_-_-p-Bromotetramisole_oxalate_COA_21994_MedChemExpress

葫芦素的生态功能及其应用前景凌冰;张茂新;王玉赞【摘要】葫芦素是一类高度氧化的四环三萜类植物次生代谢物质,是葫芦科30多属100多种植物的特征化合物.葫芦素在植物体内作为异源化学信息素起到保护葫芦科植物免受众多植食性动物和病原菌的侵害.另一方面,在葫芦科植物上取食的一些昆虫则利用葫芦素作为其寄主识别的信号物质.由于葫芦素特殊的化学结构和生物学活性,葫芦科植物与植食性动物之间的这种复杂关系已被广泛研究.总结葫芦素的分布、生物合成途径、及其对高等动物、昆虫和病原体的防御作用的研究概况.并对这类植物次生物质在有害生物综合治理中的应用及前景作了介绍与展望.【期刊名称】《生态学报》【年(卷),期】2010(030)003【总页数】14页(P780-793)【关键词】葫芦素;植物防御;生态功能;应用前景【作者】凌冰;张茂新;王玉赞【作者单位】华南农业大学昆虫生态研究室,广州,510642;华南农业大学昆虫生态研究室,广州,510642;华南农业大学昆虫生态研究室,广州,510642【正文语种】中文葫芦素(cucurbitacins)是一类高度氧化的四环三萜类植物次生物质，是葫芦科30多属100多种植物的特征化合物[1]。

葫芦素在生态系统中作为异源化学信息素(allomones)起到保护葫芦科植物免受众多植食性动物和病原菌的侵害[2- 4]。

另一方面，在葫芦科植物上取食的一些昆虫则利用葫芦素作为其寄主识别的信号[5- 7]。

葫芦素在植物-植食性昆虫、植物-植食性昆虫-天敌以及植物-病原菌之间相互作用和协同进化的化学生态学一直是科学家们的研究热点[8- 10]。

随着对葫芦素药理学的深入研究，葫芦素的细胞毒性、抗癌活性、抗炎活性和保肝作用也备受关注[11- 12]。

近年来，国内外学者对葫芦素的化学生态学活性、生物合成途径及其作用机制进行了大量的研究，期望搞清楚葫芦素在植物生命活动以及生态系统中可能扮演的角色，进而以分子生物学的手段明晰重要化合物产生的分子机理，或以葫芦素为主研制成植物保护剂，控制病虫害发生为害，减少化学农药的使用；或以葫芦素为标记选育和培育抗性品种。

乳酸化修饰组学英文Lactate-modified ProteomicsProteomics, the large-scale study of proteins, has emerged as a powerful tool in the field of biological research. One of the key aspects of proteomics is the investigation of post-translational modifications (PTMs), which are chemical changes that occur to proteins after their synthesis. Among the various PTMs, lactate-modification, also known as lactoylation, has gained significant attention in recent years.Lactoylation is a reversible PTM in which a lactate moiety is covalently attached to specific amino acid residues within a protein. This modification can have profound effects on the structure, function, and localization of the modified proteins, making it a crucial regulator of cellular processes. The study of lactoylation, or lactate-modified proteomics, has become an increasingly important field in the quest to understand the complex mechanisms underlying biological systems.One of the primary reasons for the growing interest in lactate-modified proteomics is the central role of lactate in cellularmetabolism. Lactate, a byproduct of anaerobic glycolysis, is typically associated with hypoxic or rapidly proliferating cells, such as those found in cancer or inflammatory environments. However, recent studies have revealed that lactate can also act as a signaling molecule, influencing various cellular processes, including gene expression, protein function, and cellular metabolism.The lactoylation of proteins can have diverse effects on their activities. For instance, lactoylation of certain transcription factors can alter their DNA-binding abilities, leading to changes in gene expression patterns. Similarly, lactoylation of metabolic enzymes can modulate their catalytic activities, thereby influencing the overall metabolic state of the cell. Additionally, lactoylation can affect protein-protein interactions, subcellular localization, and even protein stability, highlighting the multifaceted nature of this PTM.To study lactate-modified proteomics, researchers employ a variety of analytical techniques, including mass spectrometry, affinity-based enrichment, and advanced bioinformatics tools. Mass spectrometry, in particular, has been a crucial tool in the identification and quantification of lactoylated proteins. By coupling mass spectrometry with sophisticated data analysis algorithms, researchers can detect and characterize the specific sites of lactoylation within a protein, as well as the relative abundance of the modified forms compared to the unmodified counterparts.The application of lactate-modified proteomics has led to significant advancements in our understanding of cellular physiology and pathology. For instance, studies have revealed the role of lactoylation in the regulation of cellular stress responses, immune function, and cancer metabolism. In the context of cancer, lactoylation of proteins involved in glycolysis, angiogenesis, and cell survival pathways has been observed, suggesting that targeting the lactate-modification machinery could be a promising therapeutic approach.Furthermore, lactate-modified proteomics has also been employed in the investigation of other disease states, such as neurodegenerative disorders, cardiovascular diseases, and metabolic syndromes. By elucidating the specific proteins and pathways affected by lactoylation in these conditions, researchers can gain valuable insights into the underlying mechanisms and potentially identify novel diagnostic biomarkers or therapeutic targets.Beyond its applications in disease research, lactate-modified proteomics also holds promise in the field of biotechnology and industrial microbiology. Understanding the role of lactoylation in the regulation of microbial enzymes, metabolic pathways, and cellular processes can aid in the optimization of fermentation processes, the development of more efficient biocatalysts, and the engineering of microorganisms for the production of valuable compounds.In conclusion, the field of lactate-modified proteomics has emerged as a crucial branch of proteomics research, offering unprecedented insights into the complex interplay between cellular metabolism and protein function. As our understanding of the biological significance of lactoylation continues to evolve, the potential applications of this field in biomedicine, biotechnology, and beyond are expected to expand, paving the way for groundbreaking discoveries and advancements in various scientific domains.。

FASTIDIOUS ANAEROBE AGAR (7531)Intended UseFastidious Anaerobe Agar is used for the cultivation of anaerobic microorganisms.Product Summary and ExplanationFastidious Anaerobe Agar is a custom formulation used for the cultivation of various fastidious anaerobes from clinical and nonclinical specimens. Anaerobic bacteria are the most common organisms colonizing humans, and a frequent cause of serious infections.1 Typically, anaerobic infections are characterized by polymicrobic mixtures of aerobic and anaerobic microbial flora, creating a challenge for anaerobic isolation.1 Principles of the ProcedurePeptone provides nitrogen and vitamin sources in Fastidious Anaerobe Agar. Sodium Chloride maintains the osmotic balance of the medium. Soluble Starch is present to absorb any toxic metabolites. Sodium Bicarbonate increases the aerotolerance by acting as an oxygen scavenger. Sodium Pyrophosphate is a buffering agent. Glucose is the carbon source. Sodium Pyruvate is added as an energy source and as an oxygen scavenger for asaccharolytic cocci, including Veillonella spp. L-Cysteine HCl•H20 is a reducing agent and growth stimulant for anaerobes. L-Arginine is added to ensure the growth of Eubacterium lentum,2 and Hemin and Vitamin K are growth factors required by several Bacteroides spp.3 Sodium Succinate improves the growth of Prevotella melaninogenica and Bacteroides spp.4 Agar is the solidifying agent.Formula / Liter Peptone...................................................................................23 gSodium Chloride.......................................................................5 gSoluble Starch...........................................................................1 gSodium Bicarbonate...............................................................0.4 g Glucose.....................................................................................1 gSodium Pyruvate.......................................................................1 gL-Cysteine HCl•H20...............................................................0.5 gSodium Pyrophosphate........................................................0.25 gL-Arginine..................................................................................1 gSodium Succinate..................................................................0.5 g Hemin...................................................................................0.01 gVitamin K............................................................................0.001 g Agar........................................................................................12 gFinal pH: 7.2 ± 0.2 at 25°CFormula may be adjusted and/or supplemented as required to meet performance specifications.Precautions1. For Laboratory Use.2. IRRITANT. Irritating to eyes, respiratory system, and skin.Directions1. Suspend 45.7 g of the medium in one liter of purified water.2. Heat with frequent agitation and boil for one minute to completely dissolve the medium.3. Autoclave at 121°C for 15 minutes.4. Prepare 5 to 10% blood agar by aseptically adding the appropriate volume of sterile defibrinated blood tomelted sterile agar medium, cooled to 45 - 50°C.Quality Control SpecificationsDehydrated Appearance: Powder is homogeneous, free flowing, and light beige to grey-green beige. Prepared Appearance: Prepared medium supplemented with 5 - 10% blood is opaque and red.Expected Cultural Response: Cultural response on Fastidious Anaerobe Agar supplemented with blood at 35°C after 48 - 72 hours of incubation under anaerobic conditions.Microorganism ResponseBacteroides fragilis ATCC® 25285growthClostridium perfringens ATCC® 13124growthPeptostreptococcus anaerobius ATCC® 27337growthThe organisms listed are the minimum that should be used for quality control testing.Test ProcedureConsult appropriate references for the isolation and identification of anaerobic bacteria.ResultsRefer to appropriate references for results.StorageStore sealed bottle containing the dehydrated medium at 2 - 30°C. Once opened and recapped, place container in a low humidity environment at the same storage temperature. Protect from moisture and light by keeping container tightly closed.ExpirationRefer to expiration date stamped on the container. The dehydrated medium should be discarded if not free flowing or appearance has changed from the original color. Expiry applies to medium in its intact container when stored as directed.Limitation of the ProcedureDue to nutritional variation, some strains may be encountered that grow poorly or fail to grow on this medium. PackagingFastidious Anaerobe Agar Code No.7531A500 g7531B 2 kg7531C10 kgReferences1. Murray, P. R., E. J. Baron, M. A. Pfaller, F. C. Tenover, and R. H. Yolken (eds.). 1995. Manual of clinical microbiology, 6th ed.American Society for Microbiology, Washington, D.C.2. Sperry, J. F. and T. D. Wilkins. 1976. Arginine, a growth-limiting factor for Eubacterium lentum. J. Bacteriol. 127:780-784.3. Gibbons, R. J. and J. B. MacDonnald. 1960. Haemin and vitamin K compounds as required factors for the cultivation of certain strains of Bacteroides melaninogenicus. J. Bacteriol. 80:164-170.4. Keudell, K. C. and A. F. Milford. 1971. Succinate as a growth factor for Bacteroides melaninogenicus. J. Bact. 108:175-178. Technical InformationContact Acumedia Manufacturers, Inc. for Technical Service or questions involving dehydrated culture media preparation or performance at (410)780-5120 or fax us at (410)780-5470.。

单词表第一章Prokaryote 原核生物Eukaryote 真核生物fractionation 分级、分馏biomolecule 生物分子organism 生物体、有机体membrane 膜nucleus 细胞核cocci 球菌bacilli 杆菌spirilla 螺旋菌Eubacteria 真细菌Archaebacteria 原细菌Gram—positive 革兰氏阳性菌Gram negative bacteria 革兰氏阴性菌Cyanobacteria 蓝细菌Plasma 细胞浆Mesosome 间体Nuleoid 拟核Sytosol 细胞质、原生质Bilayer 双分子层（膜）Protein 蛋白质Lipid 脂类Carbohydrate 糖类、碳水化合物osmotic pressure 渗透压Peptidoglycan 肽聚糖Subcellular 亚细胞的Ganelle 细胞器Genetic 遗传的Chromosome 染色体ribosomal ribonucleic acid rRNA Endoplasmic reticulum 内质网Phospholipid 磷脂Detoxification 解毒Golgi apparatus 高尔基体Refresh 更新Mitochondria 线粒体oxidative phosphorylation 氧化磷酸化fatty acid 脂肪酸degradation 降解Chloroplasts 叶绿体thylakoid vesicles 类囊体photosynthesis 光合作用Lysosomes 溶酶体Macromolecule 大分子Enzyme 酶Cytoskeleton 细胞支架Metabolic 新陈代谢的Centrifugation 离心Isolate 分离Equilibrium 平衡Density 密度Friction 摩擦力Velocity 速率Supernatant 上清夜Pellet 沉淀第二章Amino acid 氨基酸Enantiomers 对映体Tetrahedral 正四面体的Hydrophobic 疏水的、憎水的Aliphatic 脂肪族的Aromatic 芳香族的Polar 极性的Charged 带电荷的Glycine Gly,甘氨酸alanine Ala,丙氨酸valine Val，缬氨酸leucine Leu，亮氨酸isoleucine Ile，异亮氨酸methionine Met，甲硫氨酸proline Pro,脯氨酸cystine Cys,半胱氨酸Phenylalanine Phe，苯丙氨酸Tyrosine Tyr,酪氨酸Tryptophan Trp，色氨酸Asparagines Asn, 天冬酰胺Glutamine Gln,谷氨酰胺Serine Ser,丝氨酸Threonine Thr,苏氨酸Varginine Arg, 精氨酸Lysine Lys,赖氨酸Histidine His,组氨酸aspartic acid Asp，天冬氨酸glutamic acid Glu,谷氨酸base 碱carboxyl 羧基isoelectric point 等电点positive 正的、阳性的negative 负的、阴性的buffering 缓冲physiological 生理的Primary structure 一级结构Secondary structure 二级结构Tertiary structure 三级结构Quaternary structure 四级结构peptide bond 肽键sequence 顺序、序列covalent Bond 共价键polypeptide 多肽terminal 末端carbonyl 羰基resonance structures 共振结构rigid 刚性的rotate 旋转trans configuration 顺式构象disulfide bonds 二硫键α-helix α—落选hydrogen bond 氢键β-pleated sheet β—折叠片parallel 平行的antiparallel 反平行的random coil 无规卷曲unique 唯一的spatial 空间的arrangement 排列、安排linear sequence 线性序列residue 残基Hydrophobic interaction疏水相互作用Interior 内部的Electrostatic force 静电力salt bridge 盐桥、盐键van der Waals force 范德华力subunit 亚基 allosteric effect 变构效应 Noncovalent interactions 非共价相互作用 protein stability 蛋白质的稳定 dimensional 空间的、维的 proton 质子donor 供体、赠与者 lone pair of electrons 孤对电子 collinear 在同一直线上 Hydrophobic force 疏水力 Nonpolar 非极性 Minimize 最小化 protein folding 蛋白质折叠 Accessory protein 辅助蛋白质molecular chaperones 分子伴侣Myoglobin 肌红蛋白Hemoglobin 血红蛋白prosthetic group 辅基 essential 必需的 heme 血红素 crevice 缝隙 protoporphyrin 原卟啉 porphyrin 卟啉 ferrous 含铁的 proximal 最接近的 cooperative 协同的 noncooperative 非协同的 dissociation curve 解离曲线 sigmoidal S 形曲线 hyperbolic 双曲线affinity 亲和性 blood capillaries 血管Bohr effect 波尔效应2,3—biphosphoglycerate 2,3—二磷酸甘油酸Mechanism 机制Relaxed state 松弛状态tense state 紧张状态hemoglobinopathies 血红蛋白分子病Sickle—cell anemia 镰刀形细胞贫血症Erythrocyte 红血球sticky patch 粘性小区therapeutic 治疗的Collagen 胶原蛋白Skin 皮肤Bone 骨骼Tendon 腱Cartilage 软骨blood vessel 血管mammal 哺乳动物fibrous 纤维状的tripeptide 三肽的triple—helical 三股螺旋的cross—linke 交联Allysine 醛基赖氨酸Antibodie 抗体immune system 免疫系统pathogen 病原体trigger 引发、触发response 响应、应答antigen 抗原antigenic determine 抗原决定簇epitope 抗原决定簇Immunolocalization 免疫定位Antibody 抗体Enzyme-linked immunosorbent assayELISA酶联免疫吸附测定purification 提纯、纯化Homogenization 匀浆solubilization 溶解Ammonium sulfate 硫酸铵Precipitation 沉淀Dialysis 透析Chromatographic techniques 层析技术gel filtration 凝胶过滤affinity chromatography 亲和层析Electrophoretic techniques 电泳技术isoelectric focusing 等电聚焦SDS polyacrylamide gel eletrophoresis SDS聚丙烯酰胺凝胶电泳semi—permeable 半透性ligand 配基inert 惰性的matrix 基质elute 洗出、流出lectin 外源凝集素glycoprotein 糖蛋白molecular sieve 分子筛polyampholytes 聚两性电解质gradient 梯度migrate 迁移、移动chymotrypsin 胰凝乳蛋白酶sequencing 测序2—mercaptoethanol ２－巯基乙醇ninhydrin 茚三酮fluorescamine 荧光胺fluorodinitrobenzene 二硝基氟苯dansyl chloride 丹磺酰氯phenyl isothiocyanate PITC苯异硫氰酸酯fragment 片断、碎片encoding 编码decipher 解读、破译anchor 锚定第三章biocatalyst 生物催化剂active site 活性中心substrate 底物The induced –fit model 诱导契合学说Stereospecificity 立体异构专一性Specificity 专一性Trypsin 胰蛋白酶Elastase 弹性蛋白酶Oxidoreductase 氧化还原酶Transferase 转移酶Hydrolase 水解酶Lyase 裂合酶Isomerase 异构酶Ligase 连接酶Ribozyme 核酶Abzyme 抗体酶catalytic antibody 抗体酶analog 类似物assay 化验、测定optimal 最佳的Coenzyme 辅酶Cofactor 辅因子apoenzyme 脱辅酶holoenzyme 全酶acetylcholinesterase 乙酰胆碱酯酶Nicotinamide 烟酰胺Adenine 腺嘌呤Dinucleotide 二核苷酸Phosphate 磷酸Oxidation 氧化reduction 还原Flavin 黄素Mononucleotide 单核苷酸Acyl 酰基thiamine pyrophosphate 焦磷酸硫胺素decarboxylase 脱羧酶Pyridoxal 吡哆醛Pyridoxamine 吡哆胺Pyridoxine 吡哆醇Ubiquinone 泛醌Isoenzymes 同功酶Kinetic 动力学lactate dehydrogenase 乳酸脱氢酶proportional 成比例的saturate 使饱和thermal 热的denaturation 变性optimum 最适宜的diversity 多样性Michaelis—Menten equation 米氏方程double—reciprocal plot 双倒数作图法inhibition 抑制Inhibitor 抑制剂Metabolite 代谢物Irreversible 不可逆的Reversible 可逆的Competitive 竞争性的Noncompetitive 非竞争性的Probe 探测Clinically 临床上Regulation 调节committed step 关键步骤activator 激活剂Adjust 调节Feedback 反馈Sequential 连续的Branched 分支的Conformational 构象的homotropic effect 同促效应heterotropic effect 异促效应Phosphofructokinase 磷酸果糖激酶Citrate 柠檬酸盐Fructose 2，6 bisphosphate 2,6-二磷酸果糖phosphorylation 磷酸化dephosphorylation 去磷酸化hydroxyl 羟基hormone 激素Glycogen phosphorylase 糖原磷酸化酶Phosphorylate 使磷酸化glycogen synthase 糖原合酶unphosphorylate 使去磷酸化proteolytic 蛋白质水解的proenzymes 酶原zymogen 酶原hydrolysis 水解pancreatic 胰腺的pancreas 胰腺small intestine 小肠blood clotting 血液凝固amplification 扩大cascade 级联第四章boundary 边界compartments 小室Mechanical 机械的signaling 发信号insoluble 不可溶的glycerophospholipids 甘油磷脂类sphingolipids 鞘脂类sterols 固醇类glycerol 甘油sphingosine 鞘氨醇sphingomyelins 鞘磷脂cholesterol 胆固醇steroid 类固醇Amphipathic 两性的Hydrophilic 亲水的Bulky 体积大的self-assemble 自组装的fluidity 流动性rotational 转动的lateral 侧向的Fluid mosaic model 流体镶嵌模型Integral 整体的、内在的Flip 翻跟头integral membrane proteins 内在膜蛋白peripheral membrane proteins外周膜蛋白asymmetry 不对称asymmetrically 不对称地membrane—spaning protein 跨膜蛋白Multiple 多重的Lipid-anchored proteins 脂锚定蛋白Heterokaryon 异核体Fusion 融合Reconstitution 重建Reincorporated 重新合并Extracellular 细胞外的Intercellular 细胞内的Passive transport 被动运输active transport 主动运输concentration 浓度diffusion 扩散saturable 可饱和的facilitated 协助的、推动的symport 同向运送antiport 逆向运送epithelial cells 上皮细胞exocytosis 分泌作用endocytosis 内吞作用phagocytosis 吞噬作用pinocytosis 胞饮作用Receptor mediated endocytosis fusion受体介导的内吞作用debris 碎片transduction 转导Lipophilic 亲脂性的Receptors 受体second messengers 第二信使第五章Nucleic acid 核酸Replication 复制Nucleotide 核苷酸Pyrimidine 嘧啶Guanine 鸟嘌呤Thymine 胸腺嘧啶Cytosine 胞嘧啶Nucleoside 核苷Deoxyribonucleoside 脱氧核糖核苷ribonucleoside 核糖核苷deoxyribonucleotide 脱氧核糖核苷酸genes 基因complementarily 互补地nucleosome 核小体loop 突环rosette 玫瑰花结semi-conservative 半保留的polymerase 聚合酶template 模板primer 引物fork 叉Bidirectional 双向的Okazaki fragments 冈崎片段semi—discontinuous 半不连续的strand 链、一股hybridization 杂交melting temperature 熔融温度renaturation 复性labeled 标记的fluorescent 荧光的tag 标记、标签annealing 退火amplify 增强、扩大The central dogma 中心法则Transcription 转录initiation 起始Elongation 延伸termination 终止promoters 启动子palindrome 回文结构processing 加工splicing 拼接reverse transcription 逆转录第六章genetic code 遗传密码intermediate 中间的、媒介codons 密码子unambiguous 明确的correspond 相应、符合degenerate 简并的mutation 变异incorporation 合并nonoverlapping 不相重叠的reading frames 阅读框aminoacyl—tRNA 氨酰—tRNA peptidyl-tRNA 肽酰-tRNA stem 茎、干、臂anticodon 反密码子translocation 移位第七章metabolism 代谢Saccharides 糖类monosaccharides 单糖aldehyde group 醛基ketone group 酮基Stereoisomers 立体异构体Oligosaccharides 寡糖Glycosidic bond 糖苷键Polysaccharides 多糖Starch 淀粉Cellulose 纤维素Dextran 葡聚糖Amylose 直链淀粉amylopectin 支链淀粉Glycolysis 糖酵解Cytoplasm 细胞质Glucose 葡萄糖Galactose 半乳糖Mannose 甘露糖Sucrose 蔗糖Trehalose 海藻糖Lactose 乳糖Hexokinase 己糖激酶Fructose 果糖Phosphoglucoisomerase 磷酸葡萄糖变位酶Bisphosphate 二磷酸glyceraldehydes 甘油醛dihydroxyacetone 二羟丙酮aldolase 醛缩酶triose 丙糖1，3-bisphosphoglycerate 1,3 二磷酸甘油酸dehydrogenase 脱氢酶3—phosphoglycerate 3—磷酸甘油酸kinase 激酶mutase 变位酶phosphoenolpyruvate 磷酸烯醇式丙酮酸enolase 烯醇化酶pyruvate 丙酮酸Gluconeogenesis 糖异生Noncarbhydrate 非糖的Liver 肝脏skeletal muscle 骨骼肌phosphorylase 磷酸化酶Phosphorolysis 磷酸化pyrophosphorylase 焦磷酸化酶glucosyl 葡萄糖基nonreducing end 非还原端Epinephrine 肾上腺素glucagon 胰高血糖素Insulin 胰岛素第八章fatty acid 脂肪酸hydrocarbon 烃、碳氢化合物carboxylic acid 羧酸Unsaturated 不饱和的Triacylglycerol 三酰甘油Acetyl 乙酰基Thioester 硫酯Carnitine 肉（毒)碱Hydration 水合作用Thiolysis 硫解Consume 消耗ketone bodies 酮体acetoacetate 乙酰乙酸D—3-hydroxybutyrate D-3-羟基丁酸Acetone 丙酮diabetes 糖尿病toxic 有毒的lethal 致命的multifunctional 多功能的malonyl 丙二酰基carboxylation 羧化condensation 缩合acetoacetyl 乙酰乙酰基hydroxybutyryl 羟丁酰基crotonyl 丁烯酰基butyryl 丁酰基hydrolyzation 水解作用palmitoyl 软脂酰基palmitate 软脂酸lipoproteins 脂蛋白globular 球状的micelle 胶束、微囊第九章Respiration 呼吸作用citric acid cycle 柠檬酸循环、三羧酸循环concomitant 伴随的isocitrate 异柠檬酸酸盐α-ketoglutarate α—酮戊二酸succinate 琥珀酸盐succinyl 琥珀酰基fumarate 延胡索酸盐malate 苹果酸盐oxaloacetate 草酰乙酸盐cytochrome 细胞色素oxidase 氧化酶reductase 还原酶Rotatory 旋转的engine 发动机第十章Nitrogen 氮Diet 常吃的食物Erythrose 赤藓糖Ribose 核糖Transamination 转氨基作用Deamination 脱氨基作用Transdeamination 联合脱氨基作用Ammonia 氨Excrete 排泄Aquatic 水生uric acid 尿酸terrestrial 陆生的reptile 爬行动物urea 尿素vertebrates 脊椎动物ornithine 鸟氨酸arginine 精氨酸citrullin 瓜氨酸permanently 不变地。

益生菌对阿尔茨海默病作用的研究进展发布时间：2021-12-14T06:08:15.523Z 来源：《中国结合医学杂志》2021年12期作者：宋鑫萍1,2，李盛钰2，金清1[导读] 阿尔茨海默病已成为威胁全球老年人生命健康的主要疾病之一，患者数量逐年攀升，其护理的经济成本高，给全球经济造成重大挑战。

近年来研究显示，益生菌在适量使用时作为有益于宿主健康的微生物，在防治阿尔茨海默病方面具有积极影响，其作用机制可能通过调节肠道菌群，影响神经免疫系统，调控神经活性物质以及代谢产物，通过肠-脑轴影响该病发生和发展。

宋鑫萍1,2，李盛钰2，金清11.延边大学农学院，吉林延吉 1330022.吉林省农业科学院农产品加工研究所，吉林长春 130033摘要：阿尔茨海默病已成为威胁全球老年人生命健康的主要疾病之一，患者数量逐年攀升，其护理的经济成本高，给全球经济造成重大挑战。

近年来研究显示，益生菌在适量使用时作为有益于宿主健康的微生物，在防治阿尔茨海默病方面具有积极影响，其作用机制可能通过调节肠道菌群，影响神经免疫系统，调控神经活性物质以及代谢产物，通过肠-脑轴影响该病发生和发展。

本文综述了近几年来国内外益生菌对阿尔茨海默病的作用进展，以及其预防和治疗阿尔茨海默病的潜在作用机制。

关键词：益生菌；阿尔茨海默病；肠道菌群；机制Recent Progress in Research on Probiotics Effect on Alzheimer’s DiseaseSONG Xinping1,2，LI Shengyu2，JI Qing1*(1.College of Agricultural, Yanbian University, Yanji 133002，China)(2.Institute of Agro-food Technology, Jilin Academy of Agricultural Sciences, Chanchun 130033, China)Abstract：Alzheimer’s disease has become one of the major diseases threatening the life and health of the global elderly. The number of patients is increasing year by year, and the economic cost of nursing is high, which poses a major challenge to the global economy. In recent years, studies have shown that probiotics, as microorganisms beneficial to the health of the host, have a positive impact on the prevention and treatment of Alzheimer’s disease. Its mechanism may be through regulating intestinal flora, affecting the nervous immune system, regulating the neuroactive substances and metabolites, and affecting the occurrence and development of the disease through thegut- brain axis. This paper reviews the progress of probiotics on Alzheimer’s disease at home and abroad in recent years, as well as its potential mechanism of prevention and treatment.Key words：probiotics; Alzheimer’s disease; gut microbiota; mechanism阿尔茨海默病（Alzheimer’s disease, AD），系中枢神经系统退行性疾病，属于老年期痴呆常见类型，临床特征主要包括：记忆力减退、认知功能障碍、行为改变、焦虑和抑郁等。

Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 67 No. 1 pp. 107ñ110, 2010ISSN 0001-6837Polish Pharmaceutical SocietyMore than 80% of the worldís population depend upon traditional medicines for various skin diseases (1). Recently, the traditional use of plants for wound healing has received attention by the sci-entific community (1, 2). Approximately one-third of all traditional medicines in use are for the treat-ment of wounds and skin disorders, compared to only 1-3 % of modern drugs (3). Wound healing is a complex process characterized by homeostasis, re-epithelization, and granulation tissue formation and remodeling of the extracellular matrix (4). Reports about medicinal plants affecting various phases of the wound healing process, such as coagulation, inflammation, fibroplasia, collagenation, epitheliza-tion and wound contraction are abundant in the sci-entific literature (5, 6). A survey of the ethnobotani-cal studies, carried out in Iran, indicated the use of several of plant species by the inhabitants of the area, especially by those habiting the rural areas, for wound healing purpose (7-9). Punica g ranatum Linn., known locally as ìG olnar-e-farsiî, is an important medicinal plant in Iran whose flowers are used as astringent, hemostatic, antibacterial, antifun-gal, antiviral and as a remedy for cut wound, bron-chitis, diarrhea, digestive problems, man sex power reconstituent, dermal infected wounds and diabetes in Unani medicinal (Iranian Traditional Medicine) literature (7-9). This flower was also used for the treatment of injuries from falls and grey hair of young man in the traditional Chinese medicine (10). Punica g ranatum contains polyphenol compound named pomegranatate, ellagic acid, 3,3í,4í-tri-O-methylellagic acid, ethyl brevifolincarboxylate, urolic and maslinic acids, and daucosterol (11, 12).Achillea kellalensis Bioss. & Hausskn. a well-known traditional herb used in tribal medicine of Iran is locally known as ìG olberrenjas or Bumadaran-e-Sabzekohî. The species of Achillea spp. have been used as a remedy for edema, burns, wounds, carminative, indigestion, skin infection, gastric ulcer, anti-bacterial, hemorrhage, dysmenor-rhoea, enema and diarrhea (7-9). Achillea kellalen-sis monoterpenoids: camphor (34.0%), borneol (12.6%), α-thujone, cineol, bornyl acetate and cam-phene (13).MATERIALS AND METHODSPlant materialsThe male abortive flowers of Punica granatum L. (Punicaceae), is a shrub or small tree and consid-ered to be a native of Iran, and the flowers of Achillea kellalensis Bioss. & Hausskn. (Asteraceae) were collected on the slopes of the Zagross Mountains (1700ñ1800 m), District of Chaharmahal and Bakhtiari, Iran, during May ñ June 2007 and authenticated by Botany Laboratory, Researches Centre of Medicinal, Aromatic and Spice Plants, Islamic Azad University, Iran.Preparation of the extractEthanol successive extract of Punica g rana-tum, yield: 10% for flower, were prepared. Ethanolic extract of flower samples tested positive for polyphenols in flower (Wang). The aqueous extract of Achillea kellalensis filtered on Whatman paper and lyophilized a residue (yield: 5%) for flower, showed the presence of monterpenoids. AnimalsMale Wistar rats (180-200 g) of 2-3 months of age were used. The animals were housed in standardTHE WOUND HEALING ACTIVITY OF FLOWER EXTRACTS OF PUNICA GRANATUM AND ACHILLEA KELLALENSIS IN WISTAR RATSABDOLLAH GHASEMI PIRBALOUTI 1,*, ABED KOOHPAYEH 1and IRAJ KARIMI2 1Researches Centre of Medicinal Plants and Ethno-veterinary, Islamic Azad University of ShahrekordBranch, Shahrekord, PO Box 166, Iran2Department of Pathology, Veterinary Medicine Faculty, Shahrekord University, Shahrekord, Iran Keywords: Punica granatum, Achillea kellalensis, wound healing, rat107*Correspondingauthor:e-mail:********************108ABDOLLAH GHASEMI PIRBALOUTI et al.environmental conditions of temperature (22 ± 3O C),humidity (60 ± 5%) and a 12-h light/dark cycle.During experimental time, rats were given standard pellet diet (Pastor Institute, Iran) and water ad libi-tum . All procedures described were reviewed and approved by the Institutional Animal Ethical Committee.Wound healing activityWound induction and evaluation extracts for properties wound healing before the beginning of the wound healing experiments, the dorsal skin of the Wistar rats were shaved. Animals were anes-thetized with 1.5 mg/kg, i.p.of Ketamin and Xylazine. A full thickness of the excision wound (circular area about 150 mm 2 and 2 mm depth) was created along the markings using toothed forceps, a surgical blade and pointed scissors (14).The animals were divided randomly into four groups of nine rats each. Group 1 was treated with nitrofurazone ointment and served as a reference standard; groups 2 and 3 were treated topically with the simple ointment prepared from extract of Achillea kellalensis and Punica g ranatum (200mg/kg/day), respectively, and group 4 was treated topically with the simple ointment (Control). The percentage of wound closure was calculated as fol-lows using the initial and final area drawn on glass slides during the experiments (15):%of wound closure = (wound area on day 0 ×wound area on day n)/wound area on day 0 ×100where n is a number of days (6th , 4th , and 16th day).During the wound healing period and at the presented time intervals, the wound area was traced manually and photographed. The wound area was calculated using Auto CAD RL 14 software. At days 6th , 9th and 16th the experiment was terminated and the wound area was removed from the surviving ani-mals for histological examination. The excision skin biopsies were fixed in 4% formaldehyde solution 48h during the experimentation period.Statistical analysisThe relative wound area was statistically ana-lyzed using one-way ANOVA by the program ìSAS ver. 6.12 fullî and comparison of the means of the wound areas at different days evaluated by Duncanís test at p < 0.05 level .RESULTS AND DISCUSIONThe ethanolic extract of Punica g ranatum flowers and aqueous extract of Achillea kellalensis flowers showed significant wound healing activityT a b l e 1. E f f e c t o f t h e t r e a t m e n t s o n t h e e v o l u t i o n o f w o u n d s i n r a t s a f t e r 6, 9 a n d 16 d a y s o f t o p i c a l a p p l i c a t i o n+: s l i g h t , ++: m o d e r a t e , +++: e x t e n s i v e , -: a b s e n tThe wound healing activity of flower extracts of Punica granatum ...109when topically administered in rats (Fig. 1.). The wound area measurement showed the wound size of the test groups were reduced early as compared to control group. The best results of histhopathological evaluation were obtained with Punica g ranatum ,when compared to the other groups as well as to the control and the standard drug (Table 1). These results offer pharmacological evidence on the folk-loric use of Punica g ranatum flowers for healing wounds.Wound healing is a process by which damaged tissue is restored as closely as possible to its normal state and wound contraction is the process of shrink-age of the area of the wound. It is mainly dependent upon the type and extent of damage, the general state of health and the ability of the tissue to repair.In our study the extract of Punica granatum signifi-cantly increased the rate of wound contraction and collagen turnover. Collagen, the major component which strengthens and supports extracellular tissue,is composed of the amino acid, hydroxyproline,which has been used as a biochemical marker for tis-sue collagen (16).The preliminary phytochemical analysis of the flower extract of Punica g ranatum showed the absence of polyphenol compound named pomegran-atate; ellagic acid, 3,3í,4í-tri-O-methylellagic acid,ethyl brevifolincarboxylate, urolic and maslinic acids, and daucosterol (10-12). Polyphenol com-pound may be responsible for antimicrobial activity.It may be either due to the individual or additive effect of the phytoconstituents that hasten the process of wound healing. The exact component of the extract that is responsible for this effect, howev-er, was not investigated. Further phytochemical studies are needed to isolate the active compound(s)responsible for these pharmacological activities. CONCLUSIONSThe present study demonstrated that Punica granatum extract was capable of promoting wound healing activity. Enhanced wound contraction and histological observations suggest that Punica grana-tum has potential in the management of wound heal-ing and suggests further study. AcknowledgmentsThe authors are thankful to Mr. F. Fadi Fard,Ph.D and Mr. M. Farid, Ph.D (Surgical) for their technical support. REFERENCES1.Annan K., Houghton P.J.: J. Ethnopharmacol.119, 141 (2008).2.Houghton P.J., Hylands P.J., Mensah A.Y.,Hensel A., Deters A.M.: J. Ethnopharmacol.100, 100 (2005).Figure 1. Comparison of means of the wound areas at different days of evolution by Duncanís test. The means with different letters are significantly different at 0.05 probability level according to Duncanís Multiple Range test110ABDOLLAH GHASEMI PIRBALOUTI et al.3.Mantle D., Gok M.A., Lennard T.W.J.: AdverseDrug React. Toxicol. Rev. 20, 89 (2001).4.Priya K.S., G nanamani A., Radhakrishnan N.,Babu M.: J. Ethnopharmacol. 83, 193 (2002).5.Asif A., Kakub G., Mehmood S., Khunum R.,Gulfraz M.: Phytother Res. 21, 589 (2007). 6.Hemmati A., Mohammadian F.: J. Herbs SpicesMed. Plants. 7, 41 (2000).7.hasemi Pirbalouti A., G olparvar A.R:Evaluation of ethnobotany in the region of Chaharmahal & Bakhtyari, West Central Iran.The Abstract book of 48th annual meeting of the Society for Economic Botany, Chicago, Ill., USA. June 4-7, 2007.8.G horbani A.: J. Ethnopharmacol. 102, 58(2005).9.Zargari A.: Medicinal Plants.UniversityPublication, Tehran, Iran, 1989 ñ 1992 (in Persian). 10.Li S.Z.: Bencao G angmu. Beijing: PeopleísHealth Press, 1982.11.Huang T.H.W., Peng G., Kota B.P.,Li G.Q.,Yamahara J., Roufogalis B.D.,Li Y.: Toxicol.Appl. Pharmacol. 207, 160 (2005).12.Wang R., Wang W., Wang L., Liu R., Ding Y.,Du L.: Fitoterapia 77, 534 (2006).13.Rustaiyan R., Masoudi S., Yari M.: J. Essent.Oil Res. 11, 19 (1999).14.Khalil E.A., Afif F.U., Al-Hussainin M.: J.Ethnopharmacol. 109, 104 (2006).15.Wall S.J., Bevan D., Thomas D.W., HardingK.G., Edwards D.R., Murphy G.: J. Invest.Dermatol. 119, 91 (2002).16.Senthil-Kumar M., Kirubanandan S., SripriyaR., Kumar Sehgal P.: J. Surg. Res. 144, 283 (2008).Received: 25. 07. 2009。

ReviewThe lysosome and neurodegenerative diseasesLisha Zhang,Rui Sheng,and Zhenghong Qin *Department of Pharmacology and Laboratory of Aging and Nervous Diseases,Soochow University School of Medicine,Suzhou 215123,China*Correspondence address.Tel/Fax:þ86-512-65880406;E-mail:zhqin5@It has long been believed that the lysosome is an impor-tant digestive organelle.There is increasing evidence that the lysosome is also involved in pathogenesis of a variety of neurodegenerative diseases,including Alzheimer’s disease,Parkinson’s disease,Huntington’s disease,and amyotrophic lateral sclerosis.Abnormal protein degradation and deposition induced by lysoso-mal dysfunction may be the primary contributor to age-related neurodegeneration.In this review,the poss-ible relationship between lysosome and various neuro-degenerative diseases is described.Keywords lysosome;neurodegenerative diseases;Alzheimer’s disease;Parkinson’s disease;Huntington’s diseaseReceived:December 16,2008Accepted:February 25,2009IntroductionLysosomes are acidic,membrane-bound organelles in which .50acid hydrolases are stored and perform the catabolism of the cells at an optimum pH in the range of 4.6–5.0[1].Lysosomes are responsible for the degra-dation of macromolecules derived from the extracellular space through endocytosis or phagocytosis,as well as from the cytoplasm through autophagy.Lysosomal storage disorders (LSDs)are a group of genetic disorders that result from a disorder of lysosomal catabolism,due to defects in specific hydrolytic enzyme,activator protein or cofactor,transport protein or enzyme required for the correct processing of other lysosomal proteins,such as mucopolysaccharidoses,sphingolipidoses,muco-lipidoses,lipidoses,glycoproteinoses,glycogenosis,lipo-fuscinoses and mucopolysaccharidoses.Neurodegenerative diseases are characterized by pro-gressive dysfunction and death of cells that frequentlyaffect specific neural systems,including Alzheimer’s disease (AD),Parkinson’s disease (PD),amyotrophic lateral sclerosis,spinal cerebellar ataxias,and spinal muscular atrophy [2].The aim of the present review is to describe the relationship between lysosome and neurode-generative diseases.Structure and Function of LysosomesLysosomes and cathepsinsAccording to its physiological function at different stages,lysosome can be divided into the primary lyso-some,the secondary lysosome,and the residual body.Primary lysosomes are membrane-bound intracellular organelles that contain a variety of hydrolytic enzymes,including acid phosphatase,glucuronidase,sulfatase,ribonuclease,and collagenase.These enzymes are syn-thesized in the rough endoplasmic reticulum and then packaged into vesicles in the Golgi apparatus.Primary lysosomes fuse with membrane-bound vacuoles that contain material to be digested,forming secondary lyso-somes.Residual bodies contain only indigestible or slowly digestible materials and within which enzymatic activities have become virtually exhausted.The main class of lysosomal proteases is represented by the cathepsin which is derived from the Greek term meaning ‘to digest’[3].Cathepsins are subdivided into three subgroups according to the amino acids of their active sites that confer catalytic activity:cysteine (cathep-sins B,C,F,H,K,L,N,O,S,T,U,W,and X),aspartyl (cathepsins D and E),and serine cathepsins (cathepsins A and G).Cathepsins are synthesized in membrane-bound ribo-somes as N-glycosylated precursors and are transferred into the endoplasmic reticulum and later into the Golgi complex.During transport to the Golgi complex,pro-cathepsins acquire modification of their carbohydrateActa Biochim Biophys Sin (2009):437–445|ªThe Author 2009.Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology,Shanghai Institutes for Biological Sciences,Chinese Academy of Sciences.DOI:10.1093/abbs/gmp031.by guest on May 11, 2011 Downloaded frommoieties,which includes the formation of the mannose 6-phosphate (M6P)residues.After binding to M6P-specific receptors,the enzyme–receptor complexes exit the trans-Golgi network in clathrin-coated vesicles and transport to the late endosomes [4].Upon fusion with the late endosomes,the dissociation of ligands occurs.When the receptors are recycled back to the Golgi apparatus,the major parts of enzymes reach lyso-somes through this targeting pathway.Subsequently,the active cathepsin can be produced after proteolytic removal of the propeptide in the acidic environments of late endosomes or lysosomes.The last step is accompanied by the actions of several proteases,such as pepsin,neutrophil elastase,and various cysteine pro-teases [5].The cathepsin activity is regulated by several mechanisms including regulation of synthesis,zymogen processing,endogenous inhibitors (e.g.stefins and cysta-tins for cysteine cathepsins),and pH stability [6,7].The cathepsins play important roles in many physiological processes such as protein degradation,antigen presen-tation,bone resorption,and hormone processing [6].Felbor et al.[8]revealed that cathepsin B 2/2/L 2/2mice showed a degree of brain atrophy not previously seen in mice.These results demonstrated that cathepsins B and L were essential for maturation and integrity of the post-natal central nervous system (CNS)and that the two pro-teases compensated for each other in vivo [8].Lysosomes and apoptosisApoptosis is the most common form of physiological cell death in multicellular organisms.Apoptosis signal-ing is classically composed of two principle pathways.One is a direct pathway from death receptor (CD95,TNF-R1,and TRAIL-R1/TRAIL-R2[9])ligation to caspase cascade activation and cell death.Death receptor ligation triggers recruitment of the precursor form of caspase-8to a death-inducing complex,through the adaptor protein FADD,which leads to caspase-8acti-vation.The other pathway triggered by stimuli such as drugs,radiation,infectious agents,and reactive oxygen species is initiated in mitochondria.After cytochrome c is released into the cytosol from the mitochondria,it binds to Apaf1and ATP,which then activate caspase-9.Under either physiological or pathological conditions,apoptosis is mostly driven by interactions among several families of proteins,i.e.caspases,Bcl-2family proteins,and inhibitor of apoptosis proteins [10].Besides the cas-pases,lysosomal proteases such as cathepsins D,B,and L have been shown to act as mediators of apoptosis in a number of cell systems [11–14].Increased expression oractivity of cathepsin D has been observed in apoptotic cells after activation of Fas/APO-12and after exposure to oxidative stress or adriamycin [15].Results show that p53has two binding sites located at the cathepsin D pro-moter gene and that cathepsin D participates in p53-dependent apoptosis.Cathepsin D showed augmen-ted activity soon after it was released and that was accompanied by increased levels of p53protein,a cath-epsin D transcription factor [16].Therefore,the mechan-ism responsible for increase in cathepsin D activity might be an effect of increased synthesis regulated by p53.Cathepsin B has also been implicated in the acti-vation of the pro-inflammatory caspases-1and -11,and the cleavage of Bcl-2family member Bid which may lead to cytochrome c release from the mitochondria and subsequent caspase activation [17].Ishisaka et al.[13]revealed the participation of cathepsin L in a direct acti-vation of caspase-3[18].It is known that lysosome is involved not only in apoptosis but also in other types of cell death.The permeabilization of the lysosome has been shown to initiate a cell death pathway in specific circumstances.Lysosomal membrane permeabilization (LMP)causes the release of cathepsins and other hydrolases from the lysosomal lumen to the cytosol.LMP is a potentially lethal event because the ectopic presence of lysosomal proteases in the cytosol causes digestion of vital proteins and the activation of additional hydrolases including cas-pases.This latter process is usually mediated indirectly,through a cascade in which LMP causes the proteolytic activation of Bid (which is cleaved by the two lysosomal cathepsins B and D).The Bid activation then induces mitochondrial outer membrane permeabilization,result-ing in cytochrome c release and apoptosome-dependent caspase activation [19].However,massive LMP often results in cell death without caspase activation,which may adopt a subapoptotic or necrotic appearance.Moreover,the pro-apoptotic Bcl-2family member Bax can translocate from the cytosol to lysosomal membranes and induce LMP [20].Lysosomes and autophagyThe lysosomal system is responsible for the degradation of several classes of macromolecules and for the turn-over of organelles by several mechanisms collectively known as autophagy.Autophagy is a regulated process of degradation and recycling of cellular constituents,participating in organelle turnover and in the bioenergetic management of starvation.This term embraces several differentThe lysosome and neurodegenerative diseasesby guest on May 11, 2011 Downloaded frommechanisms:macroautophagy,microautophagy, chaperone-mediated autophagy(CMA),and crinophagy [21].In macroautophagy,the cytoplasm is sequestered into double-membrane structures known as autophago-somes that fuse with endosomes and lysosomes.After fusion,the vacuolar materials are degraded and recycled. In microautophagy,small cytosolic portions are interna-lized via lysosomal invaginations,and proteins are con-tinuously degraded in the lumen of this organelle even under resting conditions.In contrast with these bulk autophagy pathways,a third lysosomal degradation pathway is CMA.In CMA,specific cytosolic proteins are transported into lysosomes via a molecular chaper-one/receptor complex.Different from the other lysoso-mal degradation pathways,vesicular traffic is not involved in CMA.Functionally,secretory lysosomes are unusual,in that they serve both as a degradative and as a secretory compartment[22].Some studies have clearly demonstrated that autop-hagy has a greater variety of physiological and patho-physiological roles than expected,such as starvation adaptation,intracellular protein and organelle clearance, development,anti-aging,elimination of microorganisms, cell death,tumor suppression,and antigen presentation [23].Autophagy may also be involved in neurodegenera-tive diseases,as recent studies reported increased autop-hagy in AD and PD.Lysosome and Neurodegenerative Diseases Lysosome and ADAD is a progressive neurodegenerative disorder charac-terized by cognition and memory impairment.AD brains are characterized by two pathological hallmarks in the cerebral cortex and hippocampus:senile plaques(SPs), consisting of deposits of b-amyloid peptide(A b), and neurofibrillary tangles(NFTs),composed of an abnormally phosphorylated form of the cytoskeleton-associated protein Tau.The pathological accumulation of A b and hyperphosphorylation of Tau may develop concomitantly within synaptic terminals and then induce loss of synapses,which is considered to be closely correlated with the cognitive decline in AD[24].Lysosomal dysfunction and A b.The identification of A b as the major component of the SPs leads to the idea that deposition of A b may induce neuronal dysfunction and cell death,which is one of the primary causes of AD[25].The two most common iso-forms of A b are A b40and A b42,which vary by the length of the C-terminals[26].A b is derived from b-amyloid precursor protein (APP)by proteolytic cleavage with a-,b-,andg-secretases.a-Secretase cuts in the middle of the partof APP which will become A b and therefore blocks A b production,whereas b-and g-secretases cleave the amino and C-terminals of the A b sequence,respectively, promoting A b formation[27].There are at least two cel-lular pathways(subcellular locations)proposed for A b production,namely the secretory pathway and the endo-somal lysosomal pathway.b-Secretase(b-APP-cleaving enzyme)is a type-1transmembrane aspartyl protease, mainly localized in endosomes and lysosomes[28],so itis mainly involved in endosomal–lysosomal pathway,but not the secretory pathway.The g-secretase often resides in a high molecular weight multimeric protein complex composed of at least four core components,i.e. presenilin1or2(PS1or PS2),nicastrin,anterior pharynx defective-1,and presenilin enhancer-2[29].Its activity has been demonstrated in both the autophago-some and the lysosome,so A b could be produced inthese compartments as well.In addition,chronic sourceof soluble,exogenous A b peptides in the blood caneven cross a defective blood–brain barrier and interactwith neurons in the brain and then accumulate withinthese cells[30].In1990,many researches showed the close relation-ship between lysosomal dysfunction and morphology inAD.Lysosomal dysfunction may be the earliest histo-logical change in AD[31].Amyloid plaques are full ofactive lysosomal hydrolases,implying that plaques may originate from lysosomal rupture.Cathepsins D and E (intracellular aspartyl proteases)are considered to influ-ence A b peptides generation within the endosomal–lysosomal pathway because they exhibit b-andg-secretase like-activity[32].For this reason,the endoso-mal–lysosomal pathway is a site for cleavage of theAPP into smaller b-amyloid-containing peptides,whichare then degraded by cathepsins.Inhibition of cathepsins activity causes a rapid and pronounced build-up of potentially amyloidogenic protein fragments[33].On theother hand,a failure to degrade aggregated A b1–42inlate endosomes or secondary lysosomes was a mechan-ism that contributed to intracellular accumulation of A bin AD.The cysteine protease cathepsin B in lysosomes degrades A b peptides,especially the aggregation-prone species A b1–42.Cathepsin B deletion increases A b1–42levels and worsens plaque deposition in miceThe lysosome and neurodegenerative diseasesby guest on May 11, 2011Downloaded fromexpressing familial AD mutant human APP [34],whereas virus-mediated overexpression of the enzyme has the opposite effect [35,36].Moreover,Ditaranto et al.demonstrated that cultured primary neurons were able to internalize soluble A b 1–42from the culture medium and accumulate inside the endosomal–lysoso-mal system.The intracellular A b 1–42is resistant to pro-tease degradation and stable for at least 48h within the cultured neurons.Incubation of cultured neurons with a cytotoxic concentration of soluble A b 1–42invokes the rapid free radical generation within lysosomes and dis-ruption of lysosomal membrane proton gradient that pre-cedes cell death [36].Lysosomal dysfunction and Tau.Tau,a microtubule-associated phosphoprotein,plays an important role in maintaining neuronal morphology.Tau protein is normally localized in the neuronal axon,where it promotes microtubule assembly and stabilizes microtu-bules.However,under pathological conditions,such as AD,hyperphosphorylated Tau accumulates in neurons in the form of paired helical filaments (PHFs)[37],which subsequently form NFTs.PHF-bearing neurons are abundant in the areas in which neuronal loss is found in AD [38].Experimentally induced lysosomal dysfunction trig-gers the development of characteristic features of the aged human brain.These include proliferation of endosomes–lysosomes,hyperphosphorylation of Tau,production of Tau protein fragments resembling those found in NFTs,and the accumulation of 16–30kDa pro-teins that incorporate the amyloid sequence [39].Bi et al.[40]found that the novel cathepsin D inhibitors block the formation of hyperphosphorylated Tau frag-ments in hippocampus of AD.Moreover,recent evidence showed that autophagic-lysosomal system also plays a role in the clearance of Tau,whereas dysfunction of this system results in the formation of Tau insoluble aggre-gates in lysosomes [41].Indeed,Tau is present in phosphorylated and aggre-gated form not only in AD but also in other pathological situations.Frontotemporal dementia with PD linked to chromosome-17(FTDP-17)is an autosomal-dominant disease with variable clinical and neuropathological fea-tures.Neuropathological changes include frontotemporal atrophy,sometimes with atrophy of the basal ganglion,substantia nigra,and amygdala.FTDP-17is caused by mutations in the gene for Tau.To investigate how Tau alterations provoke neurodegeneration,Lim et al.[42]generated transgenic mice expressing human Tau with four tubulin-binding repeats and three FTDP-17mutations:G272V,P301L,and R406W.Ultrastructural analysis of mutant Tau-positive neurons revealed a pre-tangle appearance,with filaments of Tau and increased numbers of lysosomes displaying aberrant morphology similar to those found in AD.Tau modifications can provoke lysosomal aberrations and suggest that this may be a cause of neurodegeneration in tauopathies [36].Lysosome and Huntington’s diseaseHuntington’s disease (HD)is an autosomal-dominant neurological disease characterized by involuntary move-ment accompanied by cognitive impairment and emotional disturbance.The most striking pathological feature of HD is atrophy,neuronal loss,and astrogliosis in the neostriatum [43].Although multiple populations of striatal neurons are affected in HD,the spiny projec-tion neurons containing g -aminobutyric acid and sub-stance P or enkephalin are most vulnerable.Other less severely affected brain regions include cerebral cortex and thalamic nuclei.Like other neurological diseases including AD and PD,HD is also a protein-misfolding disease.It is caused by a CAG trinucleotide repeat expansion in the hunting-tin gene,which results in an expansion of the polygluta-mine tract in the amino N-terminus of the huntingtin protein.Normal individuals have 35CAG repeats,whereas HD is caused by 36repeats.The increase in the length of polyglutamine tract alters biochemical and biophysical properties of proteins.As a result,these pro-teins are prone to form stable b -sheet structure and assemble into oligomers.The bio-hallmark of mutant huntingtin is the formation of intranuclear inclusions and cytoplasmic aggregates in neurons in vulnerable brain areas.Expression of mutant huntingtin in cultured cells also causes the formation of intranuclear inclusions and aggregates in the cytoplasm.The inclusions and aggre-gates are usually formed by small N-terminal huntingtin fragments and are co-localized with other cellular pro-teins involved in proteolysis,vesicle trafficking,and protein degradation [44].The formation of huntingtin aggregates and intranuclear inclusions has been proposed to play a role in HD pathogenesis.Huntingtin protein (htt)cleavage may be a crucial,causal event in the pathogenesis of HD,and the most obvious consequence of htt cleavage is the release of N-terminal fragments containing the polyglutamine tract [45].Fragments containing polyglutamine tracts of normal size do not accumulate within cells.In contrast,The lysosome and neurodegenerative diseasesby guest on May 11, 2011 Downloaded fromfragments containing expanded polyglutamine tracts may fold into a structure that resists threading into the protea-some core,resulting in delayed clearance and accumu-lation within the cytoplasmic or nuclear compartment of the cell[46].Therefore,the production and accumulation of N-terminal huntingtin(N-htt)fragments may be criti-cal in the pathogenic process.Huntingtin processing occurs through proteasome and endosomal–lysosomal pathways.Caspase-3and calpain are proteases that cleave htt to produce stable N-htt frag-ments[47,48].N-terminal mutant huntingtin(N-mhtt) fragments cause cell death in vitro.Mutant N-htt frag-ments accumulate in HD neurons because they resist degradation by the proteasome[49–51].In addition,a decline in proteasome function with age may contribute to mutant N-htt fragment accumulation[52].Yet,mutant htt expression or proteasome inhibition in vitro can increase levels of lysosomal proteases[49,50,53]. Degradation of truncated huntingtin by an autophagic mechanism was reported[50,54].It was found that inhi-biting autophagy with3-methyladenine increased accumulation of mutant huntingtin and huntingtin aggre-gates,whereas stimulating autophagy with rapamycin reduced both huntingtin accumulation and huntingtin aggregates.Our recent studies found that autophagy was involved in activation of cathepsins and caspase-3 induced by overexpression of huntingtin.Both cathepsin D and L levels increased upon expression of huntingtin. In vitro studies revealed that wilt-type huntingtin was efficiently degraded by cathepsin D,whereas mutant huntingtin was more resistant to cathepsin D[50]. Biochemical analysis of lysates from HD patient brain suggests that mutant htt is more resistant to degradation than wild-type htt[46].Autophagy may stimulate hun-tingtin cleavage and degradation through activation of caspase-3and cathepsin D.The autophagic mechanism may also contribute to the formation of huntingtin bodies[47].Increases in cathepsin D and H activity have been found in affected areas in HD brain[48]. Lysosome and PDPD is a neurodegenerative disorder characterized by resting tremor,rigidity,hypokinesia,and postural instability.It is caused by the degeneration of dopamin-ergic(DA)neurons in the substantia nigra.The patho-genic hallmark of PD is the accumulation and aggregation of a-synuclein(a-syn)in susceptible neurons.The brain regions that are affected in PD exhibit neuronal intracytoplasmic inclusions that are termed Lewy bodies(LBs)when they are present in cell bodies and Lewy neurites in neuron processes.These inclusion bodies are particularly rich in aggregateda-syn,but also contain numerous other proteins,includ-ing components of the ubiquitin–proteasome system, molecular chaperones,and lipids[55–57].The syn family of peptides is a group of presynaptic proteins with three members:a-,b-,and g-syn[58,59]. These pro-proteins are characterized by natively unfolded structures with highly conserved N termini and divergentC-terminal acidic regions[60].Importantly,a-syn is dis-tinct from other members of the syn family in that it pos-sesses a highly hydrophobic central region that has been identified as a non-amyloid-b component(NAC)of AD amyloid[61].a-Syn is normally enriched in nerve term-inals involved in synaptic function.During normal agingand in PD,levels of natively folded a-syn increase inthe cytoplasm of substantia nigra neurons[62].a-Syn islikely to play a key role in the development of PD aswell as other synucleinopathies.In animal models,over-expression of full-length or C-terminally truncated a-synhas been shown to produce PD pathology.In vitro exper-iments,using either recombinant or endogenous a-synas substrates and purified cathepsin D or lysosomes,have demonstrated that cathepsin D degrades a-synvery efficiently and that limited proteolysis resultedin the generation of C-terminally truncated species. Knockdown of cathepsin D in cells overexpressing wild-type a-syn increased total a-syn levels by28%.And pepstatin A(the inhibitor of cathepsin D)completely blocked the degradation of a-syn in purified lysosomes. Furthermore,lysosomes isolated from cathepsin D knockdown cells showed a marked reduction in a-syn degrading activity,indicating that cathepsin D is themain lysosomal enzyme involved in a-syn degradation [63].Recently,the colleagues of our lab observed the nuclear translocation of cathepsin L in nigral DA neurons.Cathepsin L may contribute to cell cycle arrestand death of DA neurons through its nuclear transloca-tion[64].a-Syn and ubiquitin are among the major componentsof LBs[65,66],suggesting again an association with PD pathogenesis.Some studies indicate that two separatea-syn mutations,A53T and A30P,are responsible for certain rare familial forms of the disease.Wild-typea-syn was selectively translocated into lysosomes for degradation by the CMA pathway.The pathogenic A53Tand A30P a-syn mutants bound to the receptor for this pathway on the lysosomal membrane,but appeared toact as uptake blockers,inhibiting both their own degra-dation and that of other substrates[67].Stable PC12cellThe lysosome and neurodegenerative diseasesby guest on May 11, 2011Downloaded fromlines expressing mutant but not wild-type a -syn show disruption of the ubiquitin-dependent proteolytic system,marked accumulation of autophagic–vesicular structures,and impairment of lysosomal hydrolysis and proteasomal function [68].In contrast to a -syn,b -syn may be neuroprotective,because this molecule has a natural deletion in the middle of the NAC-associated region.Supporting this notion,neuropathological features of a -syn transgenic (tg)mice,such as formation of LBs and motor function deficits [69],are significantly ameliorated in a -and b -syn bigenic mice compared with a -syn single tg mice [70,71].Furthermore,b -syn directly inhibited aggrega-tion and proto-fibrillar formation of a -syn under cell-free conditions [70,72,73].Although g -syn also inhibits a -syn aggregation [72],the role of this molecule in neu-roprotection is not completely clear.Lysosome and Niemann–Pick disease type CThe LSDs are caused by the defective activity of lysoso-mal proteins,which results in the intra-lysosomal accumulation of non-degraded metabolites.Today,over 30kinds of diseases in LSDs have been found.LSDs can be grouped according to characterization of the defective enzyme or protein [74].Niemann–Pick C (NPC)is a very important type of LSDs.NPC belongs to the Niemann–Pick disease group of lipidoses along with Niemann–Pick types A and B.NPC is different from type A or B.NPA represents a classical acute neu-ropathic form of the disease,whereas NPB is a chronic form without nervous system involvement.In types A and B,the main problem in the body is the complete or partial lack of an enzyme called sphingomyelinase.Although clinically similar to NPA and NPB,NPC’s sphingomyelinase is functional [75].NPC is a neurovisceral lysosomal lipid storage dis-order of autosomal recessive inheritance characterized at the cellular level by accumulation of unesterified choles-terol and glycolipids in the endosomal–lysosomal system.The disease is often diagnosed in early child-hood,with patients typically displaying cerebellar ataxia,difficulty in speaking and swallowing,and progressive dementia.In NPC,cholesterol and glycolipids have varied roles in the cell.Cholesterol is normally used to either build the cell or forms a complex molecule called an ester.In the case of an individual with NPC,there are large amounts of cholesterol that are not used as a build-ing material and also do not form esters.This cholesterol begins to accumulate within the cells throughout the body,especially in the spleen,liver,bone marrow,andbrain.These unprocessed cholesterol as well as glyco-lipids stored in the brain cause progressive neurological damage.Mutations in either of the two human NPC genes,NPC1and NPC2,cause a fatal neurodegenerative disease associated with abnormal cholesterol accumu-lation in cells.Approximately 95%of the NPC cases are caused by genetic mutations in the NPC1gene,referred to as type C1;5%are caused by mutations in the NPC2gene,referred to as type C2[76].The NPC1gene pro-duces a protein that is located in membranes inside the cell and is involved in the movement of cholesterol and lipids within cells [77].A deficiency of this protein leads to the abnormal build-up of lipids and cholesterol within cell membranes.The NPC2gene produces a protein that binds and transports cholesterol [78,79],although its exact function is not fully understood.The increased cholesterol in NPC late endosomes and lysosomes inter-feres with transport of proteins between these compart-ments [80].The lysosomal hydrolase,cathepsin B,was upregulated in NPC cells.Both cathepsins B and D can function as b -secretase enzymes and are partially mis-localized to early endosomes in NPC [81,82].In this review,we are most interested in the close relationship between NPC and AD.Although NPC differs in major respects from AD,intriguing parallels exist in the cellular pathology of these two diseases,including neurofibrillary tangle formation,prominent lysosome system dysfunction,and influences of apolipo-protein E4genotype [83].These findings suggest that lipids are playing important roles in the development of neurodegenerative diseases.So,it can demonstrate that the widely used cholesterol-lowering drugs simvastatin and lovastatin reduce intracellular and extracellular levels of A b 1–42peptides in primary cultures of hippocampal neurons and mixed cortical neurons [84].Furthermore,it evidences that dysfunction of the lysosomal in brain plays an important role in protein deposition diseases.Concluding RemarksIn general,alterations in the lysosme degradation have been described in normal brain aging and in age-related neurodegenerative diseases including AD,HD,PD,and NPC.Cathepsins are now recognized as having more complex functions than simply being garbage disposers,and their imbalance during aging and age-related dis-eases may provoke deleterious effects on CNS neurons (Table 1).Lysosomes may be ‘bioreactor’sites for the unfolding and partial degradation of membrane proteinsThe lysosome and neurodegenerative diseasesby guest on May 11, 2011 Downloaded from。