TWI652057B - Uses of resveratrol - Google Patents
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Abstract
白藜蘆醇（resveratrol）之應用，包括使用白藜蘆醇以提升幹細胞之降血糖效益的方法，以及使用白藜蘆醇於製造一降血糖套組。該方法係包含以白藜蘆醇處理幹細胞；該套組係包含一第一部分以及一第二部分，該第一部分係包含幹細胞，且該第二部分係包含白藜蘆醇。經由以白藜蘆醇處理幹細胞，可提升幹細胞之降血糖效益，尤其可提升幹細胞之降低因胰臟損傷所造成之高血糖的效益。The use of resveratrol includes the use of resveratrol to enhance the hypoglycemic efficacy of stem cells, and the use of resveratrol to produce a hypoglycemic kit. The method comprises treating stem cells with resveratrol; the kit comprises a first portion comprising a stem cell and a second portion comprising resveratrol. By treating stem cells with resveratrol, the hypoglycemic effect of stem cells can be enhanced, and in particular, the benefit of stem cells to reduce hyperglycemia caused by pancreatic damage can be improved.
Description
本發明係關於白藜蘆醇之應用，尤其是關於使用白藜蘆醇以提升幹細胞之降血糖效益的應用，特別是降低因為胰臟損傷所造成之高血糖的應用。其中，相較於未經處理的幹細胞，經白藜蘆醇處理之幹細胞係可提供較高之降血糖效益。本發明亦關於提供該增進之降血糖效益的套組。The present invention relates to the use of resveratrol, and more particularly to the use of resveratrol to enhance the hypoglycemic efficacy of stem cells, particularly the use of hyperglycemia due to pancreatic damage. Among them, resveratrol-treated stem cell lines provide higher blood glucose lowering efficiency than untreated stem cells. The invention is also directed to a kit that provides the enhanced blood glucose lowering benefit.
糖尿病是一種慢性新陳代謝失調疾病，主要病因為血中葡萄糖的代謝機制出現異常。已知胰臟所分泌的胰島素在血中葡萄糖的代謝中扮演重要角色，當生物體中胰島素的分泌量不足或對胰島素的敏感性不佳時，血中葡萄糖將因無法正常代謝而累積，造成血中葡萄糖濃度上升。一般而言，糖尿病可分為三種類型：第一型糖尿病、第二型糖尿病、及姙娠型糖尿病。其中，第一型糖尿病的成因是胰島素分泌不足，而造成此現象的因素為例如：自體免疫疾病造成胰臟細胞死亡、遺傳型胰臟功能低下、或病毒所造成的胰臟受損等。第二型糖尿病則是胰島素對血中葡萄糖的結合能力降低所造成。至於姙娠型糖尿病，則是因懷孕所造成，但此一類型之糖尿病患者的高血糖症狀，通常會隨著姙娠期中止而結束。Diabetes is a chronic metabolic disorder, the main cause of which is the abnormal metabolism of glucose in the blood. It is known that insulin secreted by the pancreas plays an important role in the metabolism of glucose in the blood. When the amount of insulin in the organism is insufficient or the sensitivity to insulin is poor, the blood glucose will accumulate due to the inability to metabolize normally. The blood glucose concentration rises. In general, diabetes can be divided into three types: type 1 diabetes, type 2 diabetes, and gestational type diabetes. Among them, the cause of type 1 diabetes is insufficient insulin secretion, and factors causing this phenomenon are, for example, pancreatic cell death caused by autoimmune diseases, infertility of hereditary pancreas, or pancreatic damage caused by viruses. Type 2 diabetes is caused by a decrease in the ability of insulin to bind glucose in the blood. As for pregnancy-induced diabetes, it is caused by pregnancy, but the symptoms of hyperglycemia in this type of diabetic patients usually end with the termination of pregnancy.
目前，臨床上對於糖尿病的治療方式主要包括：生活習慣的控制（例如：運動及飲食控制等）、藥物治療（例如：胰島素注射、口服降血糖藥物等）、胰臟移植等。而近年來亦有文獻提及可使用幹細胞來修復臟器及治療糖尿病，此可參見例如：BioMed Research International Volume 2015, Article ID 592915，該文獻全文併於此處以供參考。然而，當輸注幹細胞到糖尿病患者體內時，患者體內的高糖環境（即，高葡萄糖濃度之血液）會對幹細胞造成傷害，因而產生修復能力下降、移動能力下降、氧化壓力上升等負面效果。At present, the clinical treatment of diabetes mainly includes: control of living habits (such as exercise and diet control), drug treatment (for example, insulin injection, oral hypoglycemic drugs, etc.), pancreas transplantation, and the like. In recent years, there have been references in the literature to the use of stem cells for the repair of organs and the treatment of diabetes, see, for example, BioMed Research International Volume 2015, Article ID 592915, which is incorporated herein by reference in its entirety. However, when infusion of stem cells into a diabetic patient, the high-sugar environment (ie, blood of high glucose concentration) in the patient's body may cause damage to the stem cells, thereby causing negative effects such as decreased repair ability, decreased mobility, and increased oxidative stress.
本案發明人研究發現，在使用幹細胞以治療糖尿病之前，先以白藜蘆醇（resveratrol）處理幹細胞，可以有效減免高糖環境對幹細胞所造成的傷害，從而提升幹細胞之降血糖效益。因此，使用前述經白藜蘆醇處理過的幹細胞，可更有效降血糖，尤其降低因胰臟損傷所造成之高血糖。The inventors of the present study found that before using stem cells to treat diabetes, the stem cells treated with resveratrol can effectively reduce the damage caused by the high glucose environment to stem cells, thereby improving the hypoglycemic effect of stem cells. Therefore, the use of the aforementioned stem cells treated with resveratrol can lower blood sugar more effectively, especially the hyperglycemia caused by pancreatic damage.
本發明之一目的，在於提供一種提升幹細胞之降血糖效益的方法，其係包含以白藜蘆醇處理該幹細胞。較佳地，該幹細胞係胚胎幹細胞、成體幹細胞、或誘導型多能幹細胞。更佳地，該幹細胞係脂肪幹細胞。其中，該經白藜蘆醇處理之幹細胞尤其係用於降低因胰臟損傷所造成之高血糖，且較佳係於幹細胞培養液中以每毫升0.1至15微克之白藜蘆醇進行該處理，更佳係於幹細胞培養液中以每毫升1至3.5微克之白藜蘆醇進行該處理。It is an object of the present invention to provide a method for increasing the hypoglycemic benefit of stem cells comprising treating the stem cells with resveratrol. Preferably, the stem cell line is an embryonic stem cell, an adult stem cell, or an induced pluripotent stem cell. More preferably, the stem cell line is adipose stem cells. Wherein the resveratrol-treated stem cells are particularly used for reducing hyperglycemia caused by pancreatic damage, and preferably in a stem cell culture solution at 0.1 to 15 micrograms per gram of resveratrol per ml. More preferably, the treatment is carried out in a stem cell culture solution at 1 to 3.5 μg per ml of resveratrol.
本發明之另一目的，在於提供一種使用白藜蘆醇於製造一降血糖套組的用途，其中該套組係包含一第一部分以及一第二部分，該第一部分係包含幹細胞，且該第二部分係包含白藜蘆醇。較佳地，該幹細胞係胚胎幹細胞、成體幹細胞、或誘導型多能幹細胞。更佳地，該幹細胞係脂肪幹細胞。較佳地，該套組係用於降低因胰臟損傷所造成之高血糖的套組。Another object of the present invention is to provide a use of resveratrol for the manufacture of a hypoglycemic kit, wherein the kit comprises a first portion and a second portion, the first portion comprising stem cells, and the first portion The second part contains resveratrol. Preferably, the stem cell line is an embryonic stem cell, an adult stem cell, or an induced pluripotent stem cell. More preferably, the stem cell line is adipose stem cells. Preferably, the kit is for reducing the set of hyperglycemia caused by pancreatic damage.
以下將描述根據本發明之部分具體實施態樣；惟，在不背離本發明精神下，本發明尚可以多種不同形式之態樣來實踐，不應將本發明保護範圍解釋為限於說明書所陳述者。此外，除非文中有另外說明，於本說明書中（尤其是在後述專利申請範圍中）所使用之「一」、「該」及類似用語應理解為包含單數及複數形式；所謂「個體」係指哺乳動物，哺乳動物可為人類或非人動物。The invention will be described in detail below with reference to the embodiments of the present invention. The present invention may be practiced in various different forms without departing from the spirit and scope of the invention. . In addition, the terms "a", "an" and "the" and "the" Mammals, mammals can be human or non-human animals.
本說明書中所使用之數值範圍（例如5至100）應理解為亦包含在該範圍中的所有有理數以及在該範圍中之任何有理數所組成的範圍，因此，本說明書中所使用之數值範圍係包含介於所列舉之最低值與最高值之間的數值的所有可能組合。另，當本文於數值前使用「約」時，實質上代表與所述數值相差在20%以內者，較佳在10%以內者，且更佳在5%以內者。The range of values used in the specification (for example, 5 to 100) is understood to include all rational numbers in the range and any range of rational numbers in the range. Therefore, the numerical range used in the present specification is Contains all possible combinations of values between the lowest and highest values listed. Further, when "about" is used herein before the numerical value, it substantially means that the difference is within 20%, preferably within 10%, and more preferably within 5%.
如上述說明，糖尿病的主要病因為胰島素分泌不足或細胞對胰島素不敏感，致使血液中的葡萄糖含量過高。其中，由於幹細胞具有修復胰臟的功效，因此可用於治療糖尿病，尤其是因胰臟損傷所造成之高血糖。然而，另一方面，高糖環境則會對幹細胞造成傷害，降低其治療效益。本案發明人研究發現，在使用幹細胞於治療糖尿病以前，先以白藜蘆醇處理幹細胞，可以有效降低高糖環境對幹細胞所造成的傷害，從而提升幹細胞於降血糖之治療效益。因此，本發明係提供一種提升幹細胞之降血糖效益的方法，其係包含以幹細胞進行治療以前，先以白藜蘆醇處理幹細胞。As explained above, the main cause of diabetes is insufficient insulin secretion or the cells are not sensitive to insulin, resulting in excessive levels of glucose in the blood. Among them, since stem cells have the effect of repairing the pancreas, they can be used for the treatment of diabetes, especially high blood sugar caused by pancreatic damage. However, on the other hand, high-sugar environments can cause damage to stem cells and reduce their therapeutic benefits. The inventors of the present study found that before using stem cells to treat diabetes, the stem cells treated with resveratrol can effectively reduce the damage caused by high-glyceic environment to stem cells, thereby improving the therapeutic effect of stem cells in lowering blood sugar. Accordingly, the present invention provides a method of increasing the hypoglycemic effect of stem cells, which comprises treating stem cells with resveratrol prior to treatment with stem cells.
白藜蘆醇是一種多酚類化合物，乃植物為了抵禦細菌或真菌入侵而產生的物質，存在於葡萄、藍莓、樹莓及桑葚的果皮以及決明屬植物中。已知白藜蘆醇具有抗氧化、保護心血管、抗癌、及抗老化等能力，可作為膳食補充劑食用。於根據本發明之方法中，所使用之白藜蘆醇可由任何合宜之來源提供，舉例言之，可由市面上購得，或由植物之萃取物純化分離而來，亦可透過化學合成方法獲得。例如，可由葡萄萃取、純化而得到可供本發明方法使用之白藜蘆醇。Resveratrol is a polyphenolic compound that is produced by plants to protect against bacterial or fungal infestation. It is found in the peels of grapes, blueberries, raspberries, and mulberries, as well as in Cassia. Resveratrol is known to have antioxidant, cardiovascular, anti-cancer, and anti-aging properties and can be used as a dietary supplement. In the method according to the invention, the resveratrol used may be provided by any suitable source, for example, commercially available, or purified from plant extracts, or obtained by chemical synthesis. . For example, resveratrol which can be used in the method of the invention can be obtained by extraction and purification from grapes.
本發明方法可適用於任何合宜之幹細胞，包括例如：胚胎幹細胞、成體幹細胞、及誘導型多能幹細胞。其中，成體幹細胞包括例如：造血幹細胞、間質幹細胞、臍帶血幹細胞、周邊血幹細胞、神經幹細胞、表皮幹細胞、肌肉幹細胞、脂肪幹細胞、胰幹細胞、眼角膜幹細胞、肝臟幹細胞、及腸上皮幹細胞。且該幹細胞可由任何合宜之來源提供，舉例言之，可以是由自體提供或由異體提供。於根據本發明方法之一具體實施態樣中，係以白藜蘆醇處理自體脂肪幹細胞。The method of the invention can be applied to any suitable stem cell, including, for example, embryonic stem cells, adult stem cells, and induced pluripotent stem cells. The adult stem cells include, for example, hematopoietic stem cells, mesenchymal stem cells, cord blood stem cells, peripheral blood stem cells, neural stem cells, epidermal stem cells, muscle stem cells, adipose stem cells, pancreatic stem cells, corneal stem cells, liver stem cells, and intestinal epithelial stem cells. And the stem cells can be provided by any convenient source, for example, either by self or by a foreign body. In a specific embodiment of the method according to the invention, the autologous adipose stem cells are treated with resveratrol.
於根據本發明之方法中，可以在任何合宜之液體介質中進行該白藜蘆醇對於幹細胞之處理，只要該液體介質不會影響白藜蘆醇之作用且不會對幹細胞造成不利的影響。舉例言之，可以在生理食鹽水或適於該幹細胞之培養液中進行，但不以此為限。其中，該幹細胞培養液可以為基礎培養液，也可以另外含有供幹細胞生長、分化所需之成分。例如，當使用本發明方法以提升脂肪幹細胞之治療效益時，可使用DMEM培養液作為基礎培養液以進行處理。In the method according to the present invention, the treatment of stem cells by the resveratrol can be carried out in any suitable liquid medium as long as the liquid medium does not affect the action of resveratrol and does not adversely affect stem cells. For example, it can be carried out in physiological saline or a culture solution suitable for the stem cells, but is not limited thereto. The stem cell culture solution may be a basal culture solution or may additionally contain components required for growth and differentiation of stem cells. For example, when the method of the present invention is used to enhance the therapeutic benefit of adipose stem cells, DMEM medium can be used as a base medium for treatment.
於根據本發明之方法進行該以白藜蘆醇對幹細胞之處理時，可以透過將白藜蘆醇以所欲最終濃度之量直接添加至含有幹細胞之溶液中而進行，也可以先將白藜蘆醇溶解於一合宜之液體中以得到一含有白藜蘆醇之溶液，再以所欲最終濃度之量將該含有白藜蘆醇溶液與該含有幹細胞之溶液混合而進行。其中，該溶解白藜蘆醇之液體可以與該含有幹細胞之溶液的液體相同或不同。When the stem cells are treated with resveratrol according to the method of the present invention, the resveratrol can be directly added to the solution containing the stem cells in a desired final concentration, or the white peony can be firstly applied. The rosin is dissolved in a suitable liquid to obtain a solution containing resveratrol, and the resveratrol-containing solution is mixed with the solution containing the stem cells in an amount to the desired final concentration. Wherein, the liquid for dissolving resveratrol may be the same as or different from the liquid of the solution containing the stem cells.
可以視幹細胞的種類而選用合宜的處理條件。其中，以處理溶液之體積為基準，通常係以每毫升處理溶液至少約0.1微克白藜蘆醇（例如：約0.1至15微克白藜蘆醇）進行該處理，較佳為每毫升約0.5微克至10微克白藜蘆醇，更佳為每毫升約1微克至3.5微克白藜蘆醇。處理時間一般為至少約0.5小時（例如：約0.5小時至24小時），較佳約1小時至12小時，更佳約2小時至6小時。舉例言之，如後附實施例所示，當於幹細胞培養液中以本發明方法處理脂肪幹細胞時，以每毫升培養液約2.3微克之白藜蘆醇（即，10微莫耳濃度白藜蘆醇）處理幹細胞歷時2小時，可有效增加脂肪幹細胞之存活率、降血糖之能力、以及修復胰臟之能力。Appropriate treatment conditions can be selected depending on the type of stem cells. Wherein, based on the volume of the treatment solution, usually at least about 0.1 micrograms of resveratrol per milliliter of treatment solution (e.g., about 0.1 to 15 micrograms of resveratrol), preferably about 0.5 micrograms per milliliter. Up to 10 micrograms of resveratrol, more preferably from about 1 microgram to 3.5 micrograms of resveratrol per milliliter. The treatment time is generally at least about 0.5 hours (e.g., about 0.5 hours to 24 hours), preferably about 1 hour to 12 hours, more preferably about 2 hours to 6 hours. For example, as shown in the appended Examples, when the adipose stem cells are treated in the stem cell culture solution by the method of the present invention, about 2.3 micrograms of resveratrol per ml of the culture solution (i.e., 10 micromolar concentration of chalk) Resveratrol treatment of stem cells for 2 hours can effectively increase the survival rate of adipose stem cells, the ability to lower blood sugar, and the ability to repair the pancreas.
根據本發明方法之經白藜蘆醇處理之幹細胞，係有效於降低因以下至少一者所造成之高血糖：第一型糖尿病、第二型糖尿病、及姙娠型糖尿病；較佳係使用於降低因第一型糖尿病所造成之高血糖；更佳係使用於降低因胰臟損傷所造成之高血糖。The resveratrol-treated stem cells according to the method of the present invention are effective for reducing hyperglycemia caused by at least one of: type 1 diabetes, type 2 diabetes, and gestational type diabetes; preferably used to reduce High blood sugar caused by type 1 diabetes; better used to reduce high blood sugar caused by pancreatic damage.
於使用根據本發明所提供之經白藜蘆醇處理之幹細胞於降血糖時，一般係於完成該處理之後6小時內施用至個體上以進行治療，較佳係於完成處理之後4小時內施用至個體上，更佳係於2小時內施用至個體上。於本發明之一具體實施態樣中，係於完成該處理後30分鐘內施用至個體上。When the resveratrol-treated stem cells according to the present invention are used for hypoglycemia, they are generally administered to an individual for treatment within 6 hours after completion of the treatment, preferably within 4 hours after completion of the treatment. More preferably, the individual is administered to the individual within 2 hours. In one embodiment of the invention, the application is applied to the individual within 30 minutes of completing the treatment.
本發明所提供之經白藜蘆醇處理之幹細胞可呈任何形式，並以任何合宜之方式施用。舉例言之，但不以此為限，該幹細胞可以針劑、細胞輸注劑等劑型提供，並藉由靜脈內或腹腔內等投藥方式施用至個體上。其中，當該幹細胞係以針劑、細胞輸注劑等劑型提供時，可於該等劑型中另含一或多種醫藥上可接受之載劑，例如：生理食鹽水。The resveratrol-treated stem cells provided by the present invention may be in any form and administered in any convenient manner. For example, but not limited thereto, the stem cells may be provided in a dosage form such as an injection or a cell infusion, and administered to an individual by intravenous or intraperitoneal administration. Wherein, when the stem cell line is provided in the form of an injection, a cell infusion or the like, one or more pharmaceutically acceptable carriers may be further included in the dosage form, for example, physiological saline.
可以一日一次、一日多次、數日一次、或數週一次等不同頻率施用根據本發明所提供之經白藜蘆醇處理之幹細胞，端視投予個體之需求、年齡、體重及健康狀況而異。舉例言之，當以細胞輸注方式將該幹細胞施用至該個體時，所採用之幹細胞用量，以該幹細胞總數計，為每公斤體重約1x10 6個細胞至約5x10 6個細胞，較佳為每公斤體重約2x10 6個細胞。 The resveratrol-treated stem cells provided according to the present invention may be administered at different frequencies, such as once a day, multiple times a day, once every other day, or several times a week, depending on the needs, age, weight and health of the individual. The situation varies. For example words, when the stem cells administered to the subject in a cell infusion, the use of stem cells amount to the dry total number of cells counted, per kg body weight of about 1x10 6 cells to about 5x10 6 cells, preferably each The kilogram weighs about 2 x 10 6 cells.
因此，本發明亦關於使用白藜蘆醇於製造一降血糖套組的用途，其中該套組係包含一第一部分以及一第二部分，該第一部分係包含幹細胞，且該第二部分係包含白藜蘆醇。其中，有關幹細胞之選用、白藜蘆醇的使用條件與方法、以及適用的病症，均如上述之說明。Accordingly, the present invention is also directed to the use of resveratrol for the manufacture of a hypoglycemic kit, wherein the kit comprises a first portion and a second portion, the first portion comprising stem cells and the second portion comprising Resveratrol. Among them, the selection of stem cells, the conditions and methods of use of resveratrol, and the applicable conditions are as described above.
於根據本發明所提供之套組中，該第一部分及第二部分係分別置於不同的容納空間，例如可分別置於不同的塑膠袋、塑膠瓶、玻璃瓶、安瓿（ampoule）、紙盒或塑膠盒中，且各該容納空間可彼此相連或分離。此外，該第一部分及第二部分可分別以任何合宜之相同或不同溫度保存。In the kit according to the present invention, the first part and the second part are respectively placed in different receiving spaces, for example, can be respectively placed in different plastic bags, plastic bottles, glass bottles, ampoules, cartons. Or in a plastic box, and each of the receiving spaces can be connected or separated from each other. Furthermore, the first portion and the second portion may each be stored at any suitable or different temperature.
第一部分及第二部分可各自含有任何不會不利影響所含活性成分（即，該幹細胞或白藜蘆醇）之活性的醫藥可接受載劑，例如：生理食鹽水、幹細胞培養液、冷凍保護劑、溶劑、油性溶劑、稀釋劑、安定劑、吸收延遲劑、崩散劑、乳化劑、抗氧化劑、黏合劑、潤滑劑、吸濕劑等。The first part and the second part may each contain any pharmaceutically acceptable carrier which does not adversely affect the activity of the active ingredient contained therein (ie, the stem cell or resveratrol), for example: physiological saline, stem cell culture, cryoprotection Agents, solvents, oily solvents, diluents, stabilizers, absorption delaying agents, disintegrating agents, emulsifiers, antioxidants, binders, lubricants, moisture absorbents, and the like.
本發明套組可更包含一第三部分，該第三部分係包含生理食鹽水或適於培養該幹細胞之培養液，較佳係置於與該第一部分及第二部分不同之容納空間（例如，塑膠袋、塑膠瓶、玻璃瓶或安瓿）中，可於使用時與該第二部分混合，以提供一含有白藜蘆醇之培養液，以處理該第一部分所含之幹細胞，提供一經白藜蘆醇處理之幹細胞。The kit of the present invention may further comprise a third portion comprising physiological saline or a culture medium suitable for culturing the stem cells, preferably in a different accommodation space than the first portion and the second portion (eg , in a plastic bag, a plastic bottle, a glass bottle or an ampoule, may be mixed with the second part during use to provide a culture solution containing resveratrol to treat the stem cells contained in the first part, providing a white Resveratrol-treated stem cells.
茲以下列實施例進一步例示說明本發明。其中該等實施例僅提供作為說明，而非用以限制本發明之保護範圍。本發明保護範圍係如後附申請專利範圍所示。The invention is further illustrated by the following examples. The embodiments are provided by way of illustration only and are not intended to limit the scope of the invention. The scope of the invention is shown in the appended claims.
實施例Example
實施例Example 11 ：細胞實驗: Cell experiment
（( 1-11-1 ）脂肪幹細胞之製備Preparation of adipose stem cells
自8個月大之Wistar公鼠（購自綠色四季公司）體內取出腹腔脂肪組織，並將該等脂肪組織切成適當大小，其後以含有抗生素（1% Penicillin及Streptomycin，購自HyClone，GE Healthcare）之生理食鹽水洗淨，再將其置於含有第二型膠原蛋白酶（0.01%，購自Sigma）的生理食鹽水中，在37°C下加熱攪拌1小時。接著，於室溫下以3000 rmp離心10分鐘。最後，將下層沉澱物取出，並於培養皿中做細胞培養以提供脂肪幹細胞。Abdominal adipose tissue was taken from an 8-month-old Wistar male mouse (purchased from Green Seasons) and the adipose tissue was cut to an appropriate size, followed by antibiotics (1% Penicillin and Streptomycin, purchased from HyClone, GE). The physiological saline of Healthcare was washed, and then placed in physiological saline containing collagenase type 2 (0.01%, purchased from Sigma), and the mixture was heated and stirred at 37 ° C for 1 hour. Then, it was centrifuged at 3000 rmp for 10 minutes at room temperature. Finally, the lower layer of the precipitate was taken out and subjected to cell culture in a petri dish to provide adipose stem cells.
（( 1-21-2 ）高糖環境對幹細胞存活率的影響The effect of high sugar environment on stem cell survival rate
將實施例（1-1）所提供之脂肪幹細胞分成三組，並分別以如下條件在24-孔盤中進行培養及處理： 1. 對照組：以10%DMEM培養基進行培養，歷時24小時； 2. 高糖組：以含有33毫莫耳濃度葡萄糖的10%DMEM培養基進行培養，歷時24小時； 3. 白藜蘆醇+高糖組：以含有10微莫耳濃度白藜蘆醇的DMEM培養基進行處理，歷時2小時，接著再以含有33毫莫耳濃度葡萄糖的10%DMEM培養基培養24小時。The adipose stem cells provided in Example (1-1) were divided into three groups, and cultured and treated in a 24-well plate under the following conditions: 1. Control group: cultured in 10% DMEM medium for 24 hours; 2. High glucose group: cultured in 10% DMEM medium containing 33 millimolar glucose for 24 hours; 3. Resveratrol + high glucose group: DMEM containing resveratrol at 10 micromolar concentration The medium was treated for 2 hours and then incubated for 24 hours in 10% DMEM medium containing 33 millimolar glucose.
然後，除去各組之培養液並以PBS緩衝液沖洗3次，接著以每毫升含有0.5毫克MTT的培養液再培養3至4小時。其後，再次以PBS緩衝液沖洗，然後於各孔加入1毫升異丙醇，並於5分鐘後進行570奈米吸光值測定。結果示於圖1，其中，各組幹細胞之存活率係以對照組之結果作為基準來進行計算（其中，**代表p值＜0.01；#代表p值＜0.05）。Then, the culture solution of each group was removed and washed 3 times with PBS buffer, followed by further culture for 3 to 4 hours with a culture solution containing 0.5 mg of MTT per ml. Thereafter, it was washed again with PBS buffer, and then 1 ml of isopropyl alcohol was added to each well, and after 5 minutes, the absorbance of 570 nm was measured. The results are shown in Fig. 1, in which the survival rate of each group of stem cells was calculated based on the results of the control group (wherein ** represents p value < 0.01; # represents p value < 0.05).
由圖1可知，相較於「對照組」，「高糖組」的幹細胞存活率（61±4%）明顯降低。此外，相較於「高糖組」，經白藜蘆醇處理之組別（即，「白藜蘆醇+高糖組」）的幹細胞存活率（82±7%）則顯著回升。上述結果顯示，高糖環境會明顯降低幹細胞之存活率，而以白藜蘆醇進行處理則可有效降低高糖環境對幹細胞的傷害。As can be seen from Fig. 1, the stem cell survival rate (61 ± 4%) of the "high glucose group" was significantly lower than that of the "control group". In addition, compared with the "high-sugar group", the stem cell survival rate (82 ± 7%) of the resveratrol-treated group (ie, "resveratrol + high glucose group") significantly increased. The above results show that high glucose environment can significantly reduce the survival rate of stem cells, while treatment with resveratrol can effectively reduce the damage of stem cells in high sugar environment.
實施例Example 22 ：動物實驗:Animal experiment
（( 2-12-1 ）動物模型的建立) Establishment of animal models
將8個月大之Wistar公鼠（購自綠色四季公司）分成四組，在12-12小時日夜循環下飼養且不限制飲食，並分別進行以下處理： 1. 對照組（下稱「對照組」）：腹腔注射0.2毫升之生理食鹽水，並自尾靜脈輸注0.2毫升之生理食鹽水； 2. 糖尿病組（下稱「DM組」）：以鏈佐黴素（STZ，購自Sigma，溶於生理食鹽水溶劑中，以55毫克／公斤體重之劑量進行腹腔注射）誘發糖尿病，並自尾靜脈輸注0.2毫升之生理食鹽水； 3. 以幹細胞治療糖尿病組（下稱「DM+ADSC組」）：以鏈佐黴素（溶於生理食鹽水溶劑中，以55毫克／公斤體重之劑量進行腹腔注射）誘發糖尿病，並自尾靜脈輸注含有1x10 6個取自實施例（1-1）之脂肪幹細胞的生理食鹽水（0.2毫升）； 4. 以經白藜蘆醇處理之幹細胞治療糖尿病組（下稱「DM+R-ADSC組」）：以鏈佐黴素（溶於生理食鹽水溶劑中，以55毫克／公斤體重之劑量進行腹腔注射）誘發糖尿病，並自尾靜脈輸注含有1x10 6個取自實施例（1-1）之脂肪幹細胞的生理食鹽水（0.2毫升），其中，該等幹細胞在輸注之前係先以白藜蘆醇（10微莫耳濃度）處理2小時。 The 8-month-old Wistar male rats (purchased from Green Seasons Company) were divided into four groups, which were kept under 12-12 hours of day and night and were not restricted in diet, and were treated as follows: 1. Control group (hereinafter referred to as "control group" ”: 0.2 ml of physiological saline was intraperitoneally injected and 0.2 ml of physiological saline was infused from the tail vein; 2. Diabetes group (hereinafter referred to as “DM group”): Streptomycin (STZ, purchased from Sigma) Diabetes was induced by intraperitoneal injection at a dose of 55 mg/kg body weight in a physiological saline solution, and 0.2 ml of physiological saline was infused from the tail vein; 3. The diabetic group was treated with stem cells (hereinafter referred to as "DM+ADSC group"). ): in streptozotocin (dissolved in physiological saline solvent, at a dose of 55 mg / kg body weight i.p.) to induce diabetes, and 1x10 6 were from Example (1-1) from the tail vein infusion containing the Physiological saline solution of adipose-derived stem cells (0.2 ml); 4. Treatment of diabetic group with stem cells treated with resveratrol (hereinafter referred to as "DM+R-ADSC group"): Streptomycin (dissolved in physiological saline solution) Medium, to 55 mg / kg The dose weight i.p.) to induce diabetes, and from the tail vein with physiological saline containing 1x10 6 were from Example (1-1) of the adipose-derived stem cells (0.2 ml), wherein these stem cell lines prior to infusion Resveratrol (10 micromolar concentration) was treated for 2 hours.
（( 2-22-2 ）經白藜蘆醇處理之幹細胞對血糖的影響Effect of stem cells treated with resveratrol on blood glucose
自實施例（2-1）所提供之各組大鼠的尾靜脈採血，並以羅氏血糖儀（Accu-Chek Active）進行空腹血糖分析。結果示於圖2（其中，***代表p值＜0.001；##及%%代表p值＜0.01）。Blood was collected from the tail vein of each group of rats provided in Example (2-1), and fasting blood glucose analysis was performed using a Roche blood glucose meter (Accu-Chek Active). The results are shown in Figure 2 (where *** represents a p-value < 0.001; ## and %% represent a p-value <0.01).
由圖2可知，「對照組」、「DM組」、「DM+ADSC組」、及「DM+R-ADSC組」的大鼠依序具有118±17毫克／分升、543±54毫克／分升、498±19毫克／分升、及431±20毫克／分升的血中葡萄糖濃度。此即，相較於「對照組」，「DM組」的血糖明顯較高，而相較於「DM組」，經幹細胞治療的組別（包含：「DM+ADSC組」、及「DM+R-ADSC組」）血糖則顯著降低，其中「DM+R-ADSC組」之降血糖效果較「DM+ADSC組」為佳。上述結果顯示，幹細胞治療可有效降低血糖，而以白藜蘆醇處理幹細胞則可有效提升幹細胞所提供之降血糖效益。As can be seen from Figure 2, the rats in the "control group", "DM group", "DM+ADSC group", and "DM+R-ADSC group" had a sequence of 118 ± 17 mg / dl and 543 ± 54 mg / Blood glucose concentration in liters, 498 ± 19 mg / dl, and 431 ± 20 mg / dl. That is, compared with the "control group", the blood glucose of the "DM group" was significantly higher, compared with the "DM group", the group treated with stem cells (including: "DM+ADSC group", and "DM+" "R-ADSC group") blood glucose was significantly reduced, and the "DM+R-ADSC group" had better blood glucose lowering effect than the "DM+ADSC group". The above results show that stem cell treatment can effectively lower blood sugar, while stem cells treated with resveratrol can effectively improve the blood glucose lowering effect provided by stem cells.
（( 2-32-3 ）經白藜蘆醇處理之幹細胞對大鼠胰臟細胞中蛋白表現的影響Effect of stem cells treated with resveratrol on protein expression in rat pancreatic cells
已知IGF1R/PI3K/Akt訊息傳遞路徑的活化，會促進細胞的增生與活化，而Bcl-xL及Bcl-2的活化會抑制細胞凋亡。此外，Cyto C、Caspase 9及Caspase 3等蛋白則屬於細胞凋亡相關蛋白。因此，在以下實驗中，將以大鼠胰臟細胞中p-IGF1R、PI3K、p-PI3K、Akt、p-Akt、Bcl-xL、及Bcl-2等細胞存活相關蛋白的表現量、及Cyto C、Caspase 9及Caspase 3等細胞凋亡相關蛋白的表現量，來評估經白藜蘆醇處理之幹細胞對大鼠胰臟細胞中蛋白表現的影響。Activation of the IGF1R/PI3K/Akt signaling pathway is known to promote cell proliferation and activation, while activation of Bcl-xL and Bcl-2 inhibits apoptosis. In addition, proteins such as Cyto C, Caspase 9, and Caspase 3 are apoptosis-related proteins. Therefore, in the following experiments, the expression levels of cell survival-related proteins such as p-IGF1R, PI3K, p-PI3K, Akt, p-Akt, Bcl-xL, and Bcl-2 in rat pancreatic cells, and Cyto will be used. The expression of apoptosis-related proteins such as C, Caspase 9 and Caspase 3 was used to evaluate the effect of resveratrol-treated stem cells on protein expression in rat pancreatic cells.
將實施例（2-1）所提供之各組大鼠犧牲，並自各組大鼠的體內取出胰臟組織樣本，接著以經山葵過氧化氫酶共軛之二級抗體（Horseradish peroxidase conjugated secondary antibody，購自Abcam plc.）進行西方墨點法，檢測該等樣本中蛋白的表現量，其中細胞存活相關蛋白（包括：p-IGF1R、PI3K、p-PI3K、Akt、p-Akt、Bcl-xL、及Bcl-2）及β-肌動蛋白（作為內部控制）表現量的分析結果示於圖3-1至3-5（其中，***代表p值＜0.001、##及%%代表p值＜0.01；*、#及%代表p值＜0.05）。而細胞凋亡相關蛋白（包括：Cyto C、Caspase 9及Caspase 3）及β-肌動蛋白（作為內部控制）表現量的分析結果則示於圖4-1至4-4（其中，*、#及$代表p值＜0.05）。Each group of rats provided in Example (2-1) was sacrificed, and a pancreatic tissue sample was taken out from the body of each group of rats, followed by a horseradish catalase-conjugated secondary antibody (Horseradish peroxidase conjugated secondary). Antibody, purchased from Abcam plc.) Western blotting method to detect protein expression in these samples, including cell survival-related proteins (including: p-IGF1R, PI3K, p-PI3K, Akt, p-Akt, Bcl- The analysis results of xL, and Bcl-2) and β-actin (as internal control) are shown in Figures 3-1 to 3-5 (where *** represents p value <0.001, ## and %%). Representative p values <0.01; *, # and % represent p values <0.05). The results of the analysis of the expression of apoptosis-related proteins (including Cyto C, Caspase 9 and Caspase 3) and β-actin (as internal control) are shown in Figures 4-1 to 4-4 (where *, # and $ represents p value <0.05).
由圖3-1至3-5可知，相較於「對照組」，「DM組」之細胞存活相關蛋白的表現量明顯下降，而經過幹細胞治療之組別（包含：「DM+ADSC組」、及「DM+R-ADSC組」）的存活相關蛋白表現量則有回升的趨勢。其中，相較於「DM+ADSC組」，「DM+R-ADSC組」的存活相關蛋白表現量顯著較高。As can be seen from Figures 3-1 to 3-5, the amount of cell survival-related protein in the "DM group" was significantly lower than that in the "control group", and the group subjected to stem cell treatment (including: "DM+ADSC group") The performance of survival-related proteins in the "DM+R-ADSC group" has a tendency to rebound. Among them, the performance of survival-related proteins in the "DM+R-ADSC group" was significantly higher than that in the "DM+ADSC group".
由圖4-1至4-4可知，相較於「對照組」，「DM組」之細胞凋亡相關蛋白的表現量明顯上升，而經過幹細胞治療的組別之凋亡相關蛋白表現量則有下降的趨勢。其中，相較於「DM+ADSC組」，「DM+R-ADSC組」凋亡相關蛋白的表現量更低。As can be seen from Figures 4-1 to 4-4, the expression of apoptosis-related proteins in the "DM group" was significantly higher than that in the "control group", while the expression of apoptosis-related proteins in the stem cell-treated group was higher. There is a downward trend. Among them, the expression of apoptosis-related proteins in the "DM+R-ADSC group" was lower than that in the "DM+ADSC group".
上述結果顯示，幹細胞治療可有效提升胰臟細胞存活相關蛋白的表現量，並降低細胞凋亡相關蛋白的表現量，從而可促進胰臟細胞存活並達到降血糖的效益，而以白藜蘆醇處理幹細胞則可有效提升幹細胞所提供之上述效益。The above results show that stem cell therapy can effectively increase the expression of pancreatic cell survival-related proteins and reduce the expression of apoptosis-related proteins, thereby promoting pancreatic cell survival and achieving hypoglycemic effects, while resveratrol Treatment of stem cells can effectively enhance the above benefits provided by stem cells.
（( 2-42-4 ）經白藜蘆醇處理之幹細胞對大鼠胰島組織的影響Effect of stem cells treated with resveratrol on islet tissue in rats
自實施例（2-1）所提供之各組大鼠的體內取出胰臟組織樣本，經石蠟包埋後，切片並進行HE染色（hematoxylin及eosin染色）。拍攝經染色之切片，並測量胰島的直徑。照片與測量之結果分別示於圖5-1及5-2（其中，**及##代表p值＜0.01；%代表p值＜0.05）。Pancreatic tissue samples were taken from the body of each group of rats provided in Example (2-1), embedded in paraffin, sectioned and subjected to HE staining (hematoxylin and eosin staining). The stained sections were taken and the diameter of the islets was measured. The results of the photographs and measurements are shown in Figures 5-1 and 5-2, respectively (where ** and ## represent p values <0.01; % represents p values <0.05).
由圖5-1及5-2可知，相較於「對照組」，「DM組」的胰島直徑顯著降低，而經過幹細胞治療的組別（包含：「DM+ADSC組」、及「DM+R-ADSC組」）之胰島直徑則顯著回升。其中，相較於「DM+ADSC組」，「DM+R-ADSC組」胰島直徑的回升更為顯著。上述結果顯示，幹細胞治療可有效修復胰島組織，並因此具有降血糖的效益，而以白藜蘆醇處理幹細胞則可有效提升幹細胞所提供之上述效益。As can be seen from Figures 5-1 and 5-2, the diameter of the islets of the "DM group" was significantly lower than that of the "control group", and the group treated with stem cells (including "DM+ADSC group" and "DM+" The islet diameter of the R-ADSC group was significantly increased. Among them, the diameter of the islet diameter of the "DM+R-ADSC group" was more significant than that of the "DM+ADSC group". The above results show that stem cell therapy can effectively repair islet tissue and thus have the effect of lowering blood sugar, while stem cells treated with resveratrol can effectively enhance the above-mentioned benefits provided by stem cells.
（( 2-52-5 ）經白藜蘆醇處理之幹細胞對大鼠胰臟纖維化的影響Effect of stem cells treated with resveratrol on pancreatic fibrosis in rats
自實施例（2-1）所提供之各組大鼠的體內取出胰臟組織樣本並分成二部分，其中第一部分經石蠟包埋後，切片並進行Masson’s Trichrome染色，結果示於圖6。第二部分則以經山葵過氧化氫酶共軛之二級抗體進行西方墨點法，分析胰臟組織中纖維化相關蛋白（包括：TGF-β）的表現量，結果示於圖7。The pancreatic tissue samples were taken from the body of each group of rats provided in Example (2-1) and divided into two parts. The first part was embedded in paraffin, sectioned and subjected to Masson's Trichrome staining, and the results are shown in Fig. 6. In the second part, the Western blotting method was performed using a secondary antibody conjugated with wasabi catalase to analyze the expression of fibrosis-related proteins (including TGF-β) in pancreatic tissue. The results are shown in Fig. 7.
由圖6可知，相較於「對照組」，「DM組」表現大量的纖維化組織。而經過幹細胞治療的組別（包含：「DM+ADSC組」、及「DM+R-ADSC組」），組織纖維化的程度明顯降低，其中又以「DM+R-ADSC組」的降低組織纖維化效果最為顯著。As can be seen from Fig. 6, the "DM group" exhibited a large amount of fibrotic tissue as compared with the "control group". In the group treated with stem cells (including "DM+ADSC group" and "DM+R-ADSC group"), the degree of tissue fibrosis was significantly reduced, and the tissue of "DM+R-ADSC group" was reduced. The effect of fibrosis is most pronounced.
而由圖7可知，相較於「對照組」，「DM組」表現大量的纖維化相關蛋白。而經過幹細胞治療的組別，纖維化相關蛋白的表現量則明顯降低，其中又以「DM+R-ADSC組」的表現量最低。As can be seen from Fig. 7, the "DM group" exhibited a large amount of fibrosis-related protein compared to the "control group". In the group treated with stem cells, the expression of fibrosis-related proteins was significantly reduced, and the performance of the "DM+R-ADSC group" was the lowest.
上述結果顯示，幹細胞治療可有效降低胰臟組織纖維化，並可藉由修復胰臟組織來達到降血糖的效益，而以白藜蘆醇處理幹細胞則可有效提升幹細胞所提供之上述效益。The above results show that stem cell therapy can effectively reduce pancreatic tissue fibrosis, and can achieve the effect of lowering blood sugar by repairing pancreatic tissue, while stem cells treated with resveratrol can effectively improve the above-mentioned benefits provided by stem cells.
如上述實施例所示，以白藜蘆醇處理幹細胞，確實可提升幹細胞之降血糖效益，因此，可以使用白藜蘆醇以製造一降血糖之套組，該套組可提供具有降血糖增進效益之幹細胞，該幹細胞尤其可用於降低因為胰臟損傷所導致之高血糖。As shown in the above examples, the treatment of stem cells with resveratrol does improve the hypoglycemic effect of stem cells. Therefore, resveratrol can be used to produce a hypoglycemic kit, which provides hypoglycemic enhancement. A beneficial stem cell that is especially useful for reducing hyperglycemia caused by pancreatic damage.
圖1所示為以MTT法檢測，白藜蘆醇對幹細胞存活率之影響，其中「對照組」、「高糖組」、及「白藜蘆醇+高糖組」依序係顯示以含10%胎牛血清之DMEM（Dulbecco's Modified Eagle Medium）（下稱10%DMEM）培養基培養幹細胞、以含有高濃度葡萄糖的10%DMEM培養基培養幹細胞、及先以白藜蘆醇處理幹細胞，再以含有高濃度葡萄糖的10%DMEM培養基培養該幹細胞的結果；Figure 1 shows the effect of resveratrol on the survival rate of stem cells by MTT assay. The "control group", "high glucose group", and "resveratrol + high sugar group" are shown in sequence. 10% fetal bovine serum in DMEM (Dulbecco's Modified Eagle Medium) (hereinafter referred to as 10% DMEM) medium cultured stem cells, cultured stem cells in 10% DMEM medium containing high concentration of glucose, and first treated stem cells with resveratrol, and then contained The result of culturing the stem cells in 10% DMEM medium with high concentration of glucose;
圖2所示為以羅氏血糖儀（Accu-Chek Active）檢測，經白藜蘆醇處理之幹細胞對大鼠空腹血糖之影響，其中包含「對照組」、糖尿病組（下稱「DM組」）、以幹細胞治療糖尿病組（下稱「DM+ADSC組」）、及以經白藜蘆醇處理之幹細胞治療糖尿病組（下稱「DM+R-ADSC組」）的結果；Figure 2 shows the effect of resveratrol-treated stem cells on fasting blood glucose in rats, measured by Accu-Chek Active, including "control group" and diabetes group (hereinafter referred to as "DM group"). The results of treatment of the diabetic group with stem cells (hereinafter referred to as "DM+ADSC group") and stem cells treated with resveratrol (hereinafter referred to as "DM+R-ADSC group");
圖3所示為以西方墨點法檢測，經白藜蘆醇處理之幹細胞對大鼠胰臟細胞存活相關蛋白（包括：p-IGF1R（Phosphorylated insulin-like growth factor-1 receptor）、PI3K（phosphoinositide 3-kinase）、p-PI3K、Akt（Protein kinase B）、p-Akt、Bcl-Xl（B-cell lymphoma-extra large）、及Bcl-2）、及β-肌動蛋白（β-actin，作為內部控制）表現量之影響，其中圖3-1為照片圖、圖3-2所示為p-PI3K與PI3K的表現量比值、圖3-3所示為p-Akt與Akt的表現量比值、圖3-4所示為Bcl-xL與β-肌動蛋白的表現量比值、圖3-5所示為Bcl-2與β-肌動蛋白的表現量比值，且圖3-1至3-5皆包含「對照組」、「DM組」、「DM+ADSC組」、及「DM+R-ADSC組」的結果；Figure 3 shows the survival of rat pancreatic cell survival-related proteins (including p-IGF1R (Phosphorylated insulin-like growth factor-1 receptor), PI3K (phosphoinositide) detected by Western blotting method. 3-kinase), p-PI3K, Akt (Protein kinase B), p-Akt, Bcl-Xl (B-cell lymphoma-extra large), and Bcl-2), and β-actin (β-actin, As an internal control, the effect of the amount of performance, Figure 3-1 is a photo, Figure 3-2 shows the ratio of p-PI3K to PI3K, and Figure 3-3 shows the performance of p-Akt and Akt. Ratio, Figure 3-4 shows the ratio of Bcl-xL to β-actin expression, and Figure 3-5 shows the ratio of Bcl-2 to β-actin expression, and Figure 3-1 3-5 include the results of "control group", "DM group", "DM+ADSC group", and "DM+R-ADSC group";
圖4所示為以西方墨點法檢測，經白藜蘆醇處理之幹細胞對大鼠胰臟細胞凋亡相關蛋白（包括：Cyto C（cytochrome c）、Caspase 9及Caspase 3）、及β-肌動蛋白（作為內部控制）表現量之影響，其中圖4-1為照片圖、圖4-2所示為Cyto C與β-肌動蛋白的表現量比值、圖4-3所示為Caspase 9與β-肌動蛋白的表現量比值、圖4-4所示為Caspase 3與β-肌動蛋白的表現量比值，且圖4-1至4-4皆包含「對照組」、「DM組」、「DM+ADSC組」、及「DM+R-ADSC組」的結果；Figure 4 shows the apoptosis-related proteins of rat pancreatic cells (including Cyto C (cytochrome c), Caspase 9 and Caspase 3) and β- detected by resveratrol-treated stem cells by Western blotting. The effect of actin (as internal control) on the performance, Figure 4-1 is a photo, Figure 4-2 shows the ratio of Cyto C to β-actin, and Figure 4-3 shows Caspase. The ratio of the expression of 9 to β-actin and the ratio of the expression of Caspase 3 to β-actin are shown in Figure 4-4, and Figures 4-1 to 4-4 both contain "control" and "DM". Results of the "Group", "DM+ADSC Group", and "DM+R-ADSC Group";
圖5所示為以HE染色（hematoxylin及eosin染色）法檢測，經白藜蘆醇處理之幹細胞對大鼠胰島組織之影響，其中圖5-1為照片圖、而圖5-2為胰島直徑的量化長條圖，且圖5-1及5-2皆包含「對照組」、「DM組」、「DM+ADSC組」、及「DM+R-ADSC組」的結果；Figure 5 shows the effect of stem cells treated with resveratrol on rat islet tissue by HE staining (hematoxylin and eosin staining), in which Figure 5-1 is a photo, and Figure 5-2 is a islet diameter. Quantitative bar graphs, and Figures 5-1 and 5-2 contain the results of "control group", "DM group", "DM+ADSC group", and "DM+R-ADSC group";
圖6所示為以Masson’s Trichrome染色法檢測，經白藜蘆醇處理之幹細胞對大鼠胰臟組織纖維化之影響，其中包含「對照組」、「DM組」、「DM+ADSC組」、及「DM+R-ADSC組」的結果；Figure 6 shows the effect of stem cells treated with resveratrol on the fibrosis of rat pancreas by Masson's Trichrome staining, including "control group", "DM group", "DM+ADSC group", And the results of the "DM+R-ADSC Group";
圖7所示為以西方墨點法檢測，經白藜蘆醇處理之幹細胞對大鼠胰臟組織中纖維化相關蛋白（包括：TGF-β）表現量之影響，其中包含「對照組」、「DM組」、「DM+ADSC組」、及「DM+R-ADSC組」的結果。Figure 7 shows the effect of stem cells treated with resveratrol on the expression of fibrosis-associated proteins (including TGF-β) in rat pancreas by Western blotting, including the "control group", The results of the "DM Group", "DM+ADSC Group", and "DM+R-ADSC Group".
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