臺灣博碩士論文加值系統

中草藥皆被報導具有改善代謝疾病的藥理活性，但其作用機制及藥效物質基礎仍不明確，大部分的文獻僅僅藉由測定少數化學成分進行定性或者定量分析，試圖利用少數具有“生物活性”的成分作用來解釋中草藥的作用機制。另一方面，中草藥在臨床前及臨床研究發現具有改善代謝疾病的作用，但由於沒有良好的質量控制 (quality control) 方法，造成品質一致性 (consistency) 產生很大問題，進而影響臨床療效。本論文試圖探討從中藥藥效作用物質基礎研究著手，研究藥用植物中常見的共通成分─沒食子酸─改善代謝疾病的藥效學及機理探討，並針對中藥質量控制方法的核心問題進行探索性試驗。
在論文的前半部分探討沒食子酸改善代謝疾病的作用。沒食子酸 (gallic acid) 是結構最簡單的一種多酚類化合物，不同膳食物質、蔬菜、水果、紅酒、茶葉及多種中藥材，皆發現沒食子酸的廣泛存在，其中茶葉是沒食子酸的重要來源。本研究利用兩種動物模型，高脂肪飼料誘導之肥胖及非酒精性脂肪肝 (nonalcoholic fatty liver disease, NAFLD) 動物模型及高脂肪飼料合併STZ誘導糖尿病及非酒精性脂肪性肝炎 (nonalcoholic hepatitis, NASH) 動物模型，探討沒食子酸改善代謝疾病之藥效學及作用機制研究。數據顯示，在肥胖及非酒精性脂肪肝小鼠模型，沒食子酸具有良好改善單純型脂肪肝 (simple steatosis) 的作用，並能減緩高膽固醇血症 (hypercholesterolemia) 及胰島素抵抗。在糖尿病及NASH模型中，沒食子酸能夠降低動物高血糖及高血脂，阻斷疾病從單純型脂肪肝進展至NASH階段之疾病進程。上述數據揭示沒食子酸具有改善代謝疾病的良好作用。本研究進一步運用基於核磁共振的代謝體學 (NMR-based metabolomics) 方法，測定小鼠體內血液、尿液及組織中之代謝物變化，從代謝體層次探討NAFLD及NASH之造成之代謝紊亂及沒食子酸之作用機制。綜合代謝體學研究結果與研究文獻比對，推測代謝疾病造成體內多條代謝通路產生紊亂，而沒食子酸的給予能夠部分逆轉代謝疾病所造成之代謝紊亂發生。本研究運用代謝體學結合基因表現分析方式尋找沒食子酸的作用機制。此結果與藥效學研究相互呼應，並發現沒食子酸改善代謝疾病的新穎機制。
針對中藥質量控制的議題，本論文進行中藥材質量優劣評價的探索性研究及中藥材採收後加工 (post-harvest processing) 方法評價。中藥材質量控制就是探討中藥材的“真偽優劣”議題。“真偽”目前已有共識，以植物型態學、生藥學、分析化學結合分子生物學方法為主要手段作為鑑定方法，能夠良好區分藥材基原真偽，然而“優劣”的議題與中醫藥理論的指導脫鉤，造成中藥材品質無法正確評價。本論文進行探索性研究，提出一種傳統經驗評價與現代科學評價相結合的系統性研究思路。以文獻綜述方式，系統性回顧中藥材優劣評價手段、民間藥材優劣標準 (中藥材商品規格等級) 及官方標準 (藥典標準)。並以大宗藥材─黃耆 (Astragalus membranaceus) 作為模式藥材，探討：(1) 傳統評價方法之重現性與傳承意義；(2) 化學評價結果與傳統評價結果之相關性；(3) 生物評價結果與傳統評價結果之相關性；(4)。本研究連結科學數據與專家藥材等級區分的結果，對經驗鑑別進行科學性意義闡述，找尋可反映出傳統經驗鑑別之客觀指標；明確其化學組成及與生物活性相關聯的活性成分，探討有別於傳統作用之新藥理活性發現及新藥理活性的藥效物質基礎。
中藥材採收後加工為影響中藥材質量的重要環節，台灣民間常用藥膳藥材─狗尾草 (Uraria crinite) 在採收後加工的方法上差異極大，因而造成藥材之品質不穩定性產生。本論文為探討狗尾草藥材不同採收後加工方法之科學性證據，以提高狗尾草藥材的品質一致性，採用了代謝體學結合生物活性評價的方式，探討三種傳統加工方法：烘乾法 (oven-drying)、陰乾法 (air-drying in the shade) 及曬乾法 (sun-drying)，對於藥材化學成分及生物活性之影響。結果發現，傳統方法中以烘乾法乾燥之藥材具有較好的生物活性，上述活性的發現可能與狗尾草傳統用於轉骨、跌打損傷類功效有密切關係，代謝體學結果指出，烘乾組藥材含有較多的黃酮類、三萜類、甜菜鹼及水楊酸成分，其化學成分的含量與生物活性有關。烘乾溫度對狗尾草藥材質量的影響為核心關鍵，以40度烘乾藥材之生物活性及成分含量最佳。上述結果揭示藥材在烘乾過程可能導致藥材內發生生物轉化，使得活性成分增加。40°C烘乾方法能提升不同批次藥材的質量，值得運用於狗尾草藥材的採收後加工處理。
綜上所述，本論文運用不同動物模型結合代謝體學的研究手段，探討沒食子酸對於代謝疾病的藥效學及代謝體變化，為沒食子酸改善代謝疾病提供有用代謝體學基礎資料，作為支持含有沒食子酸的不同藥用植物或是功能性食品 (functional food) 之科學依據。本論文針對中藥質量控制的優劣評價方法提供了新的研究思路，亦提供了狗尾草鮮藥材採收後加工的科學證據。

The material basis of the pharmacological effects of Chinese Materia medica is poorly understood and an efficient quality control method available for Chinese Materia medica (CMM) is insufficient. These issues have led to various problems including inconsistent quality of product. Therefore, this study focuses on two aspects: firstly an investigation of the protective effects of a common component of pharmaceutical plants on metabolic diseases, and, secondly, the development of a new methodology for the quality control of CMM.
Gallic acid (GA), a naturally abundant plant phenolic compound present in vegetables and fruits, has been shown to have potent anti-oxidative and anti-obesity activity. However, the effects of GA on metabolic disease are poorly understood. In the first part of this study, the beneficial effects of GA administration on a nutritional hepatosteatosis model and on a high‐fat diet‐fed, streptozotocin (HFD/STZ) treated diabetes model were investigated using a more “holistic view” approach, namely 1H NMR-based metabolomics. The aim was to confirm the efficacy of gallic acid in this context and to obtain information that might lead to a better understanding of the mode of action of gallic acid. Liver histopathology and serum biochemical examinations indicated that the daily administration of GA protects against hepatic steatosis, obesity, hypercholesterolemia, and insulin resistance among the HFD-induced NAFLD mice and against nonalcoholic steatohepatitis and hyperglycemia among HFD/STZ-induced diabetes mice. The findings show that GA has beneficial effects with respect to both models and that this in part occurs through a reversal of HFD or HFD/STZ caused disturbances to a range of metabolic pathways, including lipid metabolism, glucose metabolism, and gut-microbiota-associated metabolism. The selected metabolites identified during this part of the study are also potentially useful as preventive action biomarkers and, furthermore, could also be used to help our understanding of the effect of GA on mice with metabolic disease.
As more people worldwide are beginning to use traditional Chinese medicine (TCM), the quality assurance issue regarding CMM has begun to raise international concerns. In the second part of this study, an exploratory study was conducted to try and develop a new approach to quality control assurance of CMM products. A number of appropriate methods have been developed over the years for the authentication of CMMs. Nevertheless, how to differentiate “good” from “bad” CMM remains a relatively undeveloped field. Unlike Western medicine, TCM has a totally different philosophical system. The traditional usage of CMM products makes it difficult to use Western medicine quality control methods in order to achieve CMM quality control. We used Astragalus radix as a model CMM and propose a new methodology for quality control of CMM products. Initially, a literature review approach was used to determine what criteria are needed to differentiate “good” from “bad” CMM. Additionally, different batches of samples were examined by a panel of experts and these individuals then scored the CMM samples independent of each other in terms of quality. On the basis of the expert scores, the various samples were classified into three classes. When the experts’ scores were examined they were found to be highly reproducible. Secondly, we used a metabolomics approach and biological response assays in order to evaluate the various different batches of Astragalus radix. Correlation analysis was then carried out and this showed it was possible to detect a number of chemical components changes that were reflected in the expert scores; however this was not true for the biological response results. These findings demonstrated that traditional usage is not equal to modern pharmacological effects and imply that when developing a useful platform for CMM evaluation there is a need to consider the traditional usage of CMM products.
Another important topic that affects the quality control of CMM products is post-harvest processing, which involves drying; this is believed to have a significant effect on the effectiveness of Uraria crinita (UC) as a CMM. UC is traditionally and widely used for digestion regulation and deworming in Taiwan. However little is known about how post-harvest operations affect chemical composition/bioactivity of UC. We assessed three drying methods (oven-drying/air-drying/sun-drying), as well as oven drying temperature, by exploring the herb’s metabolic profile and biological activity profile. NMR spectra showed that extracts from UC contained various secondary metabolites namely triterpenoids, apigenin, glycosides and salicylic acid, as well as a range of primary metabolites. Multivariate analysis showed a clear separation of the samples into three groups that were consistent with their biological activity assays. These findings can ascribed to the presence of higher amounts of secondary metabolites in the oven-dried samples. The recommended oven-drying method gave good reproducibility when two batches were compared using the same PCA score plot as samples from other groups. Thus metabolomics is a useful tool when evaluating processing methods. An appropriate post-harvest drying method is a good approach to increase the bioactivity and quality of UC, both being required to fulfill Good Agricultural and Collection Practices.
Taken as a whole, this study suggests that a metabolomics approach is a useful platform for the functional evaluation of natural products. The targets of GA treatment are lipid metabolism and ketogenesis, glucose metabolism and gut-microbiota metabolism. The current investigation provides further evidence supporting GA as a natural dietary compound that is able to ameliorate NAFLD and other metabolic disorders. The findings also suggest that QC is still a very important key issue that will affect CMM development in the future. An appropriate post-harvesting process and a good QC method are necessary if there are to be improvements in the quality of CMM.

摘要 I
Abstract IV
目錄 VI
圖目錄 X
表目錄 XII
一、 研究目的及研究架構 1
二、 文獻回顧 5
1. 非酒精性脂肪肝介紹 5
2. 非酒精性脂肪肝治療方法 6
3. 非酒精性脂肪肝動物模型 9
3.1 基因剃除動物模型 9
3.2 飲食誘導模型 9
3.3 基因飲食複合模型 11
4. 糖尿病介紹 12
5. 糖尿病藥物治療 13
6. 糖尿病動物模型 16
6.1 誘導性動物模型 16
6.2 自發性動物模型 17
6.3 特定基因敲除動物模型 17
7. 代謝體學介紹 18
7.1 代謝體學定義與研究範疇 18
7.2 代謝體學在代謝疾病的研究應用 19
三、 沒食子酸改善高脂肪飲食誘導非酒精性脂肪肝小鼠藥效學及代謝體研究 23
摘要 23
1. 前言 24
2. 研究方法 26
2.1 化學藥品與試劑 26
2.2 動物實驗與樣本收集 26
2.3 血清生化值分析及血清胰島素測定 27
2.4 肝臟組織分析 28
2.5 代謝體學分析樣本製備：血液、尿液以及組織樣本 28
2.6 NMR代謝體學數據處理方法 31
2.7 數據統計方法 33
3. 結果與討論 34
3.1 沒食子酸改善高脂肪飲食誘導非酒精性脂肪肝小鼠之脂肪肝形成 34
3.2 基於1H NMR代謝體學的代謝輪廓分析 39
3.3 運用基於NMR的代謝體學方法評價高脂飲食誘導之脂肪肝小鼠模型 50
3.4 運用監督模式識別方法PLS-DA評價沒食子酸對於高脂飲食誘導之脂肪肝療效 58
3.5 沒食子酸改善高脂飲食誘導之非酒精性脂肪肝的代謝紊亂：生物化學觀點 59
4. 結論 64
四、 沒食子酸減緩高脂肪飲食合併STZ誘導糖尿病及非酒精性脂肪肝小鼠藥效學及代謝體研究 66
摘要 66
1. 前言 67
2. 研究方法 70
2.1 化學藥品與試劑 70
2.2 動物實驗與樣本收集 70
2.3 血清生化值分析及血清胰島素測定 72
2.4 口服葡萄糖耐受性試驗 73
2.5 組織病理學分析 73
2.5 代謝體學分析 73
2.6 即時螢光定量PCR分析 74
2.7 統計分析 74
3. 實驗結果 75
3.1 沒食子酸對於高脂飼料合併STZ誘導糖尿病小鼠藥效學 75
3.2 沒食子酸對於高脂飼料合併STZ誘導糖尿病小鼠代謝體學研究 81
3.3 肝臟脂肪代謝基因表現分析 93
4. 討論 94
5. 結論 98
6. 補充資料 100
五、 中藥材質量優劣的思考：以黃耆藥材為例，探討經驗鑑別、化學鑑別及生物鑑別之關聯性研究 118
摘要 118
1. 前言 119
1.1 中藥材質量研究就是探究中藥材的“真偽優劣” 119
1.2 中藥材質量的評控方法 120
1.3 中藥材商品規格等級 124
1.4 藥典在中藥材質量控制中的角色 127
1.5 黃耆簡介 127
1.6 本研究提出之研究思路 131
2. 研究方法 133
2.1 藥材收集 133
2.2 感官經驗評價 134
2.3 化學評價 135
2.4 生物評價 136
2.5 相關性統計分析 141
3. 實驗結果 142
3.1基於Delphi法之專家經驗評價重現性研究 142
3.2 不同批次藥材之化學成分分析結果 145
3.3 不同批次藥材生物活性分析結果 148
4. 討論 154
5. 結論 156
六、 探討不同採收後加工方法對於台灣民間常用之藥膳原料─狗尾草化學成分及生物活性之變化 158
摘要 158
1. 前言 159
2. 研究方法 161
2.1 化學藥品與試劑 161
2.2 藥材樣本收集與乾燥方法 162
2.3 細胞培養 162
2.4 生物活性分析 163
2.5 代謝體學分析 164
2.6 數據處理與多元統計分析 165
3. 實驗結果 167
3.1 不同採收後加工方法之狗尾草藥材代謝輪廓分析 167
3.2 不同烘乾溫度之狗尾草藥材代謝輪廓分析 178
3.3 不同採收後加工方法之狗尾草樣本生物活性分析 182
4. 討論 183
4.1 狗尾草具有之成分與生物活性與其傳統功效之相關性與新作用發現 183
4.2 烘乾之採收後加工方法顯著增加藥材生物活性及有效成分的含量 184
4.3 不同代謝路徑之生物轉化作用可能參予乾燥過程活性成分之積累 185
5. 結論 187
6. 補充數據 188
七、 總結與展望 190
八、 參考文獻 191
九、 作者在學期間發表的學術論文與研究成果 209
圖目錄
Figure 1 研究假說。 2
Figure 2 不同體學在研究疾病所扮演的角色。本圖以骨關節炎為例。 3
Figure 3 非酒精性脂肪肝的病程變化與胰島素抗性、高胰島素血症與肥胖的關聯性。 6
Figure 4 非酒精性脂肪性肝病的治療靶點。 8
Figure 5 肝臟脂肪堆積機制。 10
Figure 6 果糖在肝臟中的代謝機制。 11
Figure 7 2型糖尿病的降糖治療：一般建議。 15
Figure 8 代謝體學分析流程。 19
Figure 9 高脂飼料誘導非酒精性脂肪肝之動物實驗設計。 26
Figure 10 代謝體學實驗及數據分析流程圖。 28
Figure 11 肝臟脂肪酸不飽和度計算之範圍區間。 32
Figure 12 沒食子酸對於高脂飼料誘導之小鼠體重及飲食量之影響。 34
Figure 13 沒食子酸改善高脂飼料誘導血中異常生化值。 36
Figure 14 沒食子酸改善高脂飼料誘導之小鼠脂肪肝形成。 38
Figure 15 沒食子酸改善高脂飼料誘導之肝臟脂質堆積。 39
Figure 16 血液及尿液代謝物鑑定圖。 40
Figure 17 高脂飲食組與正常飼料組之血清及尿液代謝體主成分分析落點圖。 50
Figure 18 高脂飲食誘導組與正常飼料組相比之血清及代謝體偏最小二乘判別分析落點圖與其模型確效圖。 52
Figure 19 OPLS-DA 落點圖、相關係數圖及S-V plots。 54
Figure 20 PLS-DA模型落點圖。 58
Figure 21 高脂飼料擾亂小鼠體內之代謝途徑圖。 65
Figure 22 高脂飼料合併STZ誘導二型糖尿病之動物實驗設計。 70
Figure 23 正常飼料餵養小鼠與高脂飼料餵養小鼠起始體重與誘導8週後體重測定。 71
Figure 24 小鼠體重與飲食量變化。 75
Figure 25 隨機血醣與口服葡萄糖耐受性試驗。 76
Figure 26 小鼠器官重量與血清生化值。 77
Figure 27 肝臟組織病理切片。 79
Figure 28 肌肉組織病理切片。 80
Figure 29 脂肪組織病理切片。 80
Figure 30 PLS-DA模型落點圖。 82
Figure 31 血清與肝臟脂質代謝。 84
Figure 32 沒食子酸影響血清潛在代謝物變化。 85
Figure 33 沒食子酸影響尿液潛在代謝物變化。 87
Figure 34 沒食子酸影響肝臟潛在代謝物變化。 89
Figure 35 沒食子酸影響肌肉潛在代謝物變化。 91
Figure 36 沒食子酸對於高脂肪飼料合併STZ誘導糖尿病小鼠肝臟脂肪酸氧化、脂肪酸重頭合成及膽固醇合成相關蛋白基因表現。 93
Figure 37 沒食子酸改善糖尿病小鼠肝臟脂質堆積的可能作用機制圖。 97
Figure 38 糖尿病小鼠造成糖尿病小鼠代謝紊亂機制圖。 99
Figure 39 中藥材質量研究與現行評價手段合理性。 119
Figure 40 本研究流程圖。 120
Figure 41 黃耆藥材傳統鑑別、化學及生物評價研究架構圖。 131
Figure 42 老藥工感官經驗鑑別判斷原始結果。 142
Figure 43 兩次Delphi法評審專家之間重現性直方圖。 144
Figure 44 基於感官經驗評價的藥材等級分等結果。 145
Figure 45 黃耆藥材UPLC Q-TOF基本峰離子層析圖。 146
Figure 46 不同專家評分等級黃耆藥材UPLC Q-TOF基本峰離子層析圖。 146
Figure 47 不同專家評分等級黃耆藥材化學成分主成分分析。 147
Figure 48 與等級相關之代謝物在各等級中變化圖。 147
Figure 49 黃耆藥材對於基於信號通路的生物反應譜的作用篩選。 148
Figure 50 不同批次藥材對於不同信號通路的生物活性比較。 149
Figure 51 黃耆藥材作用信號通路相關分析。 150
Figure 52 TLR-2/ luciferase報告基因試驗。 152
Figure 53 黃耆ER-、ER-及NRF2通路作用物質基礎。 154
Figure 54 狗尾草傳統採收後加工方法。 160
Figure 55 研究路線圖。 161
Figure 56 不同加工方法之狗尾草藥材萃取物NMR圖譜。 168
Figure 57 不同加工方法之代謝體多變量分析。 175
Figure 58不同加工方法藥材各代謝物間變化之相對變化熱點圖。 177
Figure 59 不同烘乾溫度代謝體多變量分析。 178
Figure 60 不同批次、不同乾燥方法及不同烘乾溫度藥材主成分分析落點圖。 181
Figure 61不同採收後加工方法對於狗尾草藥材之生物活性影響。 182
Figure 62 研究提出40°C烘乾方法造成之狗尾草藥材採收後加工之變化代謝途徑。 187
Figure 63 非酒精性脂肪肝的病程變化與沒食子酸的作用點。 190
表目錄
Table 1 糖代謝狀況分類 13
Table 2 代謝體學方法學優缺點 18
Table 3 代謝體學發現脂肪肝生物標誌物 20
Table 4 代謝體學發現糖尿病生物標誌物 22
Table 5 沒食子酸在不同茶葉中的含量 24
Table 6 飼料熱量來原組成 27
Table 7 實驗中使用之NMR序列 30
Table 8 實驗中NMR序列參數設定值 30
Table 9 論文中圖譜數據處理採用之歸一化方法 32
Table 10 小鼠血清代謝物之核磁共振訊號歸屬 41
Table 11 小鼠尿液中代謝物之核磁共振訊號歸屬 45
Table 12 NMR signals assignment of lipid-soluble metabolites of liver in mice. 49
Table 13 血清及尿液中差異之代謝物統計分析及其參與之代謝途徑 55
Table 14 飼料熱量來源組成 71
Table 15 血清代謝物統計分析及其參與之代謝途徑 86
Table 16 尿液代謝物統計分析及其參與之代謝途徑 88
Table 17 肝臟水溶性代謝物統計分析及其參與之代謝途徑 90
Table 18 肌肉代謝物統計分析及其參與之代謝途徑 92
Table 19 血清代謝物鑑定 100
Table 20 尿液代謝物鑑定 104
Table 21 肝臟水溶性代謝物鑑定 108
Table 22 肝臟脂溶性代謝物鑑定 113
Table 23 肌肉水溶性代謝物鑑定 115
Table 24中藥性狀鑑別有關的科學性研究舉例 121
Table 25 中藥利用化學評價模式質控的研究舉例 123
Table 26 中藥利用生物評價模式質控的研究舉例 124
Table 27 中藥材商品規格等級的科學性研究舉例 125
Table 28 黃耆藥材來源訊息 133
Table 29 熟悉程度與判斷依據量化表 134
Table 30 本研究使用之不同細胞株及實驗條件 138
Table 31 專家教育背景、工作單位性質、從業年限及專家重現性 143
Table 32 狗尾草萃取物代謝物指認 169
Table 33 不同加工方法之狗尾草藥材代謝物峰面積積分值 176
Table 34 不同烘乾溫度之狗尾草藥材代謝物峰面積積分值 180

1. Xiao, J., et al., Recent advances in the herbal treatment of non-alcoholic Fatty liver disease. J Tradit Complement Med, 2013. 3(2): p. 88-94.
2. Liu, Z.L., et al., Herbal medicines for fatty liver diseases. Cochrane Database Syst Rev, 2013. 8: p. CD009059.
3. Subramanian, A.P., et al., Gallic acid: prospects and molecular mechanisms of its anticancer activity. RSC Adv, 2015. 5(45): p. 35608-35621.
4. Manach, C., et al., Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am J Clin Nutr, 2005. 81(1 Suppl): p. 230S-242S.
5. Francisco A Toma´s-Barbera´n, M.N.C., Dietary hydroxybenzoic acid derivatives - nature, occurrence and dietary burden. J Sci Food Agric, 2000. 80(7): p. 1024-1032.
6. Sanyal, R., et al., Inhibition of the genotoxic effects of heterocyclic amines in human derived hepatoma cells by dietary bioantimutagens. Mutagenesis, 1997. 12(4): p. 297-303.
7. Hsu, C.L. and G.C. Yen, Effect of gallic acid on high fat diet-induced dyslipidaemia, hepatosteatosis and oxidative stress in rats. Br J Nutr, 2007. 98(4): p. 727-35.
8. Jang, A., et al., Comparison of hypolipidemic activity of synthetic gallic acid-linoleic acid ester with mixture of gallic acid and linoleic acid, gallic acid, and linoleic acid on high-fat diet induced obesity in C57BL/6 Cr Slc mice. Chem Biol Interact, 2008. 174(2): p. 109-17.
9. Oi, Y., et al., Antiobesity effects of Chinese black tea (Pu-erh tea) extract and gallic acid. Phytother Res, 2012. 26(4): p. 475-81.
10. Gandhi, G.R., et al., Gallic acid attenuates high-fat diet fed-streptozotocin-induced insulin resistance via partial agonism of PPARgamma in experimental type 2 diabetic rats and enhances glucose uptake through translocation and activation of GLUT4 in PI3K/p-Akt signaling pathway. Eur J Pharmacol, 2014. 745: p. 201-16.
11. Punithavathi, V.R., et al., Protective effects of gallic acid on hepatic lipid peroxide metabolism, glycoprotein components and lipids in streptozotocin-induced type II diabetic Wistar rats. J Biochem Mol Toxicol, 2011. 25(2): p. 68-76.
12. Punithavathi, V.R., et al., Antihyperglycaemic, antilipid peroxidative and antioxidant effects of gallic acid on streptozotocin induced diabetic Wistar rats. Eur J Pharmacol, 2011. 650(1): p. 465-71.
13. Patel, S.S. and R.K. Goyal, Cardioprotective effects of gallic acid in diabetes-induced myocardial dysfunction in rats. Pharmacognosy Res, 2011. 3(4): p. 239-45.
14. Ahad, A., et al., Gallic acid ameliorates renal functions by inhibiting the activation of p38 MAPK in experimentally induced type 2 diabetic rats and cultured rat proximal tubular epithelial cells. Chem Biol Interact, 2015. 240: p. 292-303.
15. Ray, K., NAFLD-the next global epidemic. Nat Rev Gastroenterol Hepatol, 2013. 10(11): p. 621.
16. Farrell, G.C., V.W. Wong, and S. Chitturi, NAFLD in Asia--as common and important as in the West. Nat Rev Gastroenterol Hepatol, 2013. 10(5): p. 307-18.
17. Goodarz Danaei, M.M.F., Yuan Lu, Gitanjali M Singh, Melanie J Cowan, Christopher J Paciorek, John K Lin, Farshad Farzadfar, Young-Ho Khang, Gretchen A Stevens, Mayuree Rao, Mohammed K Ali, Leanne M Riley, Carolyn A Robinson, Majid Ezzati, on behalf of the Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group (Blood Glucose), National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2·7 million participants. The Lancet, 2011. 378(9785): p. 31-40.
18. Lo, L., et al., Diabetes is a progression factor for hepatic fibrosis in a high fat fed mouse obesity model of non-alcoholic steatohepatitis. J Hepatol, 2011. 55(2): p. 435-44.
19. Katz, R., Biomarkers and surrogate markers: an FDA perspective. NeuroRx, 2004. 1(2): p. 189-95.
20. Blanco, F.J. and C. Ruiz-Romero, Osteoarthritis: Metabolomic characterization of metabolic phenotypes in OA. Nat Rev Rheumatol, 2012. 8(3): p. 130-2.
21. Taylor, J., et al., Application of metabolomics to plant genotype discrimination using statistics and machine learning. Bioinformatics, 2002. 18 Suppl 2: p. S241-8.
22. Chiu, N.-y.C., Kuang-hsiung The illustrated medicinal plants of Taiwan. 1986: SMC PUBLISHING INC.
23. Hinna Hamid, S.A., Asif Ali, M. Alam and S.H. Ansari, Antiinflammatory and analgesic activity of Uraria lagopoides. Pharmaceutical Biology, 2004. 42(2): p. 114-116.
24. Rahman, M.M., S. Gibbons, and A.I. Gray, Isoflavanones from Uraria picta and their antimicrobial activity. Phytochemistry, 2007. 68(12): p. 1692-7.
25. Jiang, Z.Y., et al., Cytotoxic flavanes from Uraria clarkei. J Asian Nat Prod Res, 2013. 15(9): p. 979-84.
26. Igboechi, A.C., E.O. Osazuwa, and U.E. Igwe, Laboratory evaluation of the acaricidal properties of extracts from Uraria picta (Leguminosae). J Ethnopharmacol, 1989. 26(3): p. 293-8.
27. Yen, G. C., H. H. Lai, and H.Y. Chou, Nitric oxide-scavenging and antioxidant effects of Uraria crinita root. Food Chem, 2001. 74(4): p. 471-478.
28. Boer, H.J., C. Vongsombath, and J. Kafer, A fly in the ointment: evaluation of traditional use of plants to repel and kill blowfly larvae in fermented fish. PLoS One, 2011. 6(12): p. e29521.
29. 范建高, 中國非酒精性脂肪性肝病診療指南(2010年修訂版). 中國醫學前沿雜誌(電子版), 2012(07): p. 4-10.
30. Wree, A., et al., From NAFLD to NASH to cirrhosis-new insights into disease mechanisms. Nat Rev Gastroenterol Hepatol, 2013. 10(11): p. 627-36.
31. Brunt, E.M., Nonalcoholic steatohepatitis: definition and pathology. Semin Liver Dis, 2001. 21(1): p. 3-16.
32. Brunt, E.M., et al., Nonalcoholic steatohepatitis: histologic features and clinical correlations with 30 blinded biopsy specimens. Hum Pathol, 2004. 35(9): p. 1070-82.
33. Adams, L.A., et al., The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology, 2005. 129(1): p. 113-21.
34. Day, C.P. and O.F. James, Steatohepatitis: a tale of two "hits"? Gastroenterology, 1998. 114(4): p. 842-5.
35. Calamita, G. and P. Portincasa, Present and future therapeutic strategies in non-alcoholic fatty liver disease. Expert Opin Ther Targets, 2007. 11(9): p. 1231-49.
36. Chalasani, N., et al., The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology, 2012. 55(6): p. 2005-23.
37. Ratziu, V., Pharmacological agents for NASH. Nat Rev Gastroenterol Hepatol, 2013. 10(11): p. 676-85.
38. Ratziu, V., et al., A position statement on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol, 2010. 53(2): p. 372-84.
39. Ratziu, V., Z. Goodman, and A. Sanyal, Current efforts and trends in the treatment of NASH. J Hepatol, 2015. 62(1 Suppl): p. S65-75.
40. Hebbard, L. and J. George, Animal models of nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol, 2011. 8(1): p. 35-44.
41. Imajo, K., et al., Rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Int J Mol Sci, 2013. 14(11): p. 21833-57.
42. 黃海燕, et al., 非酒精性脂肪性肝病動物實驗模型研究進展. 臨床肝膽病雜誌, 2014(09): p. 948-953.
43. Dowman, J.K., J.W. Tomlinson, and P.N. Newsome, Pathogenesis of non-alcoholic fatty liver disease. QJM, 2010. 103(2): p. 71-83.
44. Lim, J.S., et al., The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome. Nat Rev Gastroenterol Hepatol, 2010. 7(5): p. 251-64.
45. Sahai, A., et al., Obese and diabetic db/db mice develop marked liver fibrosis in a model of nonalcoholic steatohepatitis: role of short-form leptin receptors and osteopontin. Am J Physiol Gastrointest Liver Physiol, 2004. 287(5): p. G1035-43.
46. Sinha-Hikim, I., et al., A novel cystine based antioxidant attenuates oxidative stress and hepatic steatosis in diet-induced obese mice. Exp Mol Pathol, 2011. 91(1): p. 419-28.
47. Kashireddy, P.V. and M.S. Rao, Lack of peroxisome proliferator-activated receptor alpha in mice enhances methionine and choline deficient diet-induced steatohepatitis. Hepatol Res, 2004. 30(2): p. 104-110.
48. Li, Y., et al., AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab, 2011. 13(4): p. 376-88.
49. Shaw, J.E., R.A. Sicree, and P.Z. Zimmet, Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract, 2010. 87(1): p. 4-14.
50. Standards of medical care in diabetes--2015: summary of revisions. Diabetes Care, 2015. 38 Suppl: p. S4.
51. 趙明, 王曉霞, and 朱小蔚, 從糖尿病診斷標準演變看對糖尿病的認識. 診斷學理論與實踐, 2014(02): p. 226-228.
52. Alberti, K.G. and P.Z. Zimmet, Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med, 1998. 15(7): p. 539-53.
53. Association, A.D., Standards of medical care in diabetes--2015. Diabetes Care, 2015. 38 Suppl: p. S1.
54. Inzucchi, S.E., et al., Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care, 2015. 38(1): p. 140-9.
55. Deacon, C.F., Dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes: a comparative review. Diabetes Obes Metab, 2011. 13(1): p. 7-18.
56. King, A.J., The use of animal models in diabetes research. Br J Pharmacol, 2012. 166(3): p. 877-94.
57. Cefalu, W.T., Animal models of type 2 diabetes: clinical presentation and pathophysiological relevance to the human condition. ILAR J, 2006. 47(3): p. 186-98.
58. Liu, Y., et al., Inhibition of soluble epoxide hydrolase attenuates high-fat-diet-induced hepatic steatosis by reduced systemic inflammatory status in mice. PLoS One, 2012. 7(6): p. e39165.
59. Wu, L.Y., et al., Green tea supplementation ameliorates insulin resistance and increases glucose transporter IV content in a fructose-fed rat model. Eur J Nutr, 2004. 43(2): p. 116-24.
60. Szkudelski, T., The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res, 2001. 50(6): p. 537-46.
61. Levin, B.E., et al., Selective breeding for diet-induced obesity and resistance in Sprague-Dawley rats. Am J Physiol, 1997. 273(2 Pt 2): p. R725-30.
62. Sotnikova, R., et al., Changes in the function and ultrastructure of vessels in the rat model of multiple low dose streptozotocin-induced diabetes. Gen Physiol Biophys, 2006. 25(3): p. 289-302.
63. Sawant, S.P., et al., Protective effect of type 2 diabetes on acetaminophen-induced hepatotoxicity in male Swiss-Webster mice. J Pharmacol Exp Ther, 2006. 316(2): p. 507-19.
64. Mu, J., et al., Chronic inhibition of dipeptidyl peptidase-4 with a sitagliptin analog preserves pancreatic beta-cell mass and function in a rodent model of type 2 diabetes. Diabetes, 2006. 55(6): p. 1695-704.
65. Park, S.H., et al., Neointimal hyperplasia after arterial injury is increased in a rat model of non-insulin-dependent diabetes mellitus. Circulation, 2001. 104(7): p. 815-9.
66. Akash, M.S., K. Rehman, and S. Chen, Goto-Kakizaki rats: its suitability as non-obese diabetic animal model for spontaneous type 2 diabetes mellitus. Curr Diabetes Rev, 2013. 9(5): p. 387-96.
67. Nicholson, J.K., J.C. Lindon, and E. Holmes, 'Metabonomics': understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica, 1999. 29(11): p. 1181-9.
68. Wang, X., et al., Urine metabolomics analysis for biomarker discovery and detection of jaundice syndrome in patients with liver disease. Mol Cell Proteomics, 2012.
69. Holmes, E., et al., Human metabolic phenotype diversity and its association with diet and blood pressure. Nature, 2008. 453(7193): p. 396-400.
70. Xuan, J., et al., Metabolomic profiling to identify potential serum biomarkers for schizophrenia and risperidone action. J Proteome Res, 2011. 10(12): p. 5433-43.
71. Wang, X., et al., Metabolomics study on the toxicity of aconite root and its processed products using ultraperformance liquid-chromatography/electrospray-ionization synapt high-definition mass spectrometry coupled with pattern recognition approach and ingenuity pathways analysis. J Proteome Res, 2012. 11(2): p. 1284-301.
72. Yang, H.J., et al., An effective assessment of simvastatin-induced toxicity with NMR-based metabonomics approach. PLoS One, 2011. 6(2): p. e16641.
73. Kim, H.J., et al., Metabolomic analysis of livers and serum from high-fat diet induced obese mice. J Proteome Res, 2011. 10(2): p. 722-31.
74. Lisec, J., et al., Gas chromatography mass spectrometry-based metabolite profiling in plants. Nat Protoc, 2006. 1(1): p. 387-96.
75. McLoughlin, G.A., et al., Analyzing the effects of psychotropic drugs on metabolite profiles in rat brain using 1H NMR spectroscopy. J Proteome Res, 2009. 8(4): p. 1943-52.
76. Bao, Y., et al., Metabonomic variations in the drug-treated type 2 diabetes mellitus patients and healthy volunteers. J Proteome Res, 2009. 8(4): p. 1623-30.
77. Wang, Y., et al., Experimental metabonomic model of dietary variation and stress interactions. J Proteome Res, 2006. 5(7): p. 1535-42.
78. Rezzi, S., et al., Nutritional metabonomics: applications and perspectives. J Proteome Res, 2007. 6(2): p. 513-25.
79. Llorach, R., et al., Nutrimetabolomic strategies to develop new biomarkers of intake and health effects. J Agric Food Chem, 2012. 60(36): p. 8797-808.
80. Nicholson, J.K. and J.C. Lindon, Systems biology: Metabonomics. Nature, 2008. 455(7216): p. 1054-6.
81. Dumas, M.E., J. Kinross, and J.K. Nicholson, Metabolic phenotyping and systems biology approaches to understanding metabolic syndrome and fatty liver disease. Gastroenterology, 2014. 146(1): p. 46-62.
82. Roberts, L.D., A. Koulman, and J.L. Griffin, Towards metabolic biomarkers of insulin resistance and type 2 diabetes: progress from the metabolome. Lancet Diabetes Endocrinol, 2014. 2(1): p. 65-75.
83. Browning, J.D. and J.D. Horton, Molecular mediators of hepatic steatosis and liver injury. J Clin Invest, 2004. 114(2): p. 147-52.
84. Cusi, K., Nonalcoholic fatty liver disease in type 2 diabetes mellitus. Curr Opin Endocrinol Diabetes Obes, 2009. 16(2): p. 141-9.
85. Maheshwari, D.T., et al., Antioxidant and hepatoprotective activities of phenolic rich fraction of Seabuckthorn (Hippophae rhamnoides L.) leaves. Food Chem Toxicol, 2011. 49(9): p. 2422-8.
86. Peng, C.H., et al., Mulberry water extracts possess an anti-obesity effect and ability to inhibit hepatic lipogenesis and promote lipolysis. J Agric Food Chem, 2011. 59(6): p. 2663-71.
87. Wang, S.H., et al., Oral administration of Trapa taiwanensis Nakai fruit skin extracts conferring hepatoprotection from CCl4-caused injury. J Agric Food Chem, 2011. 59(8): p. 3686-92.
88. Lee, J.E., et al., Metabolic dependence of green tea on plucking positions revisited: a metabolomic study. J Agric Food Chem, 2011. 59(19): p. 10579-85.
89. Ma, J., et al., Bioactive novel polyphenols from the fruit of Manilkara zapota (Sapodilla). J Nat Prod, 2003. 66(7): p. 983-6.
90. Hsiang, C.Y., et al., Toona sinensis and its major bioactive compound gallic acid inhibit LPS-induced inflammation in nuclear factor-kappaB transgenic mice as evaluated by in vivo bioluminescence imaging. Food Chem, 2013. 136(2): p. 426-34.
91. Kroes, B.H., et al., Anti-inflammatory activity of gallic acid. Planta Med, 1992. 58(6): p. 499-504.
92. Inoue, M., et al., Selective induction of cell death in cancer cells by gallic acid. Biol Pharm Bull, 1995. 18(11): p. 1526-30.
93. Niho, N., et al., Subchronic toxicity study of gallic acid by oral administration in F344 rats. Food Chem Toxicol, 2001. 39(11): p. 1063-70.
94. Kim, H.K., Y.H. Choi, and R. Verpoorte, NMR-based plant metabolomics: where do we stand, where do we go? Trends Biotechnol, 2011. 29(6): p. 267-75.
95. Sheng, X., et al., Rhein ameliorates fatty liver disease through negative energy balance, hepatic lipogenic regulation, and immunomodulation in diet-induced obese mice. Am J Physiol Endocrinol Metab, 2011. 300(5): p. E886-93.
96. Beckonert, O., et al., Metabolic profiling, metabolomic and metabonomic procedures for NMR spectroscopy of urine, plasma, serum and tissue extracts. Nat Protoc, 2007. 2(11): p. 2692-703.
97. Xu, W., et al., Streptozotocin-Induced Dynamic Metabonomic Changes in Rat Biofluids. J Proteome Res, 2012.
98. He, Q., et al., Dietary supplementation with l-arginine partially counteracts serum metabonome induced by weaning stress in piglets. J Proteome Res, 2011. 10(11): p. 5214-21.
99. He, Q., et al., Metabolomic analysis of the response of growing pigs to dietary L-arginine supplementation. Amino Acids, 2009. 37(1): p. 199-208.
100. Nicholson, J.K., et al., 750 MHz 1H and 1H-13C NMR spectroscopy of human blood plasma. Anal Chem, 1995. 67(5): p. 793-811.
101. Dumas, M.E., et al., Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice. Proc Natl Acad Sci U S A, 2006. 103(33): p. 12511-6.
102. Salek, R.M., et al., A metabolomic comparison of urinary changes in type 2 diabetes in mouse, rat, and human. Physiol Genomics, 2007. 29(2): p. 99-108.
103. Zhao, X.J., et al., Systems responses of rats to mequindox revealed by metabolic and transcriptomic profiling. J Proteome Res, 2012. 11(9): p. 4712-21.
104. Trygg, J., E. Holmes, and T. Lundstedt, Chemometrics in metabonomics. J Proteome Res, 2007. 6(2): p. 469-79.
105. Rolo, A.P., J.S. Teodoro, and C.M. Palmeira, Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis. Free Radic Biol Med, 2012. 52(1): p. 59-69.
106. Fox, C.S., et al., Abdominal visceral and subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham Heart Study. Circulation, 2007. 116(1): p. 39-48.
107. Rajalakshmi, K., H. Devaraj, and S. Niranjali Devaraj, Assessment of the no-observed-adverse-effect level (NOAEL) of gallic acid in mice. Food Chem Toxicol, 2001. 39(9): p. 919-22.
108. http://www.fda.gov/cder/Guidance/5541fnl.pdf. Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. 2005; Available from: http://www.fda.gov/cder/Guidance/5541fnl.pdf.
109. Zhang, L., et al., Systems responses of rats to aflatoxin B1 exposure revealed with metabonomic changes in multiple biological matrices. J Proteome Res, 2011. 10(2): p. 614-23.
110. Klein, J., Membrane breakdown in acute and chronic neurodegeneration: focus on choline-containing phospholipids. J Neural Transm, 2000. 107(8-9): p. 1027-63.
111. Grootveld, M., et al., High resolution proton NMR investigations of rat blood plasma. Assignment of resonances for the molecularly mobile carbohydrate side-chains of 'acute-phase' glycoproteins. FEBS Lett, 1993. 322(3): p. 266-76.
112. Laffel, L., Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev, 1999. 15(6): p. 412-26.
113. Yuzefovych, L.V., et al., Mitochondrial DNA damage and dysfunction, and oxidative stress are associated with endoplasmic reticulum stress, protein degradation and apoptosis in high fat diet-induced insulin resistance mice. PLoS One, 2013. 8(1): p. e54059.
114. Vinaixa, M., et al., Metabolomic assessment of the effect of dietary cholesterol in the progressive development of fatty liver disease. J Proteome Res, 2010. 9(5): p. 2527-38.
115. Gupte, A.A., et al., Heat treatment improves glucose tolerance and prevents skeletal muscle insulin resistance in rats fed a high-fat diet. Diabetes, 2009. 58(3): p. 567-78.
116. Lee, W.M., et al., Antibodies to polymerized human serum albumin in acute and chronic liver disease. Hepatology, 1987. 7(5): p. 906-12.
117. Samuel, V.T. and G.I. Shulman, Mechanisms for insulin resistance: common threads and missing links. Cell, 2012. 148(5): p. 852-71.
118. Miyazaki, T. and Y. Matsuzaki, Taurine and liver diseases: a focus on the heterogeneous protective properties of taurine. Amino Acids, 2012.
119. Ghandforoush-Sattari, M. and S. Mashayekhi, Evaluation of taurine as a biomarker of liver damage in paracetamol poisoning. Eur J Pharmacol, 2008. 581(1-2): p. 171-6.
120. Waterfield, C.J., et al., Taurine, a possible urinary marker of liver damage: a study of taurine excretion in carbon tetrachloride-treated rats. Arch Toxicol, 1991. 65(7): p. 548-55.
121. Timbrell, J.A. and C.J. Waterfield, Changes in taurine as an indicator of hepatic dysfunction and biochemical perturbations. Studies in vivo and in vitro. Adv Exp Med Biol, 1996. 403: p. 125-34.
122. Brand, H.S., G.G. Jorning, and R.A. Chamuleau, Changes in urinary taurine and hypotaurine excretion after two-thirds hepatectomy in the rat. Amino Acids, 1998. 15(4): p. 373-83.
123. Melis, G.C., et al., Glutamine: recent developments in research on the clinical significance of glutamine. Curr Opin Clin Nutr Metab Care, 2004. 7(1): p. 59-70.
124. Poeze, M., et al., Decreased plasma glutamate in early phases of septic shock with acute liver dysfunction is an independent predictor of survival. Clin Nutr, 2008. 27(4): p. 523-30.
125. Mehta, K., et al., Nonalcoholic fatty liver disease: pathogenesis and the role of antioxidants. Nutr Rev, 2002. 60(9): p. 289-93.
126. Klein, M.S., et al., Discrimination of steatosis and NASH in mice using nuclear magnetic resonance spectroscopy. metabolomics, 2011. 7(2): p. 237-246.
127. Bialonska, D., et al., The influence of pomegranate by-product and punicalagins on selected groups of human intestinal microbiota. Int J Food Microbiol, 2010. 140(2-3): p. 175-82.
128. Lever, M. and S. Slow, The clinical significance of betaine, an osmolyte with a key role in methyl group metabolism. Clin Biochem, 2010. 43(9): p. 732-44.
129. Song, Z., et al., Involvement of AMP-activated protein kinase in beneficial effects of betaine on high-sucrose diet-induced hepatic steatosis. Am J Physiol Gastrointest Liver Physiol, 2007. 293(4): p. G894-902.
130. Abdelmalek, M.F., et al., Betaine, a promising new agent for patients with nonalcoholic steatohepatitis: results of a pilot study. Am J Gastroenterol, 2001. 96(9): p. 2711-7.
131. Knip, M., et al., Safety of high-dose nicotinamide: a review. Diabetologia, 2000. 43(11): p. 1337-45.
132. Commission, E. Opinion of the Scientific Committee on Food on the Upper Tolerable Intake of nicotinic acid and nicotinamide (niacin). [online] 2002; Available from: http://ec.europa.eu/food/fs/sc/scf/out80j_en.pdf.
133. Ringeissen, S., et al., Potential urinary and plasma biomarkers of peroxisome proliferation in the rat: identification of N-methylnicotinamide and N-methyl-4-pyridone-3-carboxamide by 1H nuclear magnetic resonance and high performance liquid chromatography. Biomarkers, 2003. 8(3-4): p. 240-71.
134. Xiao, J., et al., Advance in dietary polyphenols as aldose reductases inhibitors: structure-activity relationship aspect. Crit Rev Food Sci Nutr, 2015. 55(1): p. 16-31.
135. Xiao, J., et al., Advance in dietary polyphenols as alpha-glucosidases inhibitors: a review on structure-activity relationship aspect. Crit Rev Food Sci Nutr, 2013. 53(8): p. 818-36.
136. Stefek, M., Natural flavonoids as potential multifunctional agents in prevention of diabetic cataract. Interdiscip Toxicol, 2011. 4(2): p. 69-77.
137. Dembinska-Kiec, A., et al., Antioxidant phytochemicals against type 2 diabetes. Br J Nutr, 2008. 99 E Suppl 1: p. ES109-17.
138. Chao, J., et al., Gallic acid ameliorated impaired glucose and lipid homeostasis in high fat diet-induced NAFLD mice. PLoS One, 2014. 9(2): p. e96969.
139. Kyriakis, E., et al., Natural flavonoids as antidiabetic agents. The binding of gallic and ellagic acids to glycogen phosphorylase b. FEBS Lett, 2015. 589(15): p. 1787-94.
140. Benalla, W., S. Bellahcen, and M. Bnouham, Antidiabetic medicinal plants as a source of alpha glucosidase inhibitors. Curr Diabetes Rev, 2010. 6(4): p. 247-54.
141. Sameermahmood, Z., et al., Gallic acid protects RINm5F beta-cells from glucolipotoxicity by its antiapoptotic and insulin-secretagogue actions. Phytother Res, 2010. 24 Suppl 1: p. S83-94.
142. Solanky, K.S., et al., NMR-based metabonomic studies on the biochemical effects of epicatechin in the rat. J Agric Food Chem, 2003. 51(14): p. 4139-45.
143. Van Dorsten, F.A., et al., Metabonomics approach to determine metabolic differences between green tea and black tea consumption. J Agric Food Chem, 2006. 54(18): p. 6929-38.
144. Wang, Y., et al., A metabonomic strategy for the detection of the metabolic effects of chamomile (Matricaria recutita L.) ingestion. J Agric Food Chem, 2005. 53(2): p. 191-6.
145. Dai, H., et al., Combined NMR and LC-MS analysis reveals the metabonomic changes in Salvia miltiorrhiza Bunge induced by water depletion. J Proteome Res, 2010. 9(3): p. 1460-75.
146. An, Y., et al., High-fat diet induces dynamic metabolic alterations in multiple biological matrices of rats. J Proteome Res, 2013. 12(8): p. 3755-68.
147. Chen, F., et al., Identifying three ecological chemotypes of Xanthium strumarium glandular trichomes using a combined NMR and LC-MS method. PLoS One, 2013. 8(10): p. e76621.
148. Li, H., et al., Combined NMR and GC-MS Analyses Revealed Dynamic Metabolic Changes Associated with the Carrageenan-Induced Rat Pleurisy. J Proteome Res, 2013. 12(12): p. 5520-34.
149. Matteoni, C.A., et al., Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology, 1999. 116(6): p. 1413-9.
150. Shi, X., et al., Gallic acid intake induces alterations to systems metabolism in rats. J Proteome Res, 2013. 12(2): p. 991-1006.
151. Xie, Z., et al., Analysis of transcriptome and metabolome profiles alterations in fatty liver induced by high-fat diet in rat. Metabolism, 2010. 59(4): p. 554-60.
152. Doan, K.V., et al., Gallic acid regulates body weight and glucose homeostasis through AMPK activation. Endocrinology, 2015. 156(1): p. 157-68.
153. Kumar, P.S., et al., Changes in periodontal health status are associated with bacterial community shifts as assessed by quantitative 16S cloning and sequencing. J Clin Microbiol, 2006. 44(10): p. 3665-73.
154. Brugman, S., et al., Antibiotic treatment partially protects against type 1 diabetes in the Bio-Breeding diabetes-prone rat. Is the gut flora involved in the development of type 1 diabetes? Diabetologia, 2006. 49(9): p. 2105-8.
155. Fung, C.P., et al., Klebsiella pneumoniae in gastrointestinal tract and pyogenic liver abscess. Emerg Infect Dis, 2012. 18(8): p. 1322-5.
156. Chow, B.S. and T.J. Allen, Mouse Models for Studying Diabetic Nephropathy. Curr Protoc Mouse Biol, 2015. 5(2): p. 85-94.
157. Alpers, C.E. and K.L. Hudkins, Mouse models of diabetic nephropathy. Curr Opin Nephrol Hypertens, 2011. 20(3): p. 278-84.
158. Brosius, F.C., 3rd, et al., Mouse models of diabetic nephropathy. J Am Soc Nephrol, 2009. 20(12): p. 2503-12.
159. Breyer, M.D., et al., Mouse models of diabetic nephropathy. J Am Soc Nephrol, 2005. 16(1): p. 27-45.
160. 肖小河, et al., 論中藥品質控制與評價模式的創新與發展. 中國中藥雜誌, 2007(14): p. 1377-1381.
161. 鄢丹, et al., 建立以臨床功用為導向的中藥品質評控格局與適宜模式的設想. 中草藥, 2013(01): p. 1-5.
162. 謝宗萬, 中藥品種傳統經驗鑒別“辨狀論質”論. 時珍國藥研究, 1994(03): p. 19-21.
163. 王淩詩 and 王良信, 中藥材性狀特徵的品質評價. 中草藥, 1999(05): p. 371-374.
164. 張學儒, et al., 從大黃藥材商品規格市場現狀論中藥材感官評價定量化研究的必要性. 中草藥, 2010(08): p. 1225-1230.
165. 王伽伯, et al., 基於Delphi法的大黃藥材商品規格感官評價科學性的研究. 中國中藥雜志, 2010(20): p. 2657-2661.
166. 楚笑輝, et al., 基於Delphi法的黃連藥材商品規格感官評價的重現性研究. 世界科學技術(中醫藥現代化), 2011(02): p. 321-327.
167. Sun, H., et al., Study on the relevance between beany flavor and main bioactive components in Radix Astragali. J Agric Food Chem, 2010. 58(9): p. 5568-73.
168. 喬琦, 肖婭蘋, and 王喆之, 山茱萸核果的解剖結構和組織化學定位. 雲南植物研究, 2004(06): p. 651-655.
169. Tong, C.S., et al., Identification of starch grains in microscopic images based on granulometric operations. Microsc Res Tech, 2007. 70(8): p. 724-32.
170. Sun, S., et al., Application of mid-infrared spectroscopy in the quality control of traditional Chinese medicines. Planta Med, 2010. 76(17): p. 1987-96.
171. Hou, J.J., et al., Ruggedness and robustness of conversion factors in method of simultaneous determination of multi-components with single reference standard. J Chromatogr A, 2011. 1218(33): p. 5618-27.
172. Yang, M., et al., Characterization of tanshinones in the roots of Salvia miltiorrhiza (Dan-shen) by high-performance liquid chromatography with electrospray ionization tandem mass spectrometry. Rapid Commun Mass Spectrom, 2006. 20(8): p. 1266-80.
173. 國家藥典委員會, 中國藥典. 2010, 中國醫藥科技出版社.
174. 行政院衛生署台灣典編修小組, 台灣中藥典. 2013, 行政院衛生署中醫藥委員會.
175. Chen, J., S. Sun, and Q. Zhou, Direct observation of bulk and surface chemical morphologies of Ginkgo biloba leaves by Fourier transform mid- and near-infrared microspectroscopic imaging. Anal Bioanal Chem, 2013. 405(29): p. 9385-400.
176. Wu, W., et al., Alkaloid profiling in crude and processed Strychnos nux-vomica seeds by matrix-assisted laser desorption/ionization-time of flight mass spectrometry. J Pharm Biomed Anal, 2007. 45(3): p. 430-6.
177. Yi, L., et al., Tissue-specific metabolite profiling of alkaloids in Sinomenii Caulis using laser microdissection and liquid chromatography-quadrupole/time of flight-mass spectrometry. J Chromatogr A, 2012. 1248: p. 93-103.
178. Wu, W., et al., Direct analysis of alkaloid profiling in plant tissue by using matrix-assisted laser desorption/ionization mass spectrometry. J Mass Spectrom, 2007. 42(1): p. 58-69.
179. Da, J., et al., Comparison of two officinal Chinese pharmacopoeia species of Ganoderma based on chemical research with multiple technologies and chemometrics analysis. J Chromatogr A, 2012. 1222: p. 59-70.
180. Ye, M., Y. Yan, and D.A. Guo, Characterization of phenolic compounds in the Chinese herbal drug Tu-Si-Zi by liquid chromatography coupled to electrospray ionization mass spectrometry. Rapid Commun Mass Spectrom, 2005. 19(11): p. 1469-84.
181. 吳婉瑩 and 果德安, 中藥國際品質標準體系構建的幾點思考. 世界科學技術-中醫藥現代化, 2014(03): p. 496-501.
182. Tilton, R., et al., A comprehensive platform for quality control of botanical drugs (PhytomicsQC): a case study of Huangqin Tang (HQT) and PHY906. Chin Med, 2010. 5: p. 30.
183. JunXian Li, D.Y., LiNa Ma, Yin Xiong, ChunXia Yan, BaoCai Li, Cheng Peng, XiaoHe Xiao, A quality evaluation strategy for Rhizoma coptidis from a variety of different sources using chromatographic fingerprinting combined with biological fingerprinting. Chinese Science Bulletin, 2013. 58(33): p. 4092-4100.
184. Wei Li, J.C., Li Yuan, Li Han-bing, Sun Qin, Luo Yun, Yan Dan, Meng Xian-li, Xiao Xiao-he, Methodological research on the quality evaluation of Radix Isatidis based on antibacterial potency. World Science and Technology, 2008. 10(2): p. 33-36.
185. 李寒冰, et al., 基於抗病毒活性檢測的板藍根品質生物評價方法及優化研究. 中草藥, 2011(08): p. 1560-1565.
186. Qin, Y., et al., Establishment of a bioassay for the toxicity evaluation and quality control of Aconitum herbs. J Hazard Mater, 2012. 199-200: p. 350-7.
187. Luo, J.Y., et al., A strategy for trade monitoring and substitution of the organs of threatened animals. Sci Rep, 2013. 3: p. 3108.
188. 蘭英 and 周瑞林. 淺談中藥材的商品規格等級. in 2005年全國中藥研究暨中藥房管理學術研討會. 2005. 中國重慶.
189. 辛甯 and 王柳萍. 中藥商品規格等級標準的商榷. in 第一屆全國中藥商品學術大會. 2008. 中國山東青島即墨.
190. 趙華葉, et al., 淺議中藥材商品規格等級標準研究方法. 中國中藥雜誌, 2015(04): p. 765-769.
191. 王伽伯, et al., 基於化學分析的大黃藥材商品規格劃分的科學合理性研究. 中國中藥雜誌, 2010(04): p. 470-476.
192. 何英梅, et al., 不同商品規格的甘肅大黃的綜合品質考察. 中國藥事, 2006(10): p. 621-623.
193. 李傲, 王家葵, and 孟憲麗, 掌葉大黃不同商品規格等級間瀉下作用及組分含量的相關性分析. 中國藥房, 2010(43): p. 4036-4038.
194. 王強, et al., 不同規格白芍中有關化學成分的HPLC分析. 中藥材, 1992(07): p. 31-32.
195. 張麗宏, et al., 白芍的傳統規格等級與內在成分的相關性研究. 中成藥, 2012(03): p. 535-538.
196. 杜偉鋒, et al., 不同等級杭白芍中3個有效成分的考察. 中成藥, 2014(02): p. 358-362.
197. 楊光, et al., 中藥材商品規格等級標準研究現狀及幾個關鍵問題的商榷. 中國中藥雜誌, 2014(09): p. 1733-1738.
198. 肖小河, et al., 中藥品質綜合量化評控體系——標準評控力金字塔. 中國中藥雜誌, 2015(01): p. 7-12.
199. 歐陽曉玫, et al., 不同商品規格的甘肅當歸的綜合品質評價. 中醫藥學報, 2005(04): p. 12-14.
200. 阮洪根, et al., 基於化學和重量指標對當歸商品等級劃分的合理性分析. 中華中醫藥雜誌, 2013(08): p. 2453-2456.
201. 康傳志, et al., 太子參商品規格等級標準研究. 中國中藥雜誌, 2014(15): p. 2873-2880.
202. 羅霄, et al., 不同發育類型的麥冬塊根中多糖含量變化規律的比較. 安徽農業科學, 2012(33): p. 16125-16126.
203. 郝穎, et al., 不同發育類型的麥冬塊根中黃酮含量變化規律比較. 安徽農業科學, 2012(33): p. 16123-16124+16128.
204. 劉衛根, et al., 不同商品等級羌活中有機酸和香豆素類化合物的測定. 中成藥, 2012(11): p. 2181-2186.
205. 劉衛根, et al., 不同商品等級羌活揮發油的比較研究. 中藥材, 2012(07): p. 1042-1045.
206. 山麗梅, et al., 三七止血活性與商品規格劃分的相關分析. 中草藥, 2011(09): p. 1779-1782.
207. 李寒冰, et al., 基於神經氨酸酶活性檢測的板藍根品質的生物評價. 藥學學報, 2009(02): p. 162-166.
208. 吳婉瑩 and 果德安, 中藥整體品質控制標準體系構建的思路與方法. 中國中藥雜誌, 2014(03): p. 351-356.
209. 秦雪梅, et al., 我國黃芪藥材資源現狀與分析. 中國中藥雜誌, 2013(19): p. 3234-3238.
210. Fu, J., et al., Review of the botanical characteristics, phytochemistry, and pharmacology of Astragalus membranaceus (Huangqi). Phytother Res, 2014. 28(9): p. 1275-83.
211. Li, X., et al., A review of recent research progress on the astragalus genus. Molecules, 2014. 19(11): p. 18850-80.
212. Dong, T.T., et al., Chemical and biological assessment of a chinese herbal decoction containing Radix Astragali and Radix Angelicae Sinensis: Determination of drug ratio in having optimized properties. J Agric Food Chem, 2006. 54(7): p. 2767-74.
213. Zhang, K., et al., Biological active ingredients of traditional Chinese herb Astragalus membranaceus on treatment of diabetes: a systematic review. Mini Rev Med Chem, 2015. 15(4): p. 315-29.
214. Agyemang, K., et al., Recent Advances in Astragalus membranaceus Anti-Diabetic Research: Pharmacological Effects of Its Phytochemical Constituents. Evid Based Complement Alternat Med, 2013. 2013: p. 654643.
215. Zhang, H.W., et al., Astragalus (a traditional Chinese medicine) for treating chronic kidney disease. Cochrane Database Syst Rev, 2014. 10: p. CD008369.
216. Li, K., et al., Potential quality evaluation method for Radix Astragali based on sweetness indicators. Molecules, 2015. 20(2): p. 3129-45.
217. 石子儀, et al., 不同來源黃芪藥材中毛蕊異黃酮葡萄糖苷和芒柄花素的定量分析. 中國中藥雜誌, 2007(09): p. 779-783.
218. 薑勇, et al., 不同來源黃芪藥材中黃芪甲苷的定量分析. 中國中藥雜誌, 2006(11): p. 930-933.
219. 李英, et al., 不同產地黃芪中黃芪甲苷含量比較研究. 中國現代中藥, 2007(09): p. 9-11.
220. 姚雪蓮, 裴彩雲, and 王宗權, 不同產地、不同採收期黃芪藥材及飲片中毛蕊異黃酮葡萄糖苷及芒柄花素含量測定. 藥物分析雜誌, 2012(05): p. 797-801+805.
221. 梁維綱, 談黃芪的商品規格及其植物來源. 中藥材科技, 1984(01): p. 40.
222. 秦雪梅, et al., 黃芪的名稱考證. 中藥材, 2014(06): p. 1077-1080.
223. 楊翠玲 and 郭愛華, 不同等級渾源黃芪中黃芪甲苷及硒元素含量測定. 中國中藥雜誌, 2011(13): p. 1720-1721.
224. 劉曉慶, et al., 不同來源、不同等級黃芪飲片中毛蕊異黃酮葡萄糖苷含量分析. 藥物分析雜誌, 2013(05): p. 874-880.
225. 趙月然, et al., 不同來源、不同等級黃芪飲片中黃芪甲苷的含量分析. 藥物分析雜誌, 2014(07): p. 1256-1263.
226. Dalkey, N. and O. Helmer, An Experimental Application of the Delphi Method to the Use of Experts. Management Science, 1963. 9(3): p. 458-467.
227. Ferri, C.P., et al., Global prevalence of dementia: a Delphi consensus study. Lancet, 2005. 366(9503): p. 2112-7.
228. Hejblum, G., et al., A web-based Delphi study on the indications of chest radiographs for patients in ICUs. Chest, 2008. 133(5): p. 1107-12.
229. Qi, L.W., et al., Rapid and sensitive screening and characterization of phenolic acids, phthalides, saponins and isoflavonoids in Danggui Buxue Tang by rapid resolution liquid chromatography/diode-array detection coupled with time-of-flight mass spectrometry. Rapid Commun Mass Spectrom, 2008. 22(16): p. 2493-509.
230. Kim, J.Y., et al., Isoliquiritigenin isolated from the roots of Glycyrrhiza uralensis inhibits LPS-induced iNOS and COX-2 expression via the attenuation of NF-kappaB in RAW 264.7 macrophages. Eur J Pharmacol, 2008. 584(1): p. 175-84.
231. Lam, W., et al., The four-herb Chinese medicine PHY906 reduces chemotherapy-induced gastrointestinal toxicity. Sci Transl Med, 2010. 2(45): p. 45ra59.
232. Oliveira-Nascimento, L., P. Massari, and L.M. Wetzler, The Role of TLR2 in Infection and Immunity. Front Immunol, 2012. 3: p. 79.
233. Hennessy, E.J., A.E. Parker, and L.A. O'Neill, Targeting Toll-like receptors: emerging therapeutics? Nat Rev Drug Discov, 2010. 9(4): p. 293-307.
234. Jin, M., et al., Structural features and biological activities of the polysaccharides from Astragalus membranaceus. Int J Biol Macromol, 2014. 64: p. 257-66.
235. Chen, H.W., et al., A novel infusible botanically-derived drug, PG2, for cancer-related fatigue: a phase II double-blind, randomized placebo-controlled study. Clin Invest Med, 2012. 35(1): p. E1-11.
236. Guo, L., et al., Astragalus polysaccharide injection integrated with vinorelbine and cisplatin for patients with advanced non-small cell lung cancer: effects on quality of life and survival. Med Oncol, 2012. 29(3): p. 1656-62.
237. Zhang, W.L., et al., Can Hedysari Radix replace Astragali Radix in Danggui Buxue Tang, a Chinese herbal decoction for woman aliment? Phytomedicine, 2013. 20(12): p. 1076-81.
238. Sirotkin, A.V. and A.H. Harrath, Phytoestrogens and their effects. Eur J Pharmacol, 2014. 741: p. 230-6.
239. Zhao, Z., P. Guo, and E. Brand, The formation of daodi medicinal materials. J Ethnopharmacol, 2012. 140(3): p. 476-81.
240. Zhang, J., et al., Quality of herbal medicines: challenges and solutions. Complement Ther Med, 2012. 20(1-2): p. 100-6.
241. Kan, W.S., pharmaceutical botany. 1971, Taipei: National Research Institute of Chinese Medicine, Ministry of Health and Welfare.
242. Medicine, N.U.o.C., Dictionary of Traditional Chinese Medicine. Vol. One. 2005, Shanghai: Shanghai Science and Technology Press.
243. Li, X.B., et al., Production of salvianolic acid B in roots of Salvia miltiorrhiza (Danshen) during the post-harvest drying process. Molecules, 2012. 17(3): p. 2388-407.
244. Bor, J.Y., H.Y. Chen, and G.C. Yen, Evaluation of antioxidant activity and inhibitory effect on nitric oxide production of some common vegetables. J Agric Food Chem, 2006. 54(5): p. 1680-6.
245. Lee, C.P. and G.C. Yen, Antioxidant activity and bioactive compounds of tea seed (Camellia oleifera Abel.) oil. J Agric Food Chem, 2006. 54(3): p. 779-84.
246. Re, R., et al., Antioxidant activity applying an improved ABTS radical cation decolorization assay. Free Radic Biol Med, 1999. 26(9-10): p. 1231-7.
247. Kim, H.K., Y.H. Choi, and R. Verpoorte, NMR-based metabolomic analysis of plants. Nat Protoc, 2010. 5(3): p. 536-49.
248. Dai, H., et al., Combined NMR and LC-DAD-MS analysis reveals comprehensive metabonomic variations for three phenotypic cultivars of Salvia Miltiorrhiza Bunge. J Proteome Res, 2010. 9(3): p. 1565-78.
249. Zhao, Y., et al., Gut microbiota composition modifies fecal metabolic profiles in mice. J Proteome Res, 2013. 12(6): p. 2987-99.
250. Lennart Eriksson, J.T., Svante Wold, CV-ANOVA for significance testing of PLS and OPLS® models. Journal of Chemometrics 2008. 22(11-12): p. 594-600.
251. Wolfender, J.L., et al., Plant metabolomics: from holistic data to relevant biomarkers. Curr Med Chem, 2013. 20(8): p. 1056-90.
252. Datta, H.K., et al., The cell biology of bone metabolism. J Clin Pathol, 2008. 61(5): p. 577-87.
253. Mao, Y.W., et al., Stimulation of osteogenic activity in human osteoblast cells by edible Uraria crinita. J Agric Food Chem, 2014. 62(24): p. 5581-8.
254. Liu, S.C., S.M. Chuang, and C.H. Tang, D-pinitol inhibits RANKL-induced osteoclastogenesis. Int Immunopharmacol, 2012. 12(3): p. 494-500.
255. Barlas, N., S. Ozer, and G. Karabulut, The estrogenic effects of apigenin, phloretin and myricetin based on uterotrophic assay in immature Wistar albino rats. Toxicol Lett, 2014. 226(1): p. 35-42.
256. Gold, R., et al., Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med, 2012. 367(12): p. 1098-107.
257. Lau, A., et al., Dual roles of Nrf2 in cancer. Pharmacol Res, 2008. 58(5-6): p. 262-70.
258. Choi, H.W., et al., Aspirin's Active Metabolite Salicylic Acid Targets High Mobility Group Box 1 to Modulate Inflammatory Responses. Mol Med, 2015.
259. Bates, S.H., R.B. Jones, and C.J. Bailey, Insulin-like effect of pinitol. Br J Pharmacol, 2000. 130(8): p. 1944-8.
260. Choi, M.S., et al., Metabolic response of soy pinitol on lipid-lowering, antioxidant and hepatoprotective action in hamsters fed-high fat and high cholesterol diet. Mol Nutr Food Res, 2009. 53(6): p. 751-9.
261. Kim, M.J., et al., Effect of pinitol on glucose metabolism and adipocytokines in uncontrolled type 2 diabetes. Diabetes Res Clin Pract, 2007. 77 Suppl 1: p. S247-51.
262. Sivakumar, S., P. Palsamy, and S.P. Subramanian, Attenuation of oxidative stress and alteration of hepatic tissue ultrastructure by D-pinitol in streptozotocin-induced diabetic rats. Free Radic Res, 2010. 44(6): p. 668-78.
263. Sivakumar, S. and S.P. Subramanian, D-pinitol attenuates the impaired activities of hepatic key enzymes in carbohydrate metabolism of streptozotocin-induced diabetic rats. Gen Physiol Biophys, 2009. 28(3): p. 233-41.
264. Sivakumar, S. and S.P. Subramanian, Pancreatic tissue protective nature of D-Pinitol studied in streptozotocin-mediated oxidative stress in experimental diabetic rats. Eur J Pharmacol, 2009. 622(1-3): p. 65-70.
265. Qin, X., et al., Metabolic fingerprinting by 1HNMR for discrimination of the two species used as Radix Bupleuri. Planta Med, 2012. 78(9): p. 926-33.
266. Treutter, D., Significance of flavonoids in plant resistance and enhancement of their biosynthesis. Plant Biol (Stuttg), 2005. 7(6): p. 581-91.
267. Lanzinger, A., et al., Metabolite profiling of barley grain subjected to induced drought stress: responses of free amino acids in differently adapted cultivars. J Agric Food Chem, 2015. 63(16): p. 4252-61.
268. Kolluru Viswanatha Chaitanya, G.K.R., Attipalli Ramachandra Reddy, Biochemical responses to drought stress in mulberry (Morus alba L.): evaluation of proline, glycine betaine and abscisic acid accumulation in five cultivars. Acta Physiologiae Plantarum, 2009. 31: p. 437-443.
269. Nasrollahi, V., et al., The effect of drought stress on the expression of key genes involved in the biosynthesis of triterpenoid saponins in liquorice (Glycyrrhiza glabra). Phytochemistry, 2014. 103: p. 32-7.
270. Guha, A., D. Sengupta, and A.R. Reddy, Physiological optimality, allocation trade-offs and antioxidant protection linked to better leaf yield performance in drought exposed mulberry. J Sci Food Agric, 2010. 90(15): p. 2649-59.
271. Shah, J., The salicylic acid loop in plant defense. Curr Opin Plant Biol, 2003. 6(4): p. 365-71.
272. Maeda, H. and N. Dudareva, The shikimate pathway and aromatic amino Acid biosynthesis in plants. Annu Rev Plant Biol, 2012. 63: p. 73-105.
273. Tzin, V. and G. Galili, New insights into the shikimate and aromatic amino acids biosynthesis pathways in plants. Mol Plant, 2010. 3(6): p. 956-72.
274. Cushman, J.C., Osmoregulation in Plants: Implications for Agriculture. American Zoologist, 2001. 41(4): p. 758-769.
275. Kenta Shirasawa, T.T., et al., Accumulation of glycinebetaine in rice plants that overexpress choline monooxygenase from spinach and evaluation of their tolerance to abiotic stress. Annals of Botany, 2006. 98: p. 565-571.
276. Newman, J.D. and J. Chappell, Isoprenoid biosynthesis in plants: carbon partitioning within the cytoplasmic pathway. Crit Rev Biochem Mol Biol, 1999. 34(2): p. 95-106.
277. Eisenreich, W., et al., The deoxyxylulose phosphate pathway of terpenoid biosynthesis in plants and microorganisms. Chem Biol, 1998. 5(9): p. R221-33.
278. Grawert, T., et al., Biochemistry of the non-mevalonate isoprenoid pathway. Cell Mol Life Sci, 2011. 68(23): p. 3797-814.