Neurological disorders are amongst the most widely studied human aliments.Yet,they are also one of the most poorly understood.Although most of these disorders are polygenic,genotype still plays an important role in th...Neurological disorders are amongst the most widely studied human aliments.Yet,they are also one of the most poorly understood.Although most of these disorders are polygenic,genotype still plays an important role in their etiologies.For example,in schizophrenia and autism spectrum disorders,there is a 40-60%concordance rate in monozygotic twins,with 60-90%heritability（Burmeister et al.,2008）.However,the mechanisms by which multiple genes and their genomic variations influence the phenotypes of the disorders remain to be understood. The complexities of the disorders are tur- ther compounded by the individual rarity of the genomic variations and their variable penetrance （Cook and Scherer, 2008）. Thus, conventional disease modeling, such as gene knockout in cells or in animals, to attain the desired disease genotype may not be the most suitable platform for tackling most neurological disorders.展开更多
The progressive loss of dopaminergic neurons in affected patient brains is one of the pathological features of Parkinson's disease,the second most common human neurodegenerative disease.Although the detailed patho...The progressive loss of dopaminergic neurons in affected patient brains is one of the pathological features of Parkinson's disease,the second most common human neurodegenerative disease.Although the detailed pathogenesis accounting for dopaminergic neuron degeneration in Parkinson's disease is still unclear,the advancement of stem cell approaches has shown promise for Parkinson's disease research and therapy.The induced pluripotent stem cells have been commonly used to generate dopaminergic neurons,which has provided valuable insights to improve our understanding of Parkinson's disease pathogenesis and contributed to anti-Parkinson's disease therapies.The current review discusses the practical approaches and potential applications of induced pluripotent stem cell techniques for generating and differentiating dopaminergic neurons from induced pluripotent stem cells.The benefits of induced pluripotent stem cell-based research are highlighted.Various dopaminergic neuron differentiation protocols from induced pluripotent stem cells are compared.The emerging three-dimension-based brain organoid models compared with conventional two-dimensional cell culture are evaluated.Finally,limitations,challenges,and future directions of induced pluripotent stem cell–based approaches are analyzed and proposed,which will be significant to the future application of induced pluripotent stem cell-related techniques for Parkinson's disease.展开更多
The circadian timing system plays a key role in orchestrating lipid metabolism. In concert with the solar cycle, the circadian system ensures that daily rhythms in lipid absorption, storage, and transport are temporal...The circadian timing system plays a key role in orchestrating lipid metabolism. In concert with the solar cycle, the circadian system ensures that daily rhythms in lipid absorption, storage, and transport are temporally coordinated with rest-activity and feeding cycles. At the cellular level, genes involved in lipid synthesis and fatty acid oxidation are rhythmically activated and repressed by core clock proteins in a tissue-specific manner. Consequently, loss of clock gene function or misalignment of circadian rhythms with feeding cycles （e.g., in shift work） results in impaired lipid homeostasis. Herein, we review recent progress in circadian rhythms research using lipidomics, i.e., large-scale profiling of lipid metabolites, to characterize circadian-regulated lipid pathways in mammals. In mice, novel regulatory circuits involved in fatty acid metabolism have been identified in adipose tissue, liver, and muscle. Extensive diversity in circadian regulation of plasma lipids has also been revealed in humans using lipidomics and other metabolomics approaches. In future studies, lipidomics platforms will be increasingly used to better understand the effects of genetic variation, shift work, food intake, and drugs on circadian-regulated lipid pathways and metabolic health.展开更多
Psoriasis is a common immune-mediated skin disorder manifesting in abnormal skin plaques,and remains a challenge in its management.Blocking the release or inflammatory effects of two proinflammatory molecules of the S...Psoriasis is a common immune-mediated skin disorder manifesting in abnormal skin plaques,and remains a challenge in its management.Blocking the release or inflammatory effects of two proinflammatory molecules of the S100-alarmin family,S100A8 and S100A9,in keratinocytes is a promising strategy for future therapeutic approaches.Undulanoids A−D(1−4),four novel sesterterpenoids possessing a highly congested pentacyclic 6/5/5/6/5 ring system with eight stereogenic centers,including three all-carbon quaternary centers,two quaternary carbon centers at the bridgehead,and a 1,4,11-trimethyltricyclo[5.3.1.04,11]undecane fragment,were isolated from Aspergillus undulatus.Their structures were elucidated by spectroscopic data and single-crystal X-ray diffraction.Strikingly,undulanoid B(2),the most promising lead compound,inhibits the expression of genes related to tumor necrosis factor and interleukin-17 signaling pathways.Furthermore,reverse target prediction,cellular thermal shift assay,and dynamic simulation indicated that compound 2 could target with the expression of S100A9 and keratinocyte proliferation.As the pioneering S100A8/A9 complex and inhibit its secretion.Moreover,compound 2 showed a potent therapeutic effect on the psoriasiform skin lesions induced by imiquimod in mice by inhibiting the expression of S100A9 and keratinocyte proliferation.As the pioneering examples of natural products demonstrate inhibitory action against S100A8/A9 complex,this discovery provides a series of compelling lead compounds with novel molecular scaffold for treating psoriasis.展开更多
Glucose-6-phosphate dehydrogenase(G6PD)is the rate-limiting enzyme in the pentose phosphate pathway(PPP)in glycolysis.Glucose metabolism is closely implicated in the regulation of mitophagy,a selective form of autopha...Glucose-6-phosphate dehydrogenase(G6PD)is the rate-limiting enzyme in the pentose phosphate pathway(PPP)in glycolysis.Glucose metabolism is closely implicated in the regulation of mitophagy,a selective form of autophagy for the degradation of damaged mitochondria.The PPP and its key enzymes such as G6PD possess important metabolic functions,including biosynthesis and maintenance of intracellular redox balance,while their implication in mitophagy is largely unknown.Here,via a whole-genome CRISPR-Cas9 screening,we identified that G6PD regulates PINK1(phosphatase and tensin homolog[PTEN]-induced kinase 1)-Parkinmediated mitophagy.The function of G6PD in mitophagy was verified via multiple approaches.G6PD deletion significantly inhibited mitophagy,which can be rescued by G6PD reconstitution.Intriguingly,while the catalytic activity of G6PD is required,the known PPP functions per se are not involved in mitophagy regulation.Importantly,we found a portion of G6PD localized at mitochondria where it interacts with PINK1.G6PD deletion resulted in an impairment in PINK1 stabilization and subsequent inhibition of ubiquitin phosphorylation,a key starting point of mitophagy.Finally,we found that G6PD deletion resulted in lower cell viability upon mitochondrial depolarization,indicating the physiological function of G6PD-mediated mitophagy in response to mitochondrial stress.In summary,our study reveals a novel role of G6PD as a key positive regulator in mitophagy,which bridges several important cellular processes,namely glucose metabolism,redox homeostasis,and mitochondrial quality control.展开更多
A pathological feature of Parkinson’s disease(PD)is the progressive loss of dopaminergic neurons and decreased dopamine(DA)content in the substantia nigra pars compacta in PD brains.DA is the neurotransmitter of dopa...A pathological feature of Parkinson’s disease(PD)is the progressive loss of dopaminergic neurons and decreased dopamine(DA)content in the substantia nigra pars compacta in PD brains.DA is the neurotransmitter of dopaminergic neurons.Accumulating evidence suggests that DA interacts with environmental and genetic factors to contribute to PD pathophysiology.Disturbances of DA synthesis,storage,transportation and metabolism have been shown to promote neurodegeneration of dopaminergic neurons in various PD models.DA is unstable and can undergo oxidation and metabolism to produce multiple reactive and toxic by-products,including reactive oxygen species,DA quinones,and 3,4-dihydroxyphenylacetaldehyde.Here we summarize and highlight recent discoveries on DA-linked pathophysiologic pathways,and discuss the potential protective and therapeutic strategies to mitigate the complications associated with DA.展开更多
文摘Neurological disorders are amongst the most widely studied human aliments.Yet,they are also one of the most poorly understood.Although most of these disorders are polygenic,genotype still plays an important role in their etiologies.For example,in schizophrenia and autism spectrum disorders,there is a 40-60%concordance rate in monozygotic twins,with 60-90%heritability（Burmeister et al.,2008）.However,the mechanisms by which multiple genes and their genomic variations influence the phenotypes of the disorders remain to be understood. The complexities of the disorders are tur- ther compounded by the individual rarity of the genomic variations and their variable penetrance （Cook and Scherer, 2008）. Thus, conventional disease modeling, such as gene knockout in cells or in animals, to attain the desired disease genotype may not be the most suitable platform for tackling most neurological disorders.
基金supported by Singapore National Medical Research Council(NMRC)grants,including CS-IRG,HLCA2022(to ZDZ),STaR,OF LCG 000207(to EKT)a Clinical Translational Research Programme in Parkinson's DiseaseDuke-Duke-NUS collaboration pilot grant(to ZDZ)。
文摘The progressive loss of dopaminergic neurons in affected patient brains is one of the pathological features of Parkinson's disease,the second most common human neurodegenerative disease.Although the detailed pathogenesis accounting for dopaminergic neuron degeneration in Parkinson's disease is still unclear,the advancement of stem cell approaches has shown promise for Parkinson's disease research and therapy.The induced pluripotent stem cells have been commonly used to generate dopaminergic neurons,which has provided valuable insights to improve our understanding of Parkinson's disease pathogenesis and contributed to anti-Parkinson's disease therapies.The current review discusses the practical approaches and potential applications of induced pluripotent stem cell techniques for generating and differentiating dopaminergic neurons from induced pluripotent stem cells.The benefits of induced pluripotent stem cell-based research are highlighted.Various dopaminergic neuron differentiation protocols from induced pluripotent stem cells are compared.The emerging three-dimension-based brain organoid models compared with conventional two-dimensional cell culture are evaluated.Finally,limitations,challenges,and future directions of induced pluripotent stem cell–based approaches are analyzed and proposed,which will be significant to the future application of induced pluripotent stem cell-related techniques for Parkinson's disease.
基金supported by the Duke-NUS Signature Research Program funded by the Agency for Science,Technology,and Research,Singapore,and the Ministry of Health,Singaporethe SingHealth Foundation(SHF),Singapore,under SHF/FG410P/2009
文摘The circadian timing system plays a key role in orchestrating lipid metabolism. In concert with the solar cycle, the circadian system ensures that daily rhythms in lipid absorption, storage, and transport are temporally coordinated with rest-activity and feeding cycles. At the cellular level, genes involved in lipid synthesis and fatty acid oxidation are rhythmically activated and repressed by core clock proteins in a tissue-specific manner. Consequently, loss of clock gene function or misalignment of circadian rhythms with feeding cycles （e.g., in shift work） results in impaired lipid homeostasis. Herein, we review recent progress in circadian rhythms research using lipidomics, i.e., large-scale profiling of lipid metabolites, to characterize circadian-regulated lipid pathways in mammals. In mice, novel regulatory circuits involved in fatty acid metabolism have been identified in adipose tissue, liver, and muscle. Extensive diversity in circadian regulation of plasma lipids has also been revealed in humans using lipidomics and other metabolomics approaches. In future studies, lipidomics platforms will be increasingly used to better understand the effects of genetic variation, shift work, food intake, and drugs on circadian-regulated lipid pathways and metabolic health.
基金financially supported by the National Key Research and Development Program of China(2021YFA0910500)the National Natural Science Foundation of China(U22A20380,82373755,82173706,82404468)+2 种基金the Fundamental Research Funds for the Central Universities(2024BRA018,China)the Science and Technology Major Project of Hubei Province(2021ACA012,China)Hubei Provincial Natural Science Foundation of China(2025AFB227).
文摘Psoriasis is a common immune-mediated skin disorder manifesting in abnormal skin plaques,and remains a challenge in its management.Blocking the release or inflammatory effects of two proinflammatory molecules of the S100-alarmin family,S100A8 and S100A9,in keratinocytes is a promising strategy for future therapeutic approaches.Undulanoids A−D(1−4),four novel sesterterpenoids possessing a highly congested pentacyclic 6/5/5/6/5 ring system with eight stereogenic centers,including three all-carbon quaternary centers,two quaternary carbon centers at the bridgehead,and a 1,4,11-trimethyltricyclo[5.3.1.04,11]undecane fragment,were isolated from Aspergillus undulatus.Their structures were elucidated by spectroscopic data and single-crystal X-ray diffraction.Strikingly,undulanoid B(2),the most promising lead compound,inhibits the expression of genes related to tumor necrosis factor and interleukin-17 signaling pathways.Furthermore,reverse target prediction,cellular thermal shift assay,and dynamic simulation indicated that compound 2 could target with the expression of S100A9 and keratinocyte proliferation.As the pioneering S100A8/A9 complex and inhibit its secretion.Moreover,compound 2 showed a potent therapeutic effect on the psoriasiform skin lesions induced by imiquimod in mice by inhibiting the expression of S100A9 and keratinocyte proliferation.As the pioneering examples of natural products demonstrate inhibitory action against S100A8/A9 complex,this discovery provides a series of compelling lead compounds with novel molecular scaffold for treating psoriasis.
基金supported by grants to S.C.L.from the Swee Liew-Wadsworth Endowment fund,National University of Singapore(NUS),Ministry of Education(MOE-T2EP30220-0014),Singaporethe National Research Foundation(NRF-ISF003-3221),Singapore+2 种基金grants to H.M.S.from University of Macao(CPG2023-0032FHS and UM-MYRG2020-00022-FHS)Macao Science and Technology Development Fund(FDCT0078/2020/A2,FDCT0031/2021/A1,FDCT0081/2022/AMJ,and FDCT 0004/2021/AKP)supported by the NUS Graduate School Research Scholarships.
文摘Glucose-6-phosphate dehydrogenase(G6PD)is the rate-limiting enzyme in the pentose phosphate pathway(PPP)in glycolysis.Glucose metabolism is closely implicated in the regulation of mitophagy,a selective form of autophagy for the degradation of damaged mitochondria.The PPP and its key enzymes such as G6PD possess important metabolic functions,including biosynthesis and maintenance of intracellular redox balance,while their implication in mitophagy is largely unknown.Here,via a whole-genome CRISPR-Cas9 screening,we identified that G6PD regulates PINK1(phosphatase and tensin homolog[PTEN]-induced kinase 1)-Parkinmediated mitophagy.The function of G6PD in mitophagy was verified via multiple approaches.G6PD deletion significantly inhibited mitophagy,which can be rescued by G6PD reconstitution.Intriguingly,while the catalytic activity of G6PD is required,the known PPP functions per se are not involved in mitophagy regulation.Importantly,we found a portion of G6PD localized at mitochondria where it interacts with PINK1.G6PD deletion resulted in an impairment in PINK1 stabilization and subsequent inhibition of ubiquitin phosphorylation,a key starting point of mitophagy.Finally,we found that G6PD deletion resulted in lower cell viability upon mitochondrial depolarization,indicating the physiological function of G6PD-mediated mitophagy in response to mitochondrial stress.In summary,our study reveals a novel role of G6PD as a key positive regulator in mitophagy,which bridges several important cellular processes,namely glucose metabolism,redox homeostasis,and mitochondrial quality control.
基金supported by grants from the Singapore National Medical Research Council(CS-IRG,HLCA2022,STaR,OF LCG 000207)a clinical translational research programme in Parkinson’s disease and a Duke-Duke-NUS collaboration pilot grant.
文摘A pathological feature of Parkinson’s disease(PD)is the progressive loss of dopaminergic neurons and decreased dopamine(DA)content in the substantia nigra pars compacta in PD brains.DA is the neurotransmitter of dopaminergic neurons.Accumulating evidence suggests that DA interacts with environmental and genetic factors to contribute to PD pathophysiology.Disturbances of DA synthesis,storage,transportation and metabolism have been shown to promote neurodegeneration of dopaminergic neurons in various PD models.DA is unstable and can undergo oxidation and metabolism to produce multiple reactive and toxic by-products,including reactive oxygen species,DA quinones,and 3,4-dihydroxyphenylacetaldehyde.Here we summarize and highlight recent discoveries on DA-linked pathophysiologic pathways,and discuss the potential protective and therapeutic strategies to mitigate the complications associated with DA.
