Cannabidiol (CBD) Protects Adipose-Derived Mesenchymal Stem Cells (ASCs) against Endoplasmic Reticulum Stress Development and Its Complications

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“Background: Recent studies suggested that individuals with metabolic disorders have altered function of adipocytes and adipose stem cell subpopulations, which impairs tissue homeostasis, promoting insulin resistance and diabetes development. The non-psychoactive phytocannabinoid CBD was found to modulate adipose tissue metabolism, however, its exact role in controlling ASCs’ fate is still poorly understood.

Objectives: This investigation aimed to elucidate whether pretreatment of ASCs with CBD can protect against ER stress development and maintain the cytophysiological properties of cells.

Methods: Human ASCs were cultured under control and adipogenic conditions. Prior to the experiments, cells in the experimental group were pretreated with CBD following the addition of an ER stress inducer-tunicamycin. After the experiments, the cells were subsequently tested for expression of the apoptotic, ER stress, and anti-inflammatory-related genes using RT-qPCR. Oxidative stress was analysed with flow cytometric assays.

Results: Cells pretreated with CBD displayed decreased apoptosis and enhanced proliferation rate. Additionally, the expression of pro-inflammatory cytokines and miRNAs was significantly reduced. The obtained results also demonstrated an obvious reduction in intracellular accumulated ROS and NO, as well as mitigated ER stress through the down-regulation of IRE-1PERKCHOP, and ATF6 transcripts upon CBD treatment.

Conclusion: The presented data provide the evidence that CBD protects ASCs against ER stress development and its complications and, thus, offers new insights for the management of obesity through the regulation of adipose tissue dynamics.”

https://pubmed.ncbi.nlm.nih.gov/36078578/

“The regenerative potential of ASCs in the treatment of multiple disorders lies in their differentiation, migration, and secretory activity. However, these conditions impair the cytophysiological properties of ASCs, limiting their application in autologous therapies. What is more, impaired ASCs in vivo suffer from reduced multipotency and produce a vast number of inflammatory cytokines and oxidative stress factors, which in turn contributes to disease progression. Hence, development of strategies that reverse their senescence and ageing, and, as a consequence, restore regenerative properties are strongly desirable.

To our knowledge, this is the first report on the impact of CBD pretreatment on metabolically impaired ASCs suffering from ER stress. Our current study revealed that CBD modulates ASCs metabolism by promoting their growth kinetics, multipotency, and viability, which due to enhanced ER stress were strongly limited. Taking into account that CBD lacks psychopharmacological activity, further studies aiming at unravelling its influence on different stem cells populations are recommended and justified. Further studies on the effects of CBD on ASCs could explore other measures of its regenerative capacity than studied in the presented research. Furthermore, unravelling the precise molecular mechanisms of action via CBD that protect ASCs against cytophysiological impairment would be valuable. While our findings are supported by the existing literature, our research was not free of limitations. An important drawback is that we did not explore which cannabinoid receptors are responsible for the observed effects of CBD. Thus, further experiments utilizing agonists and antagonists of cannabinoid receptors are necessary to elucidate which of them are involved in CBD’s way of action.

Taking into consideration that ASCs are nowadays a commonly applied tool in regenerative medicine, the ability to enhance their stemness and regenerative potential may contribute not only to more effective therapies but also to significantly reducing the costs associated with their isolation and expansion.”

https://www.mdpi.com/1660-4601/19/17/10864/htm

Cannabidiol ameliorates the anxiogenic and compulsive-like behaviors induced by chronic consumption of a high-carbohydrate diet in male mice

SpringerLink

“The excessive consumption of ultra-processed foods and the development of obesity has been associated with several comorbidities, including psychiatric disorders. Excess fat tissue promotes a low-intensity inflammatory state, mainly in the white tissue, which is essential in developing metabolic alterations and influences brain homeostasis.

In this scenario, Cannabidiol (CBD), a compound from Cannabis sativa, has presented anxiolytic and anti-inflammatory effects in murine models.

This study verified whether CBD treatment would ameliorate the compulsive-like and anxiety-like behaviors observed after mice’s chronic consumption of a high-refined carbohydrate (HC) diet.

BALB/c male mice received a control or HC diet for 12 weeks followed by vehicle and CBD (30 mg/Kg, i.p.) administration, and their behavior was evaluated in the Marble Burying test (MB) and Novel Suppressing Feeding test (NSF).

The sub-chronic, but not acute, treatment with CBD attenuated the compulsive-like and anxiogenic-like behavior induced by the HC diet.

Our data reinforced the harmful effects of the HC diet’s chronic consumption on compulsive and anxious behaviors and the potential of CBD as a drug treatment for psychiatric disorders associated with obesity.”

https://pubmed.ncbi.nlm.nih.gov/36040711/

https://link.springer.com/article/10.1007/s11011-022-01071-9

Cannabinoids and PPAR Ligands: The Future in Treatment of Polycystic Ovary Syndrome Women with Obesity and Reduced Fertility

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“Cannabinoids (CBs) are used to treat chronic pain, chemotherapy-induced nausea and vomiting, and multiple sclerosis spasticity. Recently, the medicinal use of CBs has attracted increasing interest as a new therapeutic in many diseases.

Data indicate a correlation between CBs and PPARs via diverse mechanisms. Both the endocannabinoid system (ECS) and peroxisome proliferator-activated receptors (PPARs) may play a significant role in PCOS and PCOS related disorders, especially in disturbances of glucose-lipid metabolism as well as in obesity and fertility. Taking into consideration the ubiquity of PCOS in the human population, it seems indispensable to search for new potential therapeutic targets for this condition.

The aim of this review is to examine the relationship between metabolic disturbances and obesity in PCOS pathology. We discuss current and future therapeutic interventions for PCOS and related disorders, with emphasis on the metabolic pathways related to PCOS pathophysiology. The link between the ECS and PPARs is a promising new target for PCOS, and we examine this relationship in depth.”

https://pubmed.ncbi.nlm.nih.gov/36010645/

“There is a great potential to use CBs and their metabolites and non-cannabinoid dual CBRs/PPAR agonists as novel interventions for PCOS and related disorders. PCOS pathophysiology is complex and poorly understood. We demonstrate that the ECS and PPARs play an important role in the pathogenesis of PCOS (including mtCB1R). The complexity of the ECS and the PPARs will allow the development of diverse therapeutic modalities targeting these interrelated systems. Further, these interventions can be used to develop personalized approaches to treatment based on individual patient characteristics.”

https://www.mdpi.com/2073-4409/11/16/2569/htm

Cannabis Use as a Protective Factor Against Overweight in HIV-Hepatitis C Virus Co-Infected People (ANRS CO13 HEPAVIH Cohort)

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“Overweight is increasingly prevalent in people living with HIV (PLWH), and is a high risk factor for metabolic disorders in this population. PLWH co-infected with hepatitis C virus (HCV) have a higher risk of metabolic disorders than their mono-infected counterparts.

The putative relationship between cannabis use and body weight found in the general population has never been documented in HIV-HCV co-infected people. We tested whether cannabis use is associated with body mass index (BMI), overweight, and underweight in HCV co-infected PLWH (N = 992). Mixed-effects linear and logistic regression models were used to study the association between cannabis use and the three outcomes over time.

After multivariable adjustment, cannabis use was inversely associated with BMI. Cannabis use was associated with a lower and higher risk of overweight and underweight, respectively. Cannabis use should be assessed and taken into account in the clinical management of the HIV-HCV co-infected population.”

https://pubmed.ncbi.nlm.nih.gov/35994579/

https://guilfordjournals.com/doi/10.1521/aeap.2022.34.4.272

Pharmacophore-based virtual screening from phytocannabinoids as antagonist r-CB1

SpringerLink

“Search for new pharmacological alternatives for obesity is based on the design and development of compounds that can aid in weight loss so that they can be used safely and effectively over a long period while maintaining their function.

The endocannabinoid system is related to obesity by increasing orexigenic signals and reducing satiety signals.

Cannabis sativa is a medicinal plant of polypharmaceutical potential that has been widely studied for various medicinal purposes.

The in silico evaluation of their natural cannabinoids (also called phytocannabinoids) for anti-obesity purpose stems from the existence of synthetic cannabinoid compounds that have already presented this result, but which did not guarantee patient safety.

In order to find new molecules from C. sativa phytocannabinoids, with the potential to interact peripherally with the pharmacological target cannabinoid receptor 1, a pharmacophore-based virtual screening was performed, including the evaluation of physicochemical, pharmacokinetic, toxicological predictions and molecular docking.

The results obtained from the ZINC12 database pointed to Zinc 69 (ZINC33053402) and Zinc 70 (ZINC19084698) molecules as promising anti-obesity agents. Molecular dynamics (MD) studies disclose that both complexes were stable by analyzing the RMSD (root mean square deviation) values, and the binding free energy values demonstrate that the selected structures can interact and inhibit their catalytic activity.”

https://pubmed.ncbi.nlm.nih.gov/35978141/

https://link.springer.com/article/10.1007/s00894-022-05219-3

The Endocannabinoid System and Eating Behaviours: a Review of the Current State of the Evidence

SpringerLink

“Purpose of the review: The endocannabinoid system (ENS) has emerged as an important factor in food intake and may have implications for nutrition research. The objective of the current report is to summarise the available evidence on the ENS and eating behaviour from both animal and human studies.

Recent findings: The literature reviewed demonstrates a clear link between the ENS and eating behaviours. Overall, studies indicate that 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA) via cannabinoid receptor-1 (CNR1) binding may stimulate hunger and food intake while oleylethanolamide (OEA) may inhibit hunger. Mechanisms of these associations are not yet well understood, although the evidence suggests that there may be interactions with other physiological systems to consider. Most studies have been conducted in animal models, with few human studies available. Additional research is warranted among human populations into the ENS and eating behaviour. Evaluation of relationships between variation in ENS genes and dietary outcomes is an important area for investigation.”

https://pubmed.ncbi.nlm.nih.gov/35980538/

https://link.springer.com/article/10.1007/s13668-022-00436-x

The Endocannabinoid System and Physical Activity-A Robust Duo in the Novel Therapeutic Approach against Metabolic Disorders

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“Rapidly increasing worldwide prevalence of obesity and related pathologies encompassing coronary heart disease, hypertension, metabolic syndrome, or type 2 diabetes constitute serious threats to global health and are associated with a significantly elevated risk of premature death. Considering the enormous burden of these pathologies, novel therapeutic and preventive patterns are indispensable.

Dysregulation of one of the most complex biological systems in the human body namely, the endocannabinoid system (ECS) may result in metabolic imbalance and development of insulin resistance, type 2 diabetes, or non-alcoholic fatty liver disease. Furthermore, many studies showed that physical exercises, depending on their type, intensity, and frequency, exert various alterations within the ECS.

Emerging evidence suggests that targeting the ECS via physical activity may produce robust beneficial effects on the course of metabolic pathologies. However, the data showing a direct correlation between the ECS and physical activity in the aspect of metabolic health are very scarce. Therefore, the aim of this review was to provide the most up-to-date state of knowledge about the interplay between the ECS activity and physical exercises in the novel therapeutic and preventive approach toward metabolic pathologies.

We believe that this paper, at least in part, will fulfill the existing gap in knowledge and encourage researchers to further explore this very complex yet interesting link between the ECS, its action in physical activity, and subsequent positive outcomes for metabolic health.”

https://pubmed.ncbi.nlm.nih.gov/35328503/

“To the best of our knowledge, this is the first review directly and comprehensively discussing the uncharted link between physical activity and its influence on the endocannabinoid signaling in the aspect of beneficial effects in the management of metabolic disorders. Considering the very alarming worldwide prevalence of these diseases as well as the unexplored potential of the topic, we believe that this paper, at least in part, will encourage researchers toward investigating this interesting, yet very complicated interplay. ECS and physical activity constitute robust and valuable therapeutic and preventive approaches that may significantly contribute to the decreased socioeconomic burden and the reduced annual number of patients suffering from obesity and other metabolic disorders. The future investigation should primarily encompass further discovery of the link between physical activity, alterations within endocannabinoid signaling and subsequently improved metabolic status of overweight, obese, and diabetic individuals.”

https://www.mdpi.com/1422-0067/23/6/3083/htm


“Exercise activates the endocannabinoid system”

https://pubmed.ncbi.nlm.nih.gov/14625449/

Weight loss outcomes are not compromised in bariatric patients using cannabis

SpringerLink

“Background: The legalization of cannabis in several states has led to increased documented use in the population. Bariatric surgery patients are no exception with estimates of anywhere from 6 to 8%. Cannabis is known to be associated with increased appetite, mood disorders, hyperphagia, and rarely, hyperemesis, which can potentially affect post-surgical weight loss. We aim to study the differences in bariatric surgery outcomes between cannabis users and non-users.

Results: A cohort of 364 sleeve gastrectomy patients met inclusion criteria, 31 (8.5%) CU and 333 (91.5%) non-CU. There was no difference in EWL between CU and non-CU at 1 week, 1 month, 3 months, 6 months, 9 months, 1 year, and 2 years. However, the CU group trended towards greater EWL at 3 years (52.9% vs. 38.1%, p = 0.094) and at 5 years (49.8% vs. 32.7%, p = 0.068). There were no significant differences between CU and non-CU with respect to either incidence or severity of PONV at one year after surgery or longer follow-up.

Conclusion: Cannabis users did not experience inferior weight loss after bariatric surgery despite common assumptions that appetite stimulation can lead to suboptimal weight loss outcomes. Our findings add to other work challenging this dogma. Larger, long-term, multicenter studies are warranted.”

https://pubmed.ncbi.nlm.nih.gov/35861881/

https://link.springer.com/article/10.1007/s00464-022-09453-x

Cannabis Extract Effects on Metabolic Parameters and Gut Microbiota Composition in a Mice Model of NAFLD and Obesity

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“Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver abnormalities and has been linked with metabolic syndrome hallmarks. Unfortunately, current treatments are limited.

This work aimed to elucidate the effects of three cannabis extracts on metabolic alteration and gut microbiota composition in a mouse model of NAFLD and obesity.

Male mice were fed with a high-fat diet (HFD) for 12 weeks. Following the establishment of obesity, the HFD-fed group was subdivided into HFD or HFD that was supplemented with one of three cannabis extracts (CN1, CN2, and CN6) for additional 8 weeks. Metabolic parameters together with intestinal microbiota composition were evaluated.

Except for several minor changes in gene expression, no profound metabolic effect was found due to cannabis extracts addition. Nevertheless, marked changes were observed in gut microbiota diversity and composition, with CN1 and CN6 exhibiting microbial abundance patterns that are associated with more beneficial outcomes.

Taken together, specific cannabis extracts’ addition to an HFD results in more favorable modifications in gut microbiota. Although no marked metabolic effect was disclosed, longer treatments duration and/or higher extracts concentrations may be needed. More research is required to ascertain this conjecture and to establish the influence of various cannabis extracts on host health in general and NAFLD in particular.”

https://pubmed.ncbi.nlm.nih.gov/35795290/

https://www.hindawi.com/journals/ecam/2022/7964018/

“Cannabis use is associated with reduced prevalence of non-alcoholic fatty liver disease: A cross-sectional study”

https://pubmed.ncbi.nlm.nih.gov/28441459/

β-Caryophyllene, a Dietary Cannabinoid, Protects Against Metabolic and Immune Dysregulation in a Diet-Induced Obesity Mouse Model

“Obesity is an abnormal or excessive accumulation of fat in the body that exacerbates metabolic and inflammatory processes, and impairs the health of afflicted individuals.

β-caryophyllene is a natural sesquiterpene that is a dietary cannabinoid with anti-inflammatory properties and potential activity against metabolic diseases.

In the present study, we evaluated the effect of β-caryophyllene on C57BL/6 mice using a diet-induced obesity model. Male mice were randomly assigned to the following groups over a 16-week period: (1) standard diet as lean control, (2) high-fat diet (HFD) as obese control, and (3) HFD + β-caryophyllene with β-caryophyllene at 50 mg/kg.

Treatment with β-caryophyllene improved various metabolic parameters including increased total body weight, fasting glucose levels, oral-glucose tolerance, insulin tolerance, fasting triglycerides, adipocyte hypertrophy, and liver macrovesicular steatosis. β-caryophyllene also modulated the levels and expression of immune response factors including adiponectin, leptin, insulin, interleukin-6, tumor necrosis factor-a, and Toll-like receptor-4.

Our data indicate that chronic supplementation with β-caryophyllene can improve relevant metabolic and immunological processes in obese mice.”

https://pubmed.ncbi.nlm.nih.gov/35792574/

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

“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