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

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

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

Targeting Endocannabinoid Signaling: FAAH and MAG Lipase Inhibitors

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 (-)-trans9-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

 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

Hemp in Veterinary Medicine: From Feed to Drug

 See the source image“Hemp (Cannabis sativa) is an angiosperm plant belonging to the Cannabaceae family. Its cultivation dates back to centuries. It has always been cultivated due to the possibility of exploiting almost all the parts of the plant: paper, fabrics, ropes, bio-compounds with excellent insulating capacity, fuel, biodegradable plastic, antibacterial detergents, and food products, such as flour, oils, seeds, herbal teas, and beer, are indeed obtained from hemp.

Hemp flowers have also always been used for their curative effects, as well as for recreational purposes due to their psychotropic effects. Cannabis contains almost 500 chemical compounds, such as phytocannabinoids, terpenes, flavonoids, amino acids, fatty acids, vitamins, and macro-, and micro-elements, among others.

When utilized as a food source, hemp shows excellent nutritional and health-promoting (nutraceutical) properties, mainly due to the high content in polyunsaturated fatty acids (especially those belonging to the ω-3 series), as well as in phenolic compounds, which seem effective in the prevention of common diseases such as gastrointestinal disorders, neurodegenerative diseases, cancer, and others.

Moreover, hemp oil and other oils (i.e., olive oil and medium-chain triglyceride-MCT-oil) enriched in CBD, as well as extracts from hemp dried flowers (Cannabis extracts), are authorized in some countries for therapeutic purposes as a second-choice approach (when conventional therapies have failed) for a certain number of clinical conditions such as pain and inflammation, epilepsy, anxiety disorders, nausea, emesis, and anorexia, among others.

The present review will synthetize the beneficial properties of hemp and hemp derivatives in animal nutrition and therapeutics.”

https://pubmed.ncbi.nlm.nih.gov/32850997/

C. sativa has been an important source of food in the Old World, as hempseeds and seed meal are excellent sources of dietary oil, fiber, and protein. Many of the constituents of C. sativa can be classified as either nutrients, nutraceuticals, or pharmaceutical ingredients.”

https://www.frontiersin.org/articles/10.3389/fvets.2020.00387/full

In vitro antioxidant and antimicrobial activity of Cannabis sativa L. cv ‘Futura 75’ essential oil

Publication Cover“In the present work, Cannabis sativa L. cv Futura 75 inflorescences, cultivated in the Abruzzo territory, were characterized for their volatile fraction through SPME-GC-MS. In addition, the essential oil extracted from these inflorescences was investigated for the antioxidant potentialities and for the terpenic profile.

The antibacterial activity of hemp essential oil (HEO) against some pathogenic and spoilage microorganisms isolated from food was also evaluated by determining the minimal inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC).

The results showed significant antioxidant capacity (DPPH: 63.38 ± 0.08 mg TE/g HEO; FRAP: 438.52 ± 6.92 mg TE/g HEO) alongside good antibacterial activity against Gram-positive bacteria such as S. aureus and L. monocytogenes (MIC 1.25-5 µL/mL).

The results obtained suggest that hemp essential oil can inhibit or reduce bacterial growth, also exerting antioxidant activity, and therefore it can find an advantageous application in the food processing field.”

https://pubmed.ncbi.nlm.nih.gov/32865042/

https://www.tandfonline.com/doi/abs/10.1080/14786419.2020.1813139?journalCode=gnpl20

The interaction between the endocannabinoid system and the renin angiotensin system and its potential implication for COVID-19 infection

 Journal of Cannabis Research | Home“Coronavirus disease 2019 (COVID-19) is spreading fast all around the world with more than fourteen millions of detected infected cases and more than 600.000 deaths by 20th July 2020. While scientist are working to find a vaccine, current epidemiological data shows that the most common comorbidities for patients with the worst prognosis, hypertension and diabetes, are often treated with angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs).

Body: Both ACE inhibitors and ARBs induce overexpression of the angiotensin converting enzyme 2 (ACE-2) receptor, which has been identified as the main receptor used by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to enter into the alveolar cells of the lungs. While cannabinoids are known to reduce hypertension, the studies testing the hypotensive effects of cannabinoids never addressed their effects on ACE-2 receptors. However, some studies have linked the endocannabinoid system (ECS) with the renin angiotensin system (RAS), including a cross-modulation between the cannabinoid receptor 1 (CB1) and angiotensin II levels.

Conclusion: Since there are around 192 million people using cannabis worldwide, we believe that the mechanism underlying the hypotensive properties of cannabinoids should be urgently studied to understand if they can also lead to ACE-2 overexpression as other antihypertensive drugs do.”

https://pubmed.ncbi.nlm.nih.gov/32835160/

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-020-00030-4

Structural and Functional Insights into Cannabinoid Receptors

 Trends in Pharmacological Sciences (@TrendsinPharma) | Twitter“Cannabinoid receptors type 1 (CB1) and 2 (CB2) are widely expressed in the human body, and are attractive drug targets in the prevention and management of central nervous system (CNS) and immune system dysfunction, respectively. Recent breakthroughs in the structural elucidation of cannabinoid receptors and their signaling complexes with G proteins, provide the important molecular basis of ligand-receptor interactions, activation and signaling mechanism, which will facilitate the next-generation drug design and the precise modulation of the endocannabinoid system. Here, we provide an overview on the structural features of cannabinoid receptors in different functional states and the diverse ligand binding modes. The major challenges and new strategies for future therapeutic applications targeting the endocannabinoid system (ECS) are also discussed.”

https://pubmed.ncbi.nlm.nih.gov/32739033/

“Cannabinoid receptors as key components of the endocannabinoid system are involved in regulating a variety of physiological and pathological activities, and their ligands are regarded as potential drug candidates for the treatment of many diseases.”

https://www.cell.com/trends/pharmacological-sciences/fulltext/S0165-6147(20)30146-2?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0165614720301462%3Fshowall%3Dtrue

Targeting Cannabinoid Receptors: Current Status and Prospects of Natural Products

ijms-logo “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.”

https://pubmed.ncbi.nlm.nih.gov/32709050/

https://www.mdpi.com/1422-0067/21/14/5064

Flavonoid and cannabinoid impact on the ocular surface

 Media Kit - Current Opinion in Allergy and Clinical Immunology | Lippincott  Audience Solutions | Wolters Kluwer“Purpose of review: To evaluate the impact of flavonoids and cannabinoids as anti-inflammatory and antiallergic treatments on the anterior surface of the eye.

Recent findings: Allergic conjunctivitis and dry eye syndrome are common ocular surface diseases that have been treated with traditional pharmacological measures, e.g. corticosteroids, antihistamines. Given the side-effect profiles of these medications and the growing interest in complementary treatment modalities as part of integrative medical interventions, well known flavonoids, such as quercetin and catechin, are under investigation for topical and systemic application methods for relief. As flavonoid derivatives, pycnogenol and epigallocatechin gallate have alleviated dry eye symptoms, including lacrimal gland inflammation, tear secretion, and the stability of the tear film. Research on ocular cannabinoid receptors and response to synthetic cannabinoids are also being considered for therapy of anterior ocular disorders. The expansion of herbal formulations provides a framework for future treatment regimens for ocular surface disorders.

Summary: Flavonoids and cannabinoids show promise as potential complementary treatment for allergic diseases because of their anti-inflammatory and antiallergic properties. Several studies implementing ocular and systemic application of these compounds show potential in becoming adjuvant treatment strategies for improving quality of life while also managing ocular surface disease processes.”

https://pubmed.ncbi.nlm.nih.gov/32796166/

https://journals.lww.com/co-allergy/Abstract/2020/10000/Flavonoid_and_cannabinoid_impact_on_the_ocular.11.aspx