CN112175860B - 植物乳杆菌菌株及其用于降低发炎与治疗高尿酸血症的用途 - Google Patents
植物乳杆菌菌株及其用于降低发炎与治疗高尿酸血症的用途 Download PDFInfo
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Abstract
本发明是涉及微生物领域，尤其是有关于植物乳杆菌菌株及其用于降低发炎与治疗高尿酸血症的用途。本发明提供一种具缓解痛风的植物乳杆菌菌株。本发明还提供一种植物乳杆菌菌株用于制备一调控介白素‑1β基因、肿瘤坏死因子‑α基因、基质金属肽酶1a基因及TIMP基质金属肽酶抑制因子1基因的表现量的组成物的用途以及用于制备一治疗痛风的组成物的用途。
Description
相关申请的交叉引用
本申请主张在2019年07月03日在中国台湾提交的中国台湾专利申请号108123471的优先权。
技术领域
本发明是涉及微生物领域，尤其是有关于植物乳杆菌菌株及其用于降低发炎与治疗高尿酸血症的用途。
背景技术
痛风(Gout)又称高尿酸血症(Hyperuricemia)，主要为一种嘌呤(Purine)代谢障碍。当人体无法将嘌呤从人体中代谢出时，体内的嘌呤会进一步氧化而形成尿酸，尿酸会以钠盐的形式沉积在关节部位，导致身体免疫系统过度反应而引发发炎现象。近年来，由于饮食结构的改变，高嘌呤食物以及啤酒饮品的摄入增加，导致痛风的发病率逐年上升，且发病年龄亦有下降的趋势。另外，有越来越多的风险因素，例如代谢综合症，较长的平均寿命和饮食上的改变，使痛风的影响变得更普遍。
目前用于治疗痛风的药物，分别有用于抑制尿酸产生的药，如别嘌呤醇(Allopurinol)；促进尿酸排泄的药，如二丙苯磺胺(Probenecid)、苯磺唑酮(Sulfinpyrazone)；以及用以减少痛风发作频率的药，如秋水仙碱(Colchicine)。然而，前述的药品已知具有发生副作用的风险，如造成皮肤过敏反应、肠胃不适、肾损害、肝损害、白血球减少等副作用。
此外，目前所使用的治疗痛风的医药品大多由化学成分所制成，长期使用不但对人体健康有害无益，且这些产品往往价格昂贵，并非为一般使用者所能负担。为了解决上述问题，本领域的技术人员亟需研发出具有缓解及治疗痛风功效的新颖医药品或食品产品以造福有此需求的广大族群。
发明内容
有鉴于此，本发明的目的为提供一种植物乳杆菌(Lactobacillus plantarum)菌株用于制备一调控介白素-1β(Interleukin-1β，IL-1β)基因、肿瘤坏死因子-α(Tumornecrosis factor-α，TNF-α)基因、基质金属肽酶1a(matrix metallopeptidase 1a，MMP1a)基因及TIMP基质金属肽酶抑制因子1(TIMP metallopeptidase inhibitor 1，TIMP1)基因的表现量的组成物的用途。
在本发明的一实施例中，该IL-1β基因、该TNF-a基因及该MMP1a基因的表现量被向下调控，该TIMP1基因的表现量被向上调控。
在本发明的一实施例中，该植物乳杆菌菌株的有效浓度为至少5x108细胞/mL。
在本发明的一实施例中，该植物乳杆菌菌株包含一失活菌体。
本发明的另一目的为提供一种植物乳杆菌(Lactobacillus plantarum)菌株用于制备一治疗痛风的组成物的用途。
在本发明的一实施例中，该植物乳杆菌菌株的有效浓度为至少1x1010细胞/天。
在本发明的一实施例中，该植物乳杆菌菌株包含一失活菌体。
在本发明的一实施例中，该组成物是一医药品或一食品产品。
在本发明的一实施例中，该植物乳杆菌菌株的寄存编号为DSM33287。
本发明的另一目的为提供一种具缓解痛风的植物乳杆菌(Lactobacillusplantarum)菌株，其以寄存编号DSM33287。
在本发明的一实施例中，该植物乳杆菌菌株包含一失活菌体。
综上所述，本发明植物乳杆菌菌株的功效在于：可藉由降低尿酸结晶所引起的发炎反应、降低尿酸值、降低关节肿胀程度、调控IL-1β基因、TNF-α基因、MMP1a基因、及TIMP1基因的表现量，达到缓解与治疗痛风的功效。
以下将进一步说明本发明的实施方式，下述所列举的实施例是用以阐明本发明，并非用以限定本发明的范围，任何熟习此技艺者，在不脱离本发明的精神和范围内，当可做些许更动与润饰，因此本发明的保护范围当视后附的申请专利范围所界定者为准。
附图说明
图1是本发明植物乳杆菌菌株TCI227在调控IL-1β基因表现上的功效的数据图，其中“***”表示与病理对照组比较，p＜0.001；
图2是本发明植物乳杆菌菌株TCI227在调控TNF-α基因表现上的功效的数据图；
图3是本发明植物乳杆菌菌株TCI227在调控MMP1a基因表现上的功效的数据图，其中“*”表示与病理对照组比较，p＜0.05；
图4是本发明植物乳杆菌菌株TCI227在调控TIMP1基因表现上的功效的数据图，其中“***”表示与病理对照组比较，p＜0.001；
图5是本发明植物乳杆菌菌株TCI227在人体试验中治疗痛风上的功效的数据图，其中“**”表示与第0周比较，p＜0.01；
图6是本发明植物乳杆菌菌株TCI227在人体试验中治疗痛风上的功效的超音波图。
具体实施方式
定义
本文中所使用数值为近似值，所有实验数据皆表示在20％的范围内，较佳为在10％的范围内，最佳为在5％的范围内。
使用Excel软件进行统计分析。数据以平均值±标准偏差(SD)表示，个此之间的差异以学生t检验(student′s t-test)分析。
依据本发明，植物乳杆菌(Lactobacillus plantarum)是一种革兰氏阳性厌氧菌，生长于高于15C但不超过45℃的温度，并可产生乳酸。
如本文中所使用的，“治疗(treating)”或“治疗(treatment)”意指缓解(alleviating)、减少(reducing)、改善(ameliorating)、减轻(relieving)或控制(controlling)一疾病(disease)或障碍(disorder)的一或多个临床征兆(clinicalsign)，以及降低(lowering)、停止(stopping)或逆转(reversing)一正在被治疗中的病况(condition)或症状(symptom)的严重性(severity)的进展(progression)。
依据本发明，医药品可利用熟习此技艺者所详知的技术而被制造成一适合于非经肠地道(parenterally)或口服地(orally)投药的剂型(dosage form)，这包括，但不限于：注射品(injection)[例如，无菌的水性溶液(sterile aqueous solution)或分散液(dispersion)]、无菌的粉末(sterile powder)、锭剂(tablet)、片剂(troche)、口含锭(lozenge)、丸剂(pill)、胶囊(capsule)、分散性粉末(dispersible powder)或细颗粒(granule)、溶液、悬浮液(suspension)、乳剂(emulsion)、糖浆(syrup)、酏剂(elixir)、浓浆(slurry)以及类似物。
依据本发明的医药品可以一选自于由下列所构成的群组中的非经肠道途径(parenteral routes)来投药：腹膜内注射(intraperitoneal injection)、皮下注射(subcutaneous injection)、肌肉内注射(intramuscular injection)以及静脉内注射(intravenous injection)。
依据本发明的医药品可包含有一被广泛地使用于药物制造技术的医药上可接受的载剂。例如，该医药上可接受的载剂可包含一或多种选自于由下列所构成的群组中的试剂：溶剂(solvent)、乳化剂(emulsifier)、悬浮剂(suspending agent)、分解剂(decomposer)、黏结剂(binding agent)、赋形剂(excipient)、安定剂(stabilizingagent)、螯合剂(chelating agent)、稀释剂(diluent)、胶凝剂(gelling agent)、防腐剂(preservative)、润滑剂(lubricant)、吸收延迟剂(absorption delaying agent)、脂质体(liposome)以及类似物。有关这些试剂的选用与数量是落在熟习此项技术的人士的专业素养与例行技术范畴内。
依据本发明，该医药上可接受的载剂包含有一选自于由下列所构成的群组中的溶剂：水、生理盐水(normal saline)、磷酸盐缓冲生理盐水(phosphate buffered saline，PBS)、含糖溶液、含有醇的水性溶液(aqueous solution containing alcohol)，以及它们的组合。
依据本发明，食品产品可被当作食品添加物(food additive)，藉由习知方法于原料制备时添加，或是于食品的制作过程中添加，而与任一种可食性材料配制成供人类与非人类动物摄食的食品产品。
依据本发明，食品产品的种类包括但不限于：饮料(beverages)、发酵食品(ferrmented foods)、烘培产品(bakery products)、健康食品(health foods)以及膳食补充品(dietary supplements)。
实施例1.植物乳杆菌菌株TCI227在降低尿酸结晶所引起的发炎反应上的效用评估
本实施例探讨植物乳杆菌菌株TCI227可否藉由调控与发炎相关的基因表现来达到降低尿酸结晶所引起的发炎反应的功效。植物乳杆菌菌株，本文命名为TCI227，寄存于DSMZ-德国微生物保存中心(Deutsche Sammlung von Mikroorgauismen undZellkulturen，DSMZ)；寄存地址：德国布伦瑞克市38124因霍芬大街7B；寄存日期为2019年9月19日，寄存编号DSM33287。
首先，制备植物乳杆菌菌株TCI227的失活菌体，制备流程如下：将本发明的植物乳杆菌TCI227的冷冻菌种保存管以MRS培养液经一次培养活化，以此活化菌液以1％殖入新的培养基中并于37℃培养16小时，后以10000rpm离心5分钟，将培养基去除并以PBS清洗，反复此动作3次，而后以PBS回溶菌体为1OD的悬浮菌液，再将此悬浮菌液以121℃，15分钟进行灭菌，即得TC1227失活菌体。
于杜贝可氏改良的依格氏培养基(Dulbecco’s Modified Eagle’s Medium，DMEM)与Ham′s F12培养基(1∶1)(添加有2mM麸酰胺酸(glutamine)及5％胎牛血清(fetal bovineserum，FBS)(Gibco))中培养老鼠软骨细胞(ATDC5；购自于美国典型培养物保藏中心(American Type Culture Collection，ATCC))于6-孔盘，2mL培养基的细胞浓度为1×105细胞/孔。在培养24小时之后，更换新的培养基。
之后，将细胞分成3组，其中包括1个空白对照组、1个病理对照组及1个实验组。其中，实验组的处理方式为将植物乳杆菌菌株TCI227的失活菌体稀释为具有5x108细胞/mL浓度的稀释液，继而将5x108细胞/mL稀释液及0.125mg/mL尿酸结晶(monosodium urate，MSU)添加至实验组的细胞中。病理对照组的处理方式为将0.125mg/mL尿酸结晶添加至病理对照组的细胞中，至于空白对照组的细胞则添加培养基。接着，于培养箱中培养各组细胞24小时，接而收取各组细胞培养物并拿来进行基因表现分析。
在本实施例中，用来分析与发炎相关的基因包括介白素-1β(Interleukin-1β，IL-1β)基因、肿瘤坏死因子-α(Tumor necrosis factor-α，TNF-α)基因、基质金属肽酶1a(matrix metallopeptidase 1a，MMP1a)基因及TIMP基质金属肽酶抑制因子1(TIMPmetallopeptidase inhibitor 1，TIMP1)基因。
以RNA萃取套组(Genemark)对上面所得到的各组细胞培养物进行RNA的萃取。对由此所得到的各组RNA取2,000ng并以
III反转录酶(Invitrogen)将萃取出的RNA反转录为cDNA。接着，以cDNA作为模版，并且使用用来扩增目标基因的引物对，包括IL-1β、TNF-α、MMP1a、及TIMP1，它们的核苷酸序列显示于下表1，在StepOne Plus实时PCR系统(ABI)中利用KAPA SYBR FAST qPCR套组(2x)(KAPA Biosystems)来进行定量实时PCR，俾以对目标基因进行扩增及定量。PCR产物的熔化曲线是在定量实时PCR反应期间进行确认。
表1
本实施例的结果显示于图1至图4。图1是本发明植物乳杆菌菌株TCI227在调控IL-1β基因表现上的功效的数据图。由图1可见，与空白对照组相较之下，病理对照组的IL-1β基因表现量有显着提升，这表示尿酸结晶会引起老鼠软骨细胞的发炎反应；而与病理对照组相较之下，实验组的IL-1β基因表现量有显着降低(降低87％)。
图2是本发明植物乳杆菌菌株TCI227在调控TNF-α基因表现上的功效的数据图。由图2可见，与空白对照组相较之下，病理对照组的TNF-α基因表现量有显着提升，这表示尿酸结晶会引起老鼠软骨细胞的发炎反应；而与病理对照组相较之下，实验组的TNF-α基因表现量有显着降低(降低28％)。
图3是本发明植物乳杆菌菌株TCI227在调控MMP1a基因表现上的功效的数据图。MMP1a基因过度表现会造成像关节炎等的疾病，由图3可见，与空白对照组相较之下，病理对照组的MMP1a基因表现量有显着提升，这表示尿酸结晶会引起老鼠软骨细胞的发炎反应；而与病理对照组相较之下，实验组的MMP1a基因表现量有显着降低(降低43％)。
图4是本发明植物乳杆菌菌株TCI227在调控TIMP1基因表现上的功效的数据图。TIMP1基因可抑制MMPs基因表现，由图4可见，与空白对照组及病理对照组相较之下，实验组的TIMP1基因表现量有显着提升(提升83％)。本实施例的结果显示，本发明植物乳杆菌菌株TCI227能有效降低尿酸结晶引发的免疫与发炎反应，藉此达到治疗痛风的功效。
实施例2.植物乳杆菌菌株TCI227在人体试验中治疗痛风上的效用评估
在本实施例中，藉由人体试验探讨本发明植物乳杆菌菌株TCI227能否治疗痛风。首先，募集3位痛风患者，受试者条件为尿酸偏高并有痛风病史者，对每位痛风患者口服投药以本发明植物乳杆菌菌株TCI227(以胶囊形式，剂量为1x1010细胞/天)，每日食用一颗，检测食用前、食用4周及8周后的血中尿酸值。实验结果显示于图5。
图5是本发明植物乳杆菌菌株TCI227在人体试验中治疗痛风上的功效的数据图。由图5可见，受试者在服用含有植物乳杆菌菌株TCI227胶囊4周及8周后，尿酸值相较于食用前(第0周)有显着降低(第8周时降低6.8％，即0.53mg/dL)。本实验结果显示，本发明植物乳杆菌菌株TCI227能藉由降低痛风患者的尿酸值达到治疗痛风的功效。
此外，对前述服用含有植物乳杆菌菌株TCI227胶囊前及8周后的痛风患者进行骨骼肌肉超音波观察，结果显示于图6。图6是本发明植物乳杆菌菌株TCI227在人体试验中治疗痛风上的功效的超音波图。由图6可见，与服用含有植物乳杆菌菌株TCI227胶囊前(第0周)比较，服用含有植物乳杆菌菌株TCI227胶囊8周后的痛风患者的关节腔肿胀程度下降，并且尿酸结晶的数量(如蓝色箭头指的白色小点即为尿酸结晶)也有减少的现象。本实验结果显示，本发明植物乳杆菌菌株TCI227能缓解尿酸所造成的关节腔的肿胀，藉此达到治疗痛风的功效。
综上所述，本发明植物乳杆菌菌株可藉由降低尿酸结晶所引起的发炎反应、降低尿酸值、降低关节肿胀程度、调控IL-1β基因、TNF-α基因、MMP1a基因、及TIMP1基因的表现量，达到缓解与治疗痛风的功效。
以上所述仅为举例性，而非为限制性者。任何未脱离本发明的精神与范畴，而对其进行的等效修改或变更，均应包含于后附的申请专利范围中。
【生物材料寄存】
植物乳杆菌(Lactobacillus plantarum)，寄存于DSMZ-德国微生物保存中心(Deutsche Sammlung von Mikroorganismen und Zellkulturen，DSMZ)；寄存地址：德国布伦瑞克市38124因霍芬大街7B；寄存日期为2019年9月19日，寄存编号DSM33287。
Claims (8)
1.一种植物乳杆菌(Lactobacillus plantarum)菌株用于制备一调控介白素-1β(Interleukin-1β,IL-1β)基因、肿瘤坏死因子-α(Tumor necrosis factor-α,TNF-α)基因、基质金属肽酶1a(matrix metallopeptidase 1a,MMP1a)基因及TIMP基质金属肽酶抑制因子1(TIMP metallopeptidase inhibitor 1,TIMP1)基因的表现量的组成物的用途，所述植物乳杆菌菌株的寄存编号为DSM33287。
2.根据权利要求1所述的用途，其特征在于，所述IL-1β基因、所述TNF-α基因及所述MMP1a基因的表现量被向下调控，所述TIMP1基因的表现量被向上调控。
3.根据权利要求1所述的用途，其特征在于，所述植物乳杆菌菌株的有效浓度为至少5x108细胞/mL。
4.一种植物乳杆菌(Lactobacillus plantarum)菌株用于制备一治疗痛风的组成物的用途，所述植物乳杆菌菌株的寄存编号为DSM33287。
5.根据权利要求4所述的用途，其特征在于，所述植物乳杆菌菌株的有效浓度为至少1x1010细胞/天。
6.根据权利要求1或4所述的用途，其特征在于，所述组成物是一医药品。
7.一种具缓解痛风的植物乳杆菌(Lactobacillus plantarum)菌株，所述植物乳杆菌菌株的寄存编号为DSM33287。
8.一种具缓解痛风的植物乳杆菌(Lactobacillus plantarum)菌株，其特征在于，包含一失活菌体，其中所述失活菌体为寄存编号DSM33287的所述植物乳杆菌菌株失活后的菌体。
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| CN108048368A (zh) * | 2018-01-25 | 2018-05-18 | 吉林省命之元生物科技有限公司 | 一株植物乳杆菌ua-416株及其应用 |
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| TWI346554B (en) * | 2008-04-30 | 2011-08-11 | Genmont Biotech Inc | Lactobacillus isolates having anti-inflammatory activities and uses of the same |
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| CN108048368A (zh) * | 2018-01-25 | 2018-05-18 | 吉林省命之元生物科技有限公司 | 一株植物乳杆菌ua-416株及其应用 |
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