前馬偕醫院神經科主治醫師 仁欣診所院長蔡正浩

Presentation on theme: "前馬偕醫院神經科主治醫師 仁欣診所院長蔡正浩"— Presentation transcript:

1 前馬偕醫院神經科主治醫師 仁欣診所院長蔡正浩
口服液態玻尿酸之臨床應用 前馬偕醫院神經科主治醫師 仁欣診所院長蔡正浩 2017/3/1

2 玻尿酸的用途與困境 口服玻尿酸的吸收 皮膚領域 退化性關節炎 防老化的應用 2017/3/1

3 玻尿酸分子化學結構與物理特性 玻尿酸三維立體結構 藍色帶代表親水部位,紅色帶代表疏水部位.
Glucuronic acid N-acetylglucosamine The repeat disaccharide of hyaluronan, -D-glucuronic acid-beta-1, 3-N-acetylglucosamine-beta-1,4- (B) 玻尿酸三維立體結構 藍色帶代表親水部位,紅色帶代表疏水部位. 呈白色，爲無定形固體，無臭無味，有強吸濕性，溶於水，不溶於有機溶劑。 2017/3/1

4 保水性: 1公克的玻尿酸可以吸收500c.c.~1000c.c的水分，相當於500~1000倍吸水能力
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5 玻尿酸的醫療用途 醫學領域 應用 一般外科 人造皮膚、傷口敷料、尿失禁治療劑、止血劑(Hemostat) 皮膚科
皮膚除皺及修補、化妝保養品、皮膚水嫩光滑 骨科 退化性關節炎之治療 口腔外科 口腔組織修補及再生 婦產科 婦女停經後症狀之改善 心臟血管外科 血管及心瓣膜修補 眼科 白內障和青光眼手術、眼角膜移植、人エ淚液、乾眼症 整型外科 隆鼻、隆乳、豐唇、器官組織整形及修補 藥物遞送 藥物的局部性遞送 2017/3/1 5

6 目前玻尿酸在各種治療上的障礙 打會痛、打完尚有腫脹痛，病人看到針頭會怕 ◆縫隙小，有傷到神經之危險，恐引起醫療糾紛
◆過去的經驗因分子量太大，口服、錠劑普遍效果不佳 ◆只針對施打玻尿酸的位置，無法全面的保養皮膚 ◆退化性關節炎（OA）玻尿酸進行關節腔注射： 打會痛、打完尚有腫脹痛，病人看到針頭會怕 ◆縫隙小，有傷到神經之危險，恐引起醫療糾紛 ◆提前被代謝掉，健保給付有斷層 很高比例的病人吃維骨力沒有效果 2017/3/1

7 ◆如果玻尿酸可以改善吸收不良的問題以口服型式補充 ，而以內生性的方式達到需要之部位，那這種治療方式是否對某些病患來說是一個更好的選擇?!!
有沒有其他有效安全的選擇?? ◆如果玻尿酸可以改善吸收不良的問題以口服型式補充 ，而以內生性的方式達到需要之部位，那這種治療方式是否對某些病患來說是一個更好的選擇?!! 2017/3/1

8 玻尿酸的用途與困境 口服玻尿酸的吸收 皮膚領域 退化性關節炎 防老化的應用 2017/3/1

9 口服玻尿酸的吸收實驗一 在口服30分鐘後，即可在血液中偵測到
該報告證明口服玻尿酸可以順利被哺乳類吸收，堆積於血液，肌肉，硬骨組織，排出體外者僅小於5% This study examined the absorption, excretion and distribution of radiolabeled hyaluronan (HA) after a single oral administration in Wistar rats and Beagle dogs. To date its therapeutic use has been limited to injections or topical applications, but there is no data on pharmacokinetics after oral intake. The gamma emitting isotope 99mtechnetium (Tc) was coupled to HA …… Less than 5% of the radioactivity appeared in feces after 72 hours in rats. Radioactivity was seen in blood, muscles, salivary glands and bone as early as 30 minutes, and peaked 4-6 hours in all non-alimentary tissues examined after oral administration. There were transient increases in radioactivity in shoulder joints and vertebrae 4 hours after oral administration of HA in both rats and Beagle dogs. Residence time (t) in Beagle blood was hours. These results demonstrate that HA is absorbed and distributed to organs and joints after a single oral administration. (FASEB, 2004). A. G. Schauss, L. G. Balogh, A. G. Polyak, D. G. Mathe, R. G. Kiraly and G. G. Janoki American Institute for Biosocial and Medical Research, Inc and National Institute for Health. 2017/3/1

10 口服玻尿酸的吸收實驗二 日本的報告證明口服玻尿酸可以順利被哺乳類小腸絨毛吸收，在口服三小時內吸收比率高達80%以上，殘留於消化道之玻尿酸小於16%。 2017/3/1

11 口服玻尿酸的吸收實驗三 Study on absorption of hyaluronic acid after an oral administration in rats <<中国药学杂志 >>2005年23期 蒋秋燕 , 凌沛学 , 黄思玲 , 林洪 , 张天民 , JIANG Qiu-yan , LING Pei-xue , HUANG Si-ling , LIN Hong , ZHANG Tian-min 目的探讨透明质酸口服吸收的机制.方法采用放射免疫法测定大鼠单 剂量口服透明质酸溶液和3种单糖(D-葡糖醛酸、N-乙酰氨基葡糖及两 者等摩尔配比)溶液后血清中透明质酸的浓度,用梯形法计算AUC.结果 生理盐水对照组和D-葡糖醛酸组的血清中透明质酸没有出现峰值;透 明质酸组在口服后约2 h,出现明显的透明质酸吸收峰;另外两个单糖 组在口服后7 h左右,出现一个明显的透明质酸合成峰.透明质酸组的 AUC0～13 h为2 417μg·h·L-1,实测ρmax为187.6μg·L-1,tmax为2.0 h.结论透明质酸口服后可以被机体吸收,且能以非单糖的 形式被机体吸收. 2017/3/1

12 HA 在人體的吸收研究 ◆口服玻尿酸只有少量會被酵素分解成醣類及熱量，玻尿酸口服後在腸道的吸收率可以達到 70~90 %
◆連續服用28天後可以達到最穩定的濃度與代謝 2017/3/1

13 口服玻尿酸之美國專利 United States Patent 6,924,273 August 2, 2005 Chondroprotective/restorative compositions and methods of use thereof Abstract The instant invention provides a method of treating or preventing osteoarthritis, joint effusion, joint inflammation and pain, synovitis, lameness, post operative arthroscopic surgery, deterioration of proper joint function including joint mobility, the reduction or inhibition of metabolic activity of chondrocytes, the activity of enzymes that degrade cartilage, the reduction or inhibition of the production of Hyaluronic acid, said method comprising orally administering to a mammalian species a therapeutically effective amount of Hyaluronic Acid or pharmaceutically acceptable salts thereof. Additionally, compositions containing hyaluronic acid; chondroitin sulfate, and glucosamine sulfate in a paste formulation are also disclosed which can be administered on their own or can be used as a feed additive. 2017/3/1

14 如果玻尿酸可口服吸收在皮膚美容上是否有幫助??!
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15 玻尿酸的用途與困境 口服玻尿酸的吸收 皮膚領域 退化性關節炎 防老化的應用 2017/3/1

16 玻尿酸在皮膚之作用 玻尿酸補充細胞間的基質與活性~消除皺紋，軟化肌膚 玻尿酸流失後的肌膚會使真皮層的含水量降低，漸漸失去彈性與光澤，同時對陽光、環境的傷害，肌膚自我修護力也下降，進一步生成皺紋、黑斑等。 (1) 表皮層epidermis (2) 真皮層dermis (3) 玻尿酸HA (4) collagen膠原蛋白 2017/3/1

17 施打玻尿酸在皮膚之應用 Hyaluronic acid injection can be used to improve the skin's contour and reduce depressions in the skin due to acne, scars, injury or lines. Immediately or within a few hours after injection the site may be red and swollen. This usually disappears within a week. Another one or two treatments (at least a week apart) may be necessary to achieve the desired correction. Hyaluronic acid implantation is not permanent. Like natural hyaluronic acid, manufactured hyaluronic acid once injected into the skin will gradually break down and be absorbed by the body. In most cases, the hyaluronic acid augmentation usually lasts between 6-9 months. Compared to collagen implants hyaluronic acid appears to have a longer augmentation effect, possibly lasting 2 to 3 times longer than the average collagen implant. To maintain the initial results, repeat hyluronic acid injections or top-up treatments will be necessary. Most people following this protocol have 2 to 3 treatments per year. 2017/3/1

18 台灣 台中榮總 口服玻尿酸之研究 以口服single dose的方式投與裸鼠，結果顯示玻尿酸在八小時之後就被傳送到全身，主要分布於皮膚當中，睪丸、關節，並可在體內持續72小時以上。細胞實驗的結果，玻尿酸的濃度越高，細胞分化，進行吞噬作用、釋放發炎反應激素的效用也越大。顯示玻尿酸具有活化免疫系統的功能。玻尿酸以口服方式確實可被哺乳類吸收，再分布於特定部位發揮其功能。細胞實驗證實小分子玻尿酸可以調控免疫系統的活性 Data on file, VGH-TC 2017/3/1

19 餵食 螢光 HA 的動物試驗追蹤結果 照片左邊的為沒有餵食螢光HA的大白鼠（對照組），右邊的大白鼠為餵食0.5 mg螢光HA，經過48小時後的螢光偵測結果 照片左邊的為沒有餵食螢光HA的大白鼠（對照組），右邊的大白鼠為餵食0.5 mg螢光HA，經過72小時後的螢光偵測結果 2017/3/1 Data on file, VGH-TC

20 玻尿酸與膠原蛋白 玻尿酸 膠原蛋白 在人體的組織內: 膠原蛋白如同鋼筋 玻尿酸如同水泥 穩定組織架構 玻尿酸在軟骨組織中的聚集作用
維持細胞活性 玻尿酸在軟骨組織中的聚集作用 玻尿酸 膠原蛋白 2017/3/1

21 玻尿酸幫助膠原蛋白合成之研究 Hyaluronic acid counteracts interleukin- 1-induced inhibition of collagen biosynthesis in cultured human chondrocytes Abstract Although, hyaluronic acid (HA) is used in the treatment of osteoarthritis for 30 years, the mechanism of its protective action on collagen metabolism disturbances in tissues during inflammation is not known. Therefore, the present study was undertaken to evaluate the mechanism of IL-1β action (inductor of experimental inflammation) on deregulation of collagen biosynthesis in cultured human chondrocytes and the effect of HA on the process. It has been found that IL-1β strongly induced inhibition of collagen biosynthesis, while HA counteracted the process. The mechanism of this phenomenon was found at both transcriptional and post-transcriptional level. IL-1 was found to down regulate the expression of mRNA for type II collagen and to inhibit prolidase activity, an enzyme that plays an important role in collagen biosynthesis at post-translational level. HA was shown to counteract the IL-1β-dependent inhibition of both processes. During experimental inflammation of chondrocytes cultured in 0.1% FBS there was no differences in the expression of β1-integrin independently of cell number and the presence of HA in growth medium. In chondrocytes cultured in 5% FBS, IL-1β up-regulated the expression of β1-integrin receptor while HA abolished the effect. The data suggest that HA-dependent up-regulation of collagen biosynthesis in IL-1β-treated chondrocytes may involve stimulation of prolidase activity in serum "starved" cells and may also originate at the transcriptional level in the cells cultured in standard conditions. Source / Source 2006, vol. 54, Pharmacological research   ISSN   , pp.   [7 page(s) (article)] 2017/3/1

22 玻尿酸加速fibroblast之增生 Hyaluronan facilitates transforming growth factor-beta1-mediated fibroblast proliferation. This study aims to understand the role of the matrix polysaccharide hyaluronan (HA) in influencing fibroblast proliferation and thereby affecting wound healing outcomes. To determine mechanisms that underlie scarred versus scar-free healing, patient-matched dermal and oral mucosal fibroblasts were used as models of scarring and non- scarring fibroblast phenotypes. Specifically, differences in HA generation between these distinct fibroblast populations have been examined and related to differences in transforming growth factor- beta(1) (TGF-beta(1))-dependent proliferative responses and Smad signaling. There was a differential growth response to TGF-beta(1), with it inducing proliferation in dermal fibroblasts but an anti- proliferative response in oral fibroblasts. Both responses were Smad3-dependent. Furthermore, the two fibroblast populations also demonstrated differences in their HA regulation, with dermal fibroblasts generating increased levels of HA, compared with oral fibroblasts. Inhibition of HA synthesis in dermal fibroblasts was shown to abrogate the TGF-beta(1)-mediated induction of proliferation. Inhibition of HA synthesis also led to an attenuation of Smad3 signaling in dermal fibroblasts. J Biol Chem Mar 7;283(10): Epub 2008 Jan 2. 2017/3/1

23 補充玻尿酸可多方保養肌膚 玻尿酸 超級保水功能 皮膚長效保濕 活化纖維母細胞 填補肌膚間隙 增生膠原蛋白 肌膚光澤白皙 增進肌膚彈性
促進血液循環 肌膚年輕水嫩 增進肌膚彈性 撫平皺紋老化 活化纖維母細胞 增生膠原蛋白 超級保水功能 皮膚長效保濕 玻尿酸 2017/3/1

24 如果玻尿酸可口服吸收在退化性關節炎是否有幫助??!
2017/3/1

25 玻尿酸的用途與困境 口服玻尿酸的吸收 皮膚領域 退化性關節炎 防老化的應用 2017/3/1

26 退化性關節炎 (OA) 退化性關節炎多發生於 45 歲以上的中老年人身 上。根據統計，在台灣隨著年齡的增加，罹患退 化性關節炎的比例隨之增加： 年齡 罹患退化性關節炎％ 30~39 1% 40~49 10% 50~59 40% 60~69 50% 70以上 70% 2017/3/1

27 骨關節炎 (Arthritis) ◆軟骨裂解的產物會導致滑液囊的慢性發炎反應。滑液囊中的吞噬細胞產生細胞媒介物，包括 interleukin 1 (IL-1ß)、tumor necrosis factor-alpha、metalloproteinase 會回到軟骨處，直接破壞組織或刺激軟骨細胞產生更多的metalloproteinase。最後，關節的結構遭受改變，為了穩定關節，便發生補償性的硬骨增生 2017/3/1

28 骨關節發炎時相關之物質 2017/3/1

29 治療退化性關節炎之策略 Osteoarthritis ◆補充可使用之玻尿酸以恢復關節液的彈性和黏度。
◆活化纖維母細胞之活性,使玻尿酸之合成再開始 ◆抑制發炎反應中IL-1ß的作用,使軟骨細胞及膠原蛋白維持增加 ◆減少OA 病人的疼痛感 Osteoarthritis 2017/3/1

30 目前治療關節炎(OA)普遍的方式 Osteoarthritis Treatment
過去20年，內科醫生對骨關節炎病患的治療是採取直接注射 HA 至膝蓋的關節液，因為這些病患的身體中原本就存在骨關節處的 HA 較薄一層，當關節活動摩擦時會感疼痛，而額外補充注射 HA 能豐厚關節保護層，暫時抑制疼痛約幾天至幾星期，一些文獻的研究目地皆是探討 HA 在這種醫療方式上扮演的角色 Sundblad L. Glycosaminoglycans and glycoproteins in synovial fluid. In: Balazs EA, Jeanloz RW, editors. The amino sugars. The chemistry and biology of compounds containing amino sugars, vol. IIA. New York: Academic Press 1965: Wobig M, Bach G, Beks P, Dickhut A, Runzheimer J, Schwieger G, et al. The role of elastoviscosity in the efficacy of viscosupplementation for osteoarthritis of the knee: a comparison of hylan G-F 20 and a lower-molecular-weight hyaluronan. Clin Ther 1999;21: Weiss C, Balazs EA, St. Onge R, Denlinger JL. Clinical studies of the intraarticular injection of HealonR (sodium hyaluronate) in the treatment of osteoarthritis of human knees. Osteoarthritis symposium. Palm Aire, Fla., October 20-22, Semin Arthritis Rheum. 1981;11(suppl 1): 143-4. 2017/3/1

31 注射玻尿酸患者與注射placebo之比較
A controlled, randomized, double-blind, parallel-design multicentre study J. Karlsson, L. S. Sjögren1 and L. S. Lohmander2 2017/3/1

32 玻尿酸幫助膠原蛋白合成之研究 Hyaluronic acid counteracts interleukin- 1-induced inhibition of collagen biosynthesis in cultured human chondrocytes Abstract Although, hyaluronic acid (HA) is used in the treatment of osteoarthritis for 30 years, the mechanism of its protective action on collagen metabolism disturbances in tissues during inflammation is not known. Therefore, the present study was undertaken to evaluate the mechanism of IL-1β action (inductor of experimental inflammation) on deregulation of collagen biosynthesis in cultured human chondrocytes and the effect of HA on the process. It has been found that IL-1β strongly induced inhibition of collagen biosynthesis, while HA counteracted the process. The mechanism of this phenomenon was found at both transcriptional and post-transcriptional level. IL-1 was found to down regulate the expression of mRNA for type II collagen and to inhibit prolidase activity, an enzyme that plays an important role in collagen biosynthesis at post-translational level. HA was shown to counteract the IL-1β-dependent inhibition of both processes. During experimental inflammation of chondrocytes cultured in 0.1% FBS there was no differences in the expression of β1-integrin independently of cell number and the presence of HA in growth medium. In chondrocytes cultured in 5% FBS, IL-1β up-regulated the expression of β1-integrin receptor while HA abolished the effect. The data suggest that HA-dependent up-regulation of collagen biosynthesis in IL-1β-treated chondrocytes may involve stimulation of prolidase activity in serum "starved" cells and may also originate at the transcriptional level in the cells cultured in standard conditions. Source / Source 2006, vol. 54, Pharmacological research   ISSN   , pp.   [7 page(s) (article)] 2017/3/1

33 玻尿酸加速fibroblast之增生 Hyaluronan facilitates transforming growth factor-beta1-mediated fibroblast proliferation. This study aims to understand the role of the matrix polysaccharide hyaluronan (HA) in influencing fibroblast proliferation and thereby affecting wound healing outcomes. To determine mechanisms that underlie scarred versus scar-free healing, patient-matched dermal and oral mucosal fibroblasts were used as models of scarring and non- scarring fibroblast phenotypes. Specifically, differences in HA generation between these distinct fibroblast populations have been examined and related to differences in transforming growth factor- beta(1) (TGF-beta(1))-dependent proliferative responses and Smad signaling. There was a differential growth response to TGF-beta(1), with it inducing proliferation in dermal fibroblasts but an anti- proliferative response in oral fibroblasts. Both responses were Smad3-dependent. Furthermore, the two fibroblast populations also demonstrated differences in their HA regulation, with dermal fibroblasts generating increased levels of HA, compared with oral fibroblasts. Inhibition of HA synthesis in dermal fibroblasts was shown to abrogate the TGF-beta(1)-mediated induction of proliferation. Inhibition of HA synthesis also led to an attenuation of Smad3 signaling in dermal fibroblasts. J Biol Chem Mar 7;283(10): Epub 2008 Jan 2. 2017/3/1

34 玻尿酸幫助軟骨細胞合成之研究 The effect of hyaluronic acid on IL-1-induced chondrocyte apoptosis in a rat model of osteoarthritis The purpose of this article was to study the effect of hyaluronic acid (HA) on chondrocyte apoptosis in a rat osteoarthritis in vitro model (exposure to IL-1) and explore its mechanism. HA could inhibit IL-1-induced chondrocyte apoptosis in our cell culture model system. It was showed that addition of HA to the medium was able in a dose-dependent way to reduce the impairment of the mitochondrial membrane potential and to restore mitochondrial ATP production. This study shows that HA could suppress in a dose-dependent way chondrocyte apoptosis in our IL-1-induced osteoarthritis model. The suppression of inflammatory cytokine activity within the joint might be one important mechanism of the clinical action of HA in the treatment of OA. 2008 Orthopaedic Research Society. J Orthop Res 2017/3/1

35 2017/3/1

36 Hyaluronan and nociception
OA Knee: excitability of nociceptors of articular nerves, nerve impulses & nerve sensitivity : hyperalgesic, spontaneously discharge, sensitive to non-noxious joint movement HA: decreased ongoing nerve activity & movement evoked nerve activity, nerve impulse decreased 60% of control, impulse discharge and firing frequency decreased to 65% and 45% of control Ion channels decreased mechanical sensitivity Rat model: abnormal gait: attenuation of prostaglandin E2, bradykinin synthesis Direct or indirect effects on substance P (excitatory amino acids, prostaglandins, NO) 2017/3/1

37 口服 玻尿酸之臨床有效性 Conclusion
Effect of a natural extract of chicken combs with a high content of hyaluronic acid (Hyal-JointR) on pain relief and quality of life in subjects with knee osteoarthritis: a pilot randomized double-blind placebo-controlled trial Published: 21 January 2008 Nutrition Journal 2008, 7:3 doi: / Methods: Twenty subjects aged ≥40 years with knee osteoarthritis (pain for at least 15 days in the previous month, symptoms present for ≥6 months, Kellgren/Lawrence score ≥2) participated in a randomized double-blind controlled trial. Ten subjects received AP (80 mg/day) and 10 placebo for 8 weeks. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and quality of life by the Short Form-36 (SF-36v2) were administered at baseline and after 4 and 8 weeks of treatment. Conclusion Daily supplementation with HA from a natural extract of chicken combs (Hyal-Joint®), 80 mg/day for 8 weeks, appeared to be effective in subjects with knee osteoarthritis for decreasing pain, improving physical function, and enhancing several aspects of quality of life. 2017/3/1

38 口服玻尿酸跟維骨力的差別 玻尿酸跟維骨力的差別?如果您已經有皺紋，表示合成玻尿酸的能力已經減退，如果人體合成速率已減低吃再多的葡萄糖胺或許效果不彰。 Glucuronic acid N-acetylglucosamine 2017/3/1

39 口服液態玻尿酸作為半成品 玻尿酸的結構主要由: 一個雙醣 N=1時分子量為415Da N-acetyl-D-glucosamine
D-glucuronic acid 平均分子量介於100萬到1000萬Dalton之間 一個雙醣 N=1時分子量為415Da 如果要合成到關節腔需要的玻尿酸 大約550萬Da, 那大概要幾個unit ? 答案是— 13253 2017/3/1

40 小孩、年輕女性合成玻尿酸的情況 2017/3/1

41 中、老年婦女合成玻尿酸的情況 2017/3/1

42 中、老年婦女使用口服小分子玻尿酸後，合成玻尿酸的情況
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43 口服玻尿酸可以達成治療骨關節炎的目標 ◆半成品的玻尿酸 可口服吸收 並在合成大分子玻尿酸上比起使用葡萄糖胺來的有效
◆活化了纖維母細胞 並使軟骨細胞的凋亡減緩 故可在骨關解腔內合成黏度夠高的高分子玻尿酸 ◆HA有抑制IL-1ß之作用，藉此可減少collagen及chondrocyte的生合成被抑制之作用，相對的使代謝速率及生成速率達成平衡 ◆HA可降低因OA引起的疼痛 2017/3/1

44 玻尿酸可口服吸收,是否可預防老化及婦女停經後症候群??!
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45 玻尿酸的用途與困境 口服玻尿酸的吸收 皮膚領域 退化性關節炎 防老化的應用 2017/3/1

46 玻尿酸流失是老化的指標 25歲的玻尿酸含量 只有嬰兒期的65% 到了60歲只剩25% 2017/3/1

47 玻尿酸的故事 The startling ABC News Prime Time Live TV program (Nov. 2000) in which Connie Chung (宗毓華) went to Yuzurihara, Japan (the "village of long life" ) and showed pictures of people who were in their 80’s and 90’s, and who had flawless skin (no wrinkles, no age spots), flexible joints, good eyesight (few wore glasses) and a full head of hair. Some had even habitually worked in the sun much of their lives, smoked tobacco and drunk copious amounts of sake. A World Health Organization (WHO) survey of 990 villages and towns in Japan found Yuzurihara had the oldest population. There are 10 times more people living beyond the age of 80 in Yuzurihara than any place in the United States. This report came on the heels of the WHO announcement that the Japanese live the most disease-free years of any country in the world. 2017/3/1

48 Progeria—早老症 症狀: (1)典型的鳥型頭，且為禿頭。 (2)身材矮小，體重不足。 (3)四肢瘦且關節變得明顯。
(4)皮下脂肪減少。 (5)梨狀胸，且鎖骨短。 (6)青筋突出。 (1)臨床實驗室檢查：尿中玻尿酸 值會增加 2017/3/1

49 Progeria—早老症 In very young children with a disease called progeria, HA is excreted in the urine at a rate 17 times that of healthy children. These progeria kids, at age 2 and 3, look like they are old, very old. They have facial wrinkles, they are bald, and they have cataracts(白內障). Progeria serves as evidence that aging is not a function of the number of birthdays but a process involving the loss of HA. Lose HA and a person will look old, regardless of his or her birth date. 2017/3/1

50 排卵期～玻尿酸大量生成，導致血液和表皮玻尿酸量增加
生理週期荷爾蒙變化 排卵期～玻尿酸大量生成，導致血液和表皮玻尿酸量增加 2017/3/1

51 Estrogen對皮膚HA生合成的影響 The mechanism of estrogen-induced increase in hyaluronic acid biosynthesis, with special reference to estrogen receptor in the mouse skin. Uzuka M, Nakajima K, Ohta S, Mori Y. The increase in hyaluronic acid and water contents induced by estradiol treatment in the mouse skin was dependent on dose and the number of treatments of estradiol. The anti-estrogen administered together with estradiol blocked the increase in hyaluronic acid content produced by treatment with estradiol alone. It was suggested that the anti-estrogen may act as an antagonist by competing for the cytoplasmic estrogen receptor on increase in hyaluronic acid synthesis. It was observed that the sensitivity in increase in hyaluronic acid biosynthesis by estradiol was related to the age of the mouse and the content of the cytoplasmic estrogen receptor in the mouse skin. It was suggested that there was a possible relationship between the increase in hyaluronic acid and cytoplasmic estrogen receptor in the mouse skin. Biochim Biophys Acta Jan 17;627(2): Related Articles, Links 2017/3/1

52 Estrogen對皮膚HA合成酵素的影響
Induction of hyaluronic acid synthetase by estrogen in the mouse skin. Uzuka M, Nakajima K, Ohta S, Mori Y. Hyaluronic acid synthetase activity was measured in male mouse skin following the topical application of estradiol in vivo. The enzyme activity increased in parallel with the hyaluronic acid content of the skin, and showed a similar response in the skin of ovariectomized female mice. The increase in enzyme activity was reduced by the anti-estrogen agents, tamoxifene citrate and clomiphene citrate, which block competitively the binding of estrogen to the estrogen receptor. The increase in hyaluronic acid synthetase activity was also reduced by topical application of cycloheximide or by subcutaneous injection of actinomycin D. The results suggest that the stimulation of hyaluronic acid synthesis in mouse skin in response to estrogen treatment is mediated through estrogen receptors and involves the induction of the enzyme hyaluronic acid synthetase. Biochim Biophys Acta Apr 3;673(4): Links 2017/3/1

53 玻尿酸對婦女停經症狀之改善 Many women taking oral HA supplements have reported that their hot flashes and symptoms of menopause have abated with use. This is not surprising. Women have been advised that oral estrogen supplementation doesn’t prevent disease, and may in fact slightly increase the risk of disease. An alternative to estrogen would be oral HA. Why do women have beautiful skin? Because estrogen elevates HA levels in the skin and body. Once natural estrogen production has ceased (menopause), the natural alternative would be oral HA. 2017/3/1

54 Relation between HA content in brain and brain weight
腦重量3 磅 腦重量2.6 磅 腦部玻尿酸 50歲 65歲 1989年的一項研究提到人會因年齡的增加而造成腦部玻尿酸的流失，解釋了為什麼腦部會因年齡增長而縮小(CIBA Foundation Symposium 143: , 1989)。50歲的成人平均的腦重量為3 磅，15 年之後的腦重量大約只有 2.6 磅。 2017/3/1