RFamide peptides, the novel regulators of mammalian HPG axis: A review

The RFamide-related peptides (RFRPs) are the group of neuropeptides synthesized predominantly from the hypothalamus that negatively affects the hypothalamo-hypophyseal-gonadal (hypothalamic–pituitary–gonadal [HPG]) axis. These peptides are first identified in quail brains and emerged as the mammalian orthologs of avian gonadotropin inhibitory hormones. The RFRP-3 neurons in the hypothalamus are present in several mammalian species. The action of RFRP-3 is mediated through a G-protein-coupled receptor called OT7T022. The predominant role of RFRP-3 is the inhibition of HPG axis with several other effects such as the regulation of metabolic activity, stress regulation, controlling of non-sexual motivated behavior, and sexual photoperiodicity in concert with other neuropeptides such as kisspeptin, neuropeptide-Y (NPY), pro-opiomelanocortin, orexin, and melanin. RFamide peptides synthesized in the granulosa cells, interstitial cells, and seminiferous tubule regulate steroidogenesis and gametogenesis in the gonads. The present review is intended to provide the recent findings that explore the role of RFRP-3 in regulating HPG axis and its potential applications in the synchronization of reproduction and its therapeutic interventions to prevent stress-induced amenorrhea.

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Effects of a Novel GPR55 Antagonist on the Arachidonic Acid Cascade in LPS-Activated Primary Microglial Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22052503 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2503

Author(s):

Soraya Wilke Saliba ◽

Franziska Gläser ◽

Anke Deckers ◽

Albrecht Keil ◽

Thomas Hurrle ◽

...

Keyword(s):

Arachidonic Acid ◽

Therapeutic Option ◽

The Novel ◽

Cns Disorders ◽

Chronic Neuroinflammation ◽

The Central Nervous System ◽

Cox 2 ◽

G Protein Coupled ◽

Cox 1

Neuroinflammation is a crucial process to maintain homeostasis in the central nervous system (CNS). However, chronic neuroinflammation is detrimental, and it is described in the pathogenesis of CNS disorders, including Alzheimer’s disease (AD) and depression. This process is characterized by the activation of immune cells, mainly microglia. The role of the orphan G-protein-coupled receptor 55 (GPR55) in inflammation has been reported in different models. However, its role in neuroinflammation in respect to the arachidonic acid (AA) cascade in activated microglia is still lacking of comprehension. Therefore, we synthesized a novel GPR55 antagonist (KIT 10, 0.1–25 µM) and tested its effects on the AA cascade in lipopolysaccharide (LPS, 10 ng / mL)-treated primary rat microglia using Western blot and EIAs. We show here that KIT 10 potently prevented the release of prostaglandin E2 (PGE2), reduced microsomal PGE2 synthase (mPGES-1) and cyclooxygenase-2 (COX-2) synthesis, and inhibited the phosphorylation of Ikappa B-alpha (IκB-α), a crucial upstream step of the inflammation-related nuclear factor-kappaB (NF-κB) signaling pathway. However, no effects were observed on COX-1 and -2 activities and mitogen-activated kinases (MAPK). In summary, the novel GPR55 receptor antagonist KIT 10 reduces neuroinflammatory parameters in microglia by inhibiting the COX-2/PGE2 pathway. Further experiments are necessary to better elucidate its effects and mechanisms. Nevertheless, the modulation of inflammation by GPR55 might be a new therapeutic option to treat CNS disorders with a neuroinflammatory background such as AD or depression.

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Novel biomarkers in kidney disease: roles for cilia, Wnt signalling and ATMIN in polycystic kidney disease

Biochemical Society Transactions ◽

10.1042/bst20160124 ◽

2016 ◽

Vol 44 (6) ◽

pp. 1745-1751 ◽

Cited By ~ 5

Author(s):

Paraskevi Goggolidou ◽

Patricia D. Wilson

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Kidney Diseases ◽

Wnt Signalling ◽

Therapeutic Interventions ◽

The Novel ◽

Kidney Dialysis ◽

Novel Biomarkers ◽

Canonical Wnt

Biomarkers, the measurable indicators of biological conditions, are fast becoming a popular approach in providing information to track disease processes that could lead to novel therapeutic interventions for chronic conditions. Inherited, chronic kidney disease affects millions of people worldwide and although pharmacological treatments exist for some conditions, there are still patients whose only option is kidney dialysis and kidney transplantation. In the past 10 years, certain chronic kidney diseases have been reclassified as ciliopathies. Cilia in the kidney are antenna-like, sensory organelles that are required for signal transduction. One of the signalling pathways that requires the primary cilium in the kidney is Wnt signalling and it has three components such as canonical Wnt, non-canonical Wnt/planar cell olarity (PCP) and non-canonical Wnt/Ca2+ signalling. Identification of the novel role of ATM INteractor (ATMIN) as an effector molecule in the non-canonical Wnt/PCP pathway has intrigued us to investigate its potential role in chronic kidney disease. ATMIN could thus be an important biomarker in disease prognosis and treatment that might lighten the burden of chronic kidney disease and also affect on its progression.

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Size-selective opening of the blood–brain barrier by targeting endothelial sphingosine 1–phosphate receptor 1

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1618659114 ◽

2017 ◽

Vol 114 (17) ◽

pp. 4531-4536 ◽

Cited By ~ 78

Author(s):

Keisuke Yanagida ◽

Catherine H. Liu ◽

Giuseppe Faraco ◽

Sylvain Galvani ◽

Helen K. Smith ◽

...

Keyword(s):

Blood Brain Barrier ◽

Brain Inflammation ◽

Brain Barrier ◽

The Novel ◽

Object Recognition Test ◽

Blood Brain ◽

Sphingosine 1 Phosphate ◽

The Central Nervous System ◽

G Protein Coupled

The vasculature of the central nervous system (CNS) forms a selective barrier termed the blood–brain barrier (BBB). Disruption of the BBB may contribute to various CNS diseases. Conversely, the intact BBB restricts efficient penetration of CNS-targeted drugs. Here, we report the BBB-regulatory role of endothelial sphingosine 1–phosphate (S1P) receptor-1, a G protein-coupled receptor known to promote the barrier function in peripheral vessels. Endothelial-specific S1pr1 knockout mice (S1pr1iECKO) showed BBB breach for small-molecular-mass fluorescence tracers (<3 kDa), but not larger tracers (>10 kDa). Chronic BBB leakiness was associated with cognitive impairment, as assessed by the novel object recognition test, but not signs of brain inflammation. Brain microvessels of S1pr1iECKO mice showed altered subcellular distribution of tight junctional proteins. Pharmacological inhibition of S1P1 function led to transient BBB breach. These data suggest that brain endothelial S1P1 maintain the BBB by regulating the proper localization of tight junction proteins and raise the possibility that endothelial S1P1 inhibition may be a strategy for transient BBB opening and delivery of small molecules into the CNS.

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The New Insight into the Role of Antimicrobial Proteins-Alarmins in the Immunopathogenesis of Psoriasis

Journal of Immunology Research ◽

10.1155/2014/628289 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 30

Author(s):

A. Batycka-Baran ◽

J. Maj ◽

R. Wolf ◽

J. C. Szepietowski

Keyword(s):

Immune Response ◽

Adaptive Immune Response ◽

Therapeutic Interventions ◽

The Novel ◽

Antimicrobial Proteins ◽

Adaptive Immune ◽

Proinflammatory Mediators ◽

Enhanced Production ◽

Important Player

The pathognesis of psoriasis still remains not fully elucidated. Recent advances favor the idea that interactions between innate and adaptive immune response drive inflammatory process in this disease. Innate antimicrobial peptides and proteins (AMPs) are diverse group of small molecules that provide the first line of defense against invading pathogens. In recent years, the novel functions of AMPs have been identified. There are three subclasses among AMPs that have gained the special interest as a potentially important player in the pathogenesis of psoriasis: cathelicidin, S100 proteins, and defensins. These AMPs have been shown to modulate and trigger host immune response in psoriasis acting as interplayer between innate and adaptive immune mechanisms. Overexpressed in psoriatic lesions, they prime immune cells for enhanced production of proinflammatory mediators and act as chemoattractant for leukocytes. Therefore, the novel term describing AMPs alarmins has been suggested. As multifunctional player in pathogenesis of psoriasis, AMPs may constitute potential target for therapeutic interventions. However, further investigations are required to establish the methods of downregulation of the aberrant proinflammatory functions of AMPs without increasing the risk of infections.

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The KCNQ4-mediated M-current regulates the circadian rhythm in mesopontine cholinergic neurons

10.1101/2020.09.11.293423 ◽

2020 ◽

Author(s):

T. Bayasgalan ◽

S. Stupniki ◽

A. Kovács ◽

A. Csemer ◽

P. Szentesi ◽

...

Keyword(s):

Potassium Current ◽

Cholinergic Neurons ◽

Pedunculopontine Nucleus ◽

Therapeutic Interventions ◽

M Current ◽

Subunit Expression ◽

Light Darkness ◽

Reticular Activating System ◽

G Protein Coupled

AbstractThe M-current is a voltage gated potassium current inhibited by muscarinic activation and affected by several other G-protein coupled receptors. Its channels are formed by KCNQ subunits, from which KCNQ4 is restricted to certain brainstem structures. We sought evidence for the function of the M-current in the pedunculopontine nucleus (PPN) and the contribution of KCNQ4 subunits to the M-current and aimed to find its functional significance in the PPN. We found that cholinergic inputs of the PPN can effectively inhibit M-current. This current is capable of synchronizing neighboring neurons and inhibition of the M-current decreases neuronal synchronization. We showed that only a subpopulation of cholinergic neurons has KCNQ4-dependent M-current. The KCNQ4 subunit expression potentially regulates the presence of other KCNQ subunits. Deletion of KCNQ4 leads to alterations in adaptation of activity to light-darkness cycles, thus representing the potential role of KCNQ4 in regulation of sleep-wakefulness cycles. The presence of this protein restricted to certain brainstem nuclei raises the possibility that it might be a potential target for selective therapeutic interventions affecting the reticular activating system.

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Mentors And The Butterfly Effect: Triggers For Discovering Signalling by Proteinases via Proteinase-Activated Receptors (PARs) And More

Clinical & Investigative Medicine ◽

10.25011/cim.v35i6.19210 ◽

2012 ◽

Vol 35 (6) ◽

pp. 378

Author(s):

Morley D Hollenberg

Keyword(s):

Inflammatory Disease ◽

Cell Function ◽

Cell Signalling ◽

The Novel ◽

Molecular Pharmacology ◽

Proteinase Activated Receptors ◽

Butterfly Effect ◽

The One ◽

G Protein Coupled

The essential role of proteinases as regulatory digestive enzymes, recognized since the late 1800s, has been underscored by the discovery that more than 2% of the genome codes for proteinases and their inhibitors. Further, by the early 1970s it was appreciated that in addition to their digestive actions, proteinases can affect cell function: (1) by the generation or degradation of peptide hormones and (2) by the direct regulation of signalling by receptors like the one for insulin. It was the discovery in the 1990s of the novel G-protein-coupled ‘proteinase-activated receptor’ (PAR) family that has caused a paradigm shift in the understanding of the way that proteinases can regulate cell signalling. This overview provides a perspective for the discovery of the PARs and my laboratory’s role in (1) understanding the molecular pharmacology of these fascinating receptors and (2) identifying the potential pathophysiological roles that the PAR family can play in inflammatory disease. In this context, the overview also portrays the essential impact that seemingly minor comments/insights provided by my lifelong mentors have had on kindling my intense interest in proteinase-mediated signalling. The ‘butterfly effect’ of those comments has led to an unexpectedly large impact on my own research directions. Hopefully my own ‘butterfly comments’ will also be heard by my trainees and other colleagues with whom I am currently working and will promote future discoveries that will be directly relevant to the treatment of inflammatory disease.

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Expression of chemerin and its receptors in rat testes and its action on testosterone secretion

Journal of Endocrinology ◽

10.1530/joe-13-0275 ◽

2013 ◽

Vol 220 (2) ◽

pp. 155-163 ◽

Cited By ~ 24

Author(s):

Lei Li ◽

Ping Ma ◽

Chen Huang ◽

Yongjun Liu ◽

Ye Zhang ◽

...

Keyword(s):

Leydig Cells ◽

Polycystic Ovarian Syndrome ◽

The Novel ◽

Developmentally Regulated ◽

Dehydrogenase Gene ◽

Gene And Protein Expression ◽

G Protein Coupled ◽

Ovarian Syndrome

The novel adipokine chemerin plays a role in the regulation of lipid and carbohydrate metabolism, and recent reports of elevated chemerin levels in polycystic ovarian syndrome and preeclampsia have pointed to an emerging role of chemerin in reproduction. We hypothesised that chemerin, like other adipokines, may function to regulate male gonadal steroidogenesis. In this study, we show that chemerin and its three receptors chemokine-like receptor 1 (CMKLR1), G-protein-coupled receptor 1 (GPR1) and chemokine (C-C motif) receptor-like 2 were expressed in male reproductive tracts, liver and white adipose tissue. CMKLR1 and GPR1 proteins were localised specifically in the Leydig cells of human and rat testes by immunohistochemistry. The expression ofchemerinand its receptors in rat testes was developmentally regulated and highly expressed in Leydig cells.In vitrotreatment with chemerin suppressed the human chorionic gonadotropin (hCG)-induced testosterone production from primary Leydig cells, which was accompanied by the inhibition of 3β-hydroxysteroid dehydrogenase gene and protein expression. The hCG-activated p44/42 MAPK (Erk1/2) pathway in Leydig cells was also inhibited by chemerin cotreatment. Together, these data suggest that chemerin is a novel regulator of male gonadal steroidogenesis.

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Neuromedin S Is a Novel Anorexigenic Hormone

Endocrinology ◽

10.1210/en.2005-0107 ◽

2005 ◽

Vol 146 (10) ◽

pp. 4217-4223 ◽

Cited By ~ 66

Author(s):

Takanori Ida ◽

Kenji Mori ◽

Mikiya Miyazato ◽

Yutaka Egi ◽

Shinsuke Abe ◽

...

Keyword(s):

Food Intake ◽

Physiological Role ◽

The Novel ◽

Feeding Regulation ◽

Before And After ◽

Multiple Unit ◽

Anorexigenic Effect ◽

Agouti Related Protein ◽

G Protein Coupled

A novel 36-amino acid neuropeptide, neuromedin S (NMS), has recently been identified in rat brain and has been shown to be an endogenous ligand for two orphan G protein-coupled receptors, FM-3/GPR66 and FM-4/TGR-1. These receptors have been identified as neuromedin U (NMU) receptor type 1 and type 2, respectively. In this study, the physiological role of the novel peptide, NMS, on feeding regulation was investigated. Intracerebroventricular (icv) injection of NMS decreased 12-h food intake during the dark period in rats. This anorexigenic effect was more potent and persistent than that observed with the same dose of NMU. Neuropeptide Y, ghrelin, and agouti-related protein-induced food intake was counteracted by coadministration of NMS. Icv administration of NMS increased proopiomelanocortin mRNA expression in the arcuate nucleus (Arc) and CRH mRNA in the paraventricular nucleus (PVN). Pretreatment with SHU9119 (antagonist for α-MSH) and α-helical corticotropin-releasing factor-(9–41) (antagonist for CRH) attenuated NMS-induced suppression of 24-h food intake. After icv injection of NMS, Fos-immunoreactive cells were detected in both the PVN and Arc. When neuronal multiple unit activity was recorded in the PVN before and after icv injection of NMS, a significant increase in firing rate was observed 5 min after administration, and this increase continued for 100 min. These results suggest that the novel peptide, NMS, may be a potent anorexigenic hormone in the hypothalamus, and that expression of proopiomelanocortin mRNA in the Arc and CRH mRNA in the PVN may be involved in NMS action on feeding.

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