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1.
To Detach, Migrate, Adhere, and Metastasize: CD97/ADGRE5 in Cancer.
Aust, G, Zheng, L, Quaas, M
Cells. 2022;(9)
Abstract
Tumorigenesis is a multistep process, during which cells acquire a series of mutations that lead to unrestrained cell growth and proliferation, inhibition of cell differentiation, and evasion of cell death. Growing tumors stimulate angiogenesis, providing them with nutrients and oxygen. Ultimately, tumor cells invade the surrounding tissue and metastasize; a process responsible for about 90% of cancer-related deaths. Adhesion G protein-coupled receptors (aGPCRs) modulate the cellular processes closely related to tumor cell biology, such as adhesion and detachment, migration, polarity, and guidance. Soon after first being described, individual human aGPCRs were found to be involved in tumorigenesis. Twenty-five years ago, CD97/ADGRE5 was discovered to be induced in one of the most severe tumors, dedifferentiated anaplastic thyroid carcinoma. After decades of research, the time has come to review our knowledge of the presence and function of CD97 in cancer. In summary, CD97 is obviously induced or altered in many tumor entities; this has been shown consistently in nearly one hundred published studies. However, its high expression at circulating and tumor-infiltrating immune cells renders the systemic targeting of CD97 in tumors difficult.
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2.
Expression and Role of the G Protein-Coupled Estrogen Receptor (GPR30/GPER) in the Development and Immune Response in Female Reproductive Cancers.
Hernández-Silva, CD, Villegas-Pineda, JC, Pereira-Suárez, AL
Frontiers in endocrinology. 2020;:544
Abstract
Cancer is a major public health issue and represents the second leading cause of death in women worldwide, as female reproductive-related neoplasms are the main cause of incidence and mortality. Female reproductive cancers have a close relationship to estrogens, the principal female sex steroid hormones. Estrogens exert their actions by the nuclear estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). ERα, and ERβ act as transcription factors mediating genomic effects. Besides, the G protein-coupled estrogen receptor (GPER, formerly known as GPR30) was recently described as a seven-transmembrane receptor that mediates non-genomic estrogenic signaling, including calcium mobilization, cAMP synthesis, cleavage of matrix metalloproteinases, transactivation of epidermal growth factor receptor (EGFR), and the subsequent activation of PI3K and MAPK signaling pathways, which are the reasons why it is related to cellular processes, such as cell-cycle progression, cellular proliferation, differentiation, apoptosis, migration, and invasion. Since its discovery, selective agonists and antagonists have been found and developed. GPER has been implicated in a variety of hormone-responsiveness tumors, such as breast, endometrial, ovarian, cervical, prostate, and testicular cancer as well as lung, hepatic, thyroid, colorectal, and adrenocortical cancers. Nevertheless, GPER actions in cancer are still debatable due to the conflicting information that has been reported to date, since many reports indicate that activation of this receptor can modulate carcinogenesis. In contrast, many others show that its activation inhibits tumor activity. Besides, estrogens play an essential role in the regulation of the immune system, but little information exists about the role of GPER activation on its modulation within cancer context. This review focuses on the role that the stimulation of GPER plays in female reproductive neoplasms, specifically breast, endometrial, ovarian, and cervical cancers, in its tumor activity and immune response regulation.
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3.
Rational design of agonists for bitter taste receptor TAS2R14: from modeling to bench and back.
Di Pizio, A, Waterloo, LAW, Brox, R, Löber, S, Weikert, D, Behrens, M, Gmeiner, P, Niv, MY
Cellular and molecular life sciences : CMLS. 2020;(3):531-542
Abstract
Human bitter taste receptors (TAS2Rs) are a subfamily of 25 G protein-coupled receptors that mediate bitter taste perception. TAS2R14 is the most broadly tuned bitter taste receptor, recognizing a range of chemically diverse agonists with micromolar-range potency. The receptor is expressed in several extra-oral tissues and is suggested to have physiological roles related to innate immune responses, male fertility, and cancer. Higher potency ligands are needed to investigate TAS2R14 function and to modulate it for future clinical applications. Here, a structure-based modeling approach is described for the design of TAS2R14 agonists beginning from flufenamic acid, an approved non-steroidal anti-inflammatory analgesic that activates TAS2R14 at sub-micromolar concentrations. Structure-based molecular modeling was integrated with experimental data to design new TAS2R14 agonists. Subsequent chemical synthesis and in vitro profiling resulted in new TAS2R14 agonists with improved potency compared to the lead. The integrated approach provides a validated and refined structural model of ligand-TAS2R14 interactions and a general framework for structure-based discovery in the absence of closely related experimental structures.
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4.
Analysis of GPRC6A variants in different pancreatitis etiologies.
Kaune, T, Ruffert, C, Hesselbarth, N, Damm, M, Krug, S, Cardinal von Widdern, J, Masson, E, Chen, JM, Rebours, V, Buscail, L, et al
Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]. 2020;(7):1262-1267
Abstract
BACKGROUND The G-protein-coupled receptor Class C Group 6 Member A (GPRC6A) is activated by multiple ligands and is important for the regulation of calcium homeostasis. Extracellular calcium is capable to increase NLRP3 inflammasome activity of the innate immune system and deletion of this proinflammatory pathway mitigated pancreatitis severity in vivo. As such this pathway and the GPRC6A receptor is a reasonable candidate gene for pancreatitis. Here we investigated the prevalence of sequence variants in the GPRC6A locus in different pancreatitis aetiologies. METHODS We selected 6 tagging SNPs with the SNPinfo LD TAG SNP Selection tool and the functional relevant SNP rs6907580 for genotyping. Cohorts from Germany, further European countries and China with up to 1,124 patients and 1,999 controls were screened for single SNPs with melting curve analysis. RESULTS We identified an association of rs1606365(G) with alcoholic chronic pancreatitis in a German (odds ratio (OR) 0.76, 95% confidence interval (CI) 0.65-0.89, p = 8 × 10-5) and a Chinese cohort (OR 0.78, 95% CI 0.64-0.96, p = 0.02). However, this association was not replicated in a combined cohort of European patients (OR 1.18, 95% CI 0.99-1.41, p = 0.07). Finally, no association was found with acute and non-alcoholic chronic pancreatitis. CONCLUSIONS Our results support a potential role of calcium sensing receptors and inflammasome activation in alcoholic chronic pancreatitis development. As the functional consequence of the associated variant is unclear, further investigations might elucidate the relevant mechanisms.
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5.
G Protein-Coupled Estrogen Receptor, GPER1, Offers a Novel Target for the Treatment of Digestive Diseases.
DeLeon, C, Wang, DQ, Arnatt, CK
Frontiers in endocrinology. 2020;:578536
Abstract
There are gender differences between men and women in many physiological functions and diseases, which indicates that female sex hormones may be important. Traditionally, estrogen exerts its biological activities by activating two classical nuclear estrogen receptors, ESR1 and ESR2. However, the roles of estrogen in the regulation of physiological functions and the pathogenesis of diseases become more complicated with the identification of the G protein-coupled estrogen receptor (GPER1). Although many GPER1-specific ligands have been developed, the therapeutic mechanisms of exclusively targeting GPER1 are not yet well understood. Translational applications and clinical trial efforts for the identified GPER1 ligands have been focused primarily on the reproductive, cardiovascular, nervous, endocrine, and immune systems. More recently, research found that GPER1 may play an important role in regulating the digestive system. Cholesterol gallstone disease, a major biliary disease, has a higher prevalence in women than in men worldwide. Emerging evidence implies that GPER1 could play an important role, independent of the classical ESR1, in the pathophysiology of cholesterol gallstones in women. This review discusses the complex signaling pathways of three estrogen receptors, highlights the development of GPER1-specific ligands, and summarizes the latest advances in the role of GPER1 in the pathogenesis of gallstone formation.
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6.
Activation of HCAR2 by niacin: benefits beyond lipid lowering.
Tuteja, S
Pharmacogenomics. 2019;(16):1143-1150
Abstract
Niacin (nicotinic acid) is a potent lipid-lowering agent that has been used for prevention of coronary heart disease. Niacin activates the HCAR2 receptor found on adipocytes, macrophages and various immune cells throughout the body. Activation of the HCAR2 receptor by niacin results in beneficial anti-inflammatory effects that are independent of lipid lowering. This review summarizes the use of niacin in treatment of dyslipidemia, the pharmacogenetics of niacin response and the potential role of HCAR2 signaling in the treatment of a variety of inflammatory and metabolic diseases.
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7.
TAS2R38 bitter taste receptor and attainment of exceptional longevity.
Melis, M, Errigo, A, Crnjar, R, Pes, GM, Tomassini Barbarossa, I
Scientific reports. 2019;(1):18047
Abstract
Bitter taste receptors play crucial roles in detecting bitter compounds not only in the oral cavity, but also in extraoral tissues where they are involved in a variety of non‒tasting physiological processes. On the other hand, disorders or modifications in the sensitivity or expression of these extraoral receptors can affect physiological functions. Here we evaluated the role of the bitter receptor TAS2R38 in attainment of longevity, since it has been widely associated with individual differences in taste perception, food preferences, diet, nutrition, immune responses and pathophysiological mechanisms. Differences in genotype distribution and haplotype frequency at the TAS2R38 gene between a cohort of centenarian and near-centenarian subjects and two control cohorts were determined. Results show in the centenarian cohort an increased frequency of subjects carrying the homozygous genotype for the functional variant of TAS2R38 (PAV/PAV) and a decreased frequency of those having homozygous genotype for the non-functional form (AVI/AVI), as compared to those determined in the two control cohorts. In conclusion, our data providing evidence of an association between genetic variants of TAS2R38 gene and human longevity, suggest that TAS2R38 bitter receptor can be involved in the molecular physiological mechanisms implied in the biological process of aging.
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8.
Tackling Pain Associated with Rheumatoid Arthritis: Proton-Sensing Receptors.
Sun, WH, Dai, SP
Advances in experimental medicine and biology. 2018;:49-64
Abstract
Rheumatoid arthritis (RA), characterized by chronic inflammation of synovial joints, is often associated with ongoing pain and increased pain sensitivity. Chronic pain that comes with RA turns independent, essentially becoming its own disease. It could partly explain that a significant number (50%) of RA patients fail to respond to current RA therapies that focus mainly on suppression of joint inflammation. The acute phase of pain seems to associate with joint inflammation in early RA. In established RA, the chronic phase of pain could be linked to inflammatory components of neuron-immune interactions and noninflammatory components. Accumulating evidence suggests that the initial inflammation and autoimmunity in RA (preclinical RA) begin outside of the joint and may originate at mucosal sites and alterations in the composition of microbiota located at mucosal sites could be essential for mucosal inflammation, triggering joint inflammation. Fibroblast-like synoviocytes in the inflamed joint respond to cytokines to release acidic components, lowering pH in synovial fluid. Extracellular proton binds to proton-sensing ion channels, and G-protein-coupled receptors in joint nociceptive fibers may contribute to sensory transduction and release of neurotransmitters, leading to pain and hyperalgesia. Activation of peripheral sensory neurons or nociceptors further modulates inflammation, resulting in neuroinflammation or neurogenic inflammation. Peripheral and central nerves work with non-neuronal cells (such as immune cells, glial cells) in concert to contribute to the chronic phase of RA-associated pain. This review will discuss actions of proton-sensing receptors on neurons or non-neuronal cells that modulate RA pathology and associated chronic pain, and it will be beneficial for the development of future therapeutic treatments.
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9.
EBI2 Expression and Function: Robust in Memory Lymphocytes and Increased by Natalizumab in Multiple Sclerosis.
Clottu, AS, Mathias, A, Sailer, AW, Schluep, M, Seebach, JD, Du Pasquier, R, Pot, C
Cell reports. 2017;(1):213-224
Abstract
The interaction between oxysterols and the G protein-coupled receptor Epstein-Barr virus-induced gene 2 (EBI2) fine-tunes immune cell migration, a mechanism efficiently targeted by several disease-modifying treatments developed to treat multiple sclerosis (MS), such as natalizumab. We previously showed that memory CD4+ T lymphocytes migrate specifically in response to 7α,25-dihydroxycholesterol (7α,25-OHC) via EBI2 in the MS murine model experimental autoimmune encephalomyelitis. However, the EBI2 expression profile in human lymphocytes in both healthy and MS donors is unknown. Here, we characterize EBI2 biology in human lymphocytes. We observed that EBI2 is functionally expressed on memory CD4+ T cells and is enhanced under natalizumab treatment. These data suggest a significant role for EBI2 in human CD4+ T cell migration, notably in patients with MS. Better knowledge of EBI2 involvement in autoimmunity may therefore lead to an improved understanding of the physiopathology of MS.
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10.
Seeing red: flushing out instigators of niacin-associated skin toxicity.
Dunbar, RL, Gelfand, JM
The Journal of clinical investigation. 2010;(8):2651-5
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Abstract
The use of niacin to improve plasma lipid levels and reduce risk of myocardial infarction is limited by noxious skin effects that result from stimulation of G protein-coupled receptor 109A (GPR109A) in skin immune cells. Niacin causes vasodilation, manifest as rubor (redness) of the head and neck, providing a visible sign associated with other, more bothersome skin complaints. The working theory is that niacin provokes Langerhans cells to produce prostaglandin D2 (PGD2), stimulating vascular DP1 receptors to cause vasodilation. In this issue of the JCI, Hanson and colleagues raise a serious challenge to this paradigm in showing that the major player in vasodilation is the keratinocyte, which produces PGE2, stimulating EP2/4 receptors, shifting the role of the Langerhans/PGD2/DP1 pathway to that of an accomplice. They also show that the antipsoriasis drug monomethyl fumarate, itself a GPR109A agonist, provokes vasodilation through the same cells. These efforts bring us one step closer to solving a key limitation of an important cardioprotective drug and reveal that the skin response to niacin is much more complicated than previously thought.