CN116286392B - 一种具有抗痤疮作用的冠突散囊菌发酵制剂及其应用 - Google Patents
一种具有抗痤疮作用的冠突散囊菌发酵制剂及其应用 Download PDFInfo
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Abstract
本专利申请公开了一种具有抗痤疮作用的冠突散囊菌发酵制剂及其应用。所述散囊菌发酵制剂是将保藏编号为CGMCC No.40472的冠突散囊菌菌株发酵而制备的制剂。冠突散囊菌菌株CGMCC No.40472的痤疮丙酸杆菌生长抑制作用、以及脂肪酶分解甘油三酯活性抑制作用均强,将该冠突散囊菌菌株发酵制备的制剂具有良好的治疗痤疮的效果。
Description
技术领域
本发明涉及一种具有抗痤疮作用的冠突散囊菌发酵制剂及其应用。
背景技术
痤疮是毛囊皮脂腺单位的一种慢性炎症性皮肤病,主要好发于青少年,对青少年的心理和社交影响很大,但青春期后往往能自然减轻或痊愈。临床表现以好发于面部的粉刺、丘疹、脓疱、结节等多形性皮损为特点。
痤疮的发生主要与皮脂分泌过多、毛囊皮脂腺导管堵塞、细菌感染和炎症反应等因素密切相关。进入青春期后人体内雄激素特别是睾酮的水平迅速升高,促进皮脂腺发育并产生大量皮脂。同时毛囊皮脂腺导管的角化异常造成导管堵塞,皮脂排出障碍,形成角质栓即微粉刺。毛囊中多种微生物尤其是痤疮丙酸杆菌大量繁殖,痤疮丙酸杆菌产生的脂肪酶分解皮脂生成游离脂肪酸,同时趋化炎症细胞和介质,最终诱导并加重炎症反应。
另一方面,冠突散囊菌是从黑茶中分离的一种益生菌,其在茶叶中形成大量金黄色闭囊壳,因此又名“金花菌”。冠突散囊菌分泌的多糖等代谢产物对人体微生物菌群的稳定及减肥降脂、抗氧化方面有明显的功效。李佳莲等研究表明,冠突散囊菌发酵液对细菌、特别是革兰氏阴性菌有明显抑制作用(李佳莲,胡博涵,赵勇彪,刘素纯,姜越君,刘仲华.冠突散囊菌发酵液的抑菌作用[J].食品科学,2011,32(11):157-160)。
目前,对于冠突散囊菌的研究主要集中在普通食品、功能饮品及保健食品领域,而关于冠突散囊菌在化妆品或护肤品中的应用研究较为少见。
发明内容
鉴于现有技术中上述情况,本发明的目的在于提供一种具有抗痤疮作用的冠突散囊菌发酵制剂及其应用。
本发明经过深入研究发现:1.冠突散囊菌具有治疗痤疮的效果;2.对痤疮丙酸杆菌生长抑制作用更强的冠突散囊菌发酵液并非治疗痤疮的效果更好;3.冠突散囊菌治疗痤疮的机制还包括通过抑制脂肪酶分解甘油三酯的活性减少脂肪酸的产生,从而减轻或消除炎症反应。
基于上述发现,发明人筛选出了对痤疮丙酸杆菌生长抑制作用强且对脂肪酶分解甘油三酯的活性抑制作用也强的冠突散囊菌菌株,并验证了该冠突散囊菌菌株的制剂具有良好的治疗痤疮的效果,从而完成了本发明。
即,本发明包括:
1.一种冠突散囊菌菌株,其保藏于中国普通微生物菌种保藏管理中心,保藏编号是CGMCC No.40472。
2.将项1所述的冠突散囊菌菌株发酵制备的制剂。
3.项2所述的制剂,其为固态发酵孢子制剂、液态发酵菌丝制剂或液态发酵上清制剂。
上述冠突散囊菌的液态发酵菌丝制剂可以通过如下制备方法进行制备,包括:
(1)菌种活化:将-20℃保存的冠突散囊菌菌种接种至PDA固体培养基上,28-30℃条件下培养培养120-144h得到活化后冠突散囊菌单菌落。
(2)冠突散囊菌种子液:将步骤(1)得到的冠突散囊菌单菌落,在超净工作台中转接于液体种子培养基中,进行冠突散囊菌的液体种子培养,其中,培养基按质量体积比为:蔗糖15g/L、蛋白胨2g/L、酵母提取物10g/L、KH2PO4 2g/L,pH5.0-5.5,转接过程主要是利用灭菌的竹签从装有活化后的冠突散囊菌试管中,接种于装有200ml培养基的500ml摇瓶中,置于28-30℃的摇床中培养96-120h,获得冠突散囊菌液体种子。
(3)冠突散囊菌发酵:将步骤(2)得到的冠突散囊菌液体种子按照8%-10%的接种量接种于10L含有液体发酵培养基(蔗糖或葡萄糖浓度为10-80g/L,优选20-30g/L;玉米浆干粉浓度为2-15g/L,优选3-5g/L;蛋白胨浓度为2-10g/L,优选3-6g/L;酵母提取物浓度为2-10g/L,优选3.0-5.5g/L;KH2PO4浓度为1-8g/L,优选1.2-2.5g/L;MgSO4·7H2O浓度为2.0-7.5g/L,优选1.5-2.2g/L;(NH4)2SO4浓度为2.5-8.0g/L,优选4.0-5.5g/L,植物提取液10-100mL/L,优选34.2-85mL/L,可以是例如黑茶提取液、绿茶提取液、葡萄籽提取液、青蒿提取物液中的至少一种),培养温度为28-30℃,pH5.0-5.5,转速为100-500rpm,通气量为5-20L/min,溶氧控制在20-40%,培养65-72h,当发酵液变红,菌丝量不再增加时停止发酵。
(4)发酵产物收集:将步骤(3)得到发酵液通过8层纱布进行过滤处理,分别收集发酵产物中的菌丝和上清液。将菌丝利用蒸馏水清洗3-5次后尽可能多的除掉水分,然后,将菌丝置于60-65℃干燥培养箱中进行干燥处理24h-48h,获得干燥处理后的冠突散囊菌菌丝。将分离后的上清液经过滤后进行收集。
(5)菌丝胞内物质提取:将步骤(4)得到的烘干菌丝进行粉碎,过100目筛后,通过高压均质机进行破壁,将胞内有效成分释放。添加一定量的纯化水,按照料液比(g:mL)为1:18-25提取,提取温度为95℃,提取时间为2h,两次提取。
(6)粗纯:将步骤(5)得到的提取物进行除色素(例如可采用硅藻土吸附、活性炭吸附、葡聚糖凝胶吸附中的至少一种),再将除色后的提取液经0.45μm过滤膜过滤后得到冠突散囊菌液态发酵制剂。
4.一种药物,其包含项1所述的冠突散囊菌菌株或项2所述的制剂。
5.根据项4所述的药物,其用于预防或治疗痤疮。
6.一种预防或治疗痤疮的方法,其包括给受试者施用项4所述的药物。所述受试者可以是例如猫、犬或人。
7.项1所述的冠突散囊菌或项2所述的制剂在制备药物中的用途。
8.根据项7所述的用途,其中,所述药物用于预防或治疗痤疮。
9.根据项7所述的用途,其中,所述药物被制备成适合施用于皮肤的形式。例如,喷雾剂、搽剂、膏剂、敷料、乳剂等。
发明的效果
本发明的冠突散囊菌菌株的痤疮丙酸杆菌生长抑制作用、以及脂肪酶分解甘油三酯活性抑制作用均强,将该冠突散囊菌菌株发酵制备的制剂具有良好的治疗痤疮的效果。
附图说明
图1为显示各种冠突散囊菌菌株的制剂对胰脂肪酶活性的抑制作用的图。
发明的具体实施方式
实施例
下面结合实施例进一步说明本申请,应当理解,实施例仅用于进一步说明和阐释本申请,并非用于限制本申请。
实施例1痤疮动物模型的建立
痤疮动物模型的建立:选取成年大鼠,雌雄各半,质量为200~220g,右耳廓皮内注射痤疮丙酸杆菌液(6×107cfu/mL)50μL,每天1次,于注射痤疮丙酸杆菌液第3天,每只大鼠再次腹腔注射痤疮丙酸杆菌液(6×107cfu/mL)1mL,每天1次,连续7d;左耳不做任何处理作为对照,可制备大鼠耳痤疮模型。本模型持续不少于14d。
痤疮丙酸杆菌液:将痤疮丙酸杆菌接种于硫乙醇钠斜面培养基中,放于厌氧产气袋中,37℃恒温培养箱24h。无菌棉签取出菌落,以无菌生理盐水洗涤3次,使得痤疮丙酸杆菌最终浓度为6×107cfu/ml,95℃水浴灭活15min,备用。
实施例2各种冠突散囊菌菌株的制剂的制备
冠突散囊菌液体发酵制剂制备
(1)菌种活化:分别将-20℃保存的菌种保藏号为CGMCC No.15395、CGMCCNo.15396、CGMCC No.15397和CGMCC No.15398冠突散囊菌菌种接种至PDA固体培养基上,28-30℃条件下培养培养120-144h得到活化后冠突散囊菌单菌落。
(2)冠突散囊菌的种子培养:将活化后的菌种在超净工作台中转接于液体种子培养基中,进行冠突散囊菌的液体种子培养,其中,培养基按质量体积比为:蔗糖15g/L、蛋白胨2g/L、酵母提取物10g/L、KH2PO4 2g/L,pH5.0-5.5,转接过程主要是利用灭菌的竹签从装有活化后的冠突散囊菌试管中,接种于装有200ml培养基的500ml摇瓶中,置于28℃的摇床中培养110h,获得冠突散囊菌液体种子。
(3)冠突散囊菌液体培养:将冠突散囊菌液体种子按照8%的接种量接种于含有10L液体发酵培养基,其中,培养基按质量体积比为:蔗糖25g/L、蛋白胨3.8g/L、玉米浆干粉4g/L、酵母提取物4.7g/L、KH2PO4 2.3g/L、MgSO4·7H2O 2.1g/L、(NH4)2SO4 5.3g/L、黑茶提取液80mL/L,培养温度为28℃,pH 5.0,转速为100-500rpm,通气量为5-20L/min,溶氧控制在20-40%,培养70h,当菌丝量不再增加时停止发酵。
(4)冠突散囊菌菌丝的收集:将发酵结束后的发酵液通过8层纱布进行过滤处理,收集发酵产物中的菌丝,将菌丝利用蒸馏水清洗3次后尽可能多的除掉水分,然后,将菌丝置于60℃干燥培养箱中进行干燥处理24h,获得干燥处理后的冠突散囊菌菌丝。
(5)菌丝胞内物质提取:将干燥后得到的菌丝通过粉碎机进行粉碎,过100目筛后,加纯化水通过高压均质机(压力为1200bar)进行破壁,将胞内有效成分释放。添加一定量的纯化水,按照料液比(g:mL)为1:20提取,提取温度为95℃,提取时间为2h,两次提取。(6)粗纯:将获得的菌丝胞内物质过葡聚糖凝胶吸附除色素,再将除色后的提取液经0.45μm过滤膜过滤后得到4种冠突散囊菌液态发酵菌丝制剂。
实施例3各种冠突散囊菌菌株的制剂对痤疮丙酸杆菌生长抑制作用的研究
本实施例通过实施例2获得的4种冠突散囊菌液态发酵制剂进行抑菌效果评价。将痤疮丙酸杆菌接种到硫乙醇酸盐固体培养基,放于厌氧产气袋中,37℃培养48h后。在超净工作台中,挑取单菌落接种于硫乙醇酸盐液体培养液中,37℃恒温摇床培养48h。用灭菌后的硫乙醇酸盐液体培养基对菌液进行稀释,使菌悬液细菌数量为106-108cfu/mL。吸取制备好的菌悬液0.1m涂布于硫乙醇酸盐固体培养基中,用无菌镊子夹取牛津杯轻轻放置于平板上,轻轻按压牛津杯,每个平板放置3个牛津杯。分别吸取实施例2中4种冠突散囊菌液态发酵菌丝制剂10μL,加入牛津杯中,37℃厌氧培养48h,测定抑菌圈直径(mm)。
表1冠突散囊菌液态发酵制剂抑菌效果
由表1可知,不同菌株制备的冠突散囊菌液态发酵制剂具有一定的抑制痤疮丙酸杆菌效果,采用编号为CGMCC No.15397菌株制备的液态发酵菌丝制剂抑菌效果最好。
实施例4各种冠突散囊菌菌株的制剂治疗痤疮效果的研究
动物分组及给药:将56只大鼠随机分为7组,其中正常组8只,造模组48只。造模完成后,造模组再分成6组:模型组8只,不给药;阳性药维A酸组8只,涂抹0.1%维A酸乳膏0.1g,1次/d;给药1组8只,涂抹冠突散囊菌液态发酵制剂(CGMCC No.15395)1.0g,1次/d;给药2组8只,涂抹冠突散囊菌液态发酵制剂(CGMCC No.15396)1.0g,1次/d;给药3组8只,涂抹冠突散囊菌液态发酵制剂(CGMCC No.15397)1.0g,1次/d;给药4组8只,涂抹冠突散囊菌液态发酵制剂(CGMCC No.15398)1.0g,1次/d。连续给药14d。
检测指标:各组大鼠造模前分别用游标卡尺测量耳廓厚度。造模后,观察各组大鼠右耳皮肤状态,确定造模是否成功。连续给药14d后,测量耳廓厚度。以耳廓肿胀率(%)=(治疗后耳廓厚度-造模前耳廓厚度)/造模前耳廓厚度×100%计算各鼠耳廓肿胀率。
表2各组大鼠耳肿胀率测定结果
组别 | 造模前厚度(mm) | 治疗后厚度(mm) | 肿胀率(%) |
正常组 | 0.425±0.027 | 0.450±0.031 | 5.782±1.258 |
模型组 | 0.421±0.031 | 0.669±0.053 | 59.125±13.731* |
阳性药组 | 0.419±0.025 | 0.519±0.043 | 24.764±7.268# |
给药1组 | 0.421±0.020 | 0.598±0.054 | 43.017±11.267 |
给药2组 | 0.422±0.023 | 0.573±0.046 | 35.872±10.153# |
给药3组 | 0.424±0.025 | 0.558±0.045 | 32.704±8.361# |
给药4组 | 0.423±0.028 | 0.531±0.042 | 27.353±6.973# |
注:*表示与正常组相比,P<0.01;#表示与模型组相比,P<0.01
由表2可知,给药后阳性药组和给药2组、给药3组、及给药4组的大鼠耳肿胀率明显低于模型组(P<0.01),说明给药2组、给药3组、及给药4组对痤疮大鼠模型的炎症有明显的抑制作用,且给药4组的治疗效果更为显著。
综合实施例3和实施例4的研究结果,发明人发现,治疗痤疮效果最好的冠突散囊菌株CGMCC No.15398,并非对痤疮丙酸杆菌生长抑制作用最强。这说明,除了抑制痤疮丙酸杆菌之外,冠突散囊菌的制剂治疗痤疮还可能存在其他机制。使用冠突散囊菌菌株CGMCCNo.15398制剂的痤疮动物模型的炎症反应更轻微,发明人据此推测,冠突散囊菌的制剂可能通过抑制脂肪酶分解甘油三酯的活性减少脂肪酸的产生,减轻或消除炎症反应,从而达到治疗痤疮的效果。因此,发明人对实施例2的冠突散囊菌菌株的制剂抑制脂肪酶活性的作用进行了研究。
实施例5各种冠突散囊菌菌株的制剂抑制脂肪酶活性的作用的研究
本实施例通过将实施例2获得的4种冠突散囊菌液态发酵制剂经冷冻干燥后配制成不同浓度后进行脂肪酶抑制性评价。
实验方法:称取一定量的胰脂肪酶溶于0.067mol/LPBS缓冲液(pH 7.38)中,配制成浓度为0.1mg/mL的胰脂肪酶溶液,置于4℃冰箱中保存备用。利用脂肪酶(LPS)测定试剂盒测定胰脂肪酶活力。pH 7.4、37℃时每克胰脂肪酶每分钟水解1μmoL三油酸甘油酯定义为1个酶活力单位(U)。以奥利司他为阳性对照,将冻干后的4种冠突散囊菌液态发酵制剂溶于0.067mol/LPBS缓冲液(pH 7.38)充分振荡混匀,配制成浓度分别为0.25,0.5,5,10,20,50mg/mL的不同溶液,与等体积的0.1mg/mL胰脂肪酶溶液混合后测定脂肪酶活力。参考公式(1)计算冻干后冠突散囊菌液态发酵制剂对胰脂肪酶的抑制率(%)。
抑制率(%)=(A-B)/B×100% (1)
A为无抑制剂存在时胰脂肪酶的活性,U/L;B为抑制后胰脂肪酶的活性,U/L。
由图1可知,四种冠突散囊菌制剂在相同浓度下时,给药组4(CGMCC No.15398)对胰脂肪酶的抑制效果最明显,且IC50值也要小于其他三个给药组,说明采用菌株编号为CGMCC No.15398发酵得到的制剂对胰脂肪酶的抑制效果要好于其它三种菌株发酵得到的制剂。
实施例6冠突散囊菌菌株的诱变
为了得到具有更好的胰脂肪酶活性的抑制效果的冠突散囊菌菌株,我们以菌株编号为CGMCC No.15398的冠突散囊菌为出发菌株进行了诱变及筛选。
(1)菌悬液的制备
取培养72h菌株编号为CGMCC No.15398的冠突散囊菌的斜面1支,用无菌生理盐水将菌苔洗下转入装有玻璃珠的小三角瓶中,震荡30min以打散菌块备用。
(2)梯度稀释涂平板及紫外线诱变
1)取备用的菌悬液以10倍的稀释法稀释成10-1-10-6,取10-4、10-5、10-6三个稀释度涂平板,每个稀释度涂平板四只,每只平板加稀释液0.1ml,用无菌玻璃棒涂均匀;
2)紫外诱变,将上面涂布均匀的平板每个梯度留一只平板作为对照,其余置于垂直距离为30cm,功率为15w的紫外灯下避光照射90min。
(3)平板培养并计数
将上述所有平板,用锡箔纸包好,置于30℃恒温培养箱培养72h后,取出分别计数,计算出未经紫外处理的平板每毫升菌液中的活菌数。同样计算出经紫外线处理后平板的活菌数,计算出致死率。
(4)诱变菌株的筛选及保藏
选取致死率大于90%平板,将长出的单菌落接种至PDA斜面,培养72h后,放置4℃保藏。经3次诱变实验,共选取65个诱变后的冠突散囊菌菌株进行保藏,并分别编号为诱变15398-1~15398-65。
实施例7痤疮丙酸杆菌抑制作用强的冠突散囊菌菌株的筛选
本实施例将实施例6获得的65株诱变后冠突散囊菌制得的液态发酵制剂进行抑菌效果评价。通过实施例3中方法,经3次实验,每组3个平行,判断诱变后菌株对痤疮丙酸杆菌抑制作用,实验结果表明编号为15398-23的诱变菌株对痤疮丙酸杆菌抑制作用最强,抑菌圈直径为13.43±0.71mm。
实施例8脂肪酶抑制作用强的冠突散囊菌菌株的筛选
本实施例将实施例6获得的65株诱变后冠突散囊菌制得的液态发酵制剂进行脂肪酶抑制作用评价。通过实施例5中方法,判断诱变后菌株对胰脂肪酶的抑制作用,最终发现在相同浓度下编号为15398-23的诱变菌株对胰脂肪酶抑制作用最强,IC50为0.397mg/mL。
结果发现,冠突散囊菌诱变15398-23的痤疮丙酸抑制作用和脂肪酶抑制作用都很强,将其保藏于中国普通微生物菌种保藏管理中心,保藏编号是CGMCC No.40472。
实施例9冠突散囊菌诱变15398-23治疗痤疮效果的研究
像实施例4那样,利用实施例1的动物模型研究了冠突散囊菌菌株诱变15398-23的治疗痤疮效果。结果表明,其是效果最好的,经测量,耳廓肿胀率为24.927±6.769,该结果明显优于实施例4中效果最好的冠突散囊菌菌株CGMCC No.15398。
Claims (6)
1.一种冠突散囊菌(Eurotium cristatum)菌株,其保藏于中国普通微生物菌种保藏管理中心,保藏编号是CGMCC No.40472。
2.将权利要求1所述的冠突散囊菌菌株发酵制备的制剂,所述制剂为液态发酵菌丝制剂。
3.一种药物,其包含权利要求1所述的冠突散囊菌菌株或权利要求2所述的制剂。
4.根据权利要求3所述的药物,其用于预防或治疗痤疮。
5.权利要求1所述的冠突散囊菌或权利要求2所述的制剂在制备用于预防或治疗痤疮的药物中的用途。
6.根据权利要求5所述的用途,其中,所述药物被制备成适合施用于皮肤的形式。
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