CN110302196A - Polyphenol oxidase product treats diabetes - Google Patents
Polyphenol oxidase product treats diabetes Download PDFInfo
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- CN110302196A CN110302196A CN201910699611.2A CN201910699611A CN110302196A CN 110302196 A CN110302196 A CN 110302196A CN 201910699611 A CN201910699611 A CN 201910699611A CN 110302196 A CN110302196 A CN 110302196A
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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Abstract
本发明涉及多酚氧化产物及其应用。本发明的目的是更有效利用多酚治疗糖尿病。本发明通过促进多酚氧化，制备多酚氧化产物治疗糖尿病。所述多酚氧化产物中不再含母体多酚，其治疗糖尿病疗效比母体多酚显著增强，其治疗糖尿病的药理包括调节肾素血管紧张素系统，抑制硫氧还蛋白结合蛋白和硒蛋白P。本发明达到提高多酚治疗糖尿病疗效的效果，为治疗糖尿病提供一种新方法。The present invention relates to polyphenol oxidation products and applications thereof. The purpose of the present invention is to more effectively utilize polyphenols for the treatment of diabetes. The invention treats diabetes by promoting the oxidation of polyphenols and preparing the oxidation products of polyphenols. The polyphenol oxidation product no longer contains parent polyphenol, and its therapeutic effect on diabetes is significantly enhanced than that of parent polyphenol, and its pharmacology for treating diabetes includes regulating renin-angiotensin system, inhibiting thioredoxin-binding protein and selenoprotein P . The invention achieves the effect of improving the curative effect of polyphenols in treating diabetes, and provides a new method for treating diabetes.
Description
技术领域technical field
本发明属于生物医药领域，具体地说，涉及多酚氧化产物及其应用。The invention belongs to the field of biomedicine, in particular to a polyphenol oxidation product and its application.
背景技术Background technique
迄今为止，在人类饮食中已发现8000多种多酚化合物，如表没食子儿茶素没食子酸酯(EGCG)，没食子酸(GA)，槲皮素，毛地黄黄酮，绿原酸。多酚含酚羟基，凭此多酚具有抗氧化、抗炎、预防癌症、心血管疾病、神经退行性疾病、肥胖和糖尿病的作用。To date, more than 8,000 polyphenolic compounds have been found in the human diet, such as epigallocatechin gallate (EGCG), gallic acid (GA), quercetin, digitonin, and chlorogenic acid. Polyphenols contain phenolic hydroxyl groups, whereby polyphenols have antioxidant, anti-inflammatory, cancer prevention, cardiovascular disease, neurodegenerative disease, obesity and diabetes effects.
然而，多酚的酚羟基易氧化聚合，形成寡聚体。多酚氧化严重时形成多聚体。母体多酚分子量通常低于2kDa，多聚体分子量可达到100kDa。大量研究说明促进多酚氧化的条件包括但不限于：pH(随pH增加多酚氧化加剧)；温度(随温度增加多酚氧化加剧)；氧化时间(随氧化时间增加多酚氧化加剧)；液态氧(随多酚浓度减少，液态氧相对于多酚更多，多酚氧化加剧)；金属离子如铜、铁。为维持多酚的抗氧化、抗炎和上述的预防作用，本领域技术人员通过各种途径竭力控制多酚氧化。目前发现添加抗坏血酸、微囊包覆等手段可有效防止多酚氧化。本发明通过制备多酚氧化产物治疗糖尿病，获得与本领域技术人员认知相反的效果。However, the phenolic hydroxyl groups of polyphenols are prone to oxidative polymerization to form oligomers. Polymers are formed when polyphenols are severely oxidized. The molecular weight of the parent polyphenol is usually less than 2kDa, and the molecular weight of the polymer can reach 100kDa. A large number of studies have shown that the conditions that promote the oxidation of polyphenols include, but are not limited to: pH (increased oxidation of polyphenols with increasing pH); temperature (intensified oxidation of polyphenols with increasing temperature); oxidation time (increased oxidation of polyphenols with increasing oxidation time); liquid state Oxygen (as the concentration of polyphenols decreases, there is more liquid oxygen relative to polyphenols, and the oxidation of polyphenols is intensified); metal ions such as copper and iron. In order to maintain the antioxidant, anti-inflammatory and above-mentioned preventive effects of polyphenols, those skilled in the art try their best to control the oxidation of polyphenols through various approaches. At present, it has been found that adding ascorbic acid and microcapsule coating can effectively prevent the oxidation of polyphenols. The present invention treats diabetes by preparing polyphenol oxidation products, and obtains the opposite effect to those skilled in the art.
发明内容SUMMARY OF THE INVENTION
本发明的目的是更有效利用多酚治疗糖尿病。The purpose of the present invention is to more effectively utilize polyphenols for the treatment of diabetes.
本发明通过控制pH、温度、氧化时间、多酚浓度使多酚充分氧化，使所制备的多酚氧化产物中不再含有母体多酚。本发明通过动物实验，说明多酚氧化产物具有以下两方面重要性质。1.多酚氧化产物治疗糖尿病疗效高于母体多酚，且随氧化程度增加，治疗糖尿病的疗效有上升趋势。2.多酚氧化产物不同于临床在用的糖尿病治疗药物，有独特药理，即双向调节肾素血管紧张素系统，抑制硫氧还蛋白结合蛋白和硒蛋白P。In the invention, the polyphenol is fully oxidized by controlling pH, temperature, oxidation time and polyphenol concentration, so that the prepared polyphenol oxidation product no longer contains the parent polyphenol. The present invention shows that the polyphenol oxidation product has the following two important properties through animal experiments. 1. The efficacy of polyphenol oxidation products in the treatment of diabetes is higher than that of parent polyphenols, and with the increase of the degree of oxidation, the efficacy of the treatment of diabetes has an upward trend. 2. The oxidation products of polyphenols are different from the clinical treatment drugs for diabetes, and have unique pharmacology, that is, two-way regulation of the renin-angiotensin system, inhibition of thioredoxin-binding protein and selenoprotein P.
本发明不仅达到更有效利用多酚治疗糖尿病的目的，还为糖尿病治疗提供了基于不同药理的治疗途径。The present invention not only achieves the purpose of using polyphenols to treat diabetes more effectively, but also provides different pharmacology-based therapeutic approaches for the treatment of diabetes.
附图说明Description of drawings
图1.制备GA氧化产物(实施例1)。Figure 1. Preparation of GA oxidation products (Example 1).
图2.制备EGCG氧化产物(实施例2)。Figure 2. Preparation of EGCG oxidation product (Example 2).
图3.多酚氧化程度与治疗糖尿病疗效关系(实施例3)。其中，*，p＜0.05；**，p＜0.01；***，p＜0.001，与E0相比。Figure 3. The relationship between the degree of polyphenol oxidation and the therapeutic effect of diabetes (Example 3). Wherein, *, p<0.05; **, p<0.01; ***, p<0.001, compared with E0.
图4.多酚氧化产物调节糖尿病机体肾素血管紧张素系统(实施例4)。其中，**，p＜0.01；***，p＜0.001，与对照相比。Figure 4. Polyphenol oxidation products modulate the renin-angiotensin system in diabetic organisms (Example 4). Wherein, **, p<0.01; ***, p<0.001, compared with control.
图5.多酚氧化产物抑制糖尿病机体硫氧还蛋白结合蛋白和硒蛋白P(实施例5)。其中，*，p＜0.05；**，p＜0.01；***，p＜0.001，与对照相比。Figure 5. Polyphenol oxidation products inhibit diabetic thioredoxin-binding protein and selenoprotein P (Example 5). Wherein, *, p<0.05; **, p<0.01; ***, p<0.001, compared with control.
具体实施方式Detailed ways
以下实施例用于说明本发明，但不用来限制本发明的范围。若未特别指明，实施例中所用的技术手段为本领域技术人员所熟知的常规手段，所用原料均为市售商品。The following examples are intended to illustrate the present invention, but not to limit the scope of the present invention. Unless otherwise specified, the technical means used in the examples are conventional means well known to those skilled in the art, and the raw materials used are all commercially available commodities.
实施例1制备GA氧化产物Example 1 Preparation of GA oxidation product
在1mL pH 8.0、0.2M的磷酸盐缓冲液中加入5mg GA，于37℃保温2h、24h和48h，产物置-80℃冰箱保存。EGCG相应的氧化产物称为G2、G24和G48。为配合此命名，GA称为G0。5 mg GA was added to 1 mL of pH 8.0, 0.2 M phosphate buffer, incubated at 37 °C for 2 h, 24 h and 48 h, and the product was stored in a -80 °C refrigerator. The corresponding oxidation products of EGCG are called G2, G24 and G48. In keeping with this nomenclature, GA is called G0.
图1A显示，随氧化时间延长，GA氧化产物的色泽逐渐加深，说明GA的氧化程度逐渐加深。图1B显示，高效液相色谱中GA的保留时间为3.3分钟。在G2、G24和G48中，GA峰消失，指示G2、G24和G48不再含GA。Figure 1A shows that with the prolongation of oxidation time, the color of GA oxidation products gradually deepens, indicating that the oxidation degree of GA gradually deepens. Figure 1B shows that the retention time of GA in HPLC was 3.3 min. In G2, G24 and G48, the GA peak disappeared, indicating that G2, G24 and G48 no longer contained GA.
实施例2制备EGCG氧化产物Example 2 Preparation of EGCG oxidation product
在1mL pH 8.0、0.2M的磷酸盐缓冲液中加入5mg EGCG，于37℃保温16h和64h，产物置-80℃冰箱保存。EGCG相应的氧化产物称为E16和E64。为配合此命名，EGCG称为E0。5 mg of EGCG was added to 1 mL of pH 8.0, 0.2 M phosphate buffer, incubated at 37 °C for 16 h and 64 h, and the product was stored in a -80 °C refrigerator. The corresponding oxidation products of EGCG are called E16 and E64. In keeping with this nomenclature, EGCG is called E0.
图2A显示，随氧化时间延长，EGCG氧化产物的色泽逐渐加深，说明EGCG的氧化程度逐渐加深。图2B显示，高效液相色谱中EGCG的保留时间为6.8分钟。在E16和E64中，EGCG峰消失，指示E16和E64不再含EGCG。Figure 2A shows that with the prolongation of oxidation time, the color of EGCG oxidation products gradually deepened, indicating that the oxidation degree of EGCG gradually deepened. Figure 2B shows that the retention time of EGCG in HPLC was 6.8 min. In E16 and E64, the EGCG peak disappeared, indicating that E16 and E64 no longer contained EGCG.
实施例3多酚氧化程度与治疗糖尿病疗效关系Example 3 The relationship between the degree of oxidation of polyphenols and the curative effect of treating diabetes
实验动物：2型糖尿病db/db鼠，体重35-40g。干预方案：25只、8周龄鼠，按血糖随机分为4组，即对照组、E0组、E16组和E64组，每组6-7只。对照组每天腹腔注射PBS(0.2M，pH8.0)，E0、E16和E64组每天按10mg/kg腹腔注射，共三周。Experimental animals: Type 2 diabetic db/db mice, weighing 35-40 g. Intervention scheme: 25, 8-week-old mice were randomly divided into 4 groups according to blood sugar, namely control group, E0 group, E16 group and E64 group, with 6-7 mice in each group. The control group was intraperitoneally injected with PBS (0.2M, pH8.0) every day, and the E0, E16 and E64 groups were intraperitoneally injected at 10 mg/kg every day for three weeks.
实验结果与结论：db/db糖尿病鼠具有糖尿病典型症状，即大量饮水(烦渴)、多尿和高血糖。图3显示，同等剂量下，E0对这些症状几乎无效，而E64有强效，E16效应介于E0和E64两者之间，说明多酚氧化程度越高，治疗糖尿病疗效越好。Experimental results and conclusions: db/db diabetic mice have typical symptoms of diabetes, namely drinking a lot of water (polydipsia), polyuria and hyperglycemia. Figure 3 shows that at the same dose, E0 is almost ineffective for these symptoms, while E64 has a strong effect, and the effect of E16 is between E0 and E64, indicating that the higher the degree of polyphenol oxidation, the better the therapeutic effect of diabetes.
实施例4多酚氧化产物调节糖尿病机体肾素血管紧张素系统Example 4 Polyphenol oxidation products regulate the renin-angiotensin system of diabetic body
实验动物：db/db鼠，体重35-40g。干预方案：12只、8周龄鼠，按血糖随机分为2组，对照组和E64组，每组6只。db/db组每天腹腔注射PBS(0.2M，pH 8.0)，E64组每天腹腔注射5mg/kg E64。干预3周后结束实验，收集肝脏、肾脏组织，使用Westernblot方法检测蛋白表达。Experimental animals: db/db mice, weighing 35-40 g. Intervention scheme: 12, 8-week-old mice were randomly divided into 2 groups according to blood glucose, the control group and the E64 group, with 6 mice in each group. The db/db group was intraperitoneally injected with PBS (0.2M, pH 8.0) every day, and the E64 group was intraperitoneally injected with 5 mg/kg E64 every day. The experiment was terminated after 3 weeks of intervention, liver and kidney tissues were collected, and protein expression was detected by Western blot.
实验结果与结论：肾素血管紧张素系统参与控制血糖，该复杂而精细系统含有益轴与有害轴。当前用于糖尿病治疗的药物(如血管紧张素转换酶抑制剂，血管紧张素受体阻滞剂，肾素抑制剂)的药理是下调有害轴，并不上调有益轴。图4A显示，E64可显著增加肝脏血管紧张素转换酶2(ACE2)和血管紧张素II二型受体(AT2R)，说明多酚氧化产物可上调肾素血管紧张素系统有益轴。图4B显示，E64可显著降低肾脏血管紧张素转换酶(ACE)和血管紧张素II(Ang II)，说明多酚氧化产物可下调肾素血管紧张素系统有害轴。这些结果显示多酚氧化产物不仅调节肾素血管紧张素系统，还具有罕见的双向调节作用，即上调有益轴和下调有害轴。Experimental results and conclusions: The renin-angiotensin system is involved in the control of blood sugar. This complex and delicate system contains beneficial and harmful axes. The pharmacology of drugs currently used in the treatment of diabetes (eg, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, renin inhibitors) is to downregulate the harmful axis and not upregulate the beneficial axis. Figure 4A shows that E64 significantly increases hepatic angiotensin-converting enzyme 2 (ACE2) and angiotensin II type 2 receptor (AT2R), suggesting that polyphenol oxidation products can upregulate the beneficial axis of the renin-angiotensin system. Figure 4B shows that E64 significantly reduces renal angiotensin-converting enzyme (ACE) and angiotensin II (Ang II), suggesting that polyphenol oxidation products can downregulate the detrimental axis of the renin-angiotensin system. These results show that polyphenol oxidation products not only modulate the renin-angiotensin system, but also have a rare bidirectional regulatory effect, namely up-regulation of beneficial axis and down-regulation of detrimental axis.
实施例5多酚氧化产物抑制糖尿病机体硫氧还蛋白结合蛋白和硒蛋白PExample 5 Inhibition of thioredoxin-binding protein and selenoprotein P by polyphenol oxidation products in diabetic organisms
实验动物：db/db鼠，体重35-40g。干预方案：18只、8周龄鼠，按血糖随机分为3组，db/db组、E64低和高剂量组，每组6只。db/db组每天腹腔注射PBS(0.2M，pH8.0)，E64低剂量组(E64-5)每天腹腔注射5mg/kg E64，E64高剂量组(E64-10)每天腹腔注射10mg/kg E64。干预3周后结束实验，收集肝脏、肾脏组织，使用Western blot方法检测蛋白表达。Experimental animals: db/db mice, weighing 35-40 g. Intervention scheme: 18, 8-week-old mice were randomly divided into 3 groups according to blood glucose, db/db group, E64 low-dose and high-dose groups, with 6 mice in each group. The db/db group was intraperitoneally injected with PBS (0.2M, pH8.0) every day, the E64 low-dose group (E64-5) was intraperitoneally injected with 5 mg/kg E64 per day, and the E64 high-dose group (E64-10) was intraperitoneally injected with 10 mg/kg E64 per day . The experiment was terminated after 3 weeks of intervention, and the liver and kidney tissues were collected, and the protein expression was detected by Western blot.
实验结果与结论：硫氧还蛋白结合蛋白和硒蛋白P是治疗糖尿病新抑制靶点，迄今尚无针对这些新抑制靶点的治疗药物。图5A和B显示，E64剂量依赖地抑制糖尿病鼠肝脏和肾脏硫氧还蛋白结合蛋白(Txnip)和硒蛋白P(SeP)。Experimental results and conclusions: Thioredoxin-binding protein and selenoprotein P are new inhibitory targets for the treatment of diabetes, and so far there are no therapeutic drugs against these new inhibitory targets. Figures 5A and B show that E64 dose-dependently inhibits thioredoxin-binding protein (Txnip) and selenoprotein P (SeP) in liver and kidney of diabetic mice.
实施例4与5的药理结果说明，多酚氧化产物治疗糖尿病具有独特的药理，即双向调节肾素血管紧张素系统，抑制硫氧还蛋白结合蛋白和硒蛋白P。The pharmacological results of Examples 4 and 5 show that the polyphenol oxidation product has a unique pharmacology in the treatment of diabetes, that is, bidirectional regulation of the renin-angiotensin system and inhibition of thioredoxin-binding protein and selenoprotein P.
上文用一般性说明及具体实施方案对本发明作了详尽的描述，但在本发明基础上，可以对之做一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。The present invention has been described in detail above with general description and specific embodiments, but on the basis of the present invention, some modifications or improvements can be made, which will be obvious to those skilled in the art. Therefore, these modifications or improvements made without departing from the spirit of the present invention fall within the scope of the claimed protection of the present invention.
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