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Heterocyclic compounds as key structures for the interaction with old and new targets in Alzheimer＇s disease therapy

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Neural Regeneration Research 2017年第8期12卷 1256-1261页

作者： Asha Hiremathad Luca Piemontese Centre for Nano and Material Sciences Jain University Jain Global Campus Kanakapura Ramanagaram Bangalore India Dipartimento di Farmacia-Scienze del Farmaco Universitfl degli Studi di Bari "Aldo Moro" Bari Italy

Nowadays, Alzheimer＇s disease（AD） is widely recognized as a real social problem. In fact, only five drugs are FDA approved for the therapy of this widespread neurodegenerative disease, but with low results so far. Three of them（rivastigmine, donepezil and galantamine） are acetylcholinesterase inhibitors, memantine is a N-methyl-D-aspartate receptor antagonist, whereas the fifth formulation is a combination of donepezil with memantine. The prevention and treatment of AD is the new challenge for pharmaceutical industry, as well as for public institutions, physicians, patients, and their families. The discovery of a new and safe way to cure this neurodegenerative disease is urgent and should not be delayed further. Because of the multiple origin of this pathology, a multi-target strategy is currently strongly pursued by researchers. In this review, we have discussed new structures designed to better the activity on the classical AD targets. We have also examined old and new potential drugs that could prove useful future for the therapy of the pathology by acting on innovative, not usual, and not yet fully explored targets like peroxisome proliferator-activated receptor（PPARs）.

关键词： Alzheimer＇s disease multi-target strategy peroxisome proliferator-activated receptors heterocycliccompounds neurodegenerative diseases

DNA mismatch repair in trinucleotide repeat instability

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Science China(Life Sciences) 2017年第10期60卷 1087-1092页

作者： Jinzhen Guo Luping Chen Guo-Min Li Department of Radiation Oncology University of Texas Southwestern Medical Center Department of Biochemistry and Molecular Medicine Norris Comprehensive Cancer Center University of Southern California Keck School of Medicine

Trinucleotide repeat expansions cause over 30 severe neuromuscular and neurodegenerative disorders, including Huntington's disease, myotonic dystrophy type 1, and fragile X syndrome. Although previous studies have substantially advanced the understanding of the disease biology, many key features remain unknown. DNA mismatch repair(MMR) plays a critical role in genome maintenance by removing DNA mismatches generated during DNA replication. However, MMR components,particularly mismatch recognition protein MutSβ and its interacting factors MutLα and MutLγ, have been implicated in trinucleotide repeat instability. In this review, we will discuss the roles of these key MMR proteins in promoting trinucleotide repeat instability.

关键词： DNA mismatch repair trinucleotide repeat instability neurodegenerative diseases MutSβ

A neuron-immune circuit regulates neurodegeneration in the hindbrain and spinal cord of Arf1-ablated mice

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National Science Review 2023年第12期10卷 98-110页

作者： Guohao Wang Shuhan Jin Jiaqi Liu Xu Li Peng Dai Yuetong Wang Steven X.Hou The Basic Research Laboratory Center for Cancer ResearchNational Cancer Institute at FrederickNational Institutes of Health Department of Cell and Developmental Biology at the School of Life Sciences State Key Laboratory of Genetic EngineeringInstitute of Metabolism and Integrative BiologyHuman Phenome Institute Department of Liver Surgery and Transplantation of Liver Cancer Institute at Zhongshan Hospital Fudan University

Neuroimmune connections have been revealed to play a central role in neurodegenerative diseases(NDs).However, the mechanisms that link the central nervous system(CNS) and peripheral immune cells are still mostly unknown. We recently found that specific ablation of the Arf1 gene in hindbrain and spinal cord neurons promoted NDs through activating the NLRP3 inflammasome in microglia via peroxided lipids and adenosine triphosphate(ATP) releasing. Here, we demonstrate that IL-1β with elevated chemokines in the neuronal Arf1-ablated mouse hindbrain and spinal cord recruited and activated γ δ T cells in meninges. The activated γ δ T cells then secreted IFN-γ that entered into parenchyma to activate the microglia-A1astrocyte-C3-neuronal C3a R neurotoxic pathway. Remarkably, the neurodegenerative phenotypes of the neuronal Arf1-ablated mice were strongly ameliorated by IFN-γ or C3 knockout. Finally, we show that the Arf1-reduction-induced neuroimmune-IFN-γ-gliosis pathway exists in human NDs, particularly in amyotrophic lateral sclerosis and multiple sclerosis. Together, our results uncover a previously unknown mechanism that links the CNS and peripheral immune cells to promote neurodegeneration.

关键词： neurodegenerative diseases disease-associated microglia γδT cells reactive astrocyte IFN- γ C3

Targeted methylation sequencing reveals dysregulated Wnt signaling in Parkinson disease

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Journal of Genetics and Genomics 2016年第10期43卷 587-592页

作者： Lusi Zhang Jie Deng Qian Pan Yan Zhan Jian-Bing Fan Kun Zhang Zhuohua Zhang Institute of Precision Medicine The Xiangya Hospital State Key Laboratory of Medical Genetics Xiangya Medical School Central South University Department of Bioengineering University of California at San Diego Anchor Dx Corporation International Bio-island

Parkinson disease（PD） is a progressive neurodegenerative movement disorder. Both environmental and genetic factors play important roles in PD etiology. A number of environmental toxins cause parkinsonism in human and animal models. Genetic studies of rare early onset familial PD cases resulted in identification of disease-linked mutations in multiple genes. Nevertheless, the potential interaction between environment and genetics in PD pathogenesis remains largely unknown. We hypothesized that environmental factors induce abnormal epigenetic regulation that is involved in the pathogenesis of both familial and sporadic PD. We determined the global methylation status of 80,000e110,000 Cp G sites in each of the five sporadic PD patient brains and five age and postmodern interval matched control brains utilizing bisulfite padlock sequencing. Multiple genes involved in neurogenesis, particularly the ones in the Wnt signaling pathway, were hypermethylated in PD brains compared to their matched control brains. Consistent with the DNA methylation changes, marked reduction of protein expression was observed for four Wnt and neurogenesis related genes（FOXC1, NEURG2, SPRY1, and CTNNB1） in midbrain dopaminergic（DA） neurons of PD. The treatment of low concentration of 1-methyl-4-phenylpyridinium（MPPt） for cells resulted in downregulation of Wnt related genes. The study revealed an important link between the epigenetic disregulation of Wnt signaling and the pathogenesis and progression of PD.

关键词： Epigenetic regulation neurodegenerative diseases Environmental toxins Neurogenesis

Neuronal conversion from glia to replenish the lost neurons

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Neural Regeneration Research 2024年第7期19卷 1446-1453页

作者： Shiyu Liang Jing Zhou Xiaolin Yu Shuai Lu Ruitian Liu National Key Laboratory of Biochemical Engineering Institute of Process EngineeringChinese Academy of SciencesBeijingChina School of Chemical Engineering University of Chinese Academy of SciencesBeijingChina Department of Geriatric Rehabilitation Beijing Rehabilitation HospitalCapital Medical UniversityBeijingChina

Neuronal injury,aging,and cerebrovascular and neurodegenerative diseases such as cerebral infarction,Alzheimer’s disease,Parkinson’s disease,frontotemporal dementia,amyotrophic lateral sclerosis,and Huntington’s disease are characte rized by significant neuronal loss.Unfo rtunately,the neurons of most mammals including humans do not possess the ability to self-regenerate.Replenishment of lost neurons becomes an appealing therapeutic strategy to reve rse the disease phenotype.Transplantation of pluripotent neural stem cells can supplement the missing neurons in the brain,but it carries the risk of causing gene mutation,tumorigenesis,severe inflammation,and obstructive hydrocephalus induced by brain edema.Conversion of neural or non-neural lineage cells into functional neurons is a promising strategy for the diseases involving neuron loss,which may overcome the above-mentioned disadvantages of neural stem cell therapy.Thus far,many strategies to transfo rm astrocytes,fibroblasts,microglia,Muller glia,NG2 cells,and other glial cells to mature and functional neurons,or for the conversion between neuronal subtypes have been developed thro ugh the regulation of transcription factors,polypyrimidine tra ct binding protein 1(PTBP1),and small chemical molecules or are based on a combination of several factors and the location in the central nervous system.However,some recent papers did not obtain expected results,and discrepancies exist.Therefore,in this review,we discuss the history of neuronal transdifferentiation,summarize the strategies for neuronal replenishment and conversion from glia,especially astrocytes,and point out that biosafety,new strategies,and the accurate origin of the truly co nverted neurons in vivo should be focused upon in future studies.It also arises the attention of replenishing the lost neurons from glia by gene therapies such as up-regulation of some transc ription factors or downregulation of PTBP1 or drug interfe rence therapies.

关键词： astrocytes neural stem cells neurodegenerative diseases neuron polypyrimidine tract binding protein 1 repair reprogramming small molecule transcription factor transdifferentiation

Unraveling the gut-brain axis:the impact of steroid hormones and nutrition on Parkinson's disease

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Neural Regeneration Research 2024年第10期19卷 2219-2228页

作者： Paula Maria Neufeld Ralf A.Nettersheim Veronika Matschke Matthias Vorgerd Sarah Stahlke Carsten Theiss Department of Cytology Institute of AnatomyMedical FacultyRuhr-University BochumBochumGermany Department of Visceral Surgery University Hospital BergmannsheilRuhr-University BochumBochumGermany Department of Neurology Heimer Institute for Muscle ResearchUniversity Hospital BergmannsheilRuhr-University BochumBochumGermany

This comprehensive review explores the intricate relationship between nutrition,the gut microbiome,steroid hormones,and Parkinson's disease within the context of the gut-brain axis.The gut-brain axis plays a pivotal role in neurodegenerative diseases like Parkinson's disease,encompassing diverse components such as the gut microbiota,immune system,metabolism,and neural pathways.The gut microbiome,profoundly influenced by dietary factors,emerges as a key player.Nutrition during the first 1000 days of life shapes the gut microbiota composition,influencing immune responses and impacting both child development and adult health.High-fat,high-sugar diets can disrupt this delicate balance,contributing to inflammation and immune dysfunction.Exploring nutritional strategies,the Mediterranean diet's anti-inflammatory and antioxidant properties show promise in reducing Parkinson's disease risk.Microbiome-targeted dietary approaches and the ketogenic diet hold the potential in improving brain disorders.Beyond nutrition,emerging research uncovers potential interactions between steroid hormones,nutrition,and Parkinson's disease.Progesterone,with its anti-inflammatory properties and presence in the nervous system,offers a novel option for Parkinson's disease therapy.Its ability to enhance neuroprotection within the enteric nervous system presents exciting prospects.The review addresses the hypothesis thatα-synuclein aggregates originate from the gut and may enter the brain via the vagus nerve.Gastrointestinal symptoms preceding motor symptoms support this hypothesis.Dysfunctional gut-brain signaling during gut dysbiosis contributes to inflammation and neurotransmitter imbalances,emphasizing the potential of microbiota-based interventions.In summary,this review uncovers the complex web of interactions between nutrition,the gut microbiome,steroid hormones,and Parkinson's disease within the gut-brain axis framework.Understanding these connections not only offers novel therapeutic insights but also illuminates the origins of neurode

关键词： diet gut-brain axis microbiome neurodegenerative diseases nutrition Parkinson's disease progesterone steroid hormones

Caspase-1 inhibition attenuates activation of BV2 microglia induced by LPS-treated RAW264.7 macrophages

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The Journal of Biomedical Research 2016年第3期30卷 225-233页

作者： Yang Pan Bo Shen Qin Gao Jun Zhu Jingde Dong Li Zhang Yingdong Zhang Department of Neurology Nanjing First Hospital affiliated to Nanjing Medical University Nanjing Jiangsu 210006 China Department of Geriatrics Nanjing Brain Hospital affiliated to Nanjing Medical University Nanjing Jiangsu 210029 China

Neuroinflammation has been recognized as a factor in the pathogenesis ofneurodegenerative diseases. Emerging evidence suggests that peripheral inflammation, besides neuroinflammation, functions as a modulator of disease progression and neuropathology in several neurodegenerative diseases. However, detailed correlations among pe- ripheral inflammation, neuroinflammation and neurodegeneration remain unknown. In the present study, we pre- pared a peripheral inflammation model with lipopolysaccharides （LPS）-stimulated RAW264.7 macrophages to ex- plore its activation on BV2 microglia. We found that LPS induced the production of IL-1β, IL-6 and TNF-a in the culture medium of RAW264.7 macrophages. We further showed that LPS plus ATP activated inflammasome, evidenced by the upregulation of caspase-1 and IL-113, which was suppressed by ZYVAD, a caspase-1 inhibitor. Furthermore, the conditioned medium obtained from LPS-treated RAW264.7 macrophages activated BV2 micro- glia, stimulating the release of IL-1β, IL-6 and TNF-a from BV2 cells. ZYVAD pretreatment markedly suppressed BV2 microglia activation induced by RAW264.7 cells conditioned medium. Taken together, our study indicates that macrophage-mediated peripheral inflammation subsequently evokes neuroinflammation and may aggravate neural damage. Inflammasome and caspase- 1 may be potential targets for modulating systemic inflammatory responses in neurodegenerative diseases.

关键词： peripheral inflammation neuroinflammation neurodegenerative diseases NLRP3 inflammasome caspase-1

Effective components of Chinese herbs reduce central nervous system function decline induced by iron overload

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Neural Regeneration Research 2015年第5期10卷 778-785页

作者： Xian-hui Dong Jiang-tao Bai Wei-na Kong Xiao-ping He Peng Yan Tie-mei Shao Wen-guo Yu Xi-qing Chai Yan-hua Wu Cong Liu Chengde Medical University Hebei Chemical and Pharmaceutical Vocational and Technical College The 266 Hospital of Chinese PLA

Abnormally increased levels of iron in the brain trigger cascade amplification in Alzheimer＇s dis- ease patients, resulting in neuronal death. This study investigated whether components extracted from the Chinese herbs epimedium herb, milkvetch root and kudzuvine root could relieve the abnormal expression of iron metabolism-related protein in Alzheimer＇s disease patients. An APPs,~JPSI^E9 double transgenic mouse model of Alzheimer＇s disease was used. The intragas- tric administration of compounds from epimedium herb, milkvetch root and kudzuvine root improved pathological alterations such as neuronal edema, increased the number of neurons, downregulated divalent metal transporter 1 expression, upregulated ferroportin 1 expression, and inhibited iron overload in the cerebral cortex of mice with Alzheimer＇s disease. These com- pounds reduced iron overload-induced impairment of the central nervous system, indicating a new strategy for developing novel drugs for the treatment of Alzheimer＇s disease.

关键词： nerve regeneration neurodegenerative diseases Alzheimer＇s disease transgenic animalmodels mice epimedium herb milkvetch root kudzuvine root divalent metal transporter 1 ferroportin 1 neural regeneration

Terahertz technology in intraoperative neurodiagnostics:A review

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Opto-Electronic Advances 2023年第5期6卷 41-67页

作者： Nikita V.Chernomyrdin Guzel R.Musina Pavel V.Nikitin Irina N.Dolganova Anna S.Kucheryavenko Anna I.Alekseeva Yuye Wang Degang Xu Qiwu Shi Valery V.Tuchin Kirill I.Zaytsev Prokhorov General Physics Institute of the Russian Academy of Sciences Moscow 119991Russia Bauman Moscow State Technical University Moscow 105005Russia Institute for Regenerative Medicine Sechenov UniversityMoscow 119991Russia Institute of Solid State Physics of the Russian Academy of Sciences Chernogolovka 142432Russia Research Institute of Human Morphology Moscow 117418Russia School of Precision Instrument and Optoelectronic Engineering Tianjin UniversityTianjin 300000China College of Materials Science and Engineering Sichuan UniversityChengdu 610000China Science Medical Center Saratov State UniversitySaratov 410012Russia Institute of Precision Mechanics and Control FRC"Saratov Scientific Centre of the Russian Academy of Sciences"Saratov 410028Russia

Terahertz(THz)technology offers novel opportunities in biology and medicine,thanks to the unique features of THzwave interactions with tissues and cells.Among them,we particularly notice strong sensitivity of THz waves to the tissue water,as a medium for biochemical reactions and a main endogenous marker for THz spectroscopy and imaging.Tissues of the brain have an exceptionally high content of water.This factor,along with the features of the structural organization and biochemistry of neuronal and glial tissues,makes the brain an exciting subject to study in the THz range.In this paper,progress and prospects of THz technology in neurodiagnostics are overviewed,including diagnosis of neurodegenerative disease,myelin deficit,tumors of the central nervous system(with an emphasis on brain gliomas),and traumatic brain injuries.Fundamental and applied challenges in study of the THz-wave–brain tissue interactions and development of the THz biomedical tools and systems for neurodiagnostics are discussed.

关键词： THz technology THz spectroscopy and imaging superresolution imaging biophotonics brain neurodiagnosis tumor glioma neurodegenerative diseases brain injury light scattering