ThePineapple - Journal Club #47: Drug Delivery | Polarization | Pregnancy | COVID

Journal Club #47: Drug Delivery, Polarization, Pregnancy, COVID

Week of 06-26-22

For this week’s journal club we have a drug delivery paper using anti-inflammatory CBD-loaded nanoparticles to treat oral mucositis. Next up we have another inflammation paper. Here the authors are looking to evaluate the effects of cannabinoid derived aryl-cyclohexanones on macrophage polarization. Then there is a paper looking at the metabolic consequence of cannabis consumption during pregnancy and lastly we have a paper evaluating the effects on CBD on endothelial cells during a SARS-COV-2 infection. This last one is a follow-up to the discussion we had here on using CBD as COVID prophylaxis.  

Note: This is a post for cannabis scientists. A weekly curation of fresh papers that help advance our understanding of cannabis and the endocannabinoid syste

Inflammation-targeted cannabidiol-loaded nanomicelles for enhanced oral mucositis treatment.

Liu Y, Qi X, Wang Y, Li M, Yuan Q, Zhao Z.

Drug Deliv. 2022 ;29(1):1272-1281. 

One of the most common complications of cancer chemotherapy is oral mucositis (OM), a serious kind of oral ulceration, but its effective treatment remains a serious challenge. In this study, we used deoxycholic acid and fucoidan to prepare inflammation-targeting nanomicelles (FD), because fucoidan can target inflammation due to its high binding affinity for P-selectin. The hydrophobic anti-inflammatory drug cannabidiol (CBD) was then loaded into the hydrophobic core of FD. The resulting CBD-loaded FD micelles (CBD/FD) had uniform particle size and morphology, as well as favorable serum stability. Moreover, administration of the FD micelles via intravenous injection or in situ dripping in an OM mouse model enhanced the accumulation and retention of CBD. CBD/FD also showed a better anti-inflammatory effect compared to free CBD after local or systemic administration in vivo, while they accelerated OM healing and inhibited Ly6G inflammatory cell infiltration and NF-κB nuclear transcription. Our results show that CBD/FD nanomicelles are a promising agent for OM treatment.

doi: 10.1080/10717544.2022.2027572. PMID: 35467472; PMCID: PMC9045765.

Effect of Aryl-Cyclohexanones and their Derivatives on Macrophage Polarization In Vitro.

Lubschinski TL, Pollo LAE, Mohr ETB, da Rosa JS, Nardino LA, Sandjo LP, Biavatti MW, Dalmarco EM.

Inflammation. 2022 Aug;45(4):1612-1630. 

Macrophages are critical in both tissue homeostasis and inflammation, and shifts in their polarization have been indicated as pivotal for the resolution of inflammatory processes. Inflammation is a complex and necessary component of the immune response to stimuli that are harmful to host homeostasis and is regulated by cellular and molecular events that remain a source of ongoing investigation. Among the compounds studied that have potential against autoimmune and inflammatory diseases, cannabinoids are currently highlighted. In this work, nineteen aryl-cyclohexanones diesters and their derivatives were synthesized based on the aryl-cyclohexane skeleton of phytocannabinoids, such as cannabidiol (CBD), and were evaluated for their anti-inflammatory and macrophage polarization potential. The results showed that Compound 4 inhibited the production of nitric oxide in RAW 264.7 macrophages. Furthermore, it reduced the levels of pro-inflammatory cytokines IL-12p70, TNF-α, IFN-γ, MCP-1, and IL-6 while, at the same time, was able to increase the production of anti-inflammatory cytokines IL-4, IL-10, and IL-13. Compound 4 also reduced macrophage apoptosis, increased the expression of the CD206 (mannose receptor) and at the same time, decreased the expression of CD284 (TLR-4 receptor) on the surface of these cells. Finally, it increased the phagocytic capacity and inhibited the phosphorylation of the p65 of NF-kβ. In conclusion, Compound 4, identified as diethyl-4-hydroxy-2-(4-methoxyphenyl)-4-methyl-6-oxocyclohexane-1-3-dicarboxylate, showed significant anti-inflammatory effect, while demonstrating the ability to transform phenotypically macrophages from the M1 phenotype (pro-inflammatory) to the M2 phenotype (anti-inflammatory). This led us to hypothesize that the main mechanism of anti-inflammatory effect of this molecule is linked to its immune modulation capacity.

doi: 10.1007/s10753-022-01646-9. Epub 2022 Mar 5. PMID: 35247115.

Fetal Exposure to Cannabis and Childhood Metabolic Outcomes: The Healthy Start Study.

Moore BF, Sauder KA, Shapiro ALB, Crume T, Kinney GL, Dabelea D.

J Clin Endocrinol Metab. 2022 Jun 16;107(7):e2862-e2869.

To assess the impact of fetal exposure to cannabis on adiposity and glucose-insulin traits in early life. We leveraged a subsample of 103 mother-child pairs from Healthy Start, an ethnically diverse Colorado-based cohort. Twelve cannabinoids/metabolites of cannabis (including Δ9-tetrahydrocannabinol and cannabidiol) were measured in maternal urine collected at ~27 weeks' gestation. Fetal exposure to cannabis was dichotomized as exposed (any cannabinoid > limit of detection [LOD]) and not exposed (all cannabinoids < LOD). Fat mass and fat-free mass were measured via air displacement plethysmography at follow-up (mean age: 4.7 years). Glucose and insulin were obtained after an overnight fast. Generalized linear models estimated the associations between fetal exposure to cannabis with adiposity measures (fat mass [kg], fat-free mass [kg], adiposity [fat mass percentage], body mass index [BMI], and BMI z-scores) and metabolic measures (glucose [mg/dL], insulin [uIU/mL], and homeostatic model assessment of insulin resistance [HOMA-IR]). Approximately 15% of the women had detectable levels of any cannabinoid, indicating fetal exposure to cannabis. Exposed offspring had higher fat mass (1.0 kg; 95% CI, 0.3-1.7), fat-free mass (1.2 kg; 95% CI, 0.4-2.0), adiposity (2.6%; 95% CI, 0.1-5.2), and fasting glucose (5.6 mg/dL; 95% CI, 0.8-10.3) compared with non exposed offspring. No associations were found with fasting insulin (in the fully adjusted model), HOMA-IR, BMI, or BMI z-scores. We provide novel evidence to suggest an association between fetal exposure to cannabis with increased adiposity and fasting glucose in childhood, a finding that should be validated in other cohorts.

doi: 10.1210/clinem/dgac101. PMID: 35357471; PMCID: PMC9202691.

Effect of cannabidiol on apoptosis and cellular interferon and interferon-stimulated gene responses to the SARS-CoV-2 genes ORF8, ORF10 and M protein.

Fernandes MF, Chan JZ, Hung CCJ, Tomczewski MV, Duncan RE.

Life Sci. 2022 Jul 15;301:120624. 

To study effects on cellular innate immune responses to ORF8, ORF10, and Membrane protein (M protein) from the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes COVID-19, in combination with cannabidiol (CBD). HEK293 cells transfected with plasmids expressing control vector, ORF8, ORF10, or M protein were assayed for cell number and markers of apoptosis at 24 h, and interferon and interferon-stimulated gene expression at 14 h, with or without CBD. Cells transfected with polyinosinic:polycytidylic acid (Poly (I:C)) were also studied as a general model of RNA-type viral infection. Reduced cell number and increased early and late apoptosis were found when expression of viral genes was combined with 1-2 μM CBD treatment, but not in control-transfected cells treated with CBD, or in cells expressing viral genes but treated only with vehicle. In cells expressing viral genes, CBD augmented expression of IFNγ, IFNλ1 and IFNλ2/3, as well as the 2'-5'-oligoadenylate synthetase (OAS) family members OAS1, OAS2, OAS3, and OASL. CBD also augmented expression of these genes in control cells not expressing viral genes, but without enhancing apoptosis. CBD similarly enhanced the cellular anti-viral response to Poly (I:C). Our results demonstrate a poor ability of HEK293 cells to respond to SARS-CoV-2 genes alone, but an augmented innate anti-viral response to these genes in the presence of CBD. Thus, CBD may prime components of the innate immune system, increasing readiness to respond to RNA-type viral infection without activating apoptosis, and could be studied for potential in prophylaxis.

doi: 10.1016/j.lfs.2022.120624. Epub 2022 May 11. PMID: 35568225; PMCID: PMC9091075.