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血衍嗎啡素 7 (LVV-hemorphin-7) 在酒精使用疾患中的疼痛異常上可能扮演的角色

為了解決CICERO Meta的問題，作者洪浩淵 這樣論述：

酒精已被證實會對痛覺產生影響，但是詳細的作用機轉仍屬未知。而血衍嗎啡素-7（LVV-hemorphin-7，以下簡稱：LVV-H7）是由血紅素的 β-chain 切斷而來，被視為一非典型類鴉片胜肽。過去文獻已發現其可結合至多種受體，也被證實具有止痛作用，但詳細作用機轉仍未完全了解。過去離體實驗已經證實，酒精可活化 LVV-H7 的生成酶–cathepsin D，進而使 LVV-H7 大量產生。此外，研究也證實長期使用酒精可能增加貧血風險，因貧血會使血紅素減少，可能也會造成 LVV-H7 降低。綜整上述，我們推測長期使用酒精可改變血中及腦中 LVV-H7 之濃度，其含量變化可能在酒精依賴性及止

痛上扮演重要之角色。在本研究中，我們使用動物模式分別探討酒精給藥前、中、後 LVV-H7 濃度之變化。其後利用額外給予 LVV-H7 及 cathepsin D 抑制劑–pepstatin 來使 LVV-H7 的含量出現變化，藉此探討 LVV-H7 是否參與酒精造成之酬賞作用與止痛。此外，我們也藉由設計 retrospective matched cohort study 及使用健保資料庫的方式，來評估酒精使用疾患（alcohol use disorder，以下簡稱：AUD）日後罹患疼痛相關疾病及使用止痛藥的風險，藉此重複驗證我們在動物實驗的研究結果。簡而言之，本研究目的為探討 LVV-H7

在酒精使用疾患中的疼痛異常上所扮演之角色。在動物實驗中，我們使用腹腔注射的方式給予雄性 Sprague-Dawley 大鼠每公斤 0.5 克的酒精（濃度為10%），藉由先連續給予 15 天再戒斷 5 天的給予方式，成功建立 passive chronic alcohol exposure 的動物模式。此部分的結果顯示：在給予酒精的初期會先產生止痛作用，但是隨著給予時間的增加，這種止痛作用會逐漸消失，然後在戒斷期間引起痛覺過敏的作用；重要的是，我們發現上述的作用可能是由 LVV-H7 的含量變化所導致。我們的實驗結果證實 LVV-H7 的含量與止痛作用呈現正相關，若 LVV-H7 的含量明顯減少

則會產生痛覺過敏的作用。此外，我們也證實 LVV-H7 的含量是由 cathepsin D 的活性和紅血球/血紅素的含量所決定，而 cathepsin D 的活性與紅血球/血紅素都會受到酒精的影響。此外，在我們的 14-year cohort study，我們發現了與未曾罹患過 AUD 之對照組相比，AUD 患者日後發生疼痛相關疾病的風險較高 [adjusted hazard ratio (aHR) = 1.290, 95% confidence interval (CI): 1.045–1.591]，日後使用止痛藥的風險也較高（aHR = 1.081, 95% CI: 1.064–1.312

），而且無論在 opioids 或是 non-opioid analgesics 的使用都有相似的上升趨勢；AUD 患者在止痛劑使用天數、止痛劑使用劑量以及止痛劑所使用的成本，也均會明顯增加。此外，在此研究中我們也發現 AUD 患者日後有較高的風險罹患貧血（aHR=2.772，95% CI：2.581–2.872），與我們在動物實驗所發現的結果一致：長期使用酒精的確會導致貧血，使紅血球/血紅素的含量均減少。由這兩部分的研究結果可得知：酒精引起的疼痛惡化與 LVV-H7 的減少有關，這可能是由於酒精引起的貧血所導致。更證實了 AUD 病人日後容易罹患疼痛相關疾病，也會有更嚴重的 opioids/

analgesics misuse 之問題；如能盡早介入及控制疼痛，將可改善此類病人的生活品質。本研究可能有助於在未來開發一種基於 LVV-H7 結構的新型止痛劑，用於治療酒精引起的疼痛障礙，從而改善酗酒者的預後。

設計和合成亞胺醣做為醣苷酶穩定劑用於治療溶小體儲積症

為了解決CICERO Meta的問題，作者李皇毅 這樣論述：

Contents摘要 iAbstract iiContents iiiFigure Contents vTable Contents ixChapter 1. Introduction 11.1. Iminosugars: Naturally Occurring Polyhydroxylated Alkaloids 11.2. Iminosugars as Therapeutic Agents 41.3. Previous Works and Current Limitations 81.4. Motivation 14Chapte

r 2. Synthesis of (3S,4S,5S)-trihydroxylpiperidine derivatives as enzyme stabilizers to improve therapeutic enzyme activity in Fabry patient cell lines 172.1. Abstract 172.2. Background 182.3. Results and Discussion 212.4. Summary and Perspective 30Chapter 3. Identification of pH-depe

ndent binding profiles of pyrrolidine-based iminosugars for the stabilization of human α-galactosidase 313.1. Abstract 313.2. Background 333.3. Results and Discussion 393.4. Summary and Perspective 61Chapter 4. Unnatural polyhydroxylated pyrrolidines as acid alpha-glucosidase (GAA) st

abilizers: Enhancement of the enzyme activity for the treatment of Pompe disease 634.1. Abstract 634.2. Background 654.3. Results and Discussion 694.4. Summary and Perspective 80Chapter 5. Flexible synthesis of highly diverse polyhydroxylated piperidines through asymmetric organocatal

ytic aldol reaction 815.1. Background 815.2. Results and Discussion 885.3. Bioevaluation 975.4. Summary and Perspective 100Chapter 6. Conclusions 101Chapter 7. Experimental Section 1057.1. Chemical Synthesis 1067.2. Experimental Procedures 1397.3. Supplementary Information

150References 169Appendix 180 Figure ContentFigure 1.1. Structures of naturally occurring iminosugars isolated from plants 2Figure 1.2. Polyhydroxylated alkaloids binding toward sugar-processing enzymes 3Figure 1.3. Iminosugars as therapeutic agents for the treatment of carbohydrate-

mediated diseases 4Figure 1.4. Lysosomal storage diseases (LSDs) and their treatment 6Figure 1.5. The general strategy of natural product-inspired combinatorial chemistry (NPICC) and its applications 8Scheme 1.1. Synthesis of pyrrolidine-based iminosugars through five-membered chiral tri-O-

benzyl cyclic nitrones prepared from four D-pentoses. 10Scheme 1.2. Synthesis of pyrrolizidine- and indolizidine-based iminosugars 11Scheme 1.3. Synthesis of six-membered chiral cyclic nitrones 12Figure 1.6. A general strategy of developing diverse iminosugars as enzyme stabilizers for LSDs

14Scheme 1.4. The main topics of this dissertation 15Figure 2.1. Graphic abstract 17Figure 2.2. Examples of small molecules as stabilizers of therapeutic enzymes 19Scheme 2.1. Synthetic design of primary structures for potential scaffolds 20Scheme 2.2. Preparation of aminomethyl-(3S,

4S,5S)-trihydroxylpiperidines from cyclic nitrones 2-1 and 2-2 22Figure 2.3. Enzyme-based and cell-based characterization of piperidines 2-3‒2-6 23Figure 2.4. Preparation of the 24-membered primary library and their inhibition activity at 10 μM against rh-α-Gal A at pH 7.0 24Scheme 2.3. Syn

thesis of derivatives 2-15‒2-19 from nitrile 2-9 25Figure 2.5. Characterization of residual enzymatic activity of rh-α-Gal A in the presence of small molecules in FD cell lines 27Figure 2.6. Binding mode of 2-21 binding with rh-α-Gal obtained from docking computation 29Figure 3.1. Graphic a

bstract 32Figure 3.2. Iminosugars for the treatment of Fabry disease 35Scheme 3.1. Synthesis of C2-deprived, C-2 extended, C-2 hydroxymethylated pyrrolidines 41Scheme 3.2. Synthesis of C-2 aminomethylated pyrrolidines 42Figure 3.3. Evaluation of enzyme stabilizing activity of pyrrolidine

-based iminosugars 45Figure 3.4. Conformations of rh-α-Gal A bound ligands 48Figure 3.5. Thermodynamic and kinetic analysis of rh-α-Gal A with iminosugars 54Figure 3.6. Co-treatment of rh-α-Gal A and iminosugars in FD cells 56Figure 3.7. Enhancement effect of 3-5 toward rh-α-Gal A in Gla

KO mice. 60Figure 4.1. Graphic abstract 64Figure 4.2. Structures of small molecules as enzyme stabilizers (or PCs) 65Figure 4.3. Strategy for the development of new enzyme stabilizers for PD 68Figure 4.4. Structures of all unnatural ADMDP stereoisomers for initial screening, and thermal

shift study of all ADMDP stereoisomers toward rh-GAA 70Scheme 4.1. Preparation of Library I and Library II from 4-17 and 4-18, respectively 71Figure 4.5. Synthesis of 4-21 to 4-25 and evaluation of their enzyme stabilizing activity 72Figure 4.6. Characterization of residual enzymatic activ

ity by treating rh-GAA in the presence or absence of small molecules in PD cells. 78Figure 4.7. GAA activity in GAA KO mice 79Scheme 5.1. Current methods to prepare multi-substituted piperidine-based chiral cyclic nitrones 82Scheme 5.2. Current organocatalysts and asymmetric organocatalytic

aldol reaction 84Scheme 5.3. Preparation of piperidine-based iminosugars through asymmetric organocatalytic aldol reaction 85Scheme 5.4. Synthesis of C-3 amino piperidines from carbohydrate derivatives 86Scheme 5.5. A general strategy and synthetic design of diverse polyhydroxylated piperi

dines 87Scheme 5.6. Retrosynthetic analysis of C-3 amino DGJ and the derivatives 88Scheme 5.7. Initial attempt to prepare C3-typed building block 1. 89Scheme 5.8. Synthesis of C3-typed building block 1. 90Scheme 5.9. Synthesis of C4–typed building block 2. 91Scheme 5.10. Proposed mech

anism for a nucleophile attacking 5-40 with or without premixing Lewis acid (LA) 93Scheme 5.11. Proposed synthesis of building block 3 93Scheme 5.12. Synthesis of C-3 derived polyhydroxylated piperidines A and B 94Scheme 5.13. Proposed transition states (Houk-List model) for the proline-cat

alyzed aldol reaction 95Scheme 5.14. Synthesis of C-2 derived polyhydroxylated piperidine C and D 96Figure 5.1. Inhibitory activity of DGJ and 5-21 and the crystal structures of rh-α-Gal A bound to DGJ 97Figure 5.2. A general strategy for the design, synthesis, and biological evaluation of

iminosugars and the collaborators 99Figure 6.1. Summary of the synthetic strategies and results of this dissertation. 101Figure S2.1. Time-dependent inactivation of rh-α-Gal A in RPMI medium. 150Figure S2.2. Structures of 24-membered acid library. 150Figure S2.3. Stabilization of rh-α

-Gal A by 2-15‒2-19 evaluated in vitro by using heat inactivation. 151Figure. S2.4. Inhibition constant (Ki) of 2-21 at pH 7.0 and its inhibition mode determined by the Lineweaver–Burk plots 151Figure S3.1. Unfolding Tm of rh-α-Gal A 153Figure S3.2. A heat-induced denaturation assay. 15

4Figure S3.3. Complex crystal structures of rh-α-Gal A with 3-8 in the active site at pH 7.2. Fobs ‒ Fcalc density maps (blue mesh was contoured at 1.5 σ) 154Figure S3.4. The raw titration data of the power supplied to the system to maintain a constant temperature against time 156Figure S3.5.

pH-Dependence of 1/Ki for (a) 3-4 and (b) DGJ 157Figure S3.6. Titration curve of (a) 3-4 and (b) 3-5 158Figure S3.7. The predicted protonated states of dibasic iminosugar (a) 3-4 and (b) 3-5 binding to rh-α-Gal A 159Figure S3.8. pH-Dependent 1H-NMR spectra of 3-5 160Figure S4.1. Time-dep

endent inactivation of rh-GAA in DMEM medium 161Figure S4.2. Structures of acid library 162Figure S4.3. Thermal shift study of iminosugars (1 mM) toward rh-GAA 163Figure. S4.4. Inhibition constant (Ki) of 4-21, 4-23 and 4-24 at pH 4.6 and its inhibition mode determined by the Lineweaver–Bur

k plots. 163Figure S4.5. Complex structure of 4-23 (orange) binding with rh-GAA 165Figure. S4.7. Characterization of residual endogenous enzymatic activity in the presence of 4-21 in M519V PD fibroblast 165Figure. S4.7. Characterization of residual endogenous enzymatic activity in the prese

nce of 4-21 in M519V PD fibroblast 166Figure. S4.8. Characterization of residual enzymatic activity of rh-GAA in the presence of 4-21 and M6P (2 mM) in D645E PD fibroblast 166Figure S5.1. 1H-1H NOESY NMR spectra. 168 Table ContentsTable 5.1. Hexosaminidases associated diseases 86Table 5

.2. Diastereoselective nucleophilic addition of vinylMgBr to aldehyde 5-40 92Table S2.1. Inhibitory activity of alkaloids toward glycosidases at 100 μM 152Table S2.2. Cytotoxicity of alkaloids at 100 μM toward normal lymphocytes 152Table S4.1. Inhibitory activity against glycosidases at 0.1

mM 164Table S4.2. Cytotoxicity of 4-21 and 4-23 toward normal fibroblast 164