Activation of Cannabinoid Receptors Attenuates Endothelin-1-induced Mitochondrial Dysfunction in Rat Ventricular Myocytes.

Image result for Journal of Cardiovascular Pharmacology.“Evidence suggests that activation of the endocannabinoid system offers cardioprotection.

Aberrant energy production by impaired mitochondria purportedly contributes to various aspects of cardiovascular disease. We investigated whether cannabinoid (CB) receptor activation would attenuate mitochondrial dysfunction induced by endothelin-1 (ET1).

Acute exposure to ET1 (4 h) in the presence of palmitate as primary energy substrate induced mitochondrial membrane depolarization, and decreased mitochondrial bioenergetics and expression of genes related to fatty acid oxidation (i.e. peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α, a driver of mitochondrial biogenesis, and carnitine palmitoyltransferase (CPT)-1β, facilitator of fatty acid uptake).

A CB1/CB2 dual agonist with limited brain penetration, CB-13, corrected these parameters. AMP-activated protein kinase (AMPK), an important regulator of energy homeostasis, mediated the ability of CB-13 to rescue mitochondrial function. In fact, the ability of CB-13 to rescue fatty acid oxidation-related bioenergetics, as well as expression of PGC-1α and CPT-1β, was abolished by pharmacological inhibition of AMPK using compound C and shRNA knockdown of AMPKα1/α2, respectively.

Interventions that target CB/AMPK signaling might represent a novel therapeutic approach to address the multi-factorial problem of cardiovascular disease.”

https://www.ncbi.nlm.nih.gov/pubmed/31815823

https://insights.ovid.com/crossref?an=00005344-900000000-98463

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Oral medicinal cannabinoids to relieve symptom burden in the palliative care of patients with advanced cancer: a double-blind, placebo controlled, randomised clinical trial of efficacy and safety of cannabidiol (CBD).

 

Image result for bmc palliative care“Despite improvements in medical care, patients with advanced cancer still experience substantial symptom distress. There is increasing interest in the use of medicinal cannabinoids, but there is little high quality evidence to guide clinicians. This study aims to define the role of cannabidiol (CBD) in the management of symptom burden in patients with advanced cancer undergoing standard palliative care.

METHODS AND DESIGN:

This study is a multicentre, randomised, placebo controlled, two arm, parallel trial of escalating doses of oral CBD. It will compare efficacy and safety outcomes of a titrated dose of CBD (100 mg/mL formulation, dose range 50 mg to 600 mg per day) against placebo. There is a 2-week patient determined titration phase, using escalating doses of CBD or placebo to reach a dose that achieves symptom relief with tolerable side effects. This is then followed by a further 2-week assessment period on the stable dose determined in collaboration with clinicians.

DISCUSSION:

A major strength of this study is that it will target symptom burden as a whole, rather than just individual symptoms, in an attempt to describe the general improvement in wellbeing previously reported by some patients in open label, non controlled trials of medicinal cannabis. Randomisation with placebo is essential because of the well-documented over reporting of benefit in uncontrolled trials and high placebo response rates in cancer pain trials. This will be the first placebo controlled clinical trial to evaluate rigorously the efficacy, safety and acceptability of CBD for symptom relief in advanced cancer patients. This study will provide the medical community with evidence to present to patients wishing to access medicinal cannabis for their cancer related symptoms.”

https://www.ncbi.nlm.nih.gov/pubmed/31810437

https://bmcpalliatcare.biomedcentral.com/articles/10.1186/s12904-019-0494-6

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CBD loaded microparticles as a potential formulation to improve paclitaxel and doxorubicin-based chemotherapy in breast cancer.

International Journal of Pharmaceutics“Cannabidiol (CBD) has emerged as a potential agent for breast cancer management.

In this work, the potential use of cannabidiol in solution (CBDsol) and encapsulated in polymeric microparticles when combined with paclitaxel (PTX) and doxorubicin (DOX) in breast cancer treatment has been evaluated for the first time using MCF-7 and MDA-MB-231 cells. CBDsol, previously administered at suboptimal concentrations (cell death <10%), enhanced the PTX and DOX effect in both breast cancer cells.

The co-administration of CBDsol and PTX or DOX showed a synergistic effect. PLGA-502 was selected as the most suitable polymer to develop CBD-loaded microparticles. The developed formulation (CBD-Mps) was effective as monotherapy, showing extended antiproliferative activity for at least 10 days, and when combined with PTX or DOX.

In fact, the use of CBD-Mps allows the combination of both, pre and co-administration strategies, with a single administration, also showing a significant increase in PTX and DOX antiproliferative activity. Finally, the anticancer effect of both CBDsol and CBD-Mps as monotherapy or in combination with PTX was also confirmed in ovo, usingMDA-MB-231-derived tumours.

This data evidences the promising inclusion of CBD in conventional breast cancer chemotherapy and the use of CBD-Mps for the extended release of this cannabinoid, optimising the effect of the chemotherapeutic agents.”

https://www.ncbi.nlm.nih.gov/pubmed/31811927

https://www.sciencedirect.com/science/article/pii/S0378517319309615?via%3Dihub

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The Cannabinoid Receptor Agonist WIN55,212-2 Ameliorates Hippocampal Neuronal Damage After Chronic Cerebral Hypoperfusion Possibly Through Inhibiting Oxidative Stress and ASK1-p38 Signaling.

 “Chronic cerebral hypoperfusion (CCH) is a major contributor to cognitive decline and degenerative processes leading to Alzheimer’s disease, vascular dementia, and aging. However, the delicate mechanism of CCH-induced neuronal damage, and therefore proper treatment, remains unclear.

WIN55,212-2 (WIN) is a nonselective cannabinoid receptor agonist that has been shown to have effects on hippocampal neuron survival. In this study, we investigated the potential roles of WIN, as well as its underlying mechanism in a rat CCH model of bilateral common carotid artery occlusion.

These findings indicated that WIN may be a potential therapeutic agent for ischemic neuronal damage, involving a mechanism associated with the suppression of oxidative stress and ASK1-p38 signaling.”

https://www.ncbi.nlm.nih.gov/pubmed/31808139

https://link.springer.com/article/10.1007%2Fs12640-019-00141-8

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Cannabinoid receptor 2 promotes the intracellular degradation of HMGB1 via the autophagy-lysosome pathway in macrophage.

International Immunopharmacology“High mobility group box 1 (HMGB1) is a late phase inflammatory mediator in many inflammatory diseases. Extracellular HMGB1 could bind to many membrane receptors to activate downstream signaling molecules and promote inflammation resulting in cell and tissue damage.

In our previous work, we found cannabinoid receptor Ⅱ(CB2R) inhibited the expression of HMGB1 in lipopolysaccharide (LPS)-induced septic models in vivo and in vitro, but the underlying mechanism is still unclear.

The present study was aimed to explore the possible pathway through which CB2R suppressed HMGB1.

Here, we found that the specific agonist of CB2R, GW405833 (GW) could induce intracellular HMGB1 degradation without influencing HMGB1 mRNA in peritoneal macrophages. Then we observed that autophagy inhibitor 3-methyladenine (3-MA) but not proteasome inhibitor MG-132 (MG) could block GW-induced HMGB1 degradation, which indicated that the autophagy-lysosome but not the ubiquitination pathway was involved in this process.

Further study showed that GW could promote the integrity of autophagy flux in macrophages in terms of increased level of LC3Ⅱand decreased expression of p62 protein. It also observed that inhibition of autophagy blocked GW-induced nuclear translocation of HMGB1 in macrophages. GW could up-regulate expression of Cathepsin B (CTSB), and inhibition of CTSB blocked GW-induced HMGB1 degradation.

In summary, all the data showed that activation of CB2R could promote the intracellular degradation of HMGB1 via the autophagy-lysosome pathway in macrophage.”

https://www.ncbi.nlm.nih.gov/pubmed/31806570

https://www.sciencedirect.com/science/article/pii/S1567576919321186?via%3Dihub

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Cannabis Exposure is Associated With a Lower Likelihood of Neurocognitive Impairment in People Living With HIV.

Image result for ovid journal “Aging and HIV have adverse effects on the central nervous system, including increased inflammation and neural injury and confer risk of neurocognitive impairment (NCI).

Previous research suggests the nonacute neurocognitive effects of cannabis in the general population are adverse or null. However, in the context of aging and HIV, cannabis use may exert beneficial effects due to its anti-inflammatory properties.

In the current study, we examined the independent and interactive effects of HIV and cannabis on NCI and the potential moderation of these effects by age.

METHODS:

Participants included 679 people living with HIV (PLHIV) and 273 people living without HIV (HIV-) (18-79 years old) who completed neurocognitive, neuromedical, and substance use assessments. NCI was defined as a demographically corrected global deficit score ≥ 0.5. Logistic regression models examined the effects of age, HIV, cannabis (history of cannabis substance use disorder and cannabis use in past year), and their 2-way and 3-way interactions on NCI.

RESULTS:

In logistic regression models, only a significant interaction of HIV X cannabis was detected (P = 0.02). Among PLHIV, cannabis was associated with a lower proportion of NCI (odds ratio = 0.53, 95% confidence interval = 0.33-0.85) but not among HIV- individuals (P = 0.40). These effects did not vary by age.

CONCLUSIONS:

Findings suggest cannabis exposure is linked to a lower odds of NCI in the context of HIV. A possible mechanism of this result is the anti-inflammatory effect of cannabis, which may be particularly important for PLHIV. Further investigations are needed to refine the effects of dose, timing, and cannabis compound on this relationship, which could inform guidelines for cannabis use among populations vulnerable to cognitive decline.”

https://www.ncbi.nlm.nih.gov/pubmed/31809361

https://insights.ovid.com/crossref?an=00126334-202001010-00008

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Cannabinoids and the Microbiota-Gut-Brain-Axis: Emerging Effects of Cannabidiol and Potential Applications to Alcohol Use Disorders.

Alcoholism: Clinical and Experimental Research banner“The endocannabinoid system (ECS) has emerged in recent years as a potential treatment target for alcohol use disorders (AUD).

In particular, the non-psychoactive cannabinoid cannabidiol (CBD) has shown preclinical promise in ameliorating numerous clinical symptoms of AUD.

There are several proposed mechanism(s) through which cannabinoids (and CBD in particular) may confer beneficial effects in the context of AUD. First, CBD may directly impact specific brain mechanisms underlying AUD to influence alcohol consumption and the clinical features of AUD. Second, CBD may influence AUD symptoms through its actions across the digestive, immune, and central nervous systems, collectively known as the microbiota-gut-brain-axis (MGBA).

Notably, emerging work suggests that alcohol and cannabinoids exert opposing effects on the MGBA.

Alcohol is linked to immune dysfunction (e.g., chronic systemic inflammation in the brain and periphery) as well as disturbances in gut microbial species (microbiota) and increased intestinal permeability. These MGBA disruptions have been associated with AUD symptoms such as craving and impaired cognitive control.

Conversely, existing preclinical data suggest that cannabinoids may confer beneficial effects on the gastrointestinal and immune system, such as reducing intestinal permeability, regulating gut bacteria and reducing inflammation. Thus, cannabinoids may exert AUD harm-reduction effects, at least in part, through their beneficial actions across the MGBA.

This review will provide a brief introduction to the ECS and the MGBA, discuss the effects of cannabinoids (particularly CBD) and alcohol in the brain, gut, and immune system (i.e., across the MGBA), and put forth a theoretical framework to inform future research questions.”

https://www.ncbi.nlm.nih.gov/pubmed/31803950

https://onlinelibrary.wiley.com/doi/abs/10.1111/acer.14256

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Effects of O-1602 and CBD on TNBS-induced colonic disturbances.

Neurogastroenterology &amp; Motility banner“This study attempted to provide the effects and mechanisms of two cannabinoids, O-1602 and cannabidiol (CBD), on colonic motility of 2,4,6-trinitro-benzene sulfonic acid (TNBS) colitis.

METHODS:

TNBS was used to induce the model of motility disorder. G protein-coupled receptor 55 (GPR55) expression was detected using real-time PCR and immunohistochemistry in colon. Pro-inflammatory cytokines and myeloperoxidase were also measured. The colonic motility was measured by upper GI transit in vivo and recorded using electrical stimulation organ bath technique in vitro. Freshly isolated smooth muscle from the rat colon were applied to determine the membrane potential and Ca2+ -ATPase activity, respectively.

KEY RESULTS:

CBD or O-1602 separately improved inflammatory conditions significantly in TNBS-induced colitis rats. However, sole CBD pretreatment reduced GPR55 expression, which was up-regulated in TNBS colitis. O-1602 and CBD each lowered MPO and IL-6 levels remarkably in TNBS colitis, while TNF-α levels experienced no change. CBD rescued the downward colonic motility in TNBS colitis in vivo; however, it decreased the upward contraction of the smooth muscle strip under electrical stimulation in vitro. Pretreatment with CBD prevented against TNBS-induced changes of Ca2+ -ATPase activity of smooth muscle cells. However, membrane potential of the smooth muscle cells decreased by TNBS experienced no change after O-1602 or CBD import.

CONCLUSIONS & INFERENCES:

The present study suggested that CBD participated in the regulation of colonic motility in rats, and the mechanisms may be involved in the regulation of inlammatory factors and Ca2+ -ATPase activity through GPR55.”

https://www.ncbi.nlm.nih.gov/pubmed/31802588

https://onlinelibrary.wiley.com/doi/abs/10.1111/nmo.13756

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A Phase I, Open-Label, Parallel-Group, Single-Dose Trial of the Pharmacokinetics, Safety, and Tolerability of Cannabidiol in Subjects with Mild to Severe Renal Impairment.

“As patients who receive cannabidiol (CBD) may have co-existing renal morbidities, it is important to understand whether dose adjustments are necessary to mitigate the risk of exposure-related toxicity. This study was conducted to evaluate the pharmacokinetics, safety, and tolerability of CBD in patients with renal impairment.

METHODS:

The pharmacokinetics and safety of a single oral 200 mg dose of a plant-derived pharmaceutical formulation of highly purified CBD in oral solution (Epidiolex® in the USA; 100 mg/mL) were assessed in subjects with mild, moderate, or severe renal impairment (n = 8/group) relative to matched subjects with normal renal function (n = 8). Blood samples were collected until 48 h post-dose and evaluated by liquid chromatography with tandem mass spectrometry. Analysis of variance was used to compare primary pharmacokinetic parameters (maximum measured plasma concentration [Cmax], oral clearance of drug from plasma [CL/F], renal clearance [CLR], area under the plasma concentration-time curve [AUC] from time zero to last measurable concentration [AUCt], and AUC from time zero to infinity [AUC]); descriptive analysis was used for secondary pharmacokinetic parameters (time to Cmax [tmax], terminal [elimination] half-life [t½], cumulative amount excreted from time zero to the last quantifiable sample [Aelast], and fraction of the systemically available drug excreted into the urine [fe]).

RESULTS:

No statistically significant differences were observed in Cmax, AUCt, AUC, or tmax values between subjects with mild, moderate, or severe renal impairment and subjects with normal renal function for CBD or its major metabolites, 7-carboxy-CBD (7-COOH-CBD) and 7-hydroxy-CBD (7-OH-CBD), and minor metabolite, 6-hydroxy-CBD (6-OH-CBD); geometric mean ratio for Cmax values ranged from 0.68 to 1.35. No differences were observed for other secondary parameters (Aelast and fe). CBD, 7-COOH-CBD, 7-OH-CBD, and 6-OH-CBD were highly protein bound (> 90%); binding was similar in all subject groups. Urine analysis for CBD recorded no appreciable amount, and thus no urinary pharmacokinetic parameters could be derived. Adverse events (AEs) affected two subjects; all five AEs were mild in severity and resolved during the trial. There were no serious AEs or discontinuations due to AEs. Laboratory, physical examination, vital sign, and 12-lead electrocardiogram findings were not clinically significant.

CONCLUSION:

Renal impairment had no effect on the metabolism of CBD after a single oral 200 mg dose. CBD was generally well tolerated in subjects with varying degrees of renal function.”

https://www.ncbi.nlm.nih.gov/pubmed/31802404

“Renal impairment status had no effect on CBD pharmacokinetics following a single oral 200 mg dose, with no statistically significant effects on Cmax, AUCt, AUC, or tmax. CBD was generally well tolerated; there were no serious or severe AEs, and no new safety concerns were identified.”

https://link.springer.com/article/10.1007%2Fs40262-019-00841-6

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Transcriptomic Analysis of Stem Cells Treated with Moringin or Cannabidiol: Analogies and Differences in Inflammation Pathways.

ijms-logo“Inflammation is a common feature of many neurodegenerative diseases.

The treatment of stem cells as a therapeutic approach to repair damage in the central nervous system represents a valid alternative.

In this study, using Next-Generation Sequencing (NGS) technology, we analyzed the transcriptomic profile of human Gingival Mesenchymal Stem Cells (hGMSCs) treated with Moringin [4-(α-l-ramanosyloxy)-benzyl isothiocyanate] (hGMSCs-MOR) or with Cannabidiol (hGMSCs-CBD) at dose of 0.5 or 5 µM, respectively. Moreover, we compared their transcriptomic profiles in order to evaluate analogies and differences in pro- and anti-inflammatory pathways.

The hGMSCs-MOR selectively downregulate TNF-α signaling from the beginning, reducing the expression of TNF-α receptor while hGMSCs-CBD limit its activity after the process started.

The treatment with CBD downregulates the pro-inflammatory pathway mediated by the IL-1 family, including its receptor while MOR is less efficient.

Furthermore, both the treatments are efficient in the IL-6 signaling. In particular, CBD reduces the effect of the pro-inflammatory JAK/STAT pathway while MOR enhances the pro-survival PI3K/AKT/mTOR.

In addition, both hGMSCs-MOR and hGMSCs-CBD improve the anti-inflammatory activity enhancing the TGF-β pathway.”

https://www.ncbi.nlm.nih.gov/pubmed/31801206

https://www.mdpi.com/1422-0067/20/23/6039

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