更新于：2024-05-01

TGR5

G蛋白偶联胆汁酸受体1

更新于：2024-05-01

基本信息

别名

胆汁酸膜受体TGR5、BG37、G protein-coupled bile acid receptor 1

+ [12]

简介

Receptor for bile acid. Bile acid-binding induces its internalization, activation of extracellular signal-regulated kinase and intracellular cAMP production. May be involved in the suppression of macrophage functions by bile acids.

关联

牛磺脱氧胆酸钠(Shaperon Co., Ltd.)

靶点

TGR5

作用机制

TGR5激动剂

在研机构

原研机构

在研适应症

非在研适应症

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

RO5527239

靶点-

作用机制

TGR5激动剂

在研机构

Roche Holding AG

原研机构

Roche Holding AG

在研适应症-

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

BAR-501

靶点

TGR5

作用机制

TGR5激动剂

在研机构

Università degli Studi di Perugia [+1]

原研机构

Università degli Studi di Perugia

在研适应症

结肠炎 [+1]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

项与 TGR5 相关的临床试验

NCT06024499 / Recruiting临床2期

A Randomized, Double-blind, Placebo-controlled, Multicenter, Phase 2 Study to Evaluate the Efficacy and Safety of HY209 Gel in Patients With Mild to Moderate Atopic Dermatitis(AD)

This is a randomized, double-blind, placebo-controlled, multi-center, phase 2 study in patients with mild to moderate Atopic Dermatitis(AD), which consists of 2 parts.

开始日期2024-03-01

申办/合作机构

Shaperon, Inc.

NCT05203367 / Not yet recruiting临床1期

Randomized, Double-Blind, Placebo-Controlled, Phase 1 Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single-Ascending Doses of BAR 502 in Healthy Subjects

This is a prospective, single-center, randomized, double-blind, placebo-controlled, single-ascending dose (SAD) phase 1 study to evaluate the safety and tolerability of single-ascending doses of BAR 502 in healthy male and female subjects.

开始日期2022-11-25

申办/合作机构

BAR Pharmaceuticals s.r.l.

NCT04530643 / Completed临床2期

A Randomized, Double-blinded, Placebo-controlled, Parallel, Multi-Center Phase II Clinical Study to Evaluate the Efficacy and Safety of HY209 Gel for Patients With Atopic Dermatitis

A Randomized, Double-blinded, Placebo-controlled, Parallel, Multi-Center Phase II Clinical Study to Evaluate the Efficacy and Safety of HY209 gel for Patients with Atopic Dermatitis

开始日期2020-08-26

申办/合作机构

Shaperon, Inc.

100 项与 TGR5 相关的临床结果

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100 项与 TGR5 相关的转化医学

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0 项与 TGR5 相关的专利（医药）

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1,003

项与 TGR5 相关的文献（医药）

2024-02-08·mSystems

The function of the gut microbiota-bile acid-TGR5 axis in diarrhea-predominant irritable bowel syndrome.

Article

作者: Kai Zhan ; Haomeng Wu ; Yongyin Xu ; Kehan Rao ; Huan Zheng ; Shumin Qin ; Yuanming Yang ; Rui Jia ; Weihuan Chen ; Shaogang Huang

Imbalanced gut microbiota (GM) and abnormal fecal bile acid (BA) are thought to be the key factors for diarrhea-predominant irritable bowel syndrome (IBS-D), but the underlying mechanism remains unclear. Herein, we explore the influence of the GM-BA-Takeda G-protein-coupled receptor 5 (TGR5) axis on IBS-D. Twenty-five IBS-D patients and fifteen healthy controls were recruited to perform BA-related metabolic and metagenomic analyses. Further, the microbiota-humanized IBS-D rat model was established by fecal microbial transplantation (FMT) to investigate the GM-BA-TGR5 axis effects on the colonic barrier and visceral hypersensitivity (VH) in IBS-D. Finally, we used chenodeoxycholic acid (CDCA), an important BA screened out by metabolome, to evaluate whether it affected diarrhea and VH via the TGR5 pathway. Clinical research showed that GM associated with bile salt hydrolase (BSH) activity such as Bacteroides ovatus was markedly reduced in the GM of IBS-D, accompanied by elevated total and primary BA levels. Moreover, we found that CDCA not only was increased as the most important primary BA in IBS-D patients but also could induce VH through upregulating TGR5 in the colon and ileum of normal rats. TGR5 inhibitor could reverse the phenotype, depression-like behaviors, pathological change, and level of fecal BSH in a microbiota-humanized IBS-D rat model. Our findings proved that human-associated FMT could successfully induce the IBS-D rat model, and the imbalanced GM-BA-TGR5 axis may promote colonic mucosal barrier dysfunction and enhance VH in IBS-D. IMPORTANCE Visceral hypersensitivity and intestinal mucosal barrier damage are important factors that cause abnormal brain-gut interaction in diarrhea-predominant irritable bowel syndrome (IBS-D). Recently, it was found that the imbalance of the gut microbiota-bile acid axis is closely related to them. Therefore, understanding the structure and function of the gut microbiota and bile acids and the underlying mechanisms by which they shape visceral hypersensitivity and mucosal barrier damage in IBS-D is critical. An examination of intestinal feces from IBS-D patients revealed that alterations in gut microbiota and bile acid metabolism underlie IBS-D and symptom onset. We also expanded beyond existing knowledge of well-studied gut microbiota and bile acid and found that Bacteroides ovatus and chenodeoxycholic acid may be potential bacteria and bile acid involved in the pathogenesis of IBS-D. Moreover, our data integration reveals the influence of the microbiota-bile acid-TGR5 axis on barrier function and visceral hypersensitivity.

2024-02-08·Scientific reports

Mogrol stimulates G-protein-coupled bile acid receptor 1 (GPBAR1/TGR5) and insulin secretion from pancreatic β-cells and alleviates hyperglycemia in mice.

Article

作者: Chisato Tanaka ; Naoki Harada ; Yoshiaki Teraoka ; Hiroki Urushizaki ; Yoh Shinmori ; Teruaki Onishi ; Yusuke Yotsumoto ; Yuta Ito ; Tomoya Kitakaze ; Takashi Inui ; Yuji Murata ; Hiroshi Inui ; Ryoichi Yamaji

Target identification is a crucial step in elucidating the mechanisms by which functional food components exert their functions. Here, we identified the G-protein-coupled bile acid receptor 1 (GPBAR1, also known as TGR5) as a target of the triterpenoid mogrol, a class of aglycone mogroside derivative from Siraitia grosvenorii. Mogrol, but not mogrosides, activated cAMP-response element-mediated transcription in a TGR5-dependent manner. Additionally, mogrol selectively activated TGR5 but not the other bile acid-responsive receptors (i.e., farnesoid X receptor, vitamin D receptor, or muscarinic acetylcholine receptor M3). Several amino acids in TGR5 (L71A^2.60, W75A^ECL1, Q77A^ECL1, R80A^ECL1, Y89A^3.29, F161A^ECL2, L166A^5.39, Y240A^6.51, S247A^6.58, Y251A^6.62, L262A^7.35, and L266A^7.39) were found to be important for mogrol-induced activation. Mogrol activated insulin secretion under low-glucose conditions in INS-1 pancreatic β-cells, which can be inhibited by a TGR5 inhibitor. Similar effects of mogrol on insulin secretion were observed in the isolated mouse islets. Mogrol administration partially but significantly alleviated hyperglycemia in KKAy diabetic mice by increasing the insulin levels without affecting the β-cell mass or pancreatic insulin content. These results suggest that mogrol stimulates insulin secretion and alleviates hyperglycemia by acting as a TGR5 agonist.

2024-02-02·Scandinavian journal of immunology

The role of bile acid receptor TGR5 in regulating inflammatory signalling.

Review

作者: Daijiao Ye ; Jiayao He ; Xiaofei He

Takeda G protein-coupled receptor 5 (TGR5) is a bile acid receptor, and its role in regulating metabolism after binding with bile acids has been established. Since the immune response depends on metabolism to provide biomolecules and energy to cope with challenging conditions, emerging evidence reveals the regulatory effects of TGR5 on the immune response. An in-depth understanding of the effect of TGR5 on immune regulation can help us disentangle the interaction of metabolism and immune response, accelerating the development of TGR5 as a therapeutic target. Herein, we reviewed more than 200 articles published in the last 20 years in PubMed, to discuss the roles of TGR5 in regulating inflammatory response, the molecular mechanism, as well as existing problems. Particularly, its anti-inflammation effect is emphasized.

项与 TGR5 相关的新闻（医药）

2024-03-23

·生物探索

Neuron | 中国药科大学洪浩/唐苏苏等合作发现胆汁酸起抗抑郁的潜在分子机制

引言虽然胆汁酸在抑郁症中起着显著的作用，但胆汁酸TGR5膜型受体在该疾病中的病理意义尚不清楚。2024年3月21日，中国药科大学洪浩、唐苏苏、浙江大学王浩共同通讯在Neuron 在线发表题为“TGR5-mediated lateral hypothalamus-dCA3-dorsolateral septum circuit regulates depressive-like behavior in male mice”的研究论文，该研究表明TGR5介导的下丘脑外侧-dCA3背外侧隔膜回路能够调节雄性小鼠的抑郁样行为。利用慢性社会失败应激和慢性约束应激的雄性小鼠抑郁模型，发现抑郁样小鼠下丘脑外侧区(LHA) GABA能神经元TGR5显著降低，其兴奋性增加。上调LHA中TGR5或抑制GABA能兴奋性可显著缓解抑郁样行为，而下调TGR5或增强GABA能兴奋性可促进应激诱导的抑郁样行为。TGR5还通过细胞外调节蛋白激酶依赖的Kv4.2通道双向调节LHA GABA能神经元的兴奋性。值得注意的是，LHA gabaergy神经元特异性地支配背侧CA3 (dCA3) CaMKIIα神经元，介导抑郁样行为。LHA GABAergic TGR5通过去抑制dCA3 CaMKIIα神经元投射到背外侧隔(DLS)发挥抗抑郁样作用。这些发现促进了人们对TGR5和LHAGABA/dCA3CaMKIIα /DLSGABA回路的理解，有助于开发抑郁症的潜在治疗策略。抑郁症是一种高度异质性的情绪障碍，是世界范围内致残的主要原因在复杂的抑郁症病因中，慢性压力是一个主要的危险因素。应激可导致细胞、分子和神经系统功能障碍，这是抑郁症的潜在治疗靶点。新出现的临床证据发现，抑郁症患者和健康人血液中的胆汁酸(BAs)水平存在显著差异，以及BAs与抑郁症症状之间的相关性。动物研究表明，全身服用牛磺酸去氧胆酸(一种亲水性BA)可产生类似抗抑郁的作用。值得注意的是，人类和动物研究都表明BA信号与抑郁症有关。Takeda G蛋白偶联受体5 (TGR5)，也称为G蛋白偶联BA受体(GPBAR1)，是第一个被发现的针对BAs的G蛋白偶联受体。虽然外周TGR5是一种已知的代谢调节因子，但最近的研究表明中枢TGR5参与能量调节。TGR5激动剂可在脑疾病中发挥有益作用。之前的研究发现慢性应激导致海马和下丘脑的TGR5减少，背侧CA3 (dCA3) CaMKIIα神经元的TGR5对抑郁样行为有调节作用，这些发现提出了关于下丘脑TGR5在抑郁症中的潜在参与的有趣问题。模式图（Credit: Neuron）人类神经影像学研究已经报道了抑郁状态下下丘脑的结构、功能和相关网络异常。神经内分泌研究表明，大多数抑郁症患者的下丘脑-垂体-肾上腺(HPA)轴过度活跃。下丘脑外侧区(LHA)，构成下丘脑的很大一部分，在协调各种生理功能(如应激、摄食和睡眠-觉醒状态)中起着重要的神经解剖学中枢作用。LHA是一种异质核，包含GABA能、谷氨酸能和肽能神经元，如食欲素和黑色素浓缩激素(MCH)。人类研究表明，主要由LHA中表达orexin或MCH的神经元合成的orexin或MCH的失调参与了抑郁症的发病机制。LHA - orexin或MCH-表达神经元外侧缰核(LHb)或伏隔核(Acb)介导应激诱导的抑郁样行为。从LHA到LHb的谷氨酸能轴突也参与应激诱导的抑郁症发病，然而，LHA GABA能神经元是否介导抑郁样行为仍不清楚。该研究检测了下丘脑TGR5在雄性小鼠抑郁样行为中的区域和细胞类型特异性作用以及TGR5介导的回路机制。该研究确定了TGR5、LHA GABA能神经元、TGR5介导的细胞信号传导和LHAGABA/ dCA3CaMKIIα/DLSGABA回路在抑郁相关状态中的作用。这项研究增强了人们对TGR5和LHA GABA能神经元作为开发潜在抗抑郁策略的新靶点的理解。原文链接https://www.cell.com/neuron/abstract/S0896-6273(24)00152-1责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文CRISPR技术进化史 | 24年Cell综述

2024-03-18

·BioSpace

Shaperon Enrolls Its First Patient in Phase 2 U.S. Clinical Trial for Atopic Dermatitis Therapy 'Nugel'

210 Patients With Multi-Racial Atopic Dermatitis...Phase 2 Clinical Trial Begins CAMBRIDGE, Mass. & SEOUL, South Korea--(BUSINESS WIRE)-- Shaperon, Inc. (Kosdaq: 378800), a biotechnology company developing innovative immune drugs, announced the enrollment of the first patient in the Phase 2 clinical trial for Nugel, its therapy for Atopic Dermatitis. This milestone marks the start of a crucial phase in Shaperon’s effort to advance treatment for patients globally. With FDA approval secured for the Global Phase 2 Clinical Trials (IND) of Nugel in September 2023, Shaperon is dedicated to evaluating its efficacy in improving the Eczema Area Severity Index (EASI) across a diverse cohort of 210 patients with mild to moderate atopic dermatitis. Employing a rigorous double-blind, placebo-controlled methodology, the trial is anticipated to conclude by the first half of 2026. Market research forecasts indicate a robust growth of over 8.7%, projecting the global atopic dermatitis market to reach $19.1 billion by 2030. Presently, patients rely on steroids and FDA-approved medications, yet there remains a pressing need for novel drugs due to their adverse effects and limited efficacy. Of particular note, more than 70% of patients exhibit positive responses to the biomarker discovered during Shaperon's phase 2 clinical trials in Korea, categorized as "A type A atopic patients." This treatment, distinguished by its superior safety and efficacy compared to existing JAK inhibitors or PDE4 inhibitors in the market, has garnered attention at U.S. and European forums. Shaperon has already initiated patent applications for this biomarker, enabling tailored treatments for patients showing exceptional responses to Nugel. Nugel represents a paradigm shift in atopic dermatitis therapy as the world's first inflammation control drug targeting 'GPCR19' action. Its unique mechanism of action, exclusive to immune-related cells, offers minimal side effects while effectively addressing inflammatory pathways. Beyond atopic dermatitis, Nugel holds promise for treating a spectrum of skin conditions, further underscoring its potential impact on global healthcare. Dr. Seung-Yong Seong, CEO of Shaperon, reaffirms Shaperon's commitment to advancing Nugel's global presence and facilitating technology transfer through the Phase 2 clinical trials. Leveraging innovative approaches such as a smartwatch-based AI medication management system demonstrates Shaperon's dedication to optimizing patient outcomes and data reliability. The establishment of Hudson Therapeutics, Shaperon's U.S.-based subsidiary, reinforces its strategic vision for global expansion and technology exports. ABOUT SHAPERON Shaperon is a clinical stage biotech company developing novel inflammasome inhibitors. Its unique mechanism of action of GPCR19-P2X7 modulation suppresses a broad spectrum of inflammatory cytokines including IL-1β, IL-18, IL-6, and TNF-α by controlling both priming and activation phase of inflammasome, whereas conventional approaches are designed to suppress only the activation phase. With this unique and novel modality which is best suited to address complex immune-mediated inflammatory disorders, Shaperon is currently developing multiple clinical programs in atopic dermatitis, cytokine release syndrome, Alzheimer’s disease, Obesity and MASH. ABOUT Hudson Therapeutics Hudson Therapeutics, a US subsidiary of Shaperon, was founded in 2023 to lead global clinical trials and business development of assets from Shaperon. Hudson’s pipeline includes immunology clinical assets in Atopic Dermatitis, Covid-19, Alzheimer’s Disease and preclinical programs focused in Obesity and other indications, combined with their nanobody platform. View source version on businesswire.com: Contacts Ellie Jung (ellie@hudsontherapeutics.com) Source: Shaperon View this news release online at:

临床2期

2024-02-29

·药时代

G蛋白偶联受体激动剂或拮抗剂治疗代谢性疾病：新药研发进度更新

常见代谢性疾病，如肥胖、代谢综合征、高脂血症、高血压、非酒精性脂肪性肝病（NAFLD）、糖尿病等，影响全球超过20%的人口，给社会带来巨大的医疗负担。每年超过1197万人死于这些疾病及其并发症，其中肥胖和高脂血症占死亡率的高位，肥胖和2型糖尿病（T2D）的死亡率仍在持续上升。目前虽然已有高效药物用于降低甘油三酯和胆固醇，胰岛素增敏剂的使用也有效减少、推迟T2D患者对胰岛素的需求，但亟需寻找更有效治疗手段以应对这些发病率高、死亡率日渐增长的代谢性疾病。近期，复旦大学基础医学院病原生物学系、教育部/卫健委医学分子病毒学重点实验室吴健教授团队阐述了G蛋白偶联受体（GPCR）调控代谢性疾病发生和进展的机制，揭示了关键GPCR如GPR55、GPR91、GPR119、GPR109a、GPR142、GPR40、GPR41、GPR43和GPR120在代谢综合征、NAFLD和糖尿病等常见代谢性疾病中的重要作用，为药物干预提供了理论基础。基于这些GPCR的药理学效应、临床前或临床试验结果，该团队还全面描绘了这些GPCR激动剂或拮抗剂药物研发现状，着重分析了小分子化合物的治疗效益和可能的安全性问题。因此，该长篇综述是继先前发表的“治疗非酒精性脂肪性肝炎药物临床试验更新”一文（《中国药理学报Acta Pharmacol Sin》 2022; 43: 1180–1190）的续篇，于2024年2月7日同刊在线发表（DOI：10.1038/s41401-023-01215-2）。英文版Acta Pharmacol Sin 在JCR分区中定为医学一区，药理学一区。GPCRs是一类重要的跨膜蛋白受体，对维持各种生理活动起着关键作用。它们接收局部或循环系统中的信号配体，参与调控包括代谢、神经传递和免疫反应在内的多种生理反应。已确定大部分GPCRs的天然配体，其中大多数是代谢产物、脂肪酸、肽类或神经递质，包括胺类、氨基酸、离子、脂质、肽类、蛋白质等。尚未确定特定配体的GPCR被称为孤儿受体。GPCR数据库（GPCRdb）记录了800多个人类GPCR的基因，已经捕获和阐明了793个GPCR结构、781个受体-配体复合物结构以及381个活跃状态下的受体结构。目前，GPCR结构生物学已揭示了229个高分辨136个GPCR-配体复合物的结构，这些结构涉及48种GPCR。大部分GPCRs在结构上相似（图1），由一个细胞外N-末端、七个跨膜结构域（TM）和一个细胞内C-末端组成。三个亲水性细胞外环（ECL）连接着七个跨膜结构域，一个高度保守的二硫键连接TM3的顶部和ECL2的中部，这个二硫键形成了配体结合域的底部。此外，还有第二个二硫键连接受体的N-末端和TM7的顶部，并形成一个伪环，即ECL4。TM3、TM5和TM6在配体结合和G蛋白偶联过程中起重要作用。三个细胞内环（ICL）与TMs一起可能引起结构变化，从而暴露用于偶联和触发下游事件的功能性G蛋白亚单位。不同类型的配体结合到静止GPCRs的配体结合域，配体与受体的偶联激活GPCRs，随之GPCRs的空间构象发生改变，导致GTP取代了Gαβγ/GDP复合物上结合在Gα亚基上的GDP，复合物解离为具有活性的Gα和Gβγ亚基，并通过下游信号分子即第二信使分子：如环磷酸腺苷（cAMP）、钙离子、肌醇三磷酸（IP3）或二酰基甘油（DAG）等发挥调节作用。GPCRs的作用是多方面的，可分为两类：（1）生理作用：通过促进葡萄糖依赖型胰岛素分泌，改善血脂异常、胰岛素抵抗和糖尿病状态；（2）病理作用：从增强炎症反应和肝细胞脂质堆积，到血管内膜脂质沉积，进而导致伴有严重代谢紊乱NAFLD和动脉粥样硬化。图1：GPCRs的信号通路及对代谢性疾病的影响GPCR与G蛋白亚单位结合，触发各种第二信使的生成，调节涵盖生理功能和病理状况的各个方面，这些病理状况包括代谢综合征、肥胖、糖尿病、NAFLD等。由于其表面可及性和特定的信号传导机制，GPCRs被认为是许多种疾病的药物干预靶点，目前批准的药物中近30%是它们的激动剂或拮抗剂。因此，针对GPCRs的特异性激动剂或拮抗剂的开发对代谢调节至关重要，可能有助于对代谢性疾病进行药理学的干预。该文概述了GPCR发挥的重要生理功能，包括脂肪和葡萄糖代谢以及胰岛素释放等生理过程。最新发现指出GPCR与其配体相互作用参与了代谢性疾病的病理过程，并且可能成为这些疾病的潜在治疗靶点。本文系统地总结了参与代谢紊乱相关的关键GPCRs及其激动剂/拮抗剂小分子化合物的成药可能性，为这类药物的研发提供了理论基础和临床试验数据（表1）。表中所列GPCRs特异性激动剂或拮抗剂小分子化合物能否成为治疗代谢性疾病的新药取决于受体表征、晶体结构、化合物设计、药理学筛选、临床评估等。这类药物的研发往往耗时费力，只有少数候选化合物最终进入IIb和III期临床试验阶段。部分GPCR19、GPCR109a、GPCR142、GPCR40和GPCR120激动剂/拮抗剂已经进入临床试验阶段；然而，GPR91、GPR55、GPR41和GPR43的激动剂/拮抗剂仍处于临床前阶段。表1：GPCR激动剂和拮抗剂治疗代谢性疾病的研发概况总之，目前已确定特定GPCR生理功能和组织分布，及其参与营养和能量代谢分子机制，已开发出一系列GPCR激动剂和拮抗剂小分子化合物，例如MBX-2982、MK0354、LY3325656、Tak-875等，部分化合物已经进入早期或晚期临床试验，为治疗代谢性疾病如代谢综合征、血脂异常、非酒精性脂肪肝病、糖尿病及其并发症找到后备新药。然而，代谢性疾病作为一类慢性进行性疾病，通常涉及多个器官或系统，且GPCR具有广泛的组织分布和复杂的生理功能，在没有消除病因的情况下，仅依靠特定GPCR的激动剂或拮抗剂难以实现疾病的根治。因此，在研发针对上述GPCR高特异性和高准确性激动剂或拮抗剂小分子化合物的同时，减少疾病的风险因素并维持健康生活方式是预防代谢性疾病最有效且经济的方法。本文第一作者为复旦大学上海医学院8年制临床医学专业金诚同学，通讯作者为复旦大学基础医学院病原生物学系吴健教授与复旦大学附属中山医院消化科刘黎黎医师。吴健教授为复旦大学中山医院消化科双聘教授，现受自然科学基金面上项目资助，曾承担科技部重大研发专项。近30年首款！渤健ALS新药或将将在欧洲获批，如果不是沾了基因疗法的光......14.6亿美元！诺和诺德又有新交易想要加速审批上市的药物退市分几步？高管被捕、试验失败、自愿撤市、专家咨询委员会反对……点击这里，欣赏更多精彩内容！

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