乙醇是胃潰瘍的潛在致病因素，與活性氧化物質 (Reactive oxygen species, ROS) 的過量產生有關。許多文獻指出，分子氫氣 (H2) 是一種滲透能力強、溫和且無毒之優秀抗氧化劑。在此研究中，我們開發了一種奈米原位產氫系統，該系統包含具有高效氫氣儲存能力的硼氫化鉀離子奈米晶體材料 (KBH4 NCs)，用於治療和預防乙醇誘導的小鼠胃潰瘍，並和可從坊間購得並製備的飽和氫水 (Hydrogen rich water, HRW) 相互比較。HRW 中溶解之氣態氫氣逸散快速，此一特性雖然可幫助氫氣擴散進入深層組織，但伴隨之不穩定性將使部分釋放的氫氣在口服給予前和口服給予期間就流失到周圍環境中。相較之下，KBH4 NCs能夠有效嵌入胃部潰瘍病灶處的缺損，與胃液反應並持續產生氫氣及硼酸，緩解受損部位的氧化壓力 (Oxidative stress) 和發炎現象，並加速修復損傷之胃組織。此外，與使用 HRW 預投藥處理的小鼠相比，經過 KBH4 NCs 預處理的小鼠對乙醇所誘發胃損傷的保護作用亦更為顯著，這表示 KBH4 NCs 除治療效果外亦具有保護能力。依本研究的所有證據，可證實我們所開發的 KBH4 NCs 可能是一種具有相當潛力的口服製劑，可用於胃潰瘍症狀的治療與保護，亦可期待改變劑型後應用於其他 ROS 所引起之諸多病症。

Ethanol is a potential causative factor of gastric ulcers, which are associated with the overproduction of reactive oxygen species. Molecular hydrogen (H2) reportedly is a benign antioxidant. In this work, an in situ H2 nanogenerator system that comprises potassium borohydride ionic nanocrystals (KBH4 NCs) with a high H2 storage capacity is developed for the treatment and prevention of ethanol-induced gastric ulcers in mice. The H2-rich water (HRW) is used as a control. As the evolution of gaseous H2 from the HRW is abrupt, most of its evolved H2 gas is lost to the surrounding environment before and during oral administration. By contrast, the KBH4 NCs are capable of being trapped at the defect sites of ulcerated regions, reacting with the gastric fluid to sustainably produce gaseous H2 and boric acid, mitigating the oxidative stress and excessive inflammation in tissues and restoring the gastric injury. Moreover, protection of gastric mucosa against the ethanol-evoked damage is more prominent in mice pretreated with KBH4 NCs than in mice pre-treated with the HRW, revealing the protective activity of KBH4 NCs. Overall data suggest that the as-developed KBH4 NCs can be a promising oral formulation for an effective gastric ulcer management.

摘要-------------------------------------------------------II
Abstract---------------------------------------------------III
Table of Contents------------------------------------------IV
List of Figures--------------------------------------------VI
Chapter 1. Intoduction-------------------------------------1
Chapter 2. Result and Discussion---------------------------5
2.1 Characteristics of KBH4 NCs----------------------------5
2.2 Disintegration of KBH4 NCs in Water--------------------7
2.3 Generations of Gaseous H2 and BA-----------------------8
2.4 In Vitro Antioxidant Ability---------------------------11
2.5 In Vitro Anti-Inflammatory Potential-------------------11
2.6 Animal Study-------------------------------------------13
2.7 Mitigation of Tissue Inflammation and Mucosal Damage---15
2.8 Healing of Gastric Ulcers------------------------------18
2.9 Prevention of Gastric Ulcers---------------------------20
Chapter 3. Conclusions-------------------------------------24
Chapter 4. Materials and methods---------------------------25
4.1 Materials----------------------------------------------25
4.2 Synthesis and Characterization of KBH4 NCs-------------25
4.3 Generation of Gaseous H2-------------------------------26
4.4 Generation of BA---------------------------------------27
4.5 Antioxidant Ability------------------------------------27
4.6 Cytotoxicity of KBH4 NCs-------------------------------27
4.7 Evaluation of Cellular ROS levels----------------------27
4.8 Assessment of Anti-Inflammatory Potential--------------28
4.9 Animal Study-------------------------------------------29
4.10 Biodistribution of Orally Administered KBH4 NCs-------29
4.11 Mitigation of Tissue Inflammation---------------------29
4.12 Healing of Gastric Ulcer------------------------------30
4.13 Prevention of Gastric Ulcers--------------------------31
4.14 Statistical Analysis----------------------------------31
Chapter 5. References--------------------------------------32

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