TWI843312B - Use of corilagin regulating melatonin synthesis pathway for expression of tryptophan hydroxylase gene, dopa decarboxylase gene, aralkylamine n-acetyltransferase gene and acetylserotonin o-methyltransferase gene, and improving circadian rhythm dysregulation - Google Patents
Use of corilagin regulating melatonin synthesis pathway for expression of tryptophan hydroxylase gene, dopa decarboxylase gene, aralkylamine n-acetyltransferase gene and acetylserotonin o-methyltransferase gene, and improving circadian rhythm dysregulation Download PDFInfo
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- TWI843312B TWI843312B TW111146153A TW111146153A TWI843312B TW I843312 B TWI843312 B TW I843312B TW 111146153 A TW111146153 A TW 111146153A TW 111146153 A TW111146153 A TW 111146153A TW I843312 B TWI843312 B TW I843312B
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Abstract
Description
本發明是有關於一種鞣花丹寧用於調控褪黑激素合成路徑之色胺酸羥化酶基因、多巴去羧酶基因、芳烷基胺N-乙醯基轉移酶基因及乙醯血清素O-甲基轉移酶基因的表現量，幫助體內自主合成血清素與褪黑激素之能力，進而改善晝夜節律失調與睡眠品質的用途。The present invention relates to the use of ellagitanninine for regulating the expression of tryptophan hydroxylase gene, dopa decarboxylase gene, arylalkylamine N-acetyltransferase gene and serotonin acetyl O-methyltransferase gene in the melatonin synthesis pathway, thereby helping the body to independently synthesize serotonin and melatonin, thereby improving diurnal rhythm disorders and sleep quality.
晝夜節律的褪黑激素合成路徑失調易導致人體缺乏血清素與褪黑激素，人體白天將色胺酸轉換為血清素，到了夜晚，再轉換為褪黑激素。血清素與情緒息息相關，可幫助穩定情緒、預防憂鬱、抑制食慾、調節體重、幫助腸道蠕動與促進傷口癒合之功效；褪黑激素能調節晝夜節律和內分泌節律，改善睡眠品質並幫助入睡，且具免疫調節、抗氧化、抗發炎、骨質疏鬆和抑制腫瘤的能力。Disorders in the melatonin synthesis pathway of the diurnal rhythm can easily lead to a lack of serotonin and melatonin in the human body. The human body converts tryptophan into serotonin during the day and then into melatonin at night. Serotonin is closely related to mood and can help stabilize mood, prevent depression, suppress appetite, regulate weight, help intestinal peristalsis and promote wound healing. Melatonin can regulate diurnal rhythm and endocrine rhythm, improve sleep quality and help fall asleep, and has the ability to regulate immunity, resist oxidation, resist inflammation, osteoporosis and inhibit tumors.
睡眠品質不佳之頻率隨年齡增加，長期下來導致壓力大、憂鬱、焦慮與失眠，身體長期存在發炎狀態，加速衰老進程，甚至提升肥胖、高血壓、糖尿病與阿茲海默症等退化疾病發生率。此外，全球於2020年COVID-19爆發，在疫情危機下，全球失眠憂鬱人口暴增，英國失眠率由先前的16.7%上升到25%，中國的失眠率由14.6% 上升到20%，希臘則有40%的人表示經歷失眠，失眠也榮登2020 年***熱搜排行，顯示全球憂鬱與失眠的嚴重性。失眠有許多成因，其一為正常覺醒-睡眠周期的中斷。此不同步(dyssynchrony)可造成病理變化。允許改正該作用之可能治療處置在於藉由調整褪黑激素能系統(melatoninergic system)將覺醒-睡眠周期再同步化(Li-Qiang Sun，生物有機和醫學化學通訊(Bioorganic & Medicinal Chemistry Letters)2005，15，1345-49)。The frequency of poor sleep quality increases with age, which leads to stress, depression, anxiety and insomnia in the long run. The body is in a state of inflammation for a long time, which accelerates the aging process and even increases the incidence of degenerative diseases such as obesity, hypertension, diabetes and Alzheimer's disease. In addition, the global COVID-19 outbreak in 2020 has caused a surge in the number of people suffering from insomnia and depression. The insomnia rate in the UK has risen from 16.7% to 25%, and the insomnia rate in China has risen from 14.6% to 20%. In Greece, 40% of people have experienced insomnia. Insomnia has also topped the Google hot search rankings in 2020, showing the severity of depression and insomnia around the world. There are many causes of insomnia, one of which is the interruption of the normal wake-sleep cycle. This dyssynchrony can lead to pathological changes. A possible therapeutic approach that allows correcting this effect is to resynchronize the wake-sleep cycle by modulating the melatonergic system (Li-Qiang Sun, Bioorganic & Medicinal Chemistry Letters 2005, 15, 1345-49).
褪黑激素為一種由負責明暗循環之資訊、控制哺乳動物晝夜節律和調整視網膜生理的松果腺分泌之激素。褪黑激素合成和其每夜的分泌係由上視束交叉核(suprachiasmatic nucleus)控制且被環境光同步化。Melatonin is a hormone secreted by the pineal gland that is responsible for information about the light-dark cycle, controlling the diurnal rhythm of mammals and regulating retinal physiology. Melatonin synthesis and its nocturnal secretion are controlled by the suprachiasmatic nucleus and synchronized by ambient light.
人類分泌褪黑激素在夜間睡眠時同時地發生，且褪黑激素含量之增加與晚上的睡意具有正相關。褪黑激素之臨床應用範圍從延遲睡眠期症候群之治療到時差治療，包括適用於夜班工作者之治療和失眠之治療。然而，目前缺乏活化體內褪黑激素合成路徑的素材，且用來改善晝夜節律失調的醫藥組成物大多存在有副作用或效果不佳的問題，並可能使身體機能逐漸低下，激增對於藥物的需求量與依賴程度。為了解決上述問題，本領域的技術人員亟需研發出具有改善晝夜節律失調，幫助體內自主合成血清素與褪黑激素，進而改善晝夜節律失調、睡眠品質與睡眠障礙的安全之來源，將其應用於新穎醫藥組成物、食品組成物或外用品組成物以造福有此需求的廣大族群，並減少目前藥物的傷害與依賴。Humans secrete melatonin at the same time as they sleep at night, and the increase in melatonin content is positively correlated with sleepiness at night. The clinical application of melatonin ranges from the treatment of delayed sleep phase syndrome to the treatment of jet lag, including the treatment of night shift workers and the treatment of insomnia. However, there is currently a lack of materials that activate the melatonin synthesis pathway in the body, and most of the pharmaceutical compositions used to improve diurnal rhythm disorders have side effects or poor effects, and may gradually reduce body functions, surging demand for and dependence on drugs. In order to solve the above problems, technicians in this field urgently need to develop a safe source that can improve circadian rhythm disorders, help the body to independently synthesize serotonin and melatonin, and thus improve circadian rhythm disorders, sleep quality and sleep disorders, and apply it to new pharmaceutical compositions, food compositions or topical compositions to benefit the vast population with such needs and reduce the harm and dependence of current drugs.
有鑑於此，本發明之目的為提供一種鞣花丹寧(corilagin)用於製備一調控色胺酸羥化酶(tryptophan hydroxylase, TPH)基因、多巴去羧酶(dopa decarboxylase, DDC)基因、芳烷基胺N-乙醯基轉移酶(aralkylamine N-acetyltransferase, AANAT)基因及乙醯血清素O-甲基轉移酶(acetylserotonin O-methyltransferase, ASMT)基因的表現量之組成物的用途。 In view of this, the object of the present invention is to provide a use of ellagitannin for preparing a composition for regulating the expression level of tryptophan hydroxylase ( TPH ) gene, dopa decarboxylase ( DDC ) gene, aralkylamine N-acetyltransferase ( AANAT ) gene and acetylserotonin O-methyltransferase ( ASMT ) gene.
在本發明的一實施例中，該 TPH基因是 TPH1基因。 In one embodiment of the present invention, the TPH gene is the TPH1 gene.
在本發明的一實施例中，該鞣花丹寧的有效濃度為12.5 M。 In one embodiment of the present invention, the effective concentration of ellagitannin is 12.5 M.
本發明之另一目的為提供一種鞣花丹寧(corilagin)用於製備一改善晝夜節律失調之組成物的用途。Another object of the present invention is to provide a use of ellagitannin (corilagin) for preparing a composition for improving diurnal rhythm disorders.
在本發明的一實施例中，該鞣花丹寧的有效濃度為12.5 M。 In one embodiment of the present invention, the effective concentration of ellagitannin is 12.5 M.
在本發明的一實施例中，該組成物是一醫藥組成物、一食品組成物或一外用品組成物。In one embodiment of the present invention, the composition is a pharmaceutical composition, a food composition or a topical composition.
在本發明的一實施例中，該組成物進一步包含一醫藥學上可接受的載劑或一可食用性材料。In one embodiment of the present invention, the composition further comprises a pharmaceutically acceptable carrier or an edible material.
在本發明的一實施例中，該組成物具有一粉末狀、一顆粒狀、一溶液狀、一膠狀、或一膏狀的劑型。In one embodiment of the present invention, the composition has a powder, a granule, a solution, a gel, or a paste form.
綜上所述，本發明鞣花丹寧的功效在於：能有效調控 TPH、 DDC、 AANAT及 ASMT基因的表現量，具有有效活化褪黑激素合成路徑，改善晝夜節律失調，幫助體內自主合成血清素與褪黑激素之能力，進而改善睡眠品質。 In summary, the efficacy of the ellagitannins of the present invention is that it can effectively regulate the expression of TPH , DDC , AANAT and ASMT genes, effectively activate the melatonin synthesis pathway, improve diurnal rhythm disorders, help the body to independently synthesize serotonin and melatonin, and thus improve sleep quality.
以下將進一步說明本發明的實施方式，下述所列舉的實施例係用以闡明本發明，並非用以限定本發明之範圍，任何熟習此技藝者，在不脫離本發明之精神和範圍內，當可做些許更動與潤飾，因此本發明之保護範圍當視後附之申請專利範圍所界定者為準。The following will further illustrate the implementation of the present invention. The following examples are used to illustrate the present invention, not to limit the scope of the present invention. Anyone skilled in the art may make some changes and modifications without departing from the spirit and scope of the present invention. Therefore, the scope of protection of the present invention shall be subject to the scope of the attached patent application.
定義Definition
本文中所使用數值為近似值，所有實驗數據皆表示在 20%的範圍內，較佳為在 10%的範圍內，最佳為在 5%的範圍內。 The values used in this article are approximate. All experimental data are expressed in 20% range, preferably within 10% range, the best is within the 5% range.
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。Unless otherwise specified herein, the terms "a", "an", "the" and similar terms used in this specification (especially in the scope of the patent application mentioned below) should be understood to include both singular and plural forms.
根據本發明所提供之組成物可以為一醫藥組成物、一食品組成物或一外用品組成物。其中，根據本發明所提供之醫藥組成物或外用品組成物可用於調控色胺酸羥化酶基因、多巴去羧酶基因、芳烷基胺N-乙醯基轉移酶基因及乙醯血清素O-甲基轉移酶基因的表現量及改善晝夜節律失調。根據本發明所提供之食品組成物亦可用於調控色胺酸羥化酶基因、多巴去羧酶基因、芳烷基胺N-乙醯基轉移酶基因及乙醯血清素O-甲基轉移酶基因的表現量及改善晝夜節律失調。The composition provided by the present invention can be a pharmaceutical composition, a food composition or an external product composition. Among them, the pharmaceutical composition or external product composition provided by the present invention can be used to regulate the expression of tryptophan hydroxylase gene, dopa decarboxylase gene, arylalkylamine N-acetyltransferase gene and serotonin O-methyltransferase gene and improve diurnal rhythm disorder. The food composition provided by the present invention can also be used to regulate the expression of tryptophan hydroxylase gene, dopa decarboxylase gene, arylalkylamine N-acetyltransferase gene and serotonin O-methyltransferase gene and improve diurnal rhythm disorder.
根據本發明所提供之醫藥組成物可以為一醫藥品、一營養補充品、一保健食品、一外用品或其任意組合，且可以進一步包含一醫藥學上可接受之賦形劑、載劑、輔劑、及/或食品添加劑。The pharmaceutical composition provided by the present invention may be a pharmaceutical product, a nutritional supplement, a health food, an external preparation or any combination thereof, and may further comprise a pharmaceutically acceptable excipient, carrier, adjuvant, and/or food additive.
根據本發明所提供之醫藥組成物係可呈任何合宜的型式，並無特殊限制，端視所欲之用途而呈對應之合宜劑型。舉例言之，但不以此為限，該醫藥組成物可以口服或非經口服(例如：經皮)之投藥方式施用至有需要之個體上。The pharmaceutical composition provided by the present invention can be in any suitable form without any particular limitation, and can be in a suitable dosage form corresponding to the intended use. For example, but not limited to this, the pharmaceutical composition can be administered orally or parenterally (e.g., transdermally) to a subject in need.
依據本發明，醫藥組成物可利用熟習此技藝者所詳知的技術而被製造成一適合於非經腸道地(parenterally)或口服地(orally)投藥的劑型(dosage form)，這包括，但不限於：注射品(injection)[例如，無菌的水性溶液(sterile aqueous solution)或分散液(dispersion)]、無菌的粉末(sterile powder)、錠劑(tablet)、片劑(troche)、***錠(lozenge)、丸劑(pill)、膠囊(capsule)、分散性粉末(dispersible powder)或細顆粒(granule)、溶液、懸浮液(suspension)、乳劑(emulsion)、糖漿(syrup)、酏劑(elixir)、濃漿(slurry)以及類似之物。According to the present invention, the pharmaceutical composition can be prepared into a dosage form suitable for parenteral or oral administration using techniques well known to those skilled in the art, including, but not limited to, injections [e.g., sterile aqueous solutions or dispersions], sterile powders, tablets, troches, lozenges, pills, capsules, dispersible powders or granules, solutions, suspensions, emulsions, syrups, elixirs, slurries and the like.
依據本發明的醫藥組成物可以一選自於由下列所構成的群組中的非經腸道途徑(parenteral routes)來投藥：腹膜內注射(intraperitoneal injection)、皮下注射(subcutaneous injection)、表皮內注射(intraepidermal injection)、皮內注射(intradermal injection)、肌肉內注射(intramuscular injection)、靜脈內注射(intravenous injection)、病灶內注射(intralesional injection)、舌下投藥(sublingual administration)以及穿皮投藥(transdermal administration)。The pharmaceutical composition according to the present invention can be administered via a parenteral route selected from the group consisting of: intraperitoneal injection, subcutaneous injection, intraepidermal injection, intradermal injection, intramuscular injection, intravenous injection, intralesional injection, sublingual administration and transdermal administration.
依據本發明的醫藥組成物可包含有一被廣泛地使用於藥物製造技術之醫藥學上可接受的載劑。例如，該醫藥學上可接受的載劑可包含一或多種選自於由下列所構成之群組中的試劑：溶劑(solvent)、乳化劑(emulsifier)、懸浮劑(suspending agent)、分解劑(decomposer)、黏結劑(binding agent)、賦形劑(excipient)、安定劑(stabilizing agent)、螯合劑(chelating agent)、稀釋劑(diluent)、膠凝劑(gelling agent)、防腐劑(preservative)、潤滑劑(lubricant)、吸收延遲劑(absorption delaying agent)、脂質體(liposome)以及類似之物。此外，依據本發明的外用品組成物可進一步包含有一被廣泛地使用於外用品製造技術之可接受的佐劑(acceptable adjuvant)。例如，該可接受的佐劑可包含有一或多種選自於下列的試劑：溶劑、膠凝劑、活性劑、防腐劑、抗氧化劑、遮蔽劑(screening agent)、螯合劑、界面活性劑、染色試劑(coloring agent)、增稠劑(thickening agent)、填料(filler)、香料以及氣味吸收劑。有關這些試劑的選用與數量是落在熟習此項技術之人士的專業素養與例行技術範疇內。The pharmaceutical composition according to the present invention may include a pharmaceutically acceptable carrier widely used in drug manufacturing technology. For example, the pharmaceutically acceptable carrier may include one or more agents selected from the group consisting of a solvent, an emulsifier, a suspending agent, a decomposer, a binding agent, an excipient, a stabilizing agent, a chelating agent, a diluent, a gelling agent, a preservative, a lubricant, an absorption delaying agent, a liposome, and the like. In addition, the topical composition according to the present invention may further include an acceptable adjuvant widely used in topical preparation technology. For example, the acceptable adjuvant may include one or more reagents selected from the following: solvent, gelling agent, active agent, preservative, antioxidant, screening agent, chelating agent, surfactant, coloring agent, thickening agent, filler, fragrance and odor absorbent. The selection and amount of these reagents are within the professional quality and routine technical scope of those familiar with this technology.
依據本發明，該醫藥學上可接受的載劑包含有一選自於由下列所構成之群組中的溶劑：水、生理鹽水(normal saline)、磷酸鹽緩衝生理鹽水(phosphate buffered saline, PBS)、含糖溶液、含有醇的水性溶液(aqueous solution containing alcohol)，及其組合。According to the present invention, the pharmaceutically acceptable carrier comprises a solvent selected from the group consisting of water, normal saline, phosphate buffered saline (PBS), sugar solution, aqueous solution containing alcohol, and combinations thereof.
以適於穿皮投藥之劑型為例，根據本發明所提供之醫藥組成物可呈供直接外用之貼布、乳液、乳霜、凝膠(例如：水凝膠)、膏狀物(例如：分散膏、軟膏)、噴霧劑、或溶液(例如：懸浮液)等形式，但不以此為限。Taking dosage forms suitable for transdermal administration as an example, the pharmaceutical composition provided by the present invention can be in the form of a patch, lotion, cream, gel (e.g., hydrogel), paste (e.g., dispersion paste, ointment), spray, or solution (e.g., suspension) for direct external use, but is not limited thereto.
根據本發明所提供之醫藥組成物係可以一日一次、一日多次、或數日一次等不同投藥頻率施用，端視投予個體之需求、年齡、體重、及健康況狀而異。於根據本發明所提供之醫藥組成物中，可視實際應用需求，調整鞣花丹寧於組成物中的含量比例。此外，該醫藥組成物可視需要另含一或多種其他活性成分(例如：抗失眠藥物)，或者與含該一或多種其他活性成分之藥物併用，以進一步加強該醫藥組成物之功效或增加製劑配方的運用靈活性與調配度，只要該其他活性成分對本發明活性成分(即，鞣花丹寧)之效益沒有不利的影響即可。The pharmaceutical composition provided by the present invention can be administered at different dosing frequencies such as once a day, multiple times a day, or once every few days, depending on the needs, age, weight, and health status of the individual being administered. In the pharmaceutical composition provided by the present invention, the content ratio of ellagitannines in the composition can be adjusted according to the actual application needs. In addition, the pharmaceutical composition can contain one or more other active ingredients (for example, anti-insomnia drugs) as needed, or be used in combination with drugs containing one or more other active ingredients to further enhance the efficacy of the pharmaceutical composition or increase the flexibility and formulation of the formulation, as long as the other active ingredients do not have an adverse effect on the benefits of the active ingredient of the present invention (i.e., ellagitannines).
視需要地，可於根據本發明所提供之醫藥組成物及食品組成物中另含有合宜用量之添加劑，例如：可提高該醫藥組成物或食品組成物於服用時的口適感及視覺感受之調味劑、調色劑、著色劑等，以及可改善該醫藥組成物或食品組成物的穩定性及儲存性之緩衝劑、保存劑、防腐劑、抗菌劑、抗真菌劑等。Optionally, the pharmaceutical composition and food composition provided according to the present invention may contain an appropriate amount of additives, for example, flavoring agents, coloring agents, etc. that can improve the taste and visual experience of the pharmaceutical composition or food composition when taken, and buffering agents, preservatives, antiseptics, antibacterial agents, antifungal agents, etc. that can improve the stability and storage properties of the pharmaceutical composition or food composition.
本發明所提供之食品組成物可以為一食品產品，並以可食用性材料配製成包含但不限於：飲料(beverages)、發酵食品(fermented foods)、烘培產品(bakery products)、保健食品(health foods)、營養補充品(nutritional supplement)以及膳食補充品(dietary supplements)。The food composition provided by the present invention can be a food product, and is prepared with edible materials to include but not limited to: beverages, fermented foods, bakery products, health foods, nutritional supplements and dietary supplements.
依據本發明，該可食性材料係選自於由水(water)、流體乳品(fluid milk products)、牛奶(milk)、濃縮牛奶(concentrated milk)；發酵乳品(fermented milk)，諸如優酪乳(yogurt)、酸乳(sour milk)、冷凍優格(frozen yogurt)、乳桿菌發酵飲料(lactic acid bacteria-fermented beverages)；奶粉(milk powder)；冰淇淋(ice cream)；乳酪(cream cheeses)；乾酪(dry cheeses)；豆奶(soybean milk)；發酵豆奶(fermented soybean milk)；蔬果汁(vegetable-fruit juices)；果汁(juices)；運動飲料(sports drinks)；甜點(confectionery)；果凍(jellies)；糖果(candies)；嬰兒食品(infant formulas)；健康食品(health foods)；動物飼料(animal feeds)；中草藥材(Chinese herbals)；膳食補充品(dietary supplements)所組成之群組。According to the present invention, the edible material is selected from water, fluid milk products, milk, concentrated milk; fermented milk, such as yogurt, sour milk, frozen yogurt, lactic acid bacteria-fermented beverages; milk powder; ice cream; cream cheeses; dry cheeses; soybean milk; fermented soybean milk; vegetable-fruit juices; juices; sports drinks; confectionery; jellies; candies; infant formulas; health food; foods); animal feeds; Chinese herbal medicines; and dietary supplements.
依據本發明，食品產品可被當作食品添加物(food additive)，藉由習知方法於原料製備時添加，或是於食品的製作過程中添加，而與任一種可食性材料配製成供人類與非人類動物攝食的食品產品。According to the present invention, the food product can be used as a food additive, which can be added to the raw materials during preparation or during the food production process by known methods, and can be formulated with any edible material into a food product for human and non-human animals to eat.
根據本發明所提供之飲料、發酵食品、烘培產品、保健食品、營養補充品、及膳食補充品係可以一日一次、一日多次、或數日一次等不同頻率食用，端視投予個體之年齡、體重、及健康狀況而異。亦可針對特定族群之需要，調整根據本發明所提供之飲料、發酵食品、烘培產品、保健食品、營養補充品、及膳食補充品中鞣花丹寧的含量，例如：調整至每日應服用的量。The beverages, fermented foods, baked products, health foods, nutritional supplements, and dietary supplements provided by the present invention can be consumed once a day, multiple times a day, or once every few days, depending on the age, weight, and health condition of the individual. The content of ellagitannins in the beverages, fermented foods, baked products, health foods, nutritional supplements, and dietary supplements provided by the present invention can also be adjusted to meet the needs of a specific group, for example, to a daily dosage.
針對根據本發明所提供之飲料、發酵食品、烘培產品、保健食品、營養補充品、及/或膳食補充品，可於其外包裝上標示建議使用量、特定族群(例如孕婦)的使用標準及條件、或與其他食品或醫藥共同服用的建議事項等，以利使用者在無醫師、藥師或相關執事人員指導下自行服用而無安全疑慮。於根據本發明所提供之食品組成物中，有關鞣花丹寧之態樣以及相關之應用，均如上述之說明。For beverages, fermented foods, baked products, health foods, nutritional supplements, and/or dietary supplements provided according to the present invention, the recommended dosage, the use standards and conditions for specific groups (such as pregnant women), or the recommended matters for taking with other foods or medicines, etc. can be marked on their outer packaging, so that users can take them without the guidance of doctors, pharmacists or related personnel without safety concerns. In the food composition provided according to the present invention, the state of ellagitannin and the related applications are as described above.
依據本發明，外用品可以為藥用化妝品，指那些在合理的醫學判斷的範圍內，適合供用於與一個體的組織接觸而沒有不當的毒性、刺激、過敏反應以及類似之物。According to the present invention, topical preparations may be medicinal cosmetics, which are suitable for use in contact with tissues of a subject without undue toxicity, irritation, allergic reaction, and the like, within the scope of reasonable medical judgment.
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。 實施例 1. 鞣花丹 寧 (corilagin) 在調控色胺酸羥化酶 1 (tryptophan hydroxylase 1, TPH1) 基因、多巴去羧酶 (dopa decarboxylase, DDC) 基因、芳烷基胺 N- 乙醯基轉移酶 (aralkylamine N-acetyltransferase, AANAT) 基因及乙醯血清素 O- 甲基轉移酶 (acetylserotonin O-methyltransferase, ASMT) 基因的表現量上的效用評估 The present invention is further illustrated by the following examples. The examples are provided for illustration only and are not intended to limit the scope of protection of the present invention. The scope of protection of the present invention is as shown in the scope of the attached patent application. Example 1. Evaluation of the efficacy of corilagin in regulating the expression of tryptophan hydroxylase 1 ( TPH1 ) gene, dopa decarboxylase ( DDC ) gene, aralkylamine N -acetyltransferase ( AANAT ) gene and acetylserotonin O -methyltransferase ( ASMT ) gene
本實施例所使用的標準品為鞣花丹寧(corilagin)(Sigma-Aldrich G0424)；所使用的細胞株為SH-SY5Y人類神經母細胞瘤細胞株，購自美國標準培養株保藏中心(American Type Culture Collection, ATCC)。本實施例所使用的細胞培養相關耗材、試劑、其對應廠商及貨號顯示於下表1。
表1
本實施例所使用的定量聚合酶鏈反應(quantitative polymerase chain reaction, qPCR)相關試劑及其對應廠商與貨號顯示於下表2。
表2
本實施例所使用的引子之對應基因及核苷酸序列顯示於下表3。
表3
有關細胞分化的操作流程如下。待SH-SY5Y細胞長到足夠數量後，將細胞以2.5 10 5平均鋪入6-孔培養盤，靜置一天使細胞平貼於培養盤底部後，以含有3% FBS的10 μM視黃酸(Retinoic acid, RA)作為分化試劑，進行6天分化，分化期間每兩天換液一次。 The operation process of cell differentiation is as follows. After SH-SY5Y cells grow to a sufficient number, the cells are cultured at 2.5 10 5 cells were evenly plated in a 6-well culture plate and allowed to rest for one day to allow the cells to adhere to the bottom of the culture plate. Then, 10 μM retinoic acid (RA) containing 3% FBS was used as the differentiation reagent for 6 days. The medium was changed every two days during the differentiation period.
有關RNA萃取的操作流程如下。將SH-SY5Y細胞以上述分化條件分化6天後，分別加入12.5 μM鞣花丹寧培養18小時後，移除培養基，以PBS潤洗，採用商業套組總RNA純化套組萃取RNA。加入350 μl RNA / 2-巰基乙醇(2-mercaptoethanol, 2-ME)溶液，以細胞刮刀刮取並收集細胞液至RNA核酸純化柱(Spin Column)，以13200 rpm離心1分鐘去除濾液，加入500 μl RNA洗滌溶液I (Wash Solution І)，以13200 rpm離心1分鐘去除濾液，加入82 μl DNase I溶液(80 μl DNase І反應緩衝液(Incubation Buffer) + 2 μl DNase І)室溫反應15分鐘後，加入500 μl RNA洗滌溶液I，以13200 rpm離心1分鐘去除濾液，加入RNA洗滌溶液Ⅱ 600 μl，以13200 rpm離心1分鐘去除濾液，重複一次，以空管離心13200 rpm 3分鐘，去除殘留酒精，將RNA核酸純化柱放入新的1.5 ml微量離心管(microcentrifuge tube)，加入30 μl無核酸酶水(Nuclease-free water) 1分鐘後，以13200 rpm離心1分鐘，取得RNA，置於-80℃備用。The operation process of RNA extraction is as follows: SH-SY5Y cells were differentiated for 6 days under the above differentiation conditions, and then 12.5 μM ellagitannin was added and cultured for 18 hours. The culture medium was removed, and the cells were washed with PBS. RNA was extracted using a commercial total RNA purification kit. Add 350 μl RNA / 2-mercaptoethanol (2-ME) solution, scrape and collect the cell fluid with a cell scraper to RNA nucleic acid purification column (Spin Column), centrifuge at 13200 rpm for 1 minute to remove the filter solution, add 500 μl RNA Wash Solution I (Wash Solution І), centrifuge at 13200 rpm for 1 minute to remove the filter solution, add 82 μl DNase I solution (80 μl DNase І reaction buffer (Incubation Buffer) + 2 μl DNase І) and react at room temperature for 15 minutes, then add 500 μl RNA Wash Solution I, centrifuge at 13200 rpm for 1 minute to remove the filter solution, add 600 μl RNA Wash Solution II, centrifuge at 13200 rpm for 1 minute to remove the filter solution, Centrifuge at 13,200 rpm for 1 minute to remove the filtrate, repeat this step, and centrifuge at 13,200 rpm for 3 minutes with an empty tube to remove the residual alcohol. Place the RNA purification column in a new 1.5 ml microcentrifuge tube, add 30 μl of nuclease-free water for 1 minute, and centrifuge at 13,200 rpm for 1 minute to obtain the RNA, which is then stored at -80°C for later use.
有關反轉錄的操作流程如下。利用超微量核酸定量光譜儀將上述取得之RNA定量，再以商業套組iScript™ cDNA合成套組(Synthesis Kit)(Bio-Rad)進行反轉錄。將20 ng RNA加入5x iScript Reaction Mix 4μl、iScript反轉錄酶(Reverse Transcriptase) 1μl及無核酸酶水至總體積20 μl，以下面表4所列條件進行反轉錄。
表4
有關即時PCR (real-time PCR)的反應組分及添加量顯示於下表5，有關加熱程序顯示於下表6。
表5
有關基因相對定量是使用定量-比較Ct (ΔΔCt)法。ΔCt = Ct 樣品或 對照組– Ct GAPDH；ΔΔCt = ΔCt 樣品– ΔCt 對照組；基因表現相對量= 2 -ΔΔCt 平均。 The relative quantification of the relevant genes was performed using the quantitative-comparative Ct (ΔΔCt) method. ΔCt = Ct sample or control group – Ct GAPDH ; ΔΔCt = ΔCt sample – ΔCt control group ; relative gene expression = 2 - ΔΔCt average .
SH-SY5Y細胞經不同濃度之鞣花丹寧處理18小時後，測量TPH1、DDC、AANAT、ASMT基因相對表現量。松果體可透過光週期信息轉化為生成褪黑激素之訊號，將體內的色胺酸(tryptophan)轉換成羥色胺酸(Hydroxytryptophan)、血清素(Serotonin)及N-乙醯血清素(N-acetylserotonin)，最終生成褪黑激素。參與褪黑激素合成路徑的調控基因有 TPH1、 DDC、 AANAT及 ASMT，然而隨著年齡增加或生活壓力影響，可能使褪黑激素合成路徑能力降低，導致血清素或褪黑激素生成量不足，產生憂鬱與晝夜節律失調等和血清素或褪黑激素不足之相關症狀。透過提升 TPH1、 DDC、 AANAT及 ASMT基因表現量，有助體內活化褪黑激素合成路徑，促使血清素或褪黑激素正常分泌，同時減少對藥物的依賴。 After SH-SY5Y cells were treated with different concentrations of ellagitannins for 18 hours, the relative expression of TPH1, DDC, AANAT, and ASMT genes was measured. The pineal gland can convert light cycle information into a signal for the production of melatonin, converting tryptophan in the body into hydroxytryptophan, serotonin, and N-acetylserotonin, ultimately producing melatonin. The regulatory genes involved in the melatonin synthesis pathway include TPH1 , DDC , AANAT and ASMT . However, with age or stress, the melatonin synthesis pathway may be reduced, leading to insufficient serotonin or melatonin production, depression and circadian rhythm disorders, and other symptoms related to serotonin or melatonin deficiency. By increasing the expression of TPH1 , DDC , AANAT and ASMT genes, it helps to activate the melatonin synthesis pathway in the body, promote the normal secretion of serotonin or melatonin, and reduce dependence on drugs.
本實施例的結果顯示於圖1。由圖1可見，鞣花丹寧於12.5 μM能有效提升褪黑激素合成路徑之關鍵基因 TPH1、 DDC、 AANAT及 ASMT基因，具有有效活化褪黑激素合成路徑，幫助體內自主合成血清素與褪黑激素之能力。 The results of this example are shown in Figure 1. As shown in Figure 1, ellagitannin at 12.5 μM can effectively increase the key genes TPH1 , DDC , AANAT and ASMT genes in the melatonin synthesis pathway, and has the ability to effectively activate the melatonin synthesis pathway and help the body to independently synthesize serotonin and melatonin.
綜上所述，本發明鞣花丹寧能有效調控 TPH、 DDC、 AANAT及 ASMT基因的表現量，具有有效活化褪黑激素合成路徑，幫助體內自主合成血清素與褪黑激素之能力，進而改善晝夜節律失調。 In summary, the ellagitannins of the present invention can effectively regulate the expression of TPH , DDC , AANAT and ASMT genes, and have the ability to effectively activate the melatonin synthesis pathway, help the body to independently synthesize serotonin and melatonin, and thus improve diurnal rhythm disorders.
以上所述僅為舉例性，而非為限制性者。任何未脫離本發明之精神與範疇，而對其進行之等效修改或變更，均應包含於後附之申請專利範圍中。The above description is for illustrative purposes only and is not intended to be limiting. Any equivalent modifications or changes made to the invention without departing from the spirit and scope of the invention shall be included in the scope of the attached patent application.
無without
圖1顯示鞣花丹寧具有調控色胺酸羥化酶1 (tryptophan hydroxylase 1, TPH1)基因、多巴去羧酶(dopa decarboxylase, DDC)基因、芳烷基胺N-乙醯基轉移酶(aralkylamine N-acetyltransferase, AANAT)基因及乙醯血清素O-甲基轉移酶(acetylserotonin O-methyltransferase, ASMT)基因的表現量之效用；*表示p ＜0.05；**表示p＜0.01；***表示p＜0.001。 Figure 1 shows that ellagitannins have the effect of regulating the expression of tryptophan hydroxylase 1 ( TPH1 ) gene, dopa decarboxylase ( DDC ) gene, aralkylamine N-acetyltransferase ( AANAT ) gene and acetylserotonin O-methyltransferase ( ASMT ) gene; * indicates p <0.05; ** indicates p <0.01; *** indicates p < 0.001.
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