Cannabidiol (CBD): a killer for inflammatory rheumatoid arthritis synovial fibroblasts

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 Cell Death & Disease“Cannabidiol (CBD) is a non-intoxicating phytocannabinoid from cannabis sativa that has demonstrated anti-inflammatory effects in several inflammatory conditions including arthritis.

In this study, we show that CBD increases intracellular calcium levels, reduces cell viability and IL-6/IL-8/MMP-3 production of rheumatoid arthritis synovial fibroblasts (RASF).

CBD reduced cell viability, proliferation, and IL-6/IL-8 production of RASF. Moreover, CBD increased intracellular calcium and uptake of the cationic viability dye PoPo3 in RASF, which was enhanced by pre-treatment with TNF.

Thus, CBD possesses anti-arthritic activity and might ameliorate arthritis via targeting synovial fibroblasts under inflammatory conditions.”

https://pubmed.ncbi.nlm.nih.gov/32873774/

“In conclusion, CBD might be beneficial as an adjuvant treatment in rheumatoid arthritis that might support the action of currently used disease-modifying anti-rheumatic drugs.”

https://www.nature.com/articles/s41419-020-02892-1

Δ9 Tetrahydrocannabinol attenuates Staphylococcal enterotoxin B-induced inflammatory lung injury and prevents mortality in mice by modulation of miR-17-92 cluster and induction of T-regulatory cells

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Logo of brjpharm“Staphylococcal enterotoxin B (SEB) is a potent activator of Vβ8+T-cells resulting in the clonal expansion of ∼30% of the T-cell pool. Consequently, this leads to the release of inflammatory cytokines, toxic shock, and eventually death.

In the current study, we investigated if Δ9tetrahydrocannabinol (THC), a cannabinoid known for its anti-inflammatory properties, could prevent SEB-induced mortality and alleviate symptoms of toxic shock.

Key Results

Exposure to SEB resulted in acute mortality, while THC treatment led to 100% survival of mice. SEB induced the miRNA-17-92 cluster, specifically miRNA-18a, which targeted Pten (phosphatase and tensin homologue), an inhibitor of the PI3K/Akt signalling pathway, thereby suppressing T-regulatory cells. In contrast, THC treatment inhibited the individual miRNAs in the cluster, reversing the effects of SEB.

Conclusions and Implications

We report, for the first time a role for the miRNA 17–92 cluster in SEB-mediated inflammation. Furthermore, our results suggest that THC is a potent anti-inflammatory compound that may serve as a novel therapeutic to suppress SEB-induced pulmonary inflammation by modulating critical miRNA involved in SEB-induced toxicity and death.

Δ9-Tetrahydrocannabinol (THC) is a marijuana plant-derived cannabinoid known for its robust anti-inflammatory and immunosuppressive properties. The anti-inflammatory and immunosuppressive effects of THC are diverse and function effectively to abrogate a number of inflammatory processes.

Taken together, our data demonstrate that THC is a strong anti-inflammatory agent capable of rescuing mice from SEB-mediated toxicity and death.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376457/

Protective Effects of Δ9‐Tetrahydrocannabinol Against Enterotoxin‐induced Acute Respiratory Distress Syndrome is Mediated by Modulation of Microbiota

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British Journal of Pharmacology“Staphylococcal enterotoxin‐B (SEB) is one of the most potent bacterial superantigens that exerts profound toxic effects by inducing cytokine storm. When SEB is inhaled, it can cause Acute Respiratory Distress Syndrome (ARDS), which is often fatal and currently there are no effective treatment modalities.

Experimental Approach

We used mouse model of SEB‐mediated ARDS to test the efficacy of Δ9‐tetrahydrocannabinol (THC). These mice were monitored for lung inflammation, alterations in gut and lung microbiota and production of short‐chain fatty acids (SCFA). Gene dysregulation of lung epithelial cells was studied by transcriptome arrays. Fecal microbiota transplantation (FMT) was performed to confirm the role of microbiota in suppressing ARDS.

Key results

While SEB triggered ARDS and 100% mortality in mice, THC protected the mice from fatality effects. Pyrosequencing analysis revealed that THC caused significant and similar alterations in microbiota in the lungs and gut of mice exposed to SEB. THC significantly increased the abundance of beneficial bacterial species, Ruminococcus gnavus, but decreased pathogenic microbiota, Akkermansia muciniphila. FMT confirmed that THC‐mediated reversal of microbial dysbiosis played crucial role in attenuation of SEB‐mediated ARDS. THC treatment also led to increase in SCFA, of which propionic acid was found to inhibit the inflammatory response. Transcriptome array showed that THC up‐regulated several genes like lysozyme‐1&2, β‐defensin‐2, claudin, zonula‐1, occludin‐1, Mucin2 and Muc5b while downregulating β‐defensin‐1.

Conclusions

Current study demonstrates for the first time that THC attenuates SEB‐mediated ARDS and toxicity by altering the microbiota in the lungs and the gut as well as promoting anti‐microbial and anti‐inflammatory pathways.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436585/

https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.15226

Δ9-Tetrahydrocannabinol Prevents Mortality from Acute Respiratory Distress Syndrome through the Induction of Apoptosis in Immune Cells, Leading to Cytokine Storm Suppression

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ijms-logo“Acute Respiratory Distress Syndrome (ARDS) causes up to 40% mortality in humans and is difficult to treat. ARDS is also one of the major triggers of mortality associated with coronavirus-induced disease (COVID-19). We used a mouse model of ARDS induced by Staphylococcal enterotoxin B (SEB), which triggers 100% mortality, to investigate the mechanisms through which Δ9-tetrahydrocannabinol (THC) attenuates ARDS.

SEB was used to trigger ARDS in C3H mice. These mice were treated with THC and analyzed for survival, ARDS, cytokine storm, and metabolome. Additionally, cells isolated from the lungs were used to perform single-cell RNA sequencing and transcriptome analysis. A database analysis of human COVID-19 patients was also performed to compare the signaling pathways with SEB-mediated ARDS.

The treatment of SEB-mediated ARDS mice with THC led to a 100% survival, decreased lung inflammation, and the suppression of cytokine storm. This was associated with immune cell apoptosis involving the mitochondrial pathway, as suggested by single-cell RNA sequencing. A transcriptomic analysis of immune cells from the lungs revealed an increase in mitochondrial respiratory chain enzymes following THC treatment. In addition, metabolomic analysis revealed elevated serum concentrations of amino acids, lysine, n-acetyl methionine, carnitine, and propionyl L-carnitine in THC-treated mice. THC caused the downregulation of miR-185, which correlated with an increase in the pro-apoptotic gene targets. Interestingly, the gene expression datasets from the bronchoalveolar lavage fluid (BALF) of human COVID-19 patients showed some similarities between cytokine and apoptotic genes with SEB-induced ARDS.

Collectively, this study suggests that the activation of cannabinoid receptors may serve as a therapeutic modality to treat ARDS associated with COVID-19.”

https://pubmed.ncbi.nlm.nih.gov/32872332/

https://www.mdpi.com/1422-0067/21/17/6244

Coronavirus Disease-2019 Treatment Strategies Targeting Interleukin-6 Signaling and Herbal Medicine

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View details for OMICS: A Journal of Integrative Biology cover image“Coronavirus disease-2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is evolving across the world and new treatments are urgently needed as with vaccines to prevent the illness and stem the contagion. The virus affects not only the lungs but also other tissues, thus lending support to the idea that COVID-19 is a systemic disease. The current vaccine and treatment development strategies ought to consider such systems medicine perspectives rather than a narrower focus on the lung infection only.

COVID-19 is associated with elevated levels of the inflammatory cytokines such as interleukin-6 (IL-6), IL-10, and interferon-gamma (IFN-γ). Elevated levels of cytokines and the cytokine storm have been linked to fatal disease. This suggests new therapeutic strategies through blocking the cytokine storm. IL-6 is one of the major cytokines associated with the cytokine storm. IL-6 is also known to display pleiotropic/diverse pathophysiological effects. We suggest the blockage of IL-6 signaling and its downstream mediators such as Janus kinases (JAKs), and signal transducer and activators of transcription (STATs) offer potential hope for the treatment of severe cases of COVID-19. Thus, repurposing of already approved IL-6-JAK-STAT signaling inhibitors as well as other anti-inflammatory drugs, including dexamethasone, is under development for severe COVID-19 cases.

We conclude this expert review by highlighting the potential role of precision herbal medicines, for example, the Cannabis sativa, provided that omics technologies can be utilized to build a robust scientific evidence base on their clinical safety and efficacy. Precision herbal medicine buttressed by omics systems science would also help identify new molecular targets for drug discovery against COVID-19.”

https://pubmed.ncbi.nlm.nih.gov/32857671/

“Cannabis sativa is a plant known to contain anti-inflammatory compounds such as cannabinoid cannabidiol. In addition to other compounds such as terpenes, these compounds have been suggested to have potential anticancer properties. Like other herbal plants, we suggest C. sativa warrants further mechanistic research in relationship to putative effects in COVID-19.”

https://www.liebertpub.com/doi/10.1089/omi.2020.0122

Cannflavins – From plant to patient: A scoping review

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Fitoterapia “Cannflavins are a group of prenylflavonoids derived from Cannabis sativa L.. Cannflavin A (CFL-A), B (CFL-B) and C (CFL-C) have been heralded for their anti-inflammatory properties in pre-clinical evaluations.

This scoping review aims to synthesise the evidence base on cannflavins to provide an overview of the current research landscape to inform research strategies to aid clinical translation.

Results: 26 full text articles were included. CFL-A and CFL-B demonstrated potent anti-inflammatory activity via inhibition of 12-o-tetradecanoylphorbol 13-acetate induced PGE2 release (CFL-A half maximal inhibitory concentration (IC50): 0.7 μM; CFL-B IC50: 0.7 μM) and microsomal prostaglandin E synthase-1 (CFL-A IC50: 1.8 μM; CFL-B IC50: 3.7 μM). Outcomes were also described in preclinical models of anti-oxidation (CFL-A), anti-parasitic activity (CFL-A, CFL-C), neuroprotection (CFL-A) and cancer (Isocannflavin B, a CFL-B isomer). In-silico screening identified that CFL-A has binding affinity with viral proteins that warrant further investigation.

Conclusions: Cannflavins demonstrate a number of promising therapeutic properties, most notably as an anti-inflammatory agent. Low yields of extraction however have previously limited research to small pre-clinical investigations. Identification of cannflavin-rich chemovars, novel extraction techniques and recent identification of a biosynthetic pathway will hopefully allow research to be scaled appropriately. In order to fully evaluate the therapeutic properties of cannflavins focused research now needs to be embedded within institutions with a track-record of clinical translation.”

https://pubmed.ncbi.nlm.nih.gov/32858172/

“Cannflavins are prenylated flavonoids derived from the Cannabis sativa L. plant with many touted therapeutic properties.”

https://www.sciencedirect.com/science/article/abs/pii/S0367326X2030294X?via%3Dihub

Meet Your Stress Management Professionals: The Endocannabinoids

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Trends in Molecular Medicine (@TrendsMolecMed) | Twitter“The endocannabinoid signaling system (ECSS) is altered by exposure to stress and mediates and modulates the effects of stress on the brain.

Considerable preclinical data support critical roles for the endocannabinoids and their target, the CB1 cannabinoid receptor, in the adaptation of the brain to repeated stress exposure.

Chronic stress exposure increases vulnerability to mental illness, so the ECSS has attracted attention as a potential therapeutic target for the prevention and treatment of stress-related psychopathology.

We discuss human genetic studies indicating that the ECSS contributes to risk for mental illness in those exposed to severe stress and trauma early in life, and we explore the potential difficulties in pharmacological manipulation of the ECSS.”

https://pubmed.ncbi.nlm.nih.gov/32868170/

https://www.cell.com/trends/molecular-medicine/fulltext/S1471-4914(20)30177-5?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1471491420301775%3Fshowall%3Dtrue

Targeting Endocannabinoid Signaling: FAAH and MAG Lipase Inhibitors

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Annual Reviews adds Remarq® across its collection of 47 journals – RedLink“Inspired by the medicinal properties of the plant Cannabis sativa and its principal component (-)-trans-Δ9-tetrahydrocannabinol (THC), researchers have developed a variety of compounds to modulate the endocannabinoid system in the human brain.

Inhibitors of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), which are the enzymes responsible for the inactivation of the endogenous cannabinoids anandamide and 2-arachidonoylglycerol, respectively, may exert therapeutic effects without inducing the adverse side effects associated with direct cannabinoid CB1 receptor stimulation by THC.

Here we review the FAAH and MAGL inhibitors that have reached clinical trials, discuss potential caveats, and provide an outlook on where the field is headed.”

https://pubmed.ncbi.nlm.nih.gov/32867595/

https://www.annualreviews.org/doi/10.1146/annurev-pharmtox-030220-112741

Cannabidiol protects keratinocyte cell membranes following exposure to UVB and hydrogen peroxide

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 Redox Biology“Keratinocytes, the major cell type of the epidermis, are particularly sensitive to environmental factors including exposure to sunlight and chemical agents. Since oxidative stress may arise as a result of these factors, compounds are actively sought that can act as protective agents.

Recently, cannabidiol (CBD), a phytocannabinoid found in Cannabis Sativa L., has gained increased interest due to its anti-inflammatory and antioxidant properties, and absence of psychoactive effects.

This prompted us to analyze the protective effects of CBD on keratinocytes exposed to UVB irradiation and hydrogen peroxide.

Together, these findings suggest that CBD could be a potential protective agent for keratinocytes against the harmful effects of irradiation and chemical environmental factors that cause oxidative stress.”

https://pubmed.ncbi.nlm.nih.gov/32863232/

“CBD could be a potential keratinocytes protector against the harmful factors.”

https://www.sciencedirect.com/science/article/pii/S2213231720308181?via%3Dihub

Chronic Cannabidiol Administration Attenuates Skeletal Muscle De Novo Ceramide Synthesis Pathway and Related Metabolic Effects in a Rat Model of High-Fat Diet-Induced Obesity

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biomolecules-logo“Numerous studies showed that sustained obesity results in accumulation of bioactive lipid derivatives in several tissues, including skeletal muscle, which further contributes to the development of metabolic disturbances and insulin resistance (IR).

The latest data indicate that a potential factor regulating lipid and glucose metabolism is a phytocannabinoid-cannabidiol (CBD), a component of medical marijuana (Cannabis). Therefore, we aimed to investigate whether chronic CBD administration influences bioactive lipid content (e.g., ceramide (CER)), as well as glucose metabolism, in the red skeletal muscle (musculus gastrocnemius) with predominant oxidative metabolism.

All experiments were conducted on an animal model of obesity, i.e., Wistar rats fed a high-fat diet (HFD) or standard rodent chow, and subsequently injected with CBD in a dose of 10 mg/kg or its solvent for two weeks. The sphingolipid content was assessed using high-performance liquid chromatography (HPLC), while, in order to determine insulin and glucose concentrations, immunoenzymatic and colorimetric methods were used. The protein expression from sphingolipid and insulin signaling pathways, as well as endocannabinoidome components, was evaluated by immunoblotting.

Unexpectedly, our experimental model revealed that the significantly intensified intramuscular de novo CER synthesis pathway in the HFD group was attenuated by chronic CBD treatment. Additionally, due to CBD administration, the content of other sphingolipid derivatives, i.e., sphingosine-1-phosphate (S1P) was restored in the high-fat feeding state, which coincided with an improvement in skeletal muscle insulin signal transduction and glycogen recovery.”

https://pubmed.ncbi.nlm.nih.gov/32859125/

https://www.mdpi.com/2218-273X/10/9/1241