药学学报

Cancer	Involvement	Reference
Colorectal cancer	Postoperative recurrence risk and survival time were not associated with GPR35 expression in the primary tumor, but high GPR35 expression after colon cancer metastasized to the lymph nodes were indicative of a poor prognosis	[36, 37]
Gastric cancer	GPR35 expression was significantly correlated with the degree of tumor differentiation, stage, lymph node metastasis and distant metastasis, and the prognosis of patients with high GPR35 expression was poor	[38]
Lung cancer	Overexpression of GPR35 was associated with poor prognosis in lung adenocarcinoma patients, but not in lung squamous cell carcinoma patients	[39]
Breast cancer	The level of GPR35 expression had no prognostic significance in breast cancer, but it was significantly associated with advanced histological grade and higher proliferation rate of breast cancer	[40]

Cancer	Involvement	Reference
Colorectal cancer	Postoperative recurrence risk and survival time were not associated with GPR35 expression in the primary tumor, but high GPR35 expression after colon cancer metastasized to the lymph nodes were indicative of a poor prognosis	[36, 37]
Gastric cancer	GPR35 expression was significantly correlated with the degree of tumor differentiation, stage, lymph node metastasis and distant metastasis, and the prognosis of patients with high GPR35 expression was poor	[38]
Lung cancer	Overexpression of GPR35 was associated with poor prognosis in lung adenocarcinoma patients, but not in lung squamous cell carcinoma patients	[39]
Breast cancer	The level of GPR35 expression had no prognostic significance in breast cancer, but it was significantly associated with advanced histological grade and higher proliferation rate of breast cancer	[40]

GPR35去孤儿化研究及其在疾病中的作用

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张启情 ¹ , 焦宇 ² , 张尊建 ¹ , 许风国 ¹^,^* , 张培 ¹^,^*

药学学报 | 综述 2023,58(8): 2139-2145

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药学学报 |综述 2023 , 58 (8) : 2139 -2145

GPR35去孤儿化研究及其在疾病中的作用

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张启情¹, 焦宇², 张尊建¹, 许风国¹^,^*, 张培¹^,^*

作者信息

1.中国药科大学, 药物质量与安全预警教育部重点实验室, 江苏南京 210009

2.中国药科大学理学院, 江苏南京 211198

通讯作者:

*许风国, Tel: 86-25-83271021, E-mail: fengguoxu@cpu.edu.cn;

张培, E-mail: peizhang@cpu.edu.cn

Recent advances in deorphanization of GPR35 and its functions in related diseases

Qi-qing ZHANG¹, Yu JIAO², Zun-jian ZHANG¹, Feng-guo XU¹^,^*, Pei ZHANG¹^,^*

Affiliations

1. Ministry of Education Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Nanjing 210009, China

2. School of Science, China Pharmaceutical University, Nanjing 211198, China

出版时间: 2023-08-12 doi: 10.16438/j.0513-4870.2023-0465

文章导航

摘要

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G蛋白偶联受体(G protein-coupled receptors, GPCRs) 是药物研发中最受关注的靶点家族, 尚存在近300种孤儿受体, 具有重大潜在药物研发价值。G蛋白偶联受体35 (G protein-coupled receptor 35, GPR35) 是一种A类、视紫红质样孤儿GPCR, 广泛参与胃肠道疾病、心血管疾病和癌症等多种疾病的发生发展, 并与免疫调节密切相关, 提示其可作为多种疾病治疗潜在靶点。然而, 目前针对GPR35的研究尚不充分, 包括GPR35真正的内源性配体尚未确证, 其在疾病中发挥作用的分子机制仍不完全清楚, 缺乏靶向GPR35的有效干预策略等。本文综述了GPR35去孤儿化研究、GPR35相关信号通路及其与多种疾病的关联, 以期为深入研究GPR35在疾病中的作用、研发靶向GPR35的药物提供参考。

关键词

G蛋白偶联受体35 / 孤儿受体 / 胃肠道疾病 / 心血管疾病 / 癌症

Abstract

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G protein-coupled receptors (GPCRs) represent the largest family of membrane proteins and are the target of approximately half of all therapeutic drugs. There are ~300 orphan GPCRs, which have great potential in drug development. G protein-coupled receptor 35 (GPR35), a rhodopsin-like orphan GPCR, is widely involved in immune regulation, gastrointestinal disorders, cardiovascular diseases, cancer, as well as other diseases, suggesting its great potential as a therapeutic target in a variety of diseases. However, the current research on GPR35 is insufficient, including the true endogenous ligand has not been confirmed, the molecular mechanism of its role in disease is not fully understood, and there is a lack of effective intervention strategies targeting GPR35. This article summarizes the deorphatization of GPR35, GPR35-related signaling pathways and their association with various diseases, in order to provide a reference for in-depth study of GPR35 in diseases and development of drugs targeting GPR35.

Key words

G protein-coupled receptor 35 / orphan receptor / gastrointestinal disorder / cardiovascular disease / cancer

引用本文

张启情, 焦宇, 张尊建, 许风国, 张培. GPR35去孤儿化研究及其在疾病中的作用. 药学学报, 2023 , 58 (8) : 2139 -2145 . DOI: 10.16438/j.0513-4870.2023-0465

Qi-qing ZHANG, Yu JIAO, Zun-jian ZHANG, Feng-guo XU, Pei ZHANG. Recent advances in deorphanization of GPR35 and its functions in related diseases[J]. Acta Pharmaceutica Sinica, 2023 , 58 (8) : 2139 -2145 . DOI: 10.16438/j.0513-4870.2023-0465

正文

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G蛋白偶联受体(G protein-coupled receptors, GPCRs) 与多种疾病的发生和进展密切相关, 是迄今最大的药物靶标家族。据统计, FDA批准药物中约有34%作用于GPCRs, 但是800多个GPCRs中仅有108个是明确的药物靶点, 还有众多GPCRs的靶点潜力和价值亟待开发^[1]。G蛋白偶联受体35 (G protein-coupled receptor 35, GPR35) 是一种A类、视紫红质样孤儿GPCR, 已有研究揭示其广泛参与胃肠道、心血管疾病及癌症等多种疾病的发生发展, 并与免疫调节密切相关, 但目前尚无靶向GPR35治疗的临床药物。本文针对GPR35的表达及相关信号通路、去孤儿化研究、与疾病关联进行综述, 以期为深入研究GPR35在疾病中的作用、研发靶向GPR35治疗的药物提供理论参考。

1 GPR35概述

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GPR35位于人类染色体2q37.3区, 可表达GPR35a和GPR35b两种亚型, 其中GPR35a由309个氨基酸组成, GPR35b的N端包含31个氨基酸的延伸, 但两种GPR35亚型间没有明显的药理学差异^[2]。大麻素受体GPR55、烟酸受体HM74和溶血磷脂酸受体LPAR4、LPAR5和LPAR6与GPR35具有较高的同源性^[3], 但其配体均不能激动GPR35, 即GPR35仍然是一种孤儿受体。此外, 小鼠和大鼠中各有一种GPR35直系同源物, 与人GPR35a的同源性为73%、72%^[2], 中等程度的同源性限制了GPR35配体和功能的跨物种研究。

2 GPR35表达及相关信号通路

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2.1 GPR35表达

目前, 有关GPR35表达的研究主要基于mRNA水平。GPR35在十二指肠、小肠、结肠、直肠和胃等胃肠道组织高水平表达, 在全脑、肌肉组织、骨髓和淋巴组织等中等程度表达; 除肠细胞外, GPR35也在巨噬细胞、单核细胞和树突状细胞等多种亚型的人免疫细胞中高水平表达(图 1)。GPR35在胃肠道及免疫系统的高表达, 提示了其在胃肠道稳态、免疫调节中起着重要作用。另外, 有研究表明, GPR35表达水平在炎症^[4]、缺氧(如心肌梗死)^[5]等条件下被上调。

2.2 GPR35相关信号通路

GPR35参与多种疾病的发生发展(图 2), 其相关信号通路的研究对GPR35功能的阐释、靶向GPR35的药物研发十分重要。就经典的GPCR信号而言, GPR35与Gα_i/o和Gα₁₃偶联并募集β-arrestin。GPR35/Gα_i/o促进c-Jun氨基末端激酶(c-Jun N-terminal kinase, JNK)^[6]、细胞外信号调节激酶1/2 (extracellular signal regulated kinase 1/2, ERK1/2)^[7]磷酸化, 进而广泛参与细胞迁移、免疫调节等生理过程, 激活过氧化物酶体增殖物激活受体γ共激活因子-1α (peroxisome proliferator-activated receptor-γ coactivator-1α, PGC-1α) 促进脂质代谢、产热和抗炎基因的表达^[8]。GPR35/Gα₁₃通过影响Ras同源类似物A (Ras homolog family member A, RhoA)/Rho激酶(Rho-associated kinase, ROCK)^[9]信号发挥肌动蛋白调节、细胞骨架重排、血管重塑等作用。GPR35还可激活Gα_i/o、Gα₁₃信号并转运到线粒体外膜与ATP酶抑制因子1 (ATPase inhibitory factor 1, ATPIF1) 结合, 从而防止缺血时ATP损失^[5]。此外, β-arrestin在信号传导中发挥支架作用, GPR35/β-arrestin与ERK1/2磷酸化和受体脱敏等有关^[10]。

除经典GPCR信号外, GPR35还间接地与多种靶点相互作用, 极大扩展了GPR35在不同细胞或组织中的功能。缺氧诱导因子-1α (hypoxia-inducible factor-1α, HIF-1α) 激活时, GPR35表达上调^{[5, 11]}。GPR35可通过不同的途径影响NOD样受体蛋白3 (NOD-like receptor protein 3, NLRP3) 炎症小体激活或降解, Sun等^[12]认为犬尿喹啉酸(kynurenic acid, KA)/GPR35引起Ca²⁺动员减弱、线粒体损伤加剧, 进而阻断NLRP3炎症小体的组装; 而Zheng等^[13]认为KA/GPR35诱导自噬溶酶体依赖的NLRP3炎症小体降解。除此之外, Pagano等^{[14, 15]}发现GPR35通过Na⁺/K⁺-ATPase促进细胞增殖、新血管生成和基质金属蛋白酶活性。

目前, 有关GPR35信号通路的研究尚处于起步阶段, 表现在不同GPR35配体触发交错的信号通路、部分GPR35功能具有相关或互补的信号通路、部分GPR35功能相关信号通路尚未明确等, 本文后续将结合特定GPR35配体及疾病类型进一步介绍GPR35相关信号通路。

3 GPR35去孤儿化研究

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3.1 GPR35潜在内源性激动剂

对受体功能和激活机制的深入研究需要识别其内源性配体, GPR35真正的内源性配体至今尚未确证, 但现有研究发现的几种内源性物质包括KA、溶血磷脂酸(lysophosphatidic acids, LPA) 和趋化因子17 (chemokine 17, CXCL17)、5-羟基吲哚乙酸(5-hydroxyindole acetic acid, 5-HIAA) 等被学者们建议为GPR35的内源性激动剂(图 3)。

KA是第一个被报道且最常用的GPR35内源性激动剂^[16], KA/GPR35参与炎症调节^[17]、脂肪细胞能量稳态^[8]和缺氧保护^[5]等多种生理病理过程。但KA是否是GPR35内源性激动剂仍存在争议, 主要原因包括: ①体外研究中KA浓度需要达到毫摩尔级别才能发挥GPR35激动作用, 但人血浆中KA水平一般仅为纳摩尔级别, 在炎症或病理状态下KA的局部浓度可以达到毫摩尔级别^[16]; ② KA还激活NMDAR、α7nAChR、AhR等靶点^[2], 即KA的体内作用涉及多靶点和复杂的调控网络, 难以特异性研究其与GPR35的相关性; ③ KA具有明显的啮齿动物选择性, KA对于小鼠、大鼠GPR35的效价比人GPR35的高40~100倍^[18]。

LPA^[19]和CXCL17^[20]也是常用的GPR35内源性激动剂。Oka等^[19]发现LPA具有GPR35激动活性, 且Kaya等^[4]认为结肠巨噬细胞中的LPA/GPR35信号可以缓解肠道炎症以维持肠道稳态。但LPA是GPR35的偏置配体, 即LPA激活GPR35下游Gα_q信号而不激活Gα_i/o、Gα₁₃或β-arrestin信号^[19], 在常用的GPR35配体筛选实验中无法激动GPR35。Maravillas-Montero等^[20]发现CXCL17在生理浓度下提高GPR35下游Ca²⁺响应、促进GPR35介导的细胞迁移, 并建议将GPR35更名为趋化因子受体8 (chemokine receptor 8, CXCR8)。但之后的研究并未重现这一发现, Binti等^[21]发现CXCL17不影响GPR35下游Ca²⁺、Gα_i/o和Gα₁₃信号, Park等^[22]发现抑制或沉默GPR35并不影响CXCL17的细胞迁移作用。

另外, 第二信使cGMP^[23]、部分酪氨酸代谢物^[24]在体外GPR35配体筛选实验中表现出GPR35激动活性, 但这些配体的筛选未涉及GPR35相关信号机制或功能, 也未经其他研究证实。最新研究发现, 5-HIAA可以激动GPR35, 且5-HIAA/GPR35信号促进中性粒细胞向炎症部位的迁移^[25]。

除配体依赖型激活方式, GPR35还有着不依赖配体的独特调控方式。Pagano等^[14]近期的研究发现, GPR35与Na⁺/K⁺-ATPase能以非配体依赖的方式相互作用, 促进结直肠肿瘤生长。

3.2 GPR35合成激动剂、抑制剂

虽然真正的GPR35内源性配体尚未达成共识, 但近年来, 作为探索GPR35的工具化合物, 其合成激动剂、抑制剂的研究取得了一定进展(图 3)。扎普司特(zaprinast) 是报道最早、应用最多的GPR35合成激动剂。因为zaprinast在人类、小鼠和大鼠GPR35直系同源物中表现出较高且相似的效力, 故常在高通量筛选中作为参考激动剂使用^[26]。此外, 针对临床药物的GPR35配体筛选实验中, cromolyn、nedocromil、lodoxamide、bufrolin等肥大细胞稳定剂、抗哮喘药物表现出GPR35激动性, 其中lodoxamide在人和大鼠GPR35上具有相似的效力但几乎不激活小鼠GPR35, 常被用于研究GPR35配体的种属差异性、GPR35结合口袋。针对Prestwick Chemical Library^®、Sequoia Libraries^®等小分子化合物库的GPR35配体筛选发现了人GPR35选择性、高效激动剂pamoic acid (PA)^[27]、“compound 1”^[28]等, 而Thimm等^[29]借助“compound 1”制备了放射性配体PSB-13253, 可用于GPR35已知配体的亲和力测定和构效关系研究。

抑制剂对GPCRs的结构表征、功能及分子机制研究也十分重要, 但迄今为止, 仅有CID2745687、ML145两种合成抑制剂可用于GPR35相关研究^[30] (图 3)。CID2745687可以抑制PA诱导的镇痛^[27]、迁移修复^[7], ML145可以抑制PA诱导的缺氧应激反应^[31]等, 但CID2745687和ML145均表现出人GPR35选择性, 而无法用于啮齿动物层面的研究。

4 GPR35与疾病关联

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4.1 胃肠道疾病

GPR35是炎症性肠病(inflammatory bowel disease, IBD) 的风险基因, 与溃疡性结肠炎(ulcerative colitis, UC)、克罗恩病(Crohn's disease, CD) 等有关。GPR35通过多种信号机制发挥肠道保护作用: Tsukahara等^[7]发现PA/GPR35促进fibronectin、integrin-5表达和ERK1/2磷酸化, 进而促进结肠黏膜修复。Kaya等^[4]发现CX3CR1⁺巨噬细胞中的LPA/GPR35促进TNF-α、醛固酮羟化酶细胞色素P450家族成员11b1 (cytochrome P450 11b1, Cyp11b1) 表达, 从而维持肠道稳态。Sun等^[12]发现KA/GPR35抑制NLRP3炎症小体的过度激活, 减少脂多糖(lipopolysaccharides, LPS) 刺激时的IL-1β的分泌。但是, Zheng等^[13]发现KA诱导NLRP3炎症小体的降解, 加剧慢性社交挫败应激抑郁小鼠的肠炎, 与Sun等^[12]研究比较, 推测GPR35对NLRP3的作用需要考虑机体处于炎症或稳态条件。综上, GPR35通过多种机制参与胃肠道稳态调节(图 4), 靶向GPR35的激动剂或抑制剂开发均具有重要的意义。

4.2 心血管疾病

GPR35虽然在心血管系统中的表达水平不高, 但其与高血压、心肌梗死和心力衰竭等多种心血管疾病相关。GPR35参与生理和病理条件下的血压调节, 与野生型小鼠相比, GPR35^-/-小鼠血压显著升高(37.5 mmHg)^[32], 而敲除GPR35可以缓解血管紧张素Ⅱ^[33]和醋酸脱氧皮质酮^[34]诱发的高血压。另外, GPR35是心力衰竭的早期标志物^[32], 12名心力衰竭患者的全基因表达分析显示心衰患者心肌组织中GPR35显著上调^[32], 新生小鼠心肌细胞在缺氧或HIF-1α激活时GPR35显著上调^[11], 深入研究发现GPR35/Gα₁₃通过RhoA/ROCK通路参与肌动蛋白调节、细胞骨架重排, 进而导致心肌重塑^[11]。此外, GPR35在心肌梗死中表达上调, 而抑制GPR35可以下调钙蛋白酶1/2 (calpain 1/2) 从而减少活性氧和线粒体依赖的细胞凋亡^[35]。另外, McCallum等^[9]发现GPR35通过RhoA/ROCK促进人血管平滑肌细胞增殖和血管内皮细胞迁移, 提示了GPR35作为血管重塑治疗新靶标的潜力, 并建议开发GPR35抑制剂用于冠状动脉搭桥术后血管再狭窄的治疗。

4.3 癌症

GPR35与结直肠癌(colorectal cancer, CRC)、胃癌、乳腺癌等多种癌症相关, 整合The Cancer Genome Atlas (TCGA) 和The Genotype-Tissue Expression (GTEx) 数据库数据发现, 与正常组织相比, GPR35在结直肠癌、胃癌和胰腺癌中表达上调, 而在卵巢癌和乳腺癌中表达不变。更重要的是, 临床数据表明, GPR35过表达与结直肠癌、非小细胞肺癌、胃癌患者的不良预后相关, 而GPR35表达水平与乳腺癌、胃癌中肿瘤分化程度、分期和转移相关(表 1^[36-40])。

此外, GPR35与癌症相关的机制研究也取得了一定进展。Pagano等^[14]发现GPR35通过两种机制促进CRC的进展, 一方面直接增加肠上皮细胞的增殖; 另一方面是协调巨噬细胞创造肿瘤生长环境的能力。进一步研究发现, 上述过程由Na⁺/K⁺-ATPase依赖的Src激酶介导, 且靶向此通路的短肽pNaKtide可以抑制结直肠肿瘤生长^[14]。此外, Wang等^[39]发现GPR35过表达通过β-arrestin/蛋白激酶B (protein kinase B, AKT) 通路导致非小细胞肺癌细胞耐药。基于此, GPR35抑制剂在癌症的治疗中具有巨大潜力。

4.4 疼痛

除胃肠道疾病、心血管疾病和癌症外, GPR35广泛参与神经病理性疼痛和伤害感受性疼痛^[41]。KA、PA和zaprinast均显著减少内脏疼痛模型中小鼠的扭体次数, KA和zaprinast导致大鼠、小鼠对热刺激的疼痛反应延迟, Ret条件敲除(导致GPR35失调) 引起小鼠机械性刺激、冷刺激的痛敏现象等。然而, 目前GPR35与疼痛相关的研究均是在啮齿动物模型上进行的, GPR35在人体疼痛治疗中的作用及相关机制亟待确证。

4.5 免疫与代谢调节

GPR35在多种免疫细胞中高水平表达, 且GPR35双向、细胞类型依赖性地调节炎症因子的释放。一方面, KA/GPR35剂量依赖性地减少LPS诱导的人外周血单核细胞中TNF-α的释放^[16], 抑制LPS+ATP诱导的THP-1细胞中IL-1β的分泌^[13], 提示了GPR35的抗炎作用; 另一方面, KA/GPR35减少iNKT细胞中IL-4的释放^[42], 即GPR35表现为促炎作用。GPR35与免疫因子释放相关的机制研究很大程度上依赖KA/GPR35信号: KA结合并激活GPR35, 导致细胞中的cAMP和Ca²⁺浓度水平降低, AKT、ERK1/2和p38激酶的磷酸化减少以及β-catenin表达水平上调, 进而抑制核因子-κB (nuclear factor-κB, NF-κB) 和激活蛋白1 (activator protein 1, AP1) 等炎症转录因子的激活, 最终导致TNF-α、IL-1β和IL-4等的分泌减少(图 5)。

除炎症因子释放, GPR35还广泛参与机体免疫稳态调节。首先, IgE抗体处理的肥大细胞、LPS诱导的炎性巨噬细胞中GPR35表达水平上调^{[4, 43]}, 提示GPR35参与先天和适应性免疫的调节。此外, Barth等^[44]发现KA/GPR35驱动白细胞的早期黏附, De Giovanni等^[25]发现5-HIAA/GPR35促进中性粒细胞向炎症、细菌清除部位的迁移。

另外, GPR35还与葡萄糖代谢、脂质代谢等过程相关, 在不同的组织或细胞中通过不同的机制参与机体能量稳态调节。Jung等^[45]发现GPR35可以激活腺苷酸激活蛋白激酶(AMP-activated protein kinase, AMPK)、沉默调节蛋白6 (sirtuin 6, SIRT6) 信号, 从而缓解骨骼肌和脂肪组织中的炎症和胰岛素抵抗; Agudelo等^[8]发现GPR35通过过氧化物酶体增殖物激活受体α (perixisome proliferation-activated receptor α, PPARα) 和PGC-1α促进脂肪组织中脂质代谢、产热和抗炎基因的表达; Nam等^[46]发现GPR35抑制肝X受体(liver X receptor, LXR)、固醇调节元件结合蛋白-1c (sterol-regulatory element binding proteins, SREBP-1c) 进而抑制肝细胞中的脂质积累。另外, GPCRs与能量代谢相关研究将GPR35归属为代谢物感应GPCRs^[47]、代谢性疾病治疗GPCRs^[48], 可联系代谢、免疫和胃肠道系统, 是哮喘、肥胖、糖尿病、脂肪肝变性等疾病治疗的潜力靶点。

5 总结与展望

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近年来, GPR35去孤儿化及其在胃肠道疾病、心血管疾病、癌症等多种疾病中功能、分子机制的研究都取得了重大进展, 其作为疾病治疗新靶点的潜力巨大。已有研究提示, GPR35激动剂可用于心肌梗死等导致的缺氧保护、促进脂质代谢、镇痛等, 而GPR35抑制剂有助于治疗结直肠肿瘤、冠状动脉搭桥后血管再堵塞等, 相关机制涉及ERK1/2、RhoA/ROCK、HIF-α、NLRP3等多种通路节点。值得注意的是, GPR35在胃肠道稳态维持、炎症调节等过程中具有双向调节作用, 需进一步研究以明确GPR35在特定条件下的功能及相关信号机制。尽管GPR35仍然是一种孤儿GPCR, 但各种内源性、合成配体的发现, 在一定程度上可以满足深入探索GPR35功能的需要。然而迄今尚无明确靶向GPR35的治疗药物, 未来GPR35的研究可着眼于明确GPR35在疾病中的功能、阐明其发挥功能的分子机制并开展相关临床研究等, 以真正转化GPR35在多种疾病治疗中的潜在价值。

作者贡献: 张启情负责文献、资料的收集整理及全文的撰写; 焦宇和张尊建参与论文修改和讨论; 许风国和张培为通讯作者, 负责内容设计和稿件修改等工作。

利益冲突: 所有作者均声明无任何利益冲突。

基金

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国家自然科学基金资助项目(82073812)
国家自然科学基金资助项目(82104117)
国家自然科学基金资助项目(82173947)
国家自然科学基金资助项目(82273896)
江苏省自然科学基金项目(BK20210427)

参考文献

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文献

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参考文献引证文献

排序方式：

[1]

Hauser AS, Attwood MM, Rask-Andersen M, et al. Trends in GPCR drug discovery: new agents, targets and indications[J]. Nat Rev Drug Discov, 2017, 16: 829-842.

https://doi.org/10.1038/nrd.2017.178

[2]

Quon T, Lin LC, Ganguly A, et al. Therapeutic opportunities and challenges in targeting the orphan G protein-coupled receptor GPR35[J]. ACS Pharmacol Transl Sci, 2020, 3: 801-812.

https://doi.org/10.1021/acsptsci.0c00079

[3]

Fredriksson R, Lagerstrom MC, Lundin LG, et al. The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints[J]. Mol Pharmacol, 2003, 63: 1256-1272.

https://doi.org/10.1124/mol.63.6.1256

[4]

Kaya B, Donas C, Wuggenig P, et al. Lysophosphatidic acid-mediated GPR35 signaling in CX3CR1⁺ macrophages regulates intestinal homeostasis[J]. Cell Rep, 2020, 32: 107979.

https://doi.org/10.1016/j.celrep.2020.107979

[5]

Wyant GA, Yu W, Doulamis IP, et al. Mitochondrial remodeling and ischemic protection by G protein-coupled receptor 35 agonists[J]. Science, 2022, 377: 621-629.

https://doi.org/10.1126/science.abm1638

[6]

Mackenzie AE, Lappin JE, Taylor DL, et al. GPR35 as a novel therapeutic target[J]. Front Endocrinol, 2011, 2: 68.

[7]

Tsukahara T, Hamouda N, Utsumi D, et al. G protein-coupled receptor 35 contributes to mucosal repair in mice via migration of colonic epithelial cells[J]. Pharmacol Res, 2017, 123: 27-39.

https://doi.org/10.1016/j.phrs.2017.06.009

[8]

Agudelo LZ, Ferreira DMS, Cervenka I, et al. Kynurenic acid and GPR35 regulate adipose tissue energy homeostasis and inflammation[J]. Cell Metab, 2018, 27: 378-392.e5.

https://doi.org/10.1016/j.cmet.2018.01.004

[9]

McCallum JE, Mackenzie AE, Divorty N, et al. G-protein-coupled receptor 35 mediates human saphenous vein vascular smooth muscle cell migration and endothelial cell proliferation[J]. J Vasc Res, 2015, 52: 383-395.

https://doi.org/10.1159/000444754

[10]

Kwon Y, Mehta S, Clark M, et al. Non-canonical beta-adrenergic activation of ERK at endosomes[J]. Nature, 2022, 611: 173-179.

https://doi.org/10.1038/s41586-022-05343-3

[11]

Ronkainen VP, Tuomainen T, Huusko J, et al. Hypoxia-inducible factor 1-induced G protein-coupled receptor 35 expression is an early marker of progressive cardiac remodelling[J]. Cardiovasc Res, 2014, 101: 69-77.

https://doi.org/10.1093/cvr/cvt226

[12]

Sun T, Xie R, He H, et al. Kynurenic acid ameliorates NLRP3 inflammasome activation by blocking calcium mobilization via GPR35[J]. Front Immunol, 2022, 13: 1019365.

https://doi.org/10.3389/fimmu.2022.1019365

[13]

Zheng X, Hu M, Zang X, et al. Kynurenic acid/GPR35 axis restricts NLRP3 inflammasome activation and exacerbates colitis in mice with social stress[J]. Brain Behav Immun, 2019, 79: 244-255.

https://doi.org/10.1016/j.bbi.2019.02.009

[14]

Pagano E, Elias JE, Schneditz G, et al. Activation of the GPR35 pathway drives angiogenesis in the tumour microenvironment[J]. Gut, 2022, 71: 509-520.

https://doi.org/10.1136/gutjnl-2020-323363

[15]

Schneditz G, Elias JE, Pagano E, et al. GPR35 promotes glycolysis, proliferation, and oncogenic signaling by engaging with the sodium potassium pump[J]. Sci Signal, 2019, 12: eaau9048.

https://doi.org/10.1126/scisignal.aau9048

[16]

Wang J, Simonavicius N, Wu X, et al. Kynurenic acid as a ligand for orphan G protein-coupled receptor GPR35[J]. J Biol Chem, 2006, 281: 22021-22028.

https://doi.org/10.1074/jbc.M603503200

[17]

Wirthgen E, Hoeflich A, Rebl A, et al. Kynurenic acid: the janus-faced role of an immunomodulatory tryptophan metabolite and its link to pathological conditions[J]. Front Immunol, 2017, 8: 1957.

[18]

Divorty N, Mackenzie AE, Nicklin SA, et al. G protein-coupled receptor 35: an emerging target in inflammatory and cardiovascular disease[J]. Front Pharmacol, 2015, 6: 41.

[19]

Oka S, Ota R, Shima M, et al. GPR35 is a novel lysophosphatidic acid receptor[J]. Biochem Biophys Res Commun, 2010, 395: 232-237.

https://doi.org/10.1016/j.bbrc.2010.03.169

[20]

Maravillas-Montero JL, Burkhardt AM, Hevezi PA, et al. Cutting edge: GPR35/CXCR8 is the receptor of the mucosal chemokine CXCL17[J]. J Immunol, 2015, 194: 29-33.

https://doi.org/10.4049/jimmunol.1401704

[21]

Binti Mohd Amir NAS, Mackenzie AE, Jenkins L, et al. Evidence for the existence of a CXCL17 receptor distinct from GPR35[J]. J Immunol, 2018, 201: 714-724.

https://doi.org/10.4049/jimmunol.1700884

[22]

Park SJ, Lee SJ, Nam SY, et al. GPR35 mediates lodoxamide-induced migration inhibitory response but not CXCL17-induced migration stimulatory response in THP-1 cells; is GPR35 a receptor for CXCL17?[J]. Br J Pharmacol, 2018, 175: 154-161.

https://doi.org/10.1111/bph.14082

[23]

Southern C, Cook JM, Neetoo-Isseljee Z, et al. Screening beta-arrestin recruitment for the identification of natural ligands for orphan G-protein-coupled receptors[J]. J Biomol Screen, 2013, 18: 599-609.

https://doi.org/10.1177/1087057113475480

[24]

Deng H, Hu H, Fang Y. Multiple tyrosine metabolites are GPR35 agonists[J]. Sci Rep, 2012, 2: 373.

https://doi.org/10.1038/srep00373

[25]

De Giovanni M, Tam H, Valet C, et al. GPR35 promotes neutrophil recruitment in response to serotonin metabolite 5-HIAA[J]. Cell, 2022, 185: 815-830.e19.

https://doi.org/10.1016/j.cell.2022.01.010

[26]

Jenkins L, Brea J, Smith NJ, et al. Identification of novel species-selective agonists of the G-protein-coupled receptor GPR35 that promote recruitment of beta-arrestin-2 and activate Gα13[J]. Biochem J, 2010, 432: 451-459.

https://doi.org/10.1042/BJ20101287

[27]

Zhao P, Sharir H, Kapur A, et al. Targeting of the orphan receptor GPR35 by pamoic acid: a potent activator of extracellular signal-regulated kinase and beta-arrestin 2 with antinociceptive activity[J]. Mol Pharmacol, 2010, 78: 560-568.

https://doi.org/10.1124/mol.110.066746

[28]

Neetoo-Isseljee Z, Mackenzie AE, Southern C, et al. High-throughput identification and characterization of novel, species-selective GPR35 agonists[J]. J Pharmacol Exp Ther, 2013, 344: 568-578.

https://doi.org/10.1124/jpet.112.201798

[29]

Thimm D, Funke M, Meyer A, et al. 6-Bromo-8-(4-[(3)H]methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic acid: a powerful tool for studying orphan G protein-coupled receptor GPR35[J]. J Med Chem, 2013, 56: 7084-7099.

https://doi.org/10.1021/jm4009373

[30]

Jenkins L, Harries N, Lappin JE, et al. Antagonists of GPR35 display high species ortholog selectivity and varying modes of action[J]. J Pharmacol Exp Ther, 2012, 343: 683-695.

https://doi.org/10.1124/jpet.112.198945

[31]

Hu HH, Deng H, Ling S, et al. Chemical genomic analysis of GPR35 signaling[J]. Integr Biol, 2017, 9: 451-463.

https://doi.org/10.1039/c7ib00005g

[32]

Min KD, Asakura M, Liao Y, et al. Identification of genes related to heart failure using global gene expression profiling of human failing myocardium[J]. Biochem Biophys Res Commun, 2010, 393: 55-60.

https://doi.org/10.1016/j.bbrc.2010.01.076

[33]

Divorty N, Milligan G, Graham D, et al. The orphan receptor GPR35 contributes to angiotensin Ⅱ-induced hypertension and cardiac dysfunction in mice[J]. Am J Hypertens, 2018, 31: 1049-1058.

https://doi.org/10.1093/ajh/hpy073

[34]

Li H, Nguyen H, Meda Venkata SP, et al. Novel role of GPR35 (G-protein-coupled receptor 35) in the regulation of endothelial cell function and blood pressure[J]. Hypertension, 2021, 78: 816-830.

https://doi.org/10.1161/HYPERTENSIONAHA.120.15423

[35]

Chen K, He L, Li Y, et al. Inhibition of GPR35 preserves mitochondrial function after myocardial infarction by targeting calpain 1/2[J]. J Cardiovasc Pharmacol, 2020, 75: 556-563.

https://doi.org/10.1097/FJC.0000000000000819

[36]

Yao H, Lv Y, Bai X, et al. Prognostic value of CXCL17 and CXCR8 expression in patients with colon cancer[J]. Oncol Lett, 2020, 20: 2711-2720.

https://doi.org/10.3892/ol.2020.11819

[37]

Ali H, Abdelmageed M, Olsson L, et al. Utility of G protein-coupled receptor 35 expression for predicting outcome in colon cancer[J]. Tumour Biol, 2019, 41: 1010428319858885.

[38]

Xu T, Shen G, Cheng M, et al. Expression and prognostic value of GPR35 in gastric cancer[J]. Chin J Clin Healthc (中国临床保健杂志), 2020, 23: 236-240.

[39]

Wang W, Han T, Tong W, et al. Overexpression of GPR35 confers drug resistance in NSCLC cells by beta-arrestin/AKT signaling[J]. Onco Targets Ther, 2018, 11: 6249-6257.

https://doi.org/10.2147/OTT.S175606

[40]

Guo YJ, Zhou YJ, Yang XL, et al. The role and clinical significance of the CXCL17-CXCR8 (GPR35) axis in breast cancer[J]. Biochem Biophys Res Commun, 2017, 493: 1159-1167.

https://doi.org/10.1016/j.bbrc.2017.09.113

[41]

Mackenzie AE, Milligan G. The emerging pharmacology and function of GPR35 in the nervous system[J]. Neuropharmacology, 2017, 113: 661-671.

https://doi.org/10.1016/j.neuropharm.2015.07.035

[42]

Fallarini S, Magliulo L, Paoletti T, et al. Expression of functional GPR35 in human iNKT cells[J]. Biochem Biophys Res Commun, 2010, 398: 420-425.

https://doi.org/10.1016/j.bbrc.2010.06.091

[43]

Yang Y, Lu JY, Wu X, et al. G-protein-coupled receptor 35 is a target of the asthma drugs cromolyn disodium and nedocromil sodium[J]. Pharmacology, 2010, 86: 1-5.

https://doi.org/10.1159/000314164

[44]

Barth MC, Ahluwalia N, Anderson TJ, et al. Kynurenic acid triggers firm arrest of leukocytes to vascular endothelium under flow conditions[J]. J Biol Chem, 2009, 284: 19189-19195.

https://doi.org/10.1074/jbc.M109.024042

[45]

Jung TW, Park J, Sun JL, et al. Administration of kynurenic acid reduces hyperlipidemia-induced inflammation and insulin resistance in skeletal muscle and adipocytes[J]. Mol Cell Endocrinol, 2020, 518: 110928.

https://doi.org/10.1016/j.mce.2020.110928

[46]

Nam SY, Park SJ, Im DS. Protective effect of lodoxamide on hepatic steatosis through GPR35[J]. Cell Signal, 2019, 53: 190-200.

https://doi.org/10.1016/j.cellsig.2018.10.001

[47]

Tan JK, Mckenzie C, Marino E, et al. Metabolite-sensing G protein-coupled receptors-facilitators of diet-related immune regulation[J]. Annu Rev Immunol, 2017, 35: 371-402.

https://doi.org/10.1146/annurev-immunol-051116-052235

[48]

Dadvar S, Ferreira DMS, Cervenka I, et al. The weight of nutrients: kynurenine metabolites in obesity and exercise[J]. J Intern Med, 2018, 284: 519-533.

https://doi.org/10.1111/joim.12830

2023年第58卷第8期

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doi: 10.16438/j.0513-4870.2023-0465

接收时间：2023-04-15
首发时间：2025-11-21
出版时间：2023-08-12

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收稿日期：2023-04-15
修回日期：2023-05-17

基金

国家自然科学基金资助项目(82073812)

国家自然科学基金资助项目(82104117)

国家自然科学基金资助项目(82173947)

国家自然科学基金资助项目(82273896)

江苏省自然科学基金项目(BK20210427)

作者信息

1.中国药科大学, 药物质量与安全预警教育部重点实验室, 江苏南京 210009

2.中国药科大学理学院, 江苏南京 211198

通讯作者:

*许风国, Tel: 86-25-83271021, E-mail: fengguoxu@cpu.edu.cn;

张培, E-mail: peizhang@cpu.edu.cn

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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