scholarly journals Relevance of Peroxisome Proliferator Activated Receptors in Multitarget Paradigm Associated with the Endocannabinoid System

2021 ◽  
Vol 22 (3) ◽  
pp. 1001
Author(s):  
Ana Lago-Fernandez ◽  
Sara Zarzo-Arias ◽  
Nadine Jagerovic ◽  
Paula Morales
Keyword(s):  
Cannabinoid Receptors ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Synergistic Effects ◽  
Synthetic Cannabinoids ◽  
Endocannabinoid System ◽  
Receptor Potential ◽  
Therapeutic Effects ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptors

Cannabinoids have shown to exert their therapeutic actions through a variety of targets. These include not only the canonical cannabinoid receptors CB1R and CB2R but also related orphan G protein-coupled receptors (GPCRs), ligand-gated ion channels, transient receptor potential (TRP) channels, metabolic enzymes, and nuclear receptors. In this review, we aim to summarize reported compounds exhibiting their therapeutic effects upon the modulation of CB1R and/or CB2R and the nuclear peroxisome proliferator-activated receptors (PPARs). Concomitant actions at CBRs and PPARα or PPARγ subtypes have shown to mediate antiobesity, analgesic, antitumoral, or neuroprotective properties of a variety of phytogenic, endogenous, and synthetic cannabinoids. The relevance of this multitargeting mechanism of action has been analyzed in the context of diverse pathologies. Synergistic effects triggered by combinatorial treatment with ligands that modulate the aforementioned targets have also been considered. This literature overview provides structural and pharmacological insights for the further development of dual cannabinoids for specific disorders.

scholarly journals Cannabinoids in Gynecological Diseases

2019 ◽  
Vol 2 (1) ◽  
pp. 14-21
Author(s):  
Petra Luschnig ◽  
Rudolf Schicho
Keyword(s):  
Cannabinoid Receptors ◽  
Transient Receptor Potential ◽  
Synthetic Cannabinoids ◽  
Endocannabinoid System ◽  
Receptor Potential ◽  
Peroxisome Proliferator ◽  
Female Reproduction ◽  
Gynecological Disorders ◽  
Peroxisome Proliferator Activated Receptors ◽  
Transient Receptor

The endocannabinoid system (ECS) is a multifunctional homeostatic system involved in many physiological and pathological conditions. The ligands of the ECS are the endo­cannabinoids, whose actions are mimicked by exogenous cannabinoids, such as phytocannabinoids and synthetic cannabinoids. Responses to the ligands of the ECS are mediated by numerous receptors like the classical cannabinoid receptors (CB1 and CB2) as well as ECS-related receptors, e.g., G protein-coupled receptors 18 and 55 (GPR18 and GPR55), transient receptor potential ion channels, and nuclear peroxisome proliferator-activated receptors. The ECS regulates almost all levels of female reproduction, starting with oocyte production through to parturition. Dysregulation of the ECS is associated with the development of gynecological disorders from fertility disorders to cancer. Cannabinoids that act at the ECS as specific agonists or antagonists may potentially influence dysregulation and, therefore, represent new therapeutic options for the therapy of gynecological disorders.

scholarly journals Endocannabinoids in the gastrointestinal tract

2016 ◽  
Vol 311 (4) ◽  
pp. G655-G666 ◽  
Author(s):  
Yunna Lee ◽  
Jeongbin Jo ◽  
Hae Young Chung ◽  
Charalabos Pothoulakis ◽  
Eunok Im
Keyword(s):  
Cannabinoid Receptors ◽  
Transient Receptor Potential ◽  
Synthetic Cannabinoids ◽  
Endocannabinoid System ◽  
Receptor Potential ◽  
Gastrointestinal Diseases ◽  
Transient Receptor Potential Channels ◽  
Therapeutic Benefits ◽  
Potential Channels ◽  
Transient Receptor

The endocannabinoid system mainly consists of endogenously produced cannabinoids (endocannabinoids) and two G protein-coupled receptors (GPCRs), cannabinoid receptors 1 and 2 (CB1 and CB2). This system also includes enzymes responsible for the synthesis and degradation of endocannabinoids and molecules required for the uptake and transport of endocannabinoids. In addition, endocannabinoid-related lipid mediators and other putative endocannabinoid receptors, such as transient receptor potential channels and other GPCRs, have been identified. Accumulating evidence indicates that the endocannabinoid system is a key modulator of gastrointestinal physiology, influencing satiety, emesis, immune function, mucosal integrity, motility, secretion, and visceral sensation. In light of therapeutic benefits of herbal and synthetic cannabinoids, the vast potential of the endocannabinoid system for the treatment of gastrointestinal diseases has been demonstrated. This review focuses on the role of the endocannabinoid system in gut homeostasis and in the pathogenesis of intestinal disorders associated with intestinal motility, inflammation, and cancer. Finally, links between gut microorganisms and the endocannabinoid system are briefly discussed.

scholarly journals Anti-Inflammatory Effects of Epoxyeicosatrienoic Acids

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Scott J. Thomson ◽  
Ara Askari ◽  
David Bishop-Bailey
Keyword(s):  
Cellular Proliferation ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Epoxyeicosatrienoic Acids ◽  
Peroxisome Proliferator ◽  
Diverse Range ◽  
Anti Inflammatory ◽  
Peroxisome Proliferator Activated Receptors ◽  
Transient Receptor

Epoxyeicosatrienoic acids (EETs) are generated by the activity of both selective and also more general cytochrome p450 (CYP) enzymes on arachidonic acid and inactivated largely by soluble epoxide hydrolase (sEH), which converts them to their corresponding dihydroxyeicosatrienoic acids (DHETs). EETs have been shown to have a diverse range of effects on the vasculature including relaxation of vascular tone, cellular proliferation, and angiogenesis as well as the migration of smooth muscle cells. This paper will highlight the growing evidence that EETs also mediate a number of anti-inflammatory effects in the cardiovascular system. In particular, numerous studies have demonstrated that potentiation of EET activity using different methods can inhibit inflammatory gene expression and signalling pathways in endothelial cells and monocytes and in models of cardiovascular diseases. The mechanisms by which EETs mediate their effects are largely unknown but may include direct binding to peroxisome proliferator-activated receptors (PPARs), G-protein coupled receptors (GPCRs), or transient receptor potential (TRP) channels, which initiate anti-inflammatory signalling cascades.

scholarly journals Cannabis sativa L. as a Natural Drug Meeting the Criteria of a Multitarget Approach to Treatment

2021 ◽  
Vol 22 (2) ◽  
pp. 778
Author(s):  
Anna Stasiłowicz ◽  
Anna Tomala ◽  
Irma Podolak ◽  
Judyta Cielecka-Piontek
Keyword(s):  
Pharmacological Activity ◽  
Transient Receptor Potential ◽  
Cannabis Sativa ◽  
Current Knowledge ◽  
Endocannabinoid System ◽  
Receptor Potential ◽  
Transient Receptor Potential Channels ◽  
Raw Material ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

Cannabis sativa L. turned out to be a valuable source of chemical compounds of various structures, showing pharmacological activity. The most important groups of compounds include phytocannabinoids and terpenes. The pharmacological activity of Cannabis (in epilepsy, sclerosis multiplex (SM), vomiting and nausea, pain, appetite loss, inflammatory bowel diseases (IBDs), Parkinson’s disease, Tourette’s syndrome, schizophrenia, glaucoma, and coronavirus disease 2019 (COVID-19)), which has been proven so far, results from the affinity of these compounds predominantly for the receptors of the endocannabinoid system (the cannabinoid receptor type 1 (CB1), type two (CB2), and the G protein-coupled receptor 55 (GPR55)) but, also, for peroxisome proliferator-activated receptor (PPAR), glycine receptors, serotonin receptors (5-HT), transient receptor potential channels (TRP), and GPR, opioid receptors. The synergism of action of phytochemicals present in Cannabis sp. raw material is also expressed in their increased bioavailability and penetration through the blood–brain barrier. This review provides an overview of phytochemistry and pharmacology of compounds present in Cannabis extracts in the context of the current knowledge about their synergistic actions and the implications of clinical use in the treatment of selected diseases.

scholarly journals Endocannabinoids and endocannabinoid-like molecules are present in foods, blood and ileal fluids from ileostomy subjects: insight into possible metabolic implications

2020 ◽  
Vol 79 (OCE2) ◽  
Author(s):  
Silvia Tagliamonte ◽  
Chris I R. Gill ◽  
Laura Kirsty Pourshahidi ◽  
Mary Slevin ◽  
Roger Lawther ◽  
...  
Keyword(s):  
Nervous System ◽  
Intestinal Tract ◽  
Cannabinoid Receptors ◽  
Endocannabinoid System ◽  
The Body ◽  
Intestinal Lumen ◽  
Healthy Population ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptors ◽  
Gastro Intestinal Tract

AbstractThe endocannabinoid system is a lipid signalling system with several regulatory functions throughout the body including regulation of appetite, food intake, macronutrient metabolism, pain sensation, blood pressure, mood, cognition and immunity. It consists of endocannabinoids (ECs), their receptors and enzymes involved in their synthesis and degradation. The two best-characterized endocannabinoids are N-arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG). They are ligands of cannabinoid receptors CB1 and CB2 which are located in the central nervous system (CNS) but also in in the enteric nervous system, in the liver and in the adipose tissue.Several structural congeners of ECs including N-acylethanolamines (NAEs) such as oleoylethanolamine (OEA), linoleyethanolamine (LEA), and palmitoyletahanolamine (PEA), show similar mechanisms of action, tissue distribution as well as pathways of formation and breakdown. They are considered “endocannabinoid-like” molecules acting through receptors that are located both in CNS and in the gastro-intestinal tract mucosa such as the G-protein coupled receptor 119 (GPR119) and peroxisome proliferator-activated receptors (PPARs). NAEs display EC50 values for human GPR119 and PPAR-α between 65 ng/mL and 1000 ng/mL. Some evidence indicated that NAEs, their phosphorylated precursors N-acylphosphatidylethanolamines (NAPEs) and ECs are also present in food. Thus, we developed a food database of these molecules and we calculated the daily dietary intake in a healthy population.This study aimed to evaluate whether the concentrations of NAPEs, NAEs and ECs in the human intestinal lumen may support their activity through the receptors lining in the gastro-intestinal tract and if they correlated with those in plasma.The observational study (16/NI/0267, Ulster University) involved 35 ileostomists (18F/17M, aged 18–70 y, BMI 17–40 kg/m2) who collected overnight fasting samples of ileal fluid and plasma. The concentrations of NAEs, NAPEs and ECs in biological samples were determined by LC-HRMS.Data showed that NAEs and NAPEs were present in ileal fluids and plasma from all subjects ranging between 46851.0–104742.8 ng/mL and 0.3–59.6 ng/mL in ileal samples and 1159.4–3985.7 ng/mL and 0.19–1.24 ng/mL in plasma, respectively. Contrarily, no ECs in ileal fluids were found except 2-AG in two ileal samples whereas they ranged between 1.6–22.3 ng/mL in plasma. Differences between genders and associations of plasma levels with individual energy intakes were found.Altogether, the data demonstrated that NAEs in the intestinal lumen are sufficient to elicit metabolic responses through the gastro-intestinal receptors.

scholarly journals Targeting Cannabinoid Receptors: Current Status and Prospects of Natural Products

2020 ◽  
Vol 21 (14) ◽  
pp. 5064 ◽  
Author(s):  
Dongchen An ◽  
Steve Peigneur ◽  
Louise Antonia Hendrickx ◽  
Jan Tytgat
Keyword(s):  
Natural Products ◽  
Cannabinoid Receptors ◽  
Structural Information ◽  
Critical Role ◽  
Synthetic Cannabinoids ◽  
Endocannabinoid System ◽  
Current Status ◽  
Therapeutic Effects ◽  
Drug Leads

Cannabinoid receptors (CB1 and CB2), as part of the endocannabinoid system, play a critical role in numerous human physiological and pathological conditions. Thus, considerable efforts have been made to develop ligands for CB1 and CB2, resulting in hundreds of phyto- and synthetic cannabinoids which have shown varying affinities relevant for the treatment of various diseases. However, only a few of these ligands are clinically used. Recently, more detailed structural information for cannabinoid receptors was revealed thanks to the powerfulness of cryo-electron microscopy, which now can accelerate structure-based drug discovery. At the same time, novel peptide-type cannabinoids from animal sources have arrived at the scene, with their potential in vivo therapeutic effects in relation to cannabinoid receptors. From a natural products perspective, it is expected that more novel cannabinoids will be discovered and forecasted as promising drug leads from diverse natural sources and species, such as animal venoms which constitute a true pharmacopeia of toxins modulating diverse targets, including voltage- and ligand-gated ion channels, G protein-coupled receptors such as CB1 and CB2, with astonishing affinity and selectivity. Therefore, it is believed that discovering novel cannabinoids starting from studying the biodiversity of the species living on planet earth is an uncharted territory.

scholarly journals Preclinical and Clinical Evidence of Therapeutic Agents for Paclitaxel-Induced Peripheral Neuropathy

2021 ◽  
Vol 22 (16) ◽  
pp. 8733
Author(s):  
Takehiro Kawashiri ◽  
Mizuki Inoue ◽  
Kohei Mori ◽  
Daisuke Kobayashi ◽  
Keisuke Mine ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Clinical Research ◽  
Cannabinoid Receptors ◽  
Transient Receptor Potential ◽  
Clinical Evidence ◽  
Trp Channels ◽  
Receptor Potential ◽  
Limiting Factor ◽  
Neuroprotective Effects ◽  
Transient Receptor

Paclitaxel is an essential drug in the chemotherapy of ovarian, non-small cell lung, breast, gastric, endometrial, and pancreatic cancers. However, it frequently causes peripheral neuropathy as a dose-limiting factor. Animal models of paclitaxel-induced peripheral neuropathy (PIPN) have been established. The mechanisms of PIPN development have been elucidated, and many drugs and agents have been proven to have neuroprotective effects in basic studies. In addition, some of these drugs have been validated in clinical studies for their inhibitory PIPN effects. This review summarizes the basic and clinical evidence for therapeutic or prophylactic effects for PIPN. In pre-clinical research, many reports exist of neuropathy inhibitors that target oxidative stress, inflammatory response, ion channels, transient receptor potential (TRP) channels, cannabinoid receptors, and the monoamine nervous system. Alternatively, very few drugs have demonstrated PIPN efficacy in clinical trials. Thus, enhancing translational research to translate pre-clinical research into clinical research is important.

scholarly journals Why do cannabinoid receptors have more than one endogenous ligand?

2012 ◽  
Vol 367 (1607) ◽  
pp. 3216-3228 ◽  
Author(s):  
Vincenzo Di Marzo ◽  
Luciano De Petrocellis
Keyword(s):  
Cannabinoid Receptors ◽  
Transient Receptor Potential ◽  
Endocannabinoid System ◽  
Receptor Potential ◽  
Peripheral Tissues ◽  
System A ◽  
Trpv1 Channels ◽  
Versatile Tool ◽  
Transient Receptor ◽  
G Protein Coupled

The endocannabinoid system was revealed following the understanding of the mechanism of action of marijuana's major psychotropic principle, Δ 9 -tetrahydrocannabinol, and includes two G-protein-coupled receptors (GPCRs; the cannabinoid CB1 and CB2 receptors), their endogenous ligands (the endocannabinoids, the best studied of which are anandamide and 2-arachidonoylglycerol (2-AG)), and the proteins that regulate the levels and activity of these receptors and ligands. However, other minor lipid metabolites different from, but chemically similar to, anandamide and 2-AG have also been suggested to act as endocannabinoids. Thus, unlike most other GPCRs, cannabinoid receptors appear to have more than one endogenous agonist, and it has been often wondered what could be the physiological meaning of this peculiarity. In 1999, it was proposed that anandamide might also activate other targets, and in particular the transient receptor potential of vanilloid type-1 (TRPV1) channels. Over the last decade, this interaction has been shown to occur both in peripheral tissues and brain, during both physiological and pathological conditions. TRPV1 channels can be activated also by another less abundant endocannabinoid, N -arachidonoyldopamine, but not by 2-AG, and have been proposed by some authors to act as ionotropic endocannabinoid receptors. This article will discuss the latest discoveries on this subject, and discuss, among others, how anandamide and 2-AG differential actions at TRPV1 and cannabinoid receptors contribute to making this signalling system a versatile tool available to organisms to fine-tune homeostasis.

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