☆ 4.7 Review

GPR35: from enigma to therapeutic target

TRENDS IN PHARMACOLOGICAL SCIENCES (2023)

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Review Immunology

Oxidized mitochondrial DNA: a protective signal gone awry

Hongxu Xian et al.

Summary: Research has found that oxidized mitochondrial DNA (Ox-mtDNA) in myeloid cells activates the NLRP3 inflammasome, leading to the production of pro-inflammatory cytokines and interferons. In addition, Ox-mtDNA can be released into circulation through gasdermin D pores. Furthermore, Ox-mtDNA can convert transient inflammation into long-term immunopathology and serve as a biomarker for autoimmune diseases.

TRENDS IN IMMUNOLOGY (2023)

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Review Cell Biology

The cryptic role of CXCL17/CXCR8 axis in the pathogenesis of cancers: a review of the latest evidence

Seyyede Fatemeh Hashemi et al.

Summary: Chemokines, including CXCL-17, play diverse roles in cancer pathogenesis. This review investigates the dual role of CXCL-17 in human malignancies and explores potential treatment options in cancer therapy.

JOURNAL OF CELL COMMUNICATION AND SIGNALING (2023)

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Article Biochemistry & Molecular Biology

GPR35 promotes neutrophil recruitment in response to serotonin metabolite 5-HIAA

Marco De Giovanni et al.

Summary: The G-protein-coupled receptor GPR35 is upregulated in activated neutrophils and plays a crucial role in their migration. The platelet-derived serotonin metabolite 5-HIAA acts as a ligand for GPR35 and promotes neutrophil recruitment to sites of inflammation via platelets and mast cells.

CELL (2022)

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Article Biochemistry & Molecular Biology

Agonist-induced phosphorylation of orthologues of the orphan receptor GPR35 functions as an activation sensor

Nina Divorty et al.

Summary: G protein-coupled receptor 35 (GPR35) plays diverse roles in lower gut inflammation and pain. The phosphorylation of specific sites in GPR35a is crucial for its interaction with arrestin-3 and the internalization of the receptor. Phospho-site-specific antisera can effectively detect the activation status of GPR35 and be used in drug discovery and target validation programs.

JOURNAL OF BIOLOGICAL CHEMISTRY (2022)

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Article Gastroenterology & Hepatology

Activation of the GPR35 pathway drives angiogenesis in the tumour microenvironment

Ester Pagano et al.

Summary: The study demonstrates that GPR35 on macrophages can enhance tumor growth by stimulating neoangiogenesis and tumor tissue remodeling. Deletion of GPR35 significantly reduces tumor growth caused by the mutant tumor suppressor adenomatous polyposis coli in inflammation-associated and spontaneous tumor models.

GUT (2022)

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Article Oncology

Expression and clinical significance of CXCL17 and GPR35 in endometrial carcinoma

Jun Hao et al.

Summary: This study suggests that CXCL17 and CXCR8 may play a significant role in the occurrence and development of endometrial carcinoma, and high expression of CXCL17 may be used as a biomarker for predicting survival.

ANTI-CANCER DRUGS (2022)

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Review Immunology

Tryptophan and the innate intestinal immunity: Crosstalk between metabolites, host innate immune cells, and microbiota

Yunke Li et al.

Summary: The intestinal mucosal barrier plays a critical role in nutrient absorption and overall health. Recent studies have shown the importance of the nutrients-bacteria-host interaction for intestinal homeostasis. Dysfunction of these interactions has been associated with metabolic disorders and intestinal diseases. Tryptophan and its metabolites have been found to regulate enterocyte proliferation, intestinal integrity, immune response, and intestinal microbiota, thus contributing to intestinal health. This review highlights the effects of tryptophan and its metabolites on the mucosal barrier and intestinal homeostasis, as well as the signaling pathways involved in tryptophan metabolism.

EUROPEAN JOURNAL OF IMMUNOLOGY (2022)

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Article Immunology

Epithelial GPR35 protects from Citrobacter rodentium infection by preserving goblet cells and mucosal barrier integrity

Hassan Melhem et al.

Summary: This study reveals the critical role of Gpr35 in goblet cell function and its regulation of goblet cell numbers and microbiota balance through maintaining normal pyroptosis levels. It is essential for maintaining intestinal health and the symbiotic relationship between host and microbiota.

MUCOSAL IMMUNOLOGY (2022)

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Article Pharmacology & Pharmacy

The GPR35 expression pattern is associated with overall survival in male patients with colorectal cancer

Tomasz Mackiewicz et al.

Summary: This study suggests that the expression of GPR35 is associated with survival rates in colorectal cancer patients and has prognostic value for male patients.

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Kynurenic acid ameliorates lipopolysaccharide-induced endometritis by regulating the GRP35/NF-κB signaling pathway

Ying Wang et al.

Summary: This study found that KYNA can protect against LPS-induced endometritis by maintaining epithelial barrier permeability and suppressing proinflammatory responses. KYNA exerts its effects by upregulating the expression of tight junction proteins occludin and ZO-1, inhibiting the secretion of inflammatory factors TNF-alpha and IL-1 beta, as well as suppressing the activation of NF-kappa B.

TOXICOLOGY AND APPLIED PHARMACOLOGY (2022)

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Article Orthopedics

Exercised accelerated the production of muscle-derived kynurenic acid in skeletal muscle and alleviated the postmenopausal osteoporosis through the Gpr35/NF?B p65 pathway

Tianshu Shi et al.

Summary: The serum level of muscle-derived kynurenic acid (Kyna) is lower in postmenopausal osteoporosis (PMOP) model mice. Exercise and exogenous Kyna treatment can alleviate the effects of PMOP through the Gpr35 receptor.

JOURNAL OF ORTHOPAEDIC TRANSLATION (2022)

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Article Immunology

Oxidized DNA fragments exit mitochondria via mPTP- and VDAC-dependent channels to activate NLRP3 inflammasome and interferon signaling

Hongxu Xian et al.

Summary: In stressed mitochondria, oxidized mtDNA fragments are released and trigger inflammation. Understanding this process is important for the development of treatments for chronic inflammatory diseases.

IMMUNITY (2022)

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Article Biochemistry & Molecular Biology

Isoforms of GPR35 have distinct extracellular N-termini that allosterically modify receptor-transducer coupling and mediate intracellular pathway bias

Hannes Schihada et al.

Summary: The G protein-coupled receptor GPR35 is involved in oncogenic signaling, bacterial infections, and inflammatory bowel disease within the intestine. This study reveals that GPR35 has two isoforms with distinct promoters and alternative splicing. The longer isoform limits G protein activation but enhances receptor-beta-arrestin interaction. Structural analysis suggests that a disulfide bridge between the N-terminus and extracellular loop 3 is crucial for G protein activation, while an additional cysteine from the extended N-terminus of the longer isoform limits agonist-induced receptor-beta-arrestin2 interaction. The findings provide insights for developing isoform-specific GPR35 ligands for mechanism-based therapies.

JOURNAL OF BIOLOGICAL CHEMISTRY (2022)

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Article Cell Biology

Insights into divalent cation regulation and G13-coupling of orphan receptor GPR35

Jia Duan et al.

Summary: This study reports the cryo-electron microscopy structure of GPR35 coupled with G(13) and bound to the anti-allergic drug lodoxamide. The structure reveals a novel divalent cation coordination site and a unique ionic regulatory mode of GPR35, providing insights into its ligand binding promiscuity. Structural comparison with other G protein subtypes-coupled GPCRs highlights significant movements in the G alpha(13) subunit and the GPR35 TM6 helix.

CELL DISCOVERY (2022)

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Review Pharmacology & Pharmacy

Recent advances in clinical trials targeting the kynurenine pathway

Ananda Staats Pires et al.

Summary: The kynurenine pathway (KP) is a crucial pathway for the metabolism of tryptophan, an essential amino acid. Activation of KP under inflammatory conditions produces various metabolites that have the potential to affect redox activity, immune response, and neurotoxicity. Dysregulation of this pathway has been implicated in a wide range of neurological diseases and psychiatric disorders.

PHARMACOLOGY & THERAPEUTICS (2022)

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Article Multidisciplinary Sciences

Mitochondrial remodeling and ischemic protection by G protein-coupled receptor 35 agonists

Gregory A. Wyant et al.

Summary: Kynurenic acid (KynA) has tissue-protective effects in ischemia models, and this study demonstrates that activation of GPR35 and interaction with ATPIF1 may be the underlying mechanism. These findings provide a rationale for developing specific GPR35 agonists for the treatment of ischemic diseases.

SCIENCE (2022)

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Editorial Material Pharmacology & Pharmacy

GPR35, ally of the anti-ischemic ATPIF1-ATP synthase interaction

Salvatore Nesci

Summary: Mitochondrial ATP synthase synthesizes ATP for cellular functions, but it can also hydrolyze ATP under various conditions to re-energize the mitochondria. ATP synthase inhibitory factor 1 (ATPIF1) inhibits this hydrolysis process. Recent research has shown that G-protein-coupled receptor 35 (GPR35) is involved in this process, providing a new framework for the discovery of potential therapeutic molecules against ischemia/reperfusion (I/R) injury.

TRENDS IN PHARMACOLOGICAL SCIENCES (2022)

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Article Immunology

Kynurenic acid ameliorates NLRP3 inflammasome activation by blocking calcium mobilization via GPR35

Tianyin Sun et al.

Summary: Kynurenic acid (KA) inhibits activation of the NLRP3 inflammasome through reducing calcium mobilization and mitochondrial damage, thus preventing inflammation and metabolic disorders.

FRONTIERS IN IMMUNOLOGY (2022)

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Article Cell Biology

ERR-activated GPR35 promotes immune infiltration level of macrophages in gastric cancer tissues

Chuanjun Shu et al.

Summary: Enhancer release and retargeting (ERR) events activate GPR35 in gastric cancer cells, promoting proliferation, migration, and immune cell exhaustion and infiltration. High GPR35 expression is associated with poor prognosis in gastric cancer patients.

CELL DEATH DISCOVERY (2022)

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Article Chemistry, Medicinal

Structure-Activity Relationship Studies of Coumarin-like Diacid Derivatives as Human G Protein-Coupled Receptor-35 (hGPR35) Agonists and a Consequent New Design Principle

Lai Wei et al.

Summary: Novel coumarin-like diacid derivatives were designed and synthesized as potent agonists of human G-protein-coupled receptor 35 (hGPR35). Compounds with two acidic groups connected to a rigid aromatic scaffold displayed excellent potency, demonstrating a general strategy for designing and recognizing GPR35 agonists.

JOURNAL OF MEDICINAL CHEMISTRY (2021)

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Review Immunology

GPR35 in Intestinal Diseases: From Risk Gene to Function

Berna Kaya et al.

Summary: Diet and gut microbial metabolites play a crucial role in mediating host immune responses and maintaining intestinal health. The metabolite-sensing GPCRs, especially GPR35, are important for signaling that affects host cell function and survival. There is a link between GPR35 and intestinal diseases, with studies showing that it is activated by metabolites such as KYNA, CXCL17, and LPA.

FRONTIERS IN IMMUNOLOGY (2021)

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Review Biochemistry & Molecular Biology

Tryptophan Metabolism and Gut-Brain Homeostasis

William Roth et al.

Summary: Tryptophan is crucial for protein synthesis and neurotransmitter production, impacting emotional regulation and nervous system development. Dysregulation of tryptophan metabolism contributes to various neurological and psychiatric disorders. The influence of gut microbes on tryptophan metabolism is being explored as a potential therapeutic target for these conditions.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2021)

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Article Biology

G-protein coupled receptor 35 (GPR35) regulates the colonic epithelial cell response to enterotoxigenic Bacteroides fragilis

Annemarie Boleij et al.

Summary: GPR35 plays a crucial role in the response of colonic epithelial cells to BFT, and GPR35 deficiency can reduce the mortality and disease severity induced by ETBF in mice.

COMMUNICATIONS BIOLOGY (2021)

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Review Biochemistry & Molecular Biology

The kynurenine pathway in chronic diseases: a compensatory mechanism or a driving force?

Niklas Joisten et al.

Summary: The dysregulation of the kynurenine pathway in tryptophan metabolism is associated with inflammation-driven pathologies, making it a potential therapeutic target for diseases such as cancer and brain disorders. It is important to consider both compensatory mechanisms and bioenergetic roles of KP metabolites in designing effective therapeutic approaches to attenuate disease progression.

TRENDS IN MOLECULAR MEDICINE (2021)

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Article Biochemistry & Molecular Biology

Disruption of GPR35 Signaling in Bone Marrow-Derived Cells Does Not Influence Vascular Inflammation and Atherosclerosis in Hyperlipidemic Mice

Roland Baumgartner et al.

Summary: Studies on G-protein-coupled receptor-35 (GPR35) suggest that its expression does not directly impact macrophage activation, vascular inflammation, and the development of atherosclerosis, as indicated by experiments on GPR35KO and WT chimeric mice.

METABOLITES (2021)

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Article Chemistry, Medicinal

G Protein-Coupled Receptor GPR35 Suppresses Lipid Accumulation in Hepatocytes

Li-Chiung Lin et al.

Summary: Experimental studies using various mouse models and a humanized GPR35 mouse model suggest that activation of the GPR35 receptor can effectively prevent and reverse lipid accumulation induced by liver X receptor stimulation. This finding highlights the potential value of targeting GPR35 in the treatment of fatty liver diseases.

ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE (2021)

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Article Multidisciplinary Sciences

DCyFIR: a high-throughput CRISPR platform for multiplexed G protein-coupled receptor profiling and ligand discovery

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2020)

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Article Cell Biology

Administration of kynurenic acid reduces hyperlipidemia-induced inflammation and insulin resistance in skeletal muscle and adipocytes

Tae Woo Jung et al.

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Hongyan Yao et al.

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Article Cell Biology

Lysophosphatidic Acid-Mediated GPR35 Signaling in CX3CR1+ Macrophages Regulates Intestinal Homeostasis

Berna Kaya et al.

CELL REPORTS (2020)

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Therapeutic Opportunities and Challenges in Targeting the Orphan G Protein-Coupled Receptor GPR35

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Combinatorial expression of GPCR isoforms affects signalling and drug responses

Maria Marti-Solano et al.

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Protective effect of lodoxamide on hepatic steatosis through GPR35

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Article Biochemistry & Molecular Biology

Receptor selectivity between the G proteins Gα12 and Gα13 is defined by a single leucine-to-isoleucine variation

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FASEB JOURNAL (2019)

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GPR35 promotes glycolysis, proliferation, and oncogenic signaling by engaging with the sodium potassium pump

Georg Schneditz et al.

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Kynurenic Acid and Gpr35 Regulate Adipose Tissue Energy Homeostasis and Inflammation

Leandro Z. Agudelo et al.

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Article Immunology

Evidence for the Existence of a CXCL17 Receptor Distinct from GPR35

Nurul A. S. Binti Mohd Amir et al.

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Disruption of GPR35 Exacerbates Dextran Sulfate Sodium-Induced Colitis in Mice

Shukkur M. Farooq et al.

DIGESTIVE DISEASES AND SCIENCES (2018)

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Overexpression of GPR35 confers drug resistance in NSCLC cells by beta-arrestin/Akt signaling

Wei Wang et al.

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Johannes M. Freudenberg et al.

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GPR35 mediates lodoxamide-induced migration inhibitory response but not CXCL17-induced migration stimulatory response in THP-1 cells; is GPR35 a receptor for CXCL17?

Soo-Jin Park et al.

BRITISH JOURNAL OF PHARMACOLOGY (2018)

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Discovery of 2H-Chromen-2-one Derivatives as G Protein-Coupled Receptor-35 Agonists

Lai Wei et al.

JOURNAL OF MEDICINAL CHEMISTRY (2017)

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Review Neurosciences

The emerging pharmacology and function of GPR35 in the nervous system

Amanda E. Mackenzie et al.

NEUROPHARMACOLOGY (2017)

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G protein-coupled receptor 35 contributes to mucosal repair in mice via migration of colonic epithelial cells

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The role and clinical significance of the CXCL17-CXCR8 (GPR35) axis in breast cancer

Ya Jie Guo et al.

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Kynurenic acid and zaprinast induce analgesia by modulating HCN channels through GPR35 activation

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The Antiallergic Mast Cell Stabilizers Lodoxamide and Bufrolin as the First High and Equipotent Agonists of Human and Rat GPR35

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MOLECULAR PHARMACOLOGY (2014)

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Article Chemistry, Medicinal

8-Benzamidochromen-4-one-2-carboxylic Acids: Potent and Selective Agonists for the Orphan G Protein-Coupled Receptor GPR35

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High-Throughput Identification and Characterization of Novel, Species-selective GPR35 Agonists

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Agonist activation of the G protein-coupled receptor GPR35 involves transmembrane domain III and is transduced via Gα13 and β-arrestin-2

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Discovery of 2-(4-Methylfuran-2(5H)-ylidene)malononitrile and Thieno[3,2-b]thiophene-2-carboxylic Acid Derivatives as G Protein-Coupled Receptor 35 (GPR35) Agonists

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GPR35 is a novel lysophosphatidic acid receptor

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Identification of novel species-selective agonists of the G-protein-coupled receptor GPR35 that promote recruitment of β-arrestin-2 and activate Gα13

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Kynurenic Acid Triggers Firm Arrest of Leukocytes to Vascular Endothelium under Flow Conditions

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Kynurenic acid as a ligand for orphan G protein-coupled receptor GPR35

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