scholarly journals Purinergic Signaling in Liver Pathophysiology

2021 ◽  
Vol 12 ◽  
Author(s):  
Shanu Jain ◽  
Kenneth A. Jacobson
Keyword(s):  
Liver Function ◽  
Purinergic Receptors ◽  
Purinergic Signaling ◽  
Critical Role ◽  
P2y Receptors ◽  
Bile Secretion ◽  
Alcoholic Fatty Liver ◽  
Disease States ◽  
Insulin Responsiveness ◽  
G Protein Coupled

Extracellular nucleosides and nucleotides activate a group of G protein-coupled receptors (GPCRs) known as purinergic receptors, comprising adenosine and P2Y receptors. Furthermore, purinergic P2X ion channels are activated by ATP. These receptors are expressed in liver resident cells and play a critical role in maintaining liver function. In the normal physiology, these receptors regulate hepatic metabolic processes such as insulin responsiveness, glycogen and lipid metabolism, and bile secretion. In disease states, ATP and other nucleotides serve as danger signals and modulate purinergic responses in the cells. Recent studies have demonstrated that purinergic receptors play a significant role in the development of metabolic syndrome associated non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fibrosis, hepatocellular carcinoma (HCC) and liver inflammation. In this concise review, we dissect the role of purinergic signaling in different liver resident cells involved in maintaining healthy liver function and in the development of the above-mentioned liver pathologies. Moreover, we discuss potential therapeutic strategies for liver diseases by targeting adenosine, P2Y and P2X receptors.

The Therapeutic Potential of Purinergic Receptors in Alzheimer’s Disease and Promising Therapeutic Modulators

2020 ◽  
Vol 20 ◽  
Author(s):  
Lili Pan ◽  
Yu Ma ◽  
Yunchun Li ◽  
Haoxing Wu ◽  
Rui Huang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Purinergic Receptors ◽  
Therapeutic Potential ◽  
Purinergic Signaling ◽  
Memory Loss ◽  
Related Research ◽  
Central Nervous System Disorders ◽  
G Protein Coupled

Abstract:: Recent studies have proven that the purinergic signaling pathway plays a key role in neurotransmission and neuromodulation, and is involved in various neurodegenerative diseases and psychiatric disorders. With the characterization of the subtypes of receptors in purinergic signaling, i.e. the P1 (adenosine), P2X (ion channel) and P2Y (G protein-coupled), more attentions were paid to the pathophysiology and therapeutic potential of purinergic signaling in central nervous system disorders. Alzheimer’s disease (AD) is a progressive and deadly neurodegenerative disease that is characterized by memory loss, cognitive impairment and dementia. However, as drug development aimed to prevent or control AD follows a series of failures in recent years, more researchers focused on the neuroprotection-related mechanisms such as purinergic signaling in AD patients to find a potential cure. This article reviews the recent discoveries of purinergic signaling in AD, summaries the potential agents as modulators for the receptors of purinergic signaling in AD related research and treatments. Thus, our paper provided an insight for purinergic signaling in the development of anti-AD therapies.

Evidences of G-Coupled Protein Receptor (GPCR) signaling in the human malaria parasite Plasmodium falciparum for sensing its microenvironment and the role of purinergic signaling in malaria parasites..

2020 ◽  
Vol 20 ◽  
Author(s):  
Pedro H. S. Pereira ◽  
Lucas Borges-Pereira ◽  
Célia R. S. Garcia
Keyword(s):  
Purinergic Receptors ◽  
Purinergic Signaling ◽  
Electrical Stimulus ◽  
Early 19Th Century ◽  
Protein Receptor ◽  
Parasite Plasmodium ◽  
Parasite Plasmodium Falciparum ◽  
Initial Resistance ◽  
G Protein Coupled

: The nucleotides were discovered in the early 19th century and a few years later the role of such molecules in the energy metabolism and cell survival was postulated. In 1972 a pioneer work by Burnstock and colleagues suggested that ATP could work also a neurotransmitter, which was known as the “purinergic hypothesis”. The idea of ATP working as signaling molecule faced initial resistance until the discovery of the receptors for ATP and other nucleotides, being called purinergic receptors. Among the purinergic receptors, the P2Y family is of great importance because it comprises G protein-coupled receptors (GPCRs). GPCRs are widespread among different organisms. These receptors work in the cells' ability to sense the external environment which involves: to sense a dangerous situation or detect a pheromone through smell; the taste of food that should not be eaten; respond to hormones that alter metabolism according to the body's need; or even transform light into an electrical stimulus to generate vision. Advances in understanding the mechanism of action of GPCRs shed light on increasingly promising treatments for diseases that have hitherto remained incurable, or the possibility of abolishing side effects from therapies widely used today.

scholarly journals Purinergic Receptors Crosstalk with CCR5 to Amplify Ca2+ Signaling

2020 ◽  
Author(s):  
Mizuho Horioka ◽  
Emilie Ceraudo ◽  
Emily Lorenzen ◽  
Thomas P. Sakmar ◽  
Thomas Huber
Keyword(s):  
Signaling Pathways ◽  
G Protein ◽  
Purinergic Receptors ◽  
P2y Receptors ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Extracellular Milieu ◽  
Immunodeficiency Virus ◽  
Intracellular Ca ◽  
G Protein Coupled

AbstractMany G protein-coupled receptors (GPCRs) signal through more than one subtype of heterotrimeric G proteins. For example, the C–C chemokine receptor type 5 (CCR5), which serves as a co-receptor to facilitate cellular entry of human immunodeficiency virus 1 (HIV-1), normally signals through the heterotrimeric G protein, Gi. However, CCR5 also exhibits G protein signaling bias and certain chemokine analogs can cause a switch to Gq pathways to induce Ca2+ signaling. We want to understand how much of the Ca2+ signaling from Gi-coupled receptors is due to G protein promiscuity and how much is due to transactivation and crosstalk with other receptors. We propose a possible mechanism underlying the apparent switching between different G protein signaling pathways. We show that chemokine-mediated Ca2+ flux in HEK293T cells expressing CCR5 can be primed and enhanced by ATP pretreatment. In addition, agonist-dependent lysosomal exocytosis results in the release of ATP to the extracellular milieu, which amplifies cellular signaling networks. ATP is quickly degraded via ADP and AMP to adenosine. ATP, ADP and adenosine activate different cell surface purinergic receptors. Endogenous Gq-coupled purinergic P2Y receptors amplify Ca2+ signaling and allow for Gi- and Gq-coupled receptor signaling pathways to converge. Associated secretory release of GPCR ligands, such as chemokines, opioids, and monoamines, should also lead to concomitant release of ATP with a synergistic effect on Ca2+ signaling. Our results suggest that crosstalk between ATP-activated purinergic receptors and other Gi-coupled GPCRs is an important cooperative mechanism to amplify the intracellular Ca2+ signaling response.

scholarly journals Inflammation, Pain, and Pressure—Purinergic Signaling in Oral Tissues

2012 ◽  
Vol 91 (12) ◽  
pp. 1103-1109 ◽  
Author(s):  
J.C. Lim ◽  
C.H. Mitchell
Keyword(s):  
Extracellular Enzymes ◽  
Purinergic Signaling ◽  
Mechanical Strain ◽  
P2y Receptors ◽  
Receptor Activation ◽  
P2x Receptors ◽  
Inflammasome Activation ◽  
Dental Research ◽  
Multiple Levels ◽  
G Protein Coupled

Signaling by extracellular purines such as ATP and adenosine has implications for dental research on multiple levels, with the association of purinergic signaling with inflammation, mechanical strain, and pain making the system particularly relevant for the specific challenges in the oral cavity. Oral tissues express a variety of G-protein-coupled P2Y receptors for ATP and P1 receptors for adenosine in addition to ionotropic P2X receptors for ATP. When these receptors are combined with the plethora of extracellular enzymes capable of manipulating extracellular agonist levels, a complex system for regulating oral health emerges, and recent findings have begun to identify a key role for purinergic signaling in oral pathophysiology. For example, the manipulation of extracellular ATP levels by P. gingivalis reduces inflammasome activation and apoptosis linked to P2X7 receptor activation. Release of ATP by periodontal ligaments may link mechanical strain to bone remodeling. Activation of P2X receptors is implicated in dental pain, and receptor antagonists represent important targets for new analgesics. Altered levels of adenosine receptors in periodontal disease also suggest a role for nucleosides in dental signaling. The intricacies of the purinergic signaling system make it well-suited for the unique concerns of dental research, and future findings will doubtless confirm this importance.

scholarly journals Overview of Non-Alcoholic Fatty Liver Disease (NAFLD) and the Role of Sugary Food Consumption and Other Dietary Components in Its Development

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1442
Author(s):  
Pau Vancells Lujan ◽  
Esther Viñas Esmel ◽  
Emilio Sacanella Meseguer
Keyword(s):  
Clinical Trials ◽  
Liver Disease ◽  
Critical Role ◽  
Dietary Treatment ◽  
Dietary Interventions ◽  
Lifestyle Modifications ◽  
Alcoholic Fatty Liver ◽  
Effective Form ◽  
Unhealthy Diet

NAFLD is the world’s most common chronic liver disease, and its increasing prevalence parallels the global rise in diabetes and obesity. It is characterised by fat accumulation in the liver evolving to non-alcoholic steatohepatitis (NASH), an inflammatory subtype that can lead to liver fibrosis and cirrhosis. Currently, there is no effective pharmacotherapeutic treatment for NAFLD. Treatment is therefore based on lifestyle modifications including changes to diet and exercise, although it is unclear what the most effective form of intervention is. The aim of this review, then, is to discuss the role of specific nutrients and the effects of different dietary interventions on NAFLD. It is well established that an unhealthy diet rich in calories, sugars, and saturated fats and low in polyunsaturated fatty acids, fibre, and micronutrients plays a critical role in the development and progression of this disease. However, few clinical trials have evaluated the effects of nutrition interventions on NAFLD. We, therefore, summarise what is currently known about the effects of macronutrients, foods, and dietary patterns on NAFLD prevention and treatment. Most current guidelines recommend low-calorie, plant-based diets, such as the Mediterranean diet, as the most effective dietary pattern to treat NAFLD. More clinical trials are required, however, to identify the best evidence-based dietary treatment approach.

scholarly journals Beneficial effect of omarigliptin on diabetic patients with non-alcoholic fatty liver disease/non-alcoholic steatohepatitis

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Sachiko Hattori ◽  
Kazuomi Nomoto ◽  
Tomohiko Suzuki ◽  
Seishu Hayashi
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Liver Function ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Hepatic Insulin Resistance ◽  
Diabetic Patients ◽  
Alcoholic Fatty Liver ◽  
Dpp4 Inhibitor ◽  
Alcoholic Fatty Liver Disease

Abstract Background Dipeptidyl peptidase 4 (DPP4) is a serine exopeptidase able to inactivate various oligopeptides, and also a hepatokine. Hepatocyte-specific overexpression of DPP4 is associated with hepatic insulin resistance and liver steatosis. Method We examined whether weekly DPP4 inhibitor omarigliptin (OMG) can improve liver function as well as levels of inflammation and insulin resistance in type 2 diabetic patients with non-alcoholic fatty liver disease (NAFLD). Further, we investigated the effects of OMG in a diabetic patient with biopsy-confirmed nonalcoholic steatohepatitis (NASH). Results In NAFLD patients, OMG significantly decreased levels of aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, homeostatic model assessment of insulin resistance (HOMA-IR), and high-sensitivity C-reactive protein (hsCRP), while no significant change was seen in hemoglobin A1c or body mass index. In the NASH patient, liver function improved markedly, and levels of the hepatic fibrosis marker FIB-4 decreased in parallel with HOMA-IR and hsCRP. Slight but clear improvements in intrahepatic fat deposition and fibrosis appeared to be seen on diagnostic ultrasonography. Conclusion Weekly administration of the DPP4 inhibitor OMG in ameliorating hepatic insulin resistance may cause beneficial effects in liver with NAFLD/NASH.

Gene of the month: BECN1

2014 ◽  
Vol 67 (8) ◽  
pp. 656-660 ◽  
Author(s):  
Sumit Sahni ◽  
Angelica M Merlot ◽  
Sukriti Krishan ◽  
Patric J Jansson ◽  
Des R Richardson
Keyword(s):  
Neurological Disorders ◽  
Viral Infections ◽  
Critical Role ◽  
Beclin 1 ◽  
Biological Processes ◽  
Disease States ◽  
Binding Partners ◽  
Future Drug ◽  
Cellular Components ◽  
Important Therapeutic Target

The BECN1 gene encodes the Beclin-1 protein, which is a well-established regulator of the autophagic pathway. It is a mammalian orthologue of the ATG6 gene in yeast and was one of the first identified mammalian autophagy-associated genes. Beclin-1 interacts with a number of binding partners in the cell which can lead to either activation (eg, via PI3KC3/Vps34, Ambra 1, UV radiation resistance-associated gene) or inhibition (eg, via Bcl-2, Rubicon) of the autophagic pathway. Apart from its role as a regulator of autophagy, it is also shown to effect important biological processes in the cell such as apoptosis and embryogenesis. Beclin-1 has also been implicated to play a critical role in the pathology of a variety of disease states including cancer, neurological disorders (eg, Alzheimer's disease, Parkinson's disease) and viral infections. Thus, understanding the functions of Beclin-1 and its interactions with other cellular components will aid in its development as an important therapeutic target for future drug development.

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