) and intra-neurofibrillary tangles(hyperphosphorylated tau protein) in the temporal lobe of the brain. Alzheimer’s disease is the most common cause of dementia and loss of memory in old adults. Inactive cholinergic neurotransmission is responsible for cognitive deficits in Alzheimer’s disease patients. Deficiency or deprivation of retinoic acid in mice is associated with loss of spatial learning and memory. Retinoids inhibit expression of chemokines and neuroinflammatory cytokines in microglia and astrocytes, which are activated in Alzheimer’s disease. Stimulation of retinoic acid receptors and retinoid X receptors slows down accumulation of amyloids, reduces neurodegeneration, and thereby prevents pathogenesis of Alzheimer’s disease in mice. In this review, we described chemistry and biochemistry of some natural and synthetic retinoids and potentials of retinoids for prevention of neuroinflammation and neurodegeneration in Alzheimer’s disease.展开更多
YAP（yes-associated protein） is a transcriptional factor that is negatively regulated by Hippo pathway, a conserved pathway for the development and size control of multiple organs. The exact function of YAP in bone h...YAP（yes-associated protein） is a transcriptional factor that is negatively regulated by Hippo pathway, a conserved pathway for the development and size control of multiple organs. The exact function of YAP in bone homeostasis remains controversial. Here we provide evidence for YAP＇s function in promoting osteogenesis, suppressing adipogenesis, and thus maintaining bone homeostasis.YAP is selectively expressed in osteoblast（OB）-lineage cells. Conditionally knocking out Yap in the OB lineage in mice reduces cell proliferation and OB differentiation and increases adipocyte formation, resulting in a trabecular bone loss. Mechanistically, YAP interacts with β-catenin and is necessary for maintenance of nuclear β-catenin level and Wnt/β-catenin signaling. Expression of β-catenin in YAP-deficient BMSCs（bone marrow stromal cells） diminishes the osteogenesis deficit. These results thus identify YAP-β-catenin as an important pathway for osteogenesis during adult bone remodeling and uncover a mechanism underlying YAP regulation of bone homeostasis.展开更多
Patients with Alzheimer’s disease(AD)often have lower bone mass than healthy individuals.However,the mechanisms underlying this change remain elusive.Previously,we found that Tg2576 mice,an AD animal model that ubiqu...Patients with Alzheimer’s disease(AD)often have lower bone mass than healthy individuals.However,the mechanisms underlying this change remain elusive.Previously,we found that Tg2576 mice,an AD animal model that ubiquitously expresses Swedish mutant amyloid precursor protein(APPswe),shows osteoporotic changes,reduced bone formation,and increased bone resorption.To understand how bone deficits develop in Tg2576 mice,we used a multiplex antibody array to screen for serum proteins that are altered in Tg2576 mice and identified hepcidin,a master regulator of iron homeostasis.We further investigated hepcidin’s function in bone homeostasis and found that hepcidin levels were increased not only in the serum but also in the liver,muscle,and osteoblast(OB)lineage cells in Tg2576 mice at both the mRNA and protein levels.We then generated mice selectively expressing hepcidin in hepatocytes or OB lineage cells,which showed trabecular bone loss and increased osteoclast(OC)-mediated bone resorption.Further cell studies suggested that hepcidin increased OC precursor proliferation and differentiation by downregulating ferroportin(FPN)expression and increasing intracellular iron levels.In OB lineage cells,APPswe enhanced hepcidin expression by inducing ER stress and increasing OC formation,in part through hepcidin.Together,these results suggest that increased hepcidin expression in hepatocytes and OB lineage cells in Tg2576 mice contributes to enhanced osteoclastogenesis and trabecular bone loss,identifying the hepcidin-FPN-iron axis as a potential therapeutic target to prevent AD-associated bone loss.展开更多
Many patients with neurodegenerative diseases,such as Alzheimer’s(AD)and Parkinson’s(PD)diseases suffer from disease progression without any satisfying clinical intervention,likely due to our lack of knowledge on ho...Many patients with neurodegenerative diseases,such as Alzheimer’s(AD)and Parkinson’s(PD)diseases suffer from disease progression without any satisfying clinical intervention,likely due to our lack of knowledge on how normal aging impacts the pathogenic mechanisms of these debilitating diseases.A growing body of literature has emerged in recent years that clearly demonstrates the involvement of glycolipids in the protein-oligomerization of neurodegenerative disorders.We hypothesize that changes in glycolipids composition are a common mechanism underlying the shift from healthy brain aging to the neuropathological processes of neurodegenerative diseases.展开更多
Mitochondrial dysfunction plays a central role in the formation of neuroinflammation and oxidative stress,which are important factors contributing to the development of brain disease.Ample evidence suggests mitochondr...Mitochondrial dysfunction plays a central role in the formation of neuroinflammation and oxidative stress,which are important factors contributing to the development of brain disease.Ample evidence suggests mitochondria are a promising target for neuroprotection.Recently,methods targeting mitochondria have been considered as potential approaches for treatment of brain disease through the inhibition of inflammation and oxidative injury.This review will discuss two widely studied approaches for the improvement of brain mitochondrial respiration,methylene blue(MB)and photobiomodulation(PBM).MB is a widely studied drug with potential beneficial effects in animal models of brain disease,as well as limited human studies.Similarly,PBM is a non-invasive treatment that promotes energy production and reduces both oxidative stress and inflammation,and has garnered increasing attention in recent years.MB and PBM have similar beneficial effects on mitochondrial function,oxidative damage,inflammation,and subsequent behavioral symptoms.However,the mechanisms underlying the energy enhancing,antioxidant,and anti-inflammatory effects of MB and PBM differ.This review will focus on mitochondrial dysfunction in several different brain diseases and the pathological improvements following MB and PBM treatment.展开更多
Microglia,the principal immune cells in the brain,play a vital role in the development and homeostasis of the central nervous system[1,2].During early brain development,microglia-mediated synapse pruning contributes t...Microglia,the principal immune cells in the brain,play a vital role in the development and homeostasis of the central nervous system[1,2].During early brain development,microglia-mediated synapse pruning contributes to eliminating excess synapses that are unnecessary in adulthood[3].Excessive microglia-mediated pruning in the adult brain is implicated in neurodegeneration-associated behav・ioral deficits[4,5].展开更多
Social animals prefer to live in groups and transfer social signals to share their physical or psychological distress and seek comfort[1,2].During this process,social buffering is an essential concept in social networ...Social animals prefer to live in groups and transfer social signals to share their physical or psychological distress and seek comfort[1,2].During this process,social buffering is an essential concept in social networks.This refers to the phenomenon wherein the presence of social partners reduces the physiological stress response in a distressed animal[3].展开更多
基金supported in part by an award from the Soy Health Research Program(SHRP,United Soybean Board,Chesterfield,MO,USA)(to SKR)a grant(SCIRF-2015-I-01) from South Carolina Spinal Cord Injury Research Fund(Columbia,SC,USA)(to SKR)earlier R01 grants(CA-091460,and NS-057811)(to SKR) from the National Institutes of Health(Bethesda,MD,USA)
文摘All retinoids, which can be natural and synthetic, are chemically related to vitamin A. Both natural and synthetic retinoids use specific nuclear receptors such as retinoic acid receptors and retinoid X receptors to activate specific signaling pathways in the cells. Retinoic acid signaling is extremely important in the central nervous system. Impairment of retinoic acid signaling pathways causes severe pathological processes in the central nervous system, especially in the adult brain. Retinoids have major roles in neural patterning, differentiation, axon outgrowth in normal development, and function of the brain. Impaired retinoic acid signaling results in neuroinflammation, oxidative stress, mitochondrial malfunction, and neurodegeneration leading to progressive Alzheimer’s disease, which is pathologically characterized by extra-neuronal accumulation of amyloid plaques(aggregated amyloid-beta) and intra-neurofibrillary tangles(hyperphosphorylated tau protein) in the temporal lobe of the brain. Alzheimer’s disease is the most common cause of dementia and loss of memory in old adults. Inactive cholinergic neurotransmission is responsible for cognitive deficits in Alzheimer’s disease patients. Deficiency or deprivation of retinoic acid in mice is associated with loss of spatial learning and memory. Retinoids inhibit expression of chemokines and neuroinflammatory cytokines in microglia and astrocytes, which are activated in Alzheimer’s disease. Stimulation of retinoic acid receptors and retinoid X receptors slows down accumulation of amyloids, reduces neurodegeneration, and thereby prevents pathogenesis of Alzheimer’s disease in mice. In this review, we described chemistry and biochemistry of some natural and synthetic retinoids and potentials of retinoids for prevention of neuroinflammation and neurodegeneration in Alzheimer’s disease.
基金supported in part by grants from the National Institutes of Health(AG051773)and VA(BX000838)
文摘YAP（yes-associated protein） is a transcriptional factor that is negatively regulated by Hippo pathway, a conserved pathway for the development and size control of multiple organs. The exact function of YAP in bone homeostasis remains controversial. Here we provide evidence for YAP＇s function in promoting osteogenesis, suppressing adipogenesis, and thus maintaining bone homeostasis.YAP is selectively expressed in osteoblast（OB）-lineage cells. Conditionally knocking out Yap in the OB lineage in mice reduces cell proliferation and OB differentiation and increases adipocyte formation, resulting in a trabecular bone loss. Mechanistically, YAP interacts with β-catenin and is necessary for maintenance of nuclear β-catenin level and Wnt/β-catenin signaling. Expression of β-catenin in YAP-deficient BMSCs（bone marrow stromal cells） diminishes the osteogenesis deficit. These results thus identify YAP-β-catenin as an important pathway for osteogenesis during adult bone remodeling and uncover a mechanism underlying YAP regulation of bone homeostasis.
基金supported in part by grants from the National Institutes of Health(AG051773)the U.S.Department of Veterans Affairs(BX000838)by the Meisel family and InMotion in Cleveland,Ohio.
文摘Patients with Alzheimer’s disease(AD)often have lower bone mass than healthy individuals.However,the mechanisms underlying this change remain elusive.Previously,we found that Tg2576 mice,an AD animal model that ubiquitously expresses Swedish mutant amyloid precursor protein(APPswe),shows osteoporotic changes,reduced bone formation,and increased bone resorption.To understand how bone deficits develop in Tg2576 mice,we used a multiplex antibody array to screen for serum proteins that are altered in Tg2576 mice and identified hepcidin,a master regulator of iron homeostasis.We further investigated hepcidin’s function in bone homeostasis and found that hepcidin levels were increased not only in the serum but also in the liver,muscle,and osteoblast(OB)lineage cells in Tg2576 mice at both the mRNA and protein levels.We then generated mice selectively expressing hepcidin in hepatocytes or OB lineage cells,which showed trabecular bone loss and increased osteoclast(OC)-mediated bone resorption.Further cell studies suggested that hepcidin increased OC precursor proliferation and differentiation by downregulating ferroportin(FPN)expression and increasing intracellular iron levels.In OB lineage cells,APPswe enhanced hepcidin expression by inducing ER stress and increasing OC formation,in part through hepcidin.Together,these results suggest that increased hepcidin expression in hepatocytes and OB lineage cells in Tg2576 mice contributes to enhanced osteoclastogenesis and trabecular bone loss,identifying the hepcidin-FPN-iron axis as a potential therapeutic target to prevent AD-associated bone loss.
基金supported by a National Institute of Neurological Disorders and Stroke grant(R01 NS100839)a Sheffield Memorial Grant of the CSRA Parkinson’s Disease Support Group,and the excellent infrastructural support of the Department of Neuroscience and Regenerative Medicine,Medical College of Georgia at Augusta University(all to YI).
文摘Many patients with neurodegenerative diseases,such as Alzheimer’s(AD)and Parkinson’s(PD)diseases suffer from disease progression without any satisfying clinical intervention,likely due to our lack of knowledge on how normal aging impacts the pathogenic mechanisms of these debilitating diseases.A growing body of literature has emerged in recent years that clearly demonstrates the involvement of glycolipids in the protein-oligomerization of neurodegenerative disorders.We hypothesize that changes in glycolipids composition are a common mechanism underlying the shift from healthy brain aging to the neuropathological processes of neurodegenerative diseases.
基金This study was supported by research grants from the United States of America:NS086929 from the National Institute of Neurological Disorders and StrokeNIA00051 from National Institute of Aging,National Institutes of Health+1 种基金AHA00169 from American Heart Association。
文摘Mitochondrial dysfunction plays a central role in the formation of neuroinflammation and oxidative stress,which are important factors contributing to the development of brain disease.Ample evidence suggests mitochondria are a promising target for neuroprotection.Recently,methods targeting mitochondria have been considered as potential approaches for treatment of brain disease through the inhibition of inflammation and oxidative injury.This review will discuss two widely studied approaches for the improvement of brain mitochondrial respiration,methylene blue(MB)and photobiomodulation(PBM).MB is a widely studied drug with potential beneficial effects in animal models of brain disease,as well as limited human studies.Similarly,PBM is a non-invasive treatment that promotes energy production and reduces both oxidative stress and inflammation,and has garnered increasing attention in recent years.MB and PBM have similar beneficial effects on mitochondrial function,oxidative damage,inflammation,and subsequent behavioral symptoms.However,the mechanisms underlying the energy enhancing,antioxidant,and anti-inflammatory effects of MB and PBM differ.This review will focus on mitochondrial dysfunction in several different brain diseases and the pathological improvements following MB and PBM treatment.
基金supported by the National Key Research and Development Program of China(2017YFB0403801)the National Natural Science Foundation of China(31971096 and 31771256)the Sigma Xi Grants in Aid of Research(GIAR)program(G03152021115804390).
文摘Microglia,the principal immune cells in the brain,play a vital role in the development and homeostasis of the central nervous system[1,2].During early brain development,microglia-mediated synapse pruning contributes to eliminating excess synapses that are unnecessary in adulthood[3].Excessive microglia-mediated pruning in the adult brain is implicated in neurodegeneration-associated behav・ioral deficits[4,5].
基金This Research Highlight was supported by grants from the USA:AG058603 from the National Institute of AgingNational Institutes of Healthand AHA00169 from the American Heart Association.
文摘Social animals prefer to live in groups and transfer social signals to share their physical or psychological distress and seek comfort[1,2].During this process,social buffering is an essential concept in social networks.This refers to the phenomenon wherein the presence of social partners reduces the physiological stress response in a distressed animal[3].
