WO2023273558A1 - Use of exocarpium citri grandis productive cough extract in preparation of drug for inhibiting human coronavirus infection - Google Patents
Use of exocarpium citri grandis productive cough extract in preparation of drug for inhibiting human coronavirus infection Download PDFInfo
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- WO2023273558A1 WO2023273558A1 PCT/CN2022/088811 CN2022088811W WO2023273558A1 WO 2023273558 A1 WO2023273558 A1 WO 2023273558A1 CN 2022088811 W CN2022088811 W CN 2022088811W WO 2023273558 A1 WO2023273558 A1 WO 2023273558A1
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Definitions
- the invention belongs to the technical field of medicine and relates to a new application of medicine, in particular to the application of Juhongtanke extract in the preparation of medicines for inhibiting human coronavirus infection.
- Coronavirus belongs to the order Coronaviridae, Coronaviridae, and the genus Coronaviridae. It is an enveloped positive-sense single-stranded RNA virus with a diameter of 80-120nm and about 30,000 bases. Its genetic material is Largest known RNA virus.
- the coronavirus consists of a nucleocapsid protein (N protein), a spike glycoprotein (S protein) at the receptor binding site, a small envelope glycoprotein (E protein), a membrane glycoprotein (M protein) responsible for transporting nutrients, Hemagglutinin glycoprotein (HE protein) and ribonucleic acid (RNA) composition.
- the International Virus Classification and Nomenclature Committee classified coronaviruses into four groups ⁇ , ⁇ , ⁇ , and ⁇ according to their genetic differences and serological characteristics, and the ⁇ group coronaviruses were further divided into four groups: A, B, C, and D. Group.
- the ⁇ and ⁇ groups are susceptible to mammals, including 7 coronaviruses that are pathogenic to humans, namely HCoV-OC43, HCoV-229E, SARS-CoV, HCoV-NL63, HCoV-HKU1, MERS-CoV and SARS- CoV-2; while the gamma and delta groups mainly infect poultry.
- Coronavirus is highly contagious and pathogenic. For the treatment of patients with coronavirus infection, the mechanism is still unclear and the treatment is difficult. No specific medicine has been developed yet. The existing treatment options are mainly symptomatic and supportive treatment. Difficult to achieve ideal therapeutic effect. In addition, since coronavirus is an RNA virus, the corresponding mismatch repair mechanism is imperfect and prone to mutation. Therefore, the development of new coronavirus drugs has great sociological and economic significance.
- CN111671742A discloses the application of sodium valproate in the preparation of medicines for the treatment of pneumonia caused by human coronavirus infection.
- This invention discloses that sodium valproate has a protective effect on cells infected by coronavirus xCOV and novel coronavirus SARS-CoV-2;
- Sodium valproate can significantly reduce the lung index of the mouse model of human coronavirus 229E pneumonia.
- the lung index of the mice in the high, medium and low dose groups of sodium valproate was significantly reduced, and there was a significant difference compared with the model control group, and the inhibition rates were respectively 45.17%, 45.71%, 40.99%.
- Sodium valproate can also significantly reduce the viral load in the lung tissue of mice, and there is a significant difference between the middle dose group and the model control group.
- Sodium valproate can significantly increase the percentage levels of CD4 + T lymphocytes and CD8 + T lymphocytes in virus-infected mice, and significantly reduce the contents of IL-2, IL-10, TNF- ⁇ , and IFN- ⁇ in the lung tissue of mice , significantly improved the lung inflammatory response; sodium valproate treatment could improve the lung inflammation and reduce the blood MIP1 ⁇ level in the LPS-induced respiratory distress mouse model.
- the above studies show that sodium valproate plays an important preventive and/or therapeutic role in primary and/or secondary lung infection diseases and/or respiratory distress caused by respiratory viruses, especially novel coronavirus infections.
- CN111544442A discloses the new use of rutin as a broad-spectrum inhibitor of coronavirus, wherein, rutin can be used as a broad-spectrum inhibitor of coronavirus for various coronavirus infections: such as Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome Syndrome (MERS) and the common cold caused by human coronavirus OC43 (HCoV-OC43).
- SARS Severe Acute Respiratory Syndrome
- MERS Middle East Respiratory Syndrome Syndrome
- HoV-OC43 human coronavirus OC43
- rutin can be used as an inhibitor of 2019 novel coronavirus 2019-nCov (COVID-19) for the prevention and treatment of 2019 novel coronavirus infection.
- Rutin can bind to the spike protein S1 of the 2019 novel coronavirus, the main protease of the coronavirus (3CLpro), and the papain-like protease (PLP), which can not only block the virus from entering the cell, but also inhibit the replication of the virus.
- CLpro main protease of the coronavirus
- PBP papain-like protease
- Juhong Tanke Recipe is composed of 8 herbs including Huajuhong, Baibu, Poria, and Shui Pinxia (made), which have the functions of clearing the lungs and reducing phlegm, regulating qi and relieving cough. Liquid, Juhong Tanke Syrup, Juhong Tanke Granules and other dosage forms.
- Zhou Huajun found that the extract of Juhong Tanke Granules could significantly inhibit the swelling of mouse auricles caused by xylene and the swelling of rat paws caused by egg whites, and also inhibit the formation of cotton ball granuloma in rats, indicating that Juhong Tanke granule extract has anti-inflammatory effect (Chinese Modern Medicine Application, Volume 5, Issue 10, May 2011). However, the prevention and treatment effect of Juhong Tanke Recipe on human coronavirus infection has not been reported before.
- the present invention provides the use of Juhongtanke extract in the preparation of drugs for inhibiting human coronavirus infection.
- the research of the present invention shows that Juhongtanke extract can inhibit human coronavirus-induced inflammatory factors TNF- ⁇ , IL- 6.
- TNF- ⁇ IL-8
- IFN- ⁇ The mRNA of IL-8 and IFN- ⁇ is overexpressed, thereby inhibiting human coronavirus.
- the invention provides the use of Juhongtanke extract in the preparation of a medicament for inhibiting human coronavirus infection.
- the orange red phlegm and cough extract includes Huajuhong, Mibabu, Poria cocos, Shui Pinellia (made), Baiqian, licorice, bitter almond and Schisandra chinensis.
- the preparation method of the orange-red phlegm and cough extract is conventional technical means, preferably, the preparation method of the orange-red phlegm and cough extract is as follows: steam distilling Huajuhong and bitter almonds, and collecting the distillate; Mix the dregs with Mibabu, Poria, Pinellia (made), Baiqian, Licorice and Schisandra, add water to decoct at least once, and filter; combine the filtrate and distillate, after concentration, add ethanol to make the alcohol content up to 75-80wt%, let it stand, take the supernatant, and concentrate to obtain the orange red phlegm and cough extract.
- the medicine includes Juhongtanke extract and a pharmaceutically acceptable carrier, wherein the dosage form of the medicine is oral preparation and/or injection preparation.
- the inhibition includes inhibiting the expression of human coronavirus-induced inflammatory factors.
- Juhongtanke extract was verified by infecting HuH-7 cells with HCoV-229E virus.
- the present invention specifically provides the use of Juhongtanke extract in the preparation of medicines for inhibiting human coronavirus HCoV-229E infection.
- the suppression described in the present invention includes suppressing the mRNA expression of inflammatory factors induced by human coronavirus HCoV-229E.
- the inflammatory factors include TNF- ⁇ , IL-6, IL-8 and IFN- ⁇ .
- the Juhongtanke extract of the present invention has an inhibitory effect on human coronavirus (HCoV-229E) infecting Huh-7 cells in vitro (selection index SI is 10.50); meanwhile, it can inhibit human coronavirus (HCoV-229E) in vitro ( HCoV-229E) induces the mRNA overexpression of inflammatory factors TNF- ⁇ , IL-6, IL-8 and IFN- ⁇ in a dose-dependent manner.
- Figure 1 shows the cytotoxicity test results of Juhongtanke extract.
- Fig. 2 is the test result of the drug efficacy of Juhong Tanke extract against human coronavirus HCoV-229E.
- Figure 3 shows the medicinal effect of Juhong Tanke extract on human coronavirus HCoV-229E inflammatory factor TNF- ⁇ .
- Figure 4 shows the medicinal effect of Juhongtanke extract on human coronavirus HCoV-229E inflammatory factor IL-6.
- Figure 5 shows the medicinal effect of Juhongtanke extract on human coronavirus HCoV-229E inflammatory factor IL-8.
- Figure 6 shows the medicinal effect of Juhong Tanke extract on human coronavirus HCoV-229E inflammatory factor IFN- ⁇ .
- the present invention provides the use of Juhongtanke extract in the preparation of medicines for inhibiting human coronavirus infection.
- Those skilled in the art can learn from the content of this article and appropriately improve the process parameters to realize it.
- all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.
- the method and application of the present invention have been described through preferred embodiments, and relevant personnel can obviously make changes or appropriate changes and combinations to the method and application herein without departing from the content, spirit and scope of the present invention to realize and apply the present invention Invent technology.
- the reagents used in the present invention are all common commercial products and can be purchased in the market.
- Juhong Tanke extract is provided by Guangzhou Baiyunshan Xingqun (Pharmaceutical) Co., Ltd. (batch number B200501).
- the Juhong Tanke extract includes the following raw materials: Huajuhong, Mibabu, Poria cocos, Shui Pinellia (system), Baiqian, licorice, almond and schisandra; preferably the orange red phlegm and cough extract, including the following raw materials in parts by weight: 200-300 parts of Huajuhong, 2-30 parts of Mibabu, 20-30 parts of Poria cocos , Shui Pinellia (system) 20-30 parts, Baiqian 40-50 parts, licorice 1-10 parts, almond 80-100 parts and Schisandra 10-20 parts.
- the preparation method of the orange-red phlegm and cough extract is as follows: distill the orange-red and bitter almonds with water vapor, and collect the distillate; mix the dregs with Mibabu, Poria cocos, Shui Pinellia (manufactured), Baiqian, licorice and Schisandra chinensis Mix, respectively add (the total weight of the dregs and honey baebu, Poria cocos, Shui Pinellia (made), Baiqian, licorice and Schisandra chinensis) 6-8 times the amount of water, 4-6 times the amount of water to decoct twice, filter After that, combine the filtrate and distillate, concentrate to a relative density of 1.05-1.25 (80°C), add ethanol to make the alcohol content reach 75-80%, let it stand for 18-24 hours, take the supernatant, and concentrate to a relative density 1.05-1.25 (80°C), the orange red phlegm and cough extract is obtained.
- HuH-7 cells were purchased from the Virus Laboratory of the State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Health.
- Embodiment 1 cytotoxicity test (MTT method)
- Test drugs as shown in Table 1;
- Inhibition rate (average OD value of normal group-average OD value of drug group)/(average OD value of normal group-average OD value of blank group) ⁇ 100%.
- the median toxic concentration (TC 50 ) of the drug was calculated by the Reed-Meunch method.
- Embodiment 2 test drug antiviral experiment
- CPE cytopathic changes
- Test drugs as shown in Table 3.
- Huh-7 cells were inoculated into 6-well plates and divided into normal group, virus group and drug efficacy group. After the cells grow to a monolayer, the culture medium is discarded, washed once with PBS, the virus group and the drug effect group are inoculated with 1000 human coronaviruses (HCoV-229E) with TCID 50 , and the normal group and the drug control group are added with 2% serum for culture. base, adsorbed at 37°C for 1 hour.
- HCV-229E human coronaviruses
- Judgment criteria for antiviral efficacy results: selection index Judging efficacy criteria, SI>1 means effective, the greater the selection index, the better the antiviral effect.
- cytokine mRNA was detected by RT-qPCR, analyzed and calculated by GraphPad Prism8.0, and the results are shown in Figure 3-6.
- Juhongtanke extract has an inhibitory effect on the cytopathic effect of Huh-7 cells infected by human coronavirus (HCoV-229E) in vitro (selection index SI is 10.50); it can inhibit human coronavirus (HCoV-229E) in vitro ( HCoV-229E) induces the mRNA overexpression of inflammatory factors TNF- ⁇ , IL-6, IL-8 and IFN- ⁇ in a dose-dependent manner.
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Abstract
An Exocarpium citri grandis productive cough extract and a use thereof. The Exocarpium citri grandis productive cough extract is prepared from Exocarpium citri grandis, Sessile stemona root, Poria cocos, Rhizoma typhonii flagelliformis, Cynanchum glaucescens, Glycyrrhiza uralensis, Bitter apricot seed, and Schisandra chinensis. The Exocarpium citri grandis productive cough extract can inhibit over-expression of mRNA of human coronavirus-induced inflammatory factors TNF-a, IL-6, IL-8, and IFN-a, thereby inhibiting human coronavirus.
Description
本发明属于医药技术领域，涉及了一种药物新用途，具体涉及一种橘红痰咳浸膏在制备抑制人冠状病毒感染的药物中的用途。The invention belongs to the technical field of medicine and relates to a new application of medicine, in particular to the application of Juhongtanke extract in the preparation of medicines for inhibiting human coronavirus infection.
冠状病毒(CoV)属套氏病毒目，冠状病毒科，冠状病毒属，为有包膜的正股单链RNA病毒，直径为80-120nm，约有3万个碱基组成，其遗传物质是已知RNA病毒中最大的。冠状病毒由核衣壳蛋白(N蛋白)、受体结合位点的刺突糖蛋白(S蛋白)、小包膜糖蛋白(E蛋白)、负责运输营养物质的膜糖蛋白(M蛋白)、血凝素糖蛋白(HE蛋白)及核糖核酸(RNA)构成。国际病毒分类命名委员会在2012年根据其遗传学差异和血清学特性将冠状病毒分为α、β、γ、δ四群，其中β群冠状病毒又进一步分为A、B、C、D四个组。α、β两群易感染哺乳动物，包含了7种对人类致病的冠状病毒，分别为HCoV-OC43、HCoV-229E、SARS-CoV、HCoV-NL63、HCoV-HKU1、MERS-CoV和SARS-CoV-2；而γ、δ两群则主要感染禽类。Coronavirus (CoV) belongs to the order Coronaviridae, Coronaviridae, and the genus Coronaviridae. It is an enveloped positive-sense single-stranded RNA virus with a diameter of 80-120nm and about 30,000 bases. Its genetic material is Largest known RNA virus. The coronavirus consists of a nucleocapsid protein (N protein), a spike glycoprotein (S protein) at the receptor binding site, a small envelope glycoprotein (E protein), a membrane glycoprotein (M protein) responsible for transporting nutrients, Hemagglutinin glycoprotein (HE protein) and ribonucleic acid (RNA) composition. In 2012, the International Virus Classification and Nomenclature Committee classified coronaviruses into four groups α, β, γ, and δ according to their genetic differences and serological characteristics, and the β group coronaviruses were further divided into four groups: A, B, C, and D. Group. The α and β groups are susceptible to mammals, including 7 coronaviruses that are pathogenic to humans, namely HCoV-OC43, HCoV-229E, SARS-CoV, HCoV-NL63, HCoV-HKU1, MERS-CoV and SARS- CoV-2; while the gamma and delta groups mainly infect poultry.
冠状病毒具有较强的传染性和致病性，对于冠状病毒感染患者的治疗，机制尚不明确，治疗难度大，目前尚未研制出特效药，现有的治疗方案以对症和支持治疗为主，难以取得理想的治疗效果。此外，由于冠状病毒是一种RNA病毒，相应的错配修复机制不完善，易发生变异。因此，新冠病毒的药物研发具有重大的社会学和经济学意义。Coronavirus is highly contagious and pathogenic. For the treatment of patients with coronavirus infection, the mechanism is still unclear and the treatment is difficult. No specific medicine has been developed yet. The existing treatment options are mainly symptomatic and supportive treatment. Difficult to achieve ideal therapeutic effect. In addition, since coronavirus is an RNA virus, the corresponding mismatch repair mechanism is imperfect and prone to mutation. Therefore, the development of new coronavirus drugs has great sociological and economic significance.
如CN111671742A公开了丙戊酸钠在制备人冠状病毒感染肺炎治疗药物中的应用，该发明公开了丙戊酸钠对冠状病毒xCOV和新型冠状病毒SARS-CoV-2感染的细胞具有保护作用；丙戊酸钠能够显著降低人冠状病毒229E肺炎小鼠模型肺指数，其中，丙戊酸钠高、中、低剂量组小鼠肺指数显著降低，与模型对照组比较有显著性差异，抑制率分别为45.17％、45.71％、40.99％。丙戊酸钠还能显著降低小鼠肺组织病毒载量，其中中剂量组与模型对照组比较有显著性差异。丙戊酸钠能够显著升高病毒感染小鼠的CD4
+T淋巴细胞、CD8
+T淋巴细胞百分比水平，明显降低小鼠肺组织中IL-2、IL-10、TNF-α、IFN-β含量，显著改善肺部炎症反应；丙戊酸钠治疗能改善LPS诱导的呼吸窘迫小鼠模型的肺部炎症，降低血液MIP1α水平。以上 研究显示，丙戊酸钠在呼吸道病毒尤其是新型冠状病毒感染导致的原发性和/或继发性肺部感染疾病和/或呼吸窘迫中发挥重要的预防和/或治疗作用。CN111544442A公开了芦丁作为冠状病毒广谱抑制剂的新用途，其中，芦丁可以作为冠状病毒的广谱抑制剂用于各种冠状病毒感染：例如严重急性呼吸综合症(SARS)，中东呼吸综合症(MERS)以及人冠状病毒OC43(HCoV-OC43)引发的普通感冒。尤其芦丁可以作为2019新型冠状病毒2019-nCov(COVID-19)的抑制剂，用于预防及治疗2019新型冠状病毒感染。芦丁可以结合2019新型冠状病毒的刺突蛋白S1以及冠状病毒主蛋白酶(3CLpro)、木瓜蛋白酶样蛋白酶(PLP)，既能够阻断病毒进入细胞，又能够抑制病毒复制，是罕见的新冠病毒的三靶点抑制剂。
For example, CN111671742A discloses the application of sodium valproate in the preparation of medicines for the treatment of pneumonia caused by human coronavirus infection. This invention discloses that sodium valproate has a protective effect on cells infected by coronavirus xCOV and novel coronavirus SARS-CoV-2; Sodium valproate can significantly reduce the lung index of the mouse model of human coronavirus 229E pneumonia. Among them, the lung index of the mice in the high, medium and low dose groups of sodium valproate was significantly reduced, and there was a significant difference compared with the model control group, and the inhibition rates were respectively 45.17%, 45.71%, 40.99%. Sodium valproate can also significantly reduce the viral load in the lung tissue of mice, and there is a significant difference between the middle dose group and the model control group. Sodium valproate can significantly increase the percentage levels of CD4 + T lymphocytes and CD8 + T lymphocytes in virus-infected mice, and significantly reduce the contents of IL-2, IL-10, TNF-α, and IFN-β in the lung tissue of mice , significantly improved the lung inflammatory response; sodium valproate treatment could improve the lung inflammation and reduce the blood MIP1α level in the LPS-induced respiratory distress mouse model. The above studies show that sodium valproate plays an important preventive and/or therapeutic role in primary and/or secondary lung infection diseases and/or respiratory distress caused by respiratory viruses, especially novel coronavirus infections. CN111544442A discloses the new use of rutin as a broad-spectrum inhibitor of coronavirus, wherein, rutin can be used as a broad-spectrum inhibitor of coronavirus for various coronavirus infections: such as Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome Syndrome (MERS) and the common cold caused by human coronavirus OC43 (HCoV-OC43). In particular, rutin can be used as an inhibitor of 2019 novel coronavirus 2019-nCov (COVID-19) for the prevention and treatment of 2019 novel coronavirus infection. Rutin can bind to the spike protein S1 of the 2019 novel coronavirus, the main protease of the coronavirus (3CLpro), and the papain-like protease (PLP), which can not only block the virus from entering the cell, but also inhibit the replication of the virus. Triple target inhibitors.
橘红痰咳方由化橘红、百部、茯苓、水半夏(制)等8味药组成，具有宣肺化痰、理气止咳之功能，目前市售药品有橘红痰咳煎膏、橘红痰咳液、橘红痰咳糖浆、橘红痰咳颗粒等多种剂型。2011年，周华俊发现橘红痰咳颗粒提取物能明显抑制二甲苯所致的小鼠耳廓肿胀和鸡蛋清所致的大鼠足跖肿胀，也能抑制大鼠棉球肉芽肿的形成，表明橘红痰咳颗粒提取物具有抗炎作用(中国现代药物应用，2011年5月第5卷第10期)。而橘红痰咳方对于人冠状病毒感染的防治作用此前并未见相关报道。Juhong Tanke Recipe is composed of 8 herbs including Huajuhong, Baibu, Poria, and Shui Pinxia (made), which have the functions of clearing the lungs and reducing phlegm, regulating qi and relieving cough. Liquid, Juhong Tanke Syrup, Juhong Tanke Granules and other dosage forms. In 2011, Zhou Huajun found that the extract of Juhong Tanke Granules could significantly inhibit the swelling of mouse auricles caused by xylene and the swelling of rat paws caused by egg whites, and also inhibit the formation of cotton ball granuloma in rats, indicating that Juhong Tanke granule extract has anti-inflammatory effect (Chinese Modern Medicine Application, Volume 5, Issue 10, May 2011). However, the prevention and treatment effect of Juhong Tanke Recipe on human coronavirus infection has not been reported before.
发明内容Contents of the invention
有鉴于此，本发明提供了橘红痰咳浸膏在制备抑制人冠状病毒感染的药物中的用途，本发明研究表明，橘红痰咳浸膏能抑制人冠状病毒诱导炎症因子TNF-α、IL-6、IL-8和IFN-α的mRNA过度表达，从而抑制人冠状病毒。In view of this, the present invention provides the use of Juhongtanke extract in the preparation of drugs for inhibiting human coronavirus infection. The research of the present invention shows that Juhongtanke extract can inhibit human coronavirus-induced inflammatory factors TNF-α, IL- 6. The mRNA of IL-8 and IFN-α is overexpressed, thereby inhibiting human coronavirus.
本发明提供了橘红痰咳浸膏在制备抑制人冠状病毒感染的药物中的用途。The invention provides the use of Juhongtanke extract in the preparation of a medicament for inhibiting human coronavirus infection.
本发明中，所述橘红痰咳浸膏，包括化橘红、蜜百部、茯苓、水半夏(制)、白前、甘草、苦杏仁和五味子。In the present invention, the orange red phlegm and cough extract includes Huajuhong, Mibabu, Poria cocos, Shui Pinellia (made), Baiqian, licorice, bitter almond and Schisandra chinensis.
本发明中，所述橘红痰咳浸膏的制备方法为常规技术手段，优选地，所述橘红痰咳浸膏的制备方法为：将化橘红和苦杏仁用水蒸气蒸馏，收集馏出液；将药渣与蜜百部、茯苓、水半夏(制)、白前、甘草和五味子混合，加水煎煮至少一次，滤过；合并滤液及馏出液，浓缩后，加入乙醇，使含醇量达75-80wt％，静置，取上清液，浓缩，即得所述橘红痰咳浸膏。In the present invention, the preparation method of the orange-red phlegm and cough extract is conventional technical means, preferably, the preparation method of the orange-red phlegm and cough extract is as follows: steam distilling Huajuhong and bitter almonds, and collecting the distillate; Mix the dregs with Mibabu, Poria, Pinellia (made), Baiqian, Licorice and Schisandra, add water to decoct at least once, and filter; combine the filtrate and distillate, after concentration, add ethanol to make the alcohol content up to 75-80wt%, let it stand, take the supernatant, and concentrate to obtain the orange red phlegm and cough extract.
本发明中，所述药物包括橘红痰咳浸膏和制药学上可接受的载体，其中，所述药物的剂型为口服制剂和/或注射制剂。In the present invention, the medicine includes Juhongtanke extract and a pharmaceutically acceptable carrier, wherein the dosage form of the medicine is oral preparation and/or injection preparation.
本发明中，所述抑制包括抑制人冠状病毒诱导炎症因子的表达。In the present invention, the inhibition includes inhibiting the expression of human coronavirus-induced inflammatory factors.
本发明实施例中，以HCoV-229E病毒浸染HuH-7细胞对橘红痰咳浸膏的功能进行验证。In the embodiment of the present invention, the function of Juhongtanke extract was verified by infecting HuH-7 cells with HCoV-229E virus.
因此，本发明具体提供了橘红痰咳浸膏在制备抑制人冠状病毒HCoV-229E感染的药物中的用途。Therefore, the present invention specifically provides the use of Juhongtanke extract in the preparation of medicines for inhibiting human coronavirus HCoV-229E infection.
本发明所述的抑制包括抑制人冠状病毒HCoV-229E诱导炎症因子的mRNA表达。The suppression described in the present invention includes suppressing the mRNA expression of inflammatory factors induced by human coronavirus HCoV-229E.
其中，所述炎症因子包括TNF-α、IL-6、IL-8和IFN-α。Wherein, the inflammatory factors include TNF-α, IL-6, IL-8 and IFN-α.
本发明的有益效果为：The beneficial effects of the present invention are:
实验证明，本发明的橘红痰咳浸膏在体外对人冠状病毒(HCoV-229E)感染Huh-7细胞致细胞病变具有抑制作用(选择指数SI为10.50)；同时，体外能抑制人冠状病毒(HCoV-229E)诱导炎症因子TNF-α、IL-6、IL-8和IFN-α的mRNA过度表达，具剂量依赖关系。Experiments have shown that the Juhongtanke extract of the present invention has an inhibitory effect on human coronavirus (HCoV-229E) infecting Huh-7 cells in vitro (selection index SI is 10.50); meanwhile, it can inhibit human coronavirus (HCoV-229E) in vitro ( HCoV-229E) induces the mRNA overexpression of inflammatory factors TNF-α, IL-6, IL-8 and IFN-α in a dose-dependent manner.
图1为橘红痰咳浸膏对细胞毒性检测结果。Figure 1 shows the cytotoxicity test results of Juhongtanke extract.
图2为橘红痰咳浸膏对人冠状病毒HCoV-229E药效检测结果。Fig. 2 is the test result of the drug efficacy of Juhong Tanke extract against human coronavirus HCoV-229E.
图3为橘红痰咳浸膏对人冠状病毒HCoV-229E炎症因子TNF-α药效。Figure 3 shows the medicinal effect of Juhong Tanke extract on human coronavirus HCoV-229E inflammatory factor TNF-α.
图4为橘红痰咳浸膏对人冠状病毒HCoV-229E炎症因子IL-6药效。Figure 4 shows the medicinal effect of Juhongtanke extract on human coronavirus HCoV-229E inflammatory factor IL-6.
图5为橘红痰咳浸膏对人冠状病毒HCoV-229E炎症因子IL-8药效。Figure 5 shows the medicinal effect of Juhongtanke extract on human coronavirus HCoV-229E inflammatory factor IL-8.
图6为橘红痰咳浸膏对人冠状病毒HCoV-229E炎症因子IFN-α药效。Figure 6 shows the medicinal effect of Juhong Tanke extract on human coronavirus HCoV-229E inflammatory factor IFN-α.
本发明提供了橘红痰咳浸膏在制备抑制人冠状病毒感染的药物中的用途，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。The present invention provides the use of Juhongtanke extract in the preparation of medicines for inhibiting human coronavirus infection. Those skilled in the art can learn from the content of this article and appropriately improve the process parameters to realize it. In particular, it should be pointed out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention. The method and application of the present invention have been described through preferred embodiments, and relevant personnel can obviously make changes or appropriate changes and combinations to the method and application herein without departing from the content, spirit and scope of the present invention to realize and apply the present invention Invent technology.
本发明采用的试剂皆为普通市售品，皆可于市场购得。The reagents used in the present invention are all common commercial products and can be purchased in the market.
其中，橘红痰咳浸膏为广州白云山星群(药业)股份有限公司提供(批号B200501)，所述橘红痰咳浸膏，包括以下原料：化橘红、蜜百部、茯苓、水半夏(制)、白前、甘草、杏仁和五味子；优选为所述橘红痰咳浸膏，包括以下重量份的原料：化橘红200-300份、蜜百部2-30份、茯苓20-30份、水半夏(制)20-30份、白前40-50份、甘草1-10份、杏仁80-100份和五味子10-20份。Among them, Juhong Tanke extract is provided by Guangzhou Baiyunshan Xingqun (Pharmaceutical) Co., Ltd. (batch number B200501). The Juhong Tanke extract includes the following raw materials: Huajuhong, Mibabu, Poria cocos, Shui Pinellia (system), Baiqian, licorice, almond and schisandra; preferably the orange red phlegm and cough extract, including the following raw materials in parts by weight: 200-300 parts of Huajuhong, 2-30 parts of Mibabu, 20-30 parts of Poria cocos , Shui Pinellia (system) 20-30 parts, Baiqian 40-50 parts, licorice 1-10 parts, almond 80-100 parts and Schisandra 10-20 parts.
所述橘红痰咳浸膏的制备方法为：将化橘红和苦杏仁用水蒸气蒸馏，收集馏出液；将药渣与蜜百部、茯苓、水半夏(制)、白前、甘草和五味子混合，分别加入(药渣与蜜百部、茯苓、水半夏(制)、白前、甘草和五味子总重量的)6-8倍量水、4-6倍量水煎煮二次，滤过，合并滤液及馏出液，浓缩至相对密度1.05-1.25(80℃)，加入乙醇，使含醇量达75-80％，静置18-24小时，取上清液，浓缩至相对密度1.05-1.25(80℃)，即得所述橘红痰咳浸膏。The preparation method of the orange-red phlegm and cough extract is as follows: distill the orange-red and bitter almonds with water vapor, and collect the distillate; mix the dregs with Mibabu, Poria cocos, Shui Pinellia (manufactured), Baiqian, licorice and Schisandra chinensis Mix, respectively add (the total weight of the dregs and honey baebu, Poria cocos, Shui Pinellia (made), Baiqian, licorice and Schisandra chinensis) 6-8 times the amount of water, 4-6 times the amount of water to decoct twice, filter After that, combine the filtrate and distillate, concentrate to a relative density of 1.05-1.25 (80°C), add ethanol to make the alcohol content reach 75-80%, let it stand for 18-24 hours, take the supernatant, and concentrate to a relative density 1.05-1.25 (80°C), the orange red phlegm and cough extract is obtained.
HuH-7细胞，购自广州呼吸健康研究院呼吸疾病国家重点实验室病毒室。HuH-7 cells were purchased from the Virus Laboratory of the State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Health.
人冠状病毒HCoV-229E，滴度为TCID
50＝10
-5/100μL，购自广州呼吸健康研究院呼吸疾病国家重点实验室病毒室-80℃保存；使用病毒滴度为100TCID
50。
Human coronavirus HCoV-229E, with a titer of TCID 50 =10 -5 /100 μL, was purchased from the virus room of the State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Health and stored at -80°C; the titer of the virus used was 100 TCID 50 .
实施例1细胞毒性试验(MTT法)Embodiment 1 cytotoxicity test (MTT method)
(1)受试药物：如表1所示；(1) Test drugs: as shown in Table 1;
表1药物名称、实验浓度和分组Table 1 Drug name, experimental concentration and grouping
(2)无菌96孔培养板，每孔加入100μL浓度为2×10
5cells/mL Huh-7细胞，37℃5％CO
2培养24小时；
(2) In a sterile 96-well culture plate, add 100 μL of Huh-7 cells at a concentration of 2×10 5 cells/mL to each well, and incubate at 37° C. in 5% CO 2 for 24 hours;
(3)96孔板单层细胞用PBS洗涤1次，每孔加入100μL 2倍梯度稀释的药物。空白对照组和正常细胞组每孔加入等体积2％血清培养基，37℃培养4日；(3) The monolayer cells of the 96-well plate were washed once with PBS, and 100 μL of 2-fold serially diluted drugs were added to each well. Add an equal volume of 2% serum medium to each well of the blank control group and normal cell group, and culture at 37°C for 4 days;
(4)每孔加入浓度为5mg/mL的MTT溶液20μL，继续孵育4小时。弃上清，每孔加入100μL DMSO，低速振荡5分钟，使结晶物充分融解；(4) Add 20 μL of MTT solution with a concentration of 5 mg/mL to each well and continue to incubate for 4 hours. Discard the supernatant, add 100 μL DMSO to each well, and shake at low speed for 5 minutes to fully melt the crystals;
(5)选择490nm波长，在酶联免疫仪上测定吸光值，计算抑制率。(5) Select a wavelength of 490nm, measure the absorbance on an enzyme-linked immunosorbent analyzer, and calculate the inhibition rate.
抑制率＝(正常组平均OD值-药物组平均OD值)/(正常组平均OD值－空白组平均OD值)×100％。Reed-Meunch法计算药物半数毒性浓度(TC
50)。
Inhibition rate=(average OD value of normal group-average OD value of drug group)/(average OD value of normal group-average OD value of blank group)×100%. The median toxic concentration (TC 50 ) of the drug was calculated by the Reed-Meunch method.
(6)实验条件：以上实验操作均在BSL-2实验室内完成。(6) Experimental conditions: The above experimental operations are all completed in the BSL-2 laboratory.
实施例2受试药物抗病毒实验 Embodiment 2 test drug antiviral experiment
(1)受试药物：如表2所示(1) Test drugs: as shown in Table 2
表2药物名称、实验浓度和分组Table 2 Drug name, experimental concentration and grouping
(2)无菌96孔培养板，每孔加入100μL浓度为2×10
5cells/mL Huh-7细胞，37℃5％CO
2培养24小时；
(2) In a sterile 96-well culture plate, add 100 μL of Huh-7 cells at a concentration of 2×10 5 cells/mL to each well, and incubate at 37° C. in 5% CO 2 for 24 hours;
(3)培养板实验组和病毒对照组加入100TCID
50病毒液100μL/孔，37℃5％CO
2培养箱吸附2h；
(3) Add 100 μL/well of 100 TCID 50 virus solution to the culture plate experimental group and the virus control group, and adsorb for 2 hours at 37° C. in a 5% CO 2 incubator;
(4)2h后，弃去96孔培养板中细胞培养液；受试药物稀释成表2中的各个浓度，每个浓度3个复孔，100μl/孔加入上述药液；(4) After 2 hours, the cell culture solution in the 96-well culture plate was discarded; the test drug was diluted to each concentration in Table 2, and each concentration was repeated in 3 wells, and 100 μl/well of the above drug solution was added;
(5)同时设立细胞对照和病毒对照(阴性对照)；(5) Set up cell control and virus control (negative control) at the same time;
(6)细胞37℃,5％C0
2孵箱孵育3-4天；
(6) Incubate the cells in a 37°C, 5% CO 2 incubator for 3-4 days;
(7)光学显微镜下观察细胞病变(CPE),细胞出现病变程度按以下6级标准记录：“-”无病变出现；“±”为细胞病变少于10％；“+”为细胞病变25％；“++”为细胞病变50％；“+++”为75％的细胞出现病变：“++++”为75％以上病变。采用Reed-Muench法或GraphPad Prism8.0计算半数抑制浓度(IC
50)。
(7) Observing cytopathic changes (CPE) under an optical microscope, the degree of cell pathological changes is recorded according to the following 6-level standards: "-" no pathological changes; "±" means less than 10% of cytopathic changes; "+" means 25% of cellular pathological changes "++" means that 50% of the cells have pathological changes; "+++" means that 75% of the cells have pathological changes; "++++" means that more than 75% of the cells have pathological changes. The half inhibitory concentration (IC 50 ) was calculated by Reed-Muench method or GraphPad Prism8.0.
(8)实验条件：以上实验操作均在BSL-2实验室内完成。(8) Experimental conditions: The above experimental operations are all completed in the BSL-2 laboratory.
实施例3 RT-qPCR检测炎症因子Example 3 RT-qPCR detection of inflammatory factors
(1)受试药物：如表3所示。(1) Test drugs: as shown in Table 3.
表3药物名称、实验浓度和分组Table 3 Drug name, experimental concentration and grouping
(2)Huh-7细胞接种至6孔板中，分为正常组、病毒组和药效组。细胞长至单层后，弃去培养液，用PBS洗一次，病毒组和药效组接种1000个TCID
50的人冠状病毒(HCoV-229E)，正常组和药物对照组加入含2％血清培养基，37℃吸附1小时。
(2) Huh-7 cells were inoculated into 6-well plates and divided into normal group, virus group and drug efficacy group. After the cells grow to a monolayer, the culture medium is discarded, washed once with PBS, the virus group and the drug effect group are inoculated with 1000 human coronaviruses (HCoV-229E) with TCID 50 , and the normal group and the drug control group are added with 2% serum for culture. base, adsorbed at 37°C for 1 hour.
(3)弃去病毒液，药效组加入不同浓度药物溶液1mL，正常组和病毒组加入等体积含2％血清培养基。37℃作用48小时后，弃上清，PBS洗细胞一次，加入TRIzol试剂裂解细胞提取RNA，RT-qPCR检测细胞因子。(3) The virus liquid was discarded, and 1 mL of drug solutions of different concentrations were added to the drug effect group, and an equal volume of medium containing 2% serum was added to the normal group and the virus group. After acting at 37°C for 48 hours, discard the supernatant, wash the cells once with PBS, add TRIzol reagent to lyse the cells to extract RNA, and detect cytokines by RT-qPCR.
(4)实验条件：以上实验操作均在BSL-2实验室内完成。(4) Experimental conditions: The above experimental operations are all completed in the BSL-2 laboratory.
抗病毒药效结果判定标准：以选择指数
判定药效标准，SI>1表示有效，选择指数越大，抗病毒效果越好。
Judgment criteria for antiviral efficacy results: selection index Judging efficacy criteria, SI>1 means effective, the greater the selection index, the better the antiviral effect.
实验结果Experimental results
1、药物毒性1. Drug toxicity
MTT实验结果表明，在Huh-7细胞中，橘红痰咳浸膏半数无毒浓度(TC
50)为16.45mg/ml，如图1所示。
The results of MTT experiment showed that in Huh-7 cells, the half non-toxic concentration (TC 50 ) of Juhongtanke extract was 16.45 mg/ml, as shown in Figure 1 .
2、抗病毒药效2. Antiviral efficacy
通过观察细胞病变(CPE)并记录实验结果，采用Reed-Muench法或GraphPad Prism8.0计算半数有效浓度(IC
50)，橘红痰咳浸膏在此次实验的治疗模式中IC
50为1.567mg/ml，如图2所示。
By observing the cytopathic changes (CPE) and recording the experimental results, the half effective concentration (IC 50 ) was calculated by using the Reed-Muench method or GraphPad Prism8.0. The IC 50 of Juhong Tanke extract in the treatment mode of this experiment was 1.567mg/ ml, as shown in Figure 2.
3、炎症细胞因子的结果3. Results of inflammatory cytokines
通过RT-qPCR检测细胞因子mRNA的表达，采用GraphPad Prism8.0分析计算，结果 如图3-6所示。The expression of cytokine mRNA was detected by RT-qPCR, analyzed and calculated by GraphPad Prism8.0, and the results are shown in Figure 3-6.
综上可知，上述实验结果表明橘红痰咳浸膏在体外对人冠状病毒(HCoV-229E)感染Huh-7细胞致细胞病变具有抑制作用(选择指数SI为10.50)；体外能抑制人冠状病毒(HCoV-229E)诱导炎症因子TNF-α、IL-6、IL-8和IFN-α的mRNA过度表达，具剂量依赖关系。In summary, the above experimental results show that Juhongtanke extract has an inhibitory effect on the cytopathic effect of Huh-7 cells infected by human coronavirus (HCoV-229E) in vitro (selection index SI is 10.50); it can inhibit human coronavirus (HCoV-229E) in vitro ( HCoV-229E) induces the mRNA overexpression of inflammatory factors TNF-α, IL-6, IL-8 and IFN-α in a dose-dependent manner.
以上是结合具体实施例对本发明进一步的描述，但这些实施例仅仅是范例性的，并不对本发明的范围构成任何限制。本领域技术人员应该理解的是，在不偏离本发明的精神和范围下可以对本发明技术方案的细节和形式进行修改或替换，但这些修改和替换均落入本发明的保护范围内。The above is a further description of the present invention in conjunction with specific embodiments, but these embodiments are only exemplary and do not constitute any limitation to the scope of the present invention. Those skilled in the art should understand that the details and forms of the technical solutions of the present invention can be modified or replaced without departing from the spirit and scope of the present invention, but these modifications and replacements all fall within the protection scope of the present invention.
Claims (10)
- 橘红痰咳浸膏在制备抑制人冠状病毒感染的药物中的应用。Application of Juhong Tanke Extract in the preparation of drugs for inhibiting human coronavirus infection.
- 根据权利要求1所述的应用，其特征在于，所述人冠状病毒为HCoV-229E。The application according to claim 1, wherein the human coronavirus is HCoV-229E.
- 根据权利要求1所述的应用，其特征在于，所述橘红痰咳浸膏，包括化橘红、蜜百部、茯苓、水半夏、白前、甘草、苦杏仁和五味子。The application according to claim 1, characterized in that the orange red phlegm and cough extract comprises Huajuhong, Mibabu, Poria cocos, Shui Pinellia, Baiqian, licorice, bitter almond and Schisandra chinensis.
- 根据权利要求3所述的应用，其特征在于，所述橘红痰咳浸膏的制备方法为：将化橘红和苦杏仁用水蒸气蒸馏，收集馏出液；将药渣与蜜百部、茯苓、水半夏、白前、甘草和五味子混合，加水煎煮至少一次，滤过；合并滤液及馏出液，浓缩后，加入乙醇，使含醇量达75-80wt％，静置，取上清液，浓缩，即得所述橘红痰咳浸膏。The application according to claim 3, characterized in that, the preparation method of the orange red phlegm and cough extract is: steam distilling the orange red and bitter almonds, collecting the distillate; Mix water Pinellia, Baiqian, licorice and Schisandra, decoct with water at least once, filter; combine the filtrate and distillate, after concentration, add ethanol to make the alcohol content reach 75-80wt%, let stand, and take the supernatant liquid, concentrated to obtain the orange red phlegm and cough extract.
- 根据权利要求1所述的应用，其特征在于，所述药物包括橘红痰咳浸膏和制药学上可接受的载体。The application according to claim 1, characterized in that the medicine comprises Juhongtanke extract and a pharmaceutically acceptable carrier.
- 根据权利要求5所述的应用，其特征在于，所述药物的剂型为口服制剂。The application according to claim 5, characterized in that, the dosage form of the medicine is an oral preparation.
- 根据权利要求5所述的应用，其特征在于，所述药物的剂型为注射制剂。The application according to claim 5, characterized in that, the dosage form of the medicine is an injection preparation.
- 根据权利要求1-7任一项所述的应用，其特征在于，所述抑制包括抑制人冠状病毒诱导炎症因子的表达。The use according to any one of claims 1-7, characterized in that the inhibition comprises inhibiting the expression of human coronavirus-induced inflammatory factors.
- 根据权利要求8所述的应用，其特征在于，所述抑制包括抑制人冠状病毒诱导炎症因子的mRNA表达。The application according to claim 8, characterized in that said inhibition comprises inhibiting the mRNA expression of human coronavirus-induced inflammatory factors.
- 根据权利要求9所述的应用，其特征在于，所述炎症因子包括TNF-α、IL-6、IL-8和IFN-α。The use according to claim 9, characterized in that the inflammatory factors include TNF-α, IL-6, IL-8 and IFN-α.
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