Plant-derived natural therapeutics targeting cannabinoid receptors in metabolic syndrome and its complications: A review

 Biomedicine & Pharmacotherapy“The endocannabinoid system (ECS) is natural physiological system in the humans. The presence of the ECS system involves different roles in body. The endocannabinoid system involves regulation of most of the centers, which regulates the hunger and leads to changes in the weight.

In the present article, we reviewed the role of natural cannabinoid compounds in metabolic disorders and related complications. We studied variety of a plant-derived cannabinoids in treating the metabolic syndrome including stoutness, fatty acid liver diseases, insulin obstruction, dementia, hypertension, lipid abnormalities, non-alcoholic steatohepatitis, endothelial damage, and polycystic ovarian syndrome and so on.

The activation of cannabinoid receptors demonstrates a significant number of beneficial approaches concerning metabolic syndrome and reduces the pro-inflammatory cytokines on account of aggravation, decreased oxidative stress and uneasiness, diminishes liver fibrosis, with reduces adiponectin.

Pre-clinical investigations of plant-derived cannabinoids resulted in promising outcomes.

The different distinctive plant-derived cannabinoids were discovered like cannabidiol (CBD), cannabinol (CBN), cannabichromene (CBC), and cannabidiol (CBG). It has been observed that endogenous cannabinoids and plant-derived cannabinoids have an advantageous impact on limiting the metabolic disorder arising due to lifestyle changes.”

https://pubmed.ncbi.nlm.nih.gov/33113429/

https://www.sciencedirect.com/science/article/pii/S0753332220310817?via%3Dihub

Cannabinoid Receptor Subtype 2 (CB2R) in a Multitarget Approach: Perspective of an Innovative Strategy in Cancer and Neurodegeneration

 Go to Volume 0, Issue 0“The cannabinoid receptor subtype 2 (CB2R) represents an interesting and new therapeutic target for its involvement in the first steps of neurodegeneration as well as in cancer onset and progression.

Several studies, focused on different types of tumors, report a promising anticancer activity induced by CB2R agonists due to their ability to reduce inflammation and cell proliferation. Moreover, in neuroinflammation, the stimulation of CB2R, overexpressed in microglial cells, exerts beneficial effects in neurodegenerative disorders.

With the aim to overcome current treatment limitations, new drugs can be developed by specifically modulating, together with CB2R, other targets involved in such multifactorial disorders.

Building on successful case studies of already developed multitarget strategies involving CB2R, in this Perspective we aim at prompting the scientific community to consider new promising target associations involving HDACs (histone deacetylases) and σ receptors by employing modern approaches based on molecular hybridization, computational polypharmacology, and machine learning algorithms.”

https://pubmed.ncbi.nlm.nih.gov/33094613/

https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c01357

Abstract Image

The Activation of Cannabinoid Type-2 Receptor with JWH-133 Protects Uterine Ischemia/Reperfusion-Induced Damage

 Pharmacology - Home - Karger Publishers“Uterus transplantation is a complex surgical procedure. Uterine ischemia/reperfusion (IR) damage occurring in this process may cause loss of function in the uterus. Cell damage must be prevented for a healthy uterine function and successful transplantation.

Cannabinoids, with their increasing clinical use, are substances with strong anti-inflammatory and antioxidative effects and have a role in immune system regulation. However, their efficacy in uterine IR damage is still unknown.

This study provides information on the potential applications cannabinoids agonist JWH-133 in uterine IR damage and, hence, in the transplant process.

Results: In the uterine IR group, NF-κB expression and MDA levels were detected at high levels. Histopathological examinations and TUNEL staining revealed extensive cell damage. On the other hand, in groups treated with JWH-133, dose-dependent NF-κB expression and MDA levels decreased (p < 0.05). Depending on the dose, the rate of surviving cells increased in TUNEL staining results.

Conclusion: The results showed that JWH-133 was effective in reducing uterine IR damage. Cannabinoids may be a new alternative that may be used in the transplantation process in the future.”

https://pubmed.ncbi.nlm.nih.gov/33105141/

https://www.karger.com/Article/Abstract/511457

Cannabinoids in Metabolic Syndrome and Cardiac Fibrosis

 SpringerLink“This article provides a concise overview of how cannabinoids and the endocannabinoid system (ECS) have significant implications for the prevention and treatment of metabolic syndrome (MetS) and for the treatment of cardiovascular disorders, including cardiac fibrosis.

Recent findings: Over the past few years, the ECS has emerged as a pivotal component of the homeostatic mechanisms for the regulation of many bodily functions, including inflammation, digestion, and energy metabolism. Therefore, the pharmacological modulation of the ECS by cannabinoids represents a novel strategy for the management of many diseases. Specifically, increasing evidence from preclinical research studies has opened new avenues for the development of cannabinoid-based therapies for the management and potential treatment of MetS and cardiovascular diseases. Current information indicates that modulation of the ECS can help maintain overall health and well-being due to its homeostatic function. From a therapeutic perspective, cannabinoids and the ECS have also been shown to play a key role in modulating pathophysiological states such as inflammatory, neurodegenerative, gastrointestinal, metabolic, and cardiovascular diseases, as well as cancer and pain. Thus, targeting and modulating the ECS with cannabinoids or cannabinoid derivatives may represent a major disease-modifying medical advancement to achieve successful treatment for MetS and certain cardiovascular diseases.”

https://pubmed.ncbi.nlm.nih.gov/33089434/

https://link.springer.com/article/10.1007%2Fs11906-020-01112-7

Therapeutic application of cannabidiol on UVA and UVB irradiated rat skin. A proteomic study

Journal of Pharmaceutical and Biomedical Analysis “UV phototherapy used in chronic skin diseases causes redox imbalance and pro-inflammatory reactions, especially in the case of unchanged skin cells.

To prevent the harmful effects of UV radiation, cannabidiol (CBD) has been used, which has antioxidant and anti-inflammatory properties. Therefore, the aim of this study was to evaluate the effect of CBD on the metabolism of skin keratinocytes in nude rats exposed to UVA/UVB radiation using a proteomic approach.

The results obtained with SDS-PAGE/nanoHPLC/QexactiveOrbiTrap show that exposure of rat’s skin to UVA/UVB radiation, as well as the action of CBD, significantly modified the expression of proteins involved in inflammation, redox balance and apoptosis.

UVA/UVB radiation significantly increased the expression and biological effectiveness of the nuclear factor associated with erythroid factor 2 (Nrf2) and cytoprotective proteins being products of its transcriptional activity, including superoxide dismutase (Cu,Zn-SOD) and the inflammatory response (nuclear receptor coactivator-3 and paralemmin-3), while CBD treatment counteracted and partially eliminated these changes.

Moreover, cannabidiol reversed changes in the UV-induced apoptotic pathways by modifying anti-apoptotic and pro-apoptotic factors (apoptosis regulator Bcl-2 and transforming growth factor-β).

The results show that CBD maintains keratinocyte proteostasis and therefore could be suggested as a protective measure in the prevention of UV-induced metabolic changes in epidermal keratinocytes.”

https://pubmed.ncbi.nlm.nih.gov/33086172/

“In summary, UVA and UVB radiation affect the proteomic profile of keratinocytes of healthy rat skin in different ways. Both types of radiation change the level of proteins involved in the regulation of cellular redox balance, inflammation, and apoptosis. In contrast, topical application of CBD to rat skin, when exposed to UV radiation, helps normalize the expression of keratinocyte proteins that are metabolically relevant by modeling their biosynthesis and degradation. Thus, CBD can maintain the proteostasis of keratinocytes. Because UV therapy is a part of the treatment of skin diseases, e.g. psoriasis, the use of CBD on unchanged skin may be suggested as a protective factor to reduce the metabolic changes caused by UV radiation in unchanged keratinocytes. This suggestion is particularly important when the beneficial effect of cannabidiol on psoriasis-induced skin lesions has recently also been confirmed.”

https://www.sciencedirect.com/science/article/pii/S0731708520315429?via%3Dihub

Cannabinoid Receptors and Their Relationship With Chronic Pain: A Narrative Review

CB1-versus-CB2-receptors “The burden of chronic pain has affected many individuals leading to distress and discomfort, alongside numerous side effects with conventional therapeutic approaches.

Cannabinoid receptors are naturally found in the human body and have long been an interest in antinociception. These include CB1 and CB2 receptors, which are promising candidates for the treatment of chronic inflammatory pain.

The mechanism of action of the receptors and how they approach pain control in inflammatory conditions show that it can be an adjunctive approach towards controlling these symptoms. Numerous studies have shown how the targeted approach towards these receptors has activated them promoting a release in cytokines, all leading to anti-inflammatory effects and immune system regulation.

Cannabinoid activation of glycine and gamma-aminobutyric acid (GABA) models also showed efficacy in pain management. Chronic conditions such as osteoarthritis were shown to also benefit from this considerable treatment. However, it is unclear how the cannabinoid system works in relation with the pain pathway. Therefore, in this review we aim to analyse the role of the cannabinoid system in chronic inflammatory pain.”

https://pubmed.ncbi.nlm.nih.gov/33072446/

https://www.cureus.com/articles/39887-cannabinoid-receptors-and-their-relationship-with-chronic-pain-a-narrative-review

Cannabinoid Receptors: An Update on Cell Signaling, Pathophysiological Roles and Therapeutic Opportunities in Neurological, Cardiovascular, and Inflammatory Diseases

ijms-logo “The identification of the human cannabinoid receptors and their roles in health and disease, has been one of the most significant biochemical and pharmacological advancements to have occurred in the past few decades. In spite of the major strides made in furthering endocannabinoid research, therapeutic exploitation of the endocannabinoid system has often been a challenging task.

An impaired endocannabinoid tone often manifests as changes in expression and/or functions of type 1 and/or type 2 cannabinoid receptors. It becomes important to understand how alterations in cannabinoid receptor cellular signaling can lead to disruptions in major physiological and biological functions, as they are often associated with the pathogenesis of several neurological, cardiovascular, metabolic, and inflammatory diseases.

This review focuses mostly on the pathophysiological roles of type 1 and type 2 cannabinoid receptors, and it attempts to integrate both cellular and physiological functions of the cannabinoid receptors. Apart from an updated review of pre-clinical and clinical studies, the adequacy/inadequacy of cannabinoid-based therapeutics in various pathological conditions is also highlighted. Finally, alternative strategies to modulate endocannabinoid tone, and future directions are also emphasized.”

https://pubmed.ncbi.nlm.nih.gov/33080916/

https://www.mdpi.com/1422-0067/21/20/7693

Cannabidiol (CBD) modulation of apelin in acute respiratory distress syndrome

“Considering lack of target-specific antiviral treatment and vaccination for COVID-19, it is absolutely exigent to have an effective therapeutic modality to reduce hospitalization and mortality rate as well as to improve COVID-19-infected patient outcomes.

In a follow-up study to our recent findings indicating the potential of Cannabidiol (CBD) in the treatment of acute respiratory distress syndrome (ARDS), here we show for the first time that CBD may ameliorate the symptoms of ARDS through up-regulation of apelin, a peptide with significant role in the central and peripheral regulation of immunity, CNS, metabolic and cardiovascular system.

CBD treatment was able to reverse the symptoms of ARDS towards a normal level. Importantly, CBD treatment increased the apelin expression significantly, suggesting a potential crosstalk between apelinergic system and CBD may be the therapeutic target in the treatment of inflammatory diseases such as COVID-19 and many other pathologic conditions.”

https://pubmed.ncbi.nlm.nih.gov/33058425/

“Cannabidiol (CBD) is a non‐psychotropic phytocannabinoid that regulates immune responses in multiple experimental disease models, including work by our laboratory showing a benefit following ARDS‐like injury in mice. Consistent with our findings, a recent commentary, based on anecdotal reports, supports the therapeutic use of CBD in COVID‐19‐infected patients. Our data demonstrate that CBD improves lung structure and exerts a potent anti‐inflammatory effect following experimental ARDS.”

https://onlinelibrary.wiley.com/doi/10.1111/jcmm.15883

The immunosuppressive effect of the endocannabinoid system on the inflammatory phenotypes of macrophages and mesenchymal stromal cells: a comparative study

SpringerLink “The inflammatory sequence is the first phase of wound healing. Macrophages (MPhs) and mesenchymal stromal cells (MSCs) respond to an inflammatory microenvironment by adapting their functional activity, which polarizes them into the pro-inflammatory phenotypes M1 and MSC1. Prolongation of the inflammatory phase results in the formation of chronic wounds. The endocannabinoid system (ECS) possesses immunomodulatory properties that may impede this cellular phenotypic switch.

Methods: We investigated the immunosuppressive influence of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) on the M1 and MSC1 cytokine secretion. Lipopolysaccharides (LPS) were used as inflammagen to stimulate MPhs and MSCs. Both inflammatory phenotypes were co-exposed to AEA or 2-AG, the specific cannabinoid receptor CB2 agonist JWH-133 served as reference. The inflammatory responses were detected by CD80/163 immuno-labelling and by ELISA measures of secreted IL-6, IL-8, MIF, TNF-α, TGF-β, and VEGF.

Results: M1 cells were found positive for CD80 expression and secreted less IL-6 and IL-8 than MSC1 cells, while both cell types produced similar amounts of MIF. TNF-α release was increased by M1, and growth factors were secreted by MSC1, only. Cannabinoid receptor ligands efficiently decreased the inflammatory response of M1, while their impact was less pronounced in MSC1.

Conclusions: The ECS down-regulated the inflammatory responses of MPhs and MSCs by decreasing the cytokine release upon LPS treatment, while CB2 appeared to be of particular importance. Hence, stimulating the ECS by manipulation of endo- or use of exogenous cannabinoids in vivo may constitute a potent therapeutic option against inflammatory disorders.”

https://pubmed.ncbi.nlm.nih.gov/33026642/

https://link.springer.com/article/10.1007%2Fs43440-020-00166-3

The CB2 Agonist β-Caryophyllene in Male and Female Rats Exposed to a Model of Persistent Inflammatory Pain

frontiers – Page 2 – Retraction Watch “Cannabinoids help in pain treatment through their action on CB1 and CB2 receptors.

β-caryophyllene (BCP), an ancient remedy to treat pain, is a sesquiterpene found in large amounts in the essential oils of various spice and food plants such as oregano, cinnamon, and black pepper. It binds to the CB2 receptor, acting as a full agonist.

Sex differences in the BCP-induced analgesic effect were studied by exposing male and female rats to a persistent/repeated painful stimulation.

In conclusion, long-term intake of BCP appears to be able to decrease pain behaviors in a model of repeated inflammatory pain in both sexes, but to a greater degree in males.”

https://pubmed.ncbi.nlm.nih.gov/33013287/

https://www.frontiersin.org/articles/10.3389/fnins.2020.00850/full

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”   http://www.ncbi.nlm.nih.gov/pubmed/23138934

“Beta-caryophyllene is a dietary cannabinoid.”   https://www.ncbi.nlm.nih.gov/pubmed/18574142