ThePineapple - Journal Club #34: Alzheimer’s | Obesity | miRNA | Pancreatic Cancer

Journal Club #34: Alzheimer’s, Obesity, miRNA, Pancreatic Cancer

Week of 03-20-22

Welcome to journal club. A weekly curation of scientific research papers in the field of cannabis science. Fair warning, these are unedited, freshly destilled scientifc publications. In other words, this post is for the cannabis scientists among you, who are likely going to spent at least one day this week eating free pizza and discussing new publications in your respective biomedical graduate departments. So, if you are a graduate student, feel free to save yourself some time and pick one of these :)

Also, if you feel we missed a particularly juicy paper, then leave a comment with the doi: number or pubmed ID ! We'll update the "journal club" as the week goes on.

Improved cognition impairment by activating cannabinoid receptor type 2: Modulating CREB/BDNF expression and impeding TLR-4/NFκBp65/M1 microglia signaling pathway in D-galactose-injected ovariectomized rats.

Abd El-Rahman SS, Fayed HM. 

PLoS One. 2022 Mar 29;17(3):e0265961. 

Alzheimer's disease (AD) is characterized by an active inflammatory response induced by the brain's deposition and accumulation of amyloid-beta (Aβ). Cannabinoid receptor type 2 (CB2R) is expressed in specific brain areas, modulating functions, and pathophysiologies in CNS. Herein, we aimed to evaluate whether activation of CB2R can improve the cognitive impairment in the experimental AD-like model and determine the involved intracellular signaling pathway. Injection of D-galactose (150 mg/kg, i.p.) was performed to urge AD-like features in bilaterally ovariectomized female rats (OVC/D-gal rats) for 8-weeks. Then, AM1241, a CB2R-agonist (3 and 6 mg/kg), was injected intraperitoneally starting from the 6th week. Treatment with AM1241, significantly down-regulated; Toll-like receptor4 (TLR4), Myd88 (TLR4-adaptor protein) genes expression, and the pro-inflammatory cytokines (NFκB p65, TNF-α, IL-6, and IL-12). In contrast, it enhanced BDNF (the brain-derived neurotrophic factor) and CREB (the cyclic AMP response element-binding protein) as well as the immune-modulatory cytokines (IL-4 and IL-10) levels. Moreover, AM1241 lessened the immune-expression of GFAP, CD68, caspase-3, and NFκB p65 markers and mended the histopathological damage observed in OVC/D-gal rats by decreasing the deposition of amyloid plaques and degenerative neuronal lesions, as well as improving their recognition and learning memory in both novel object recognition and Morris water maze tests. In conclusion, activating CB2R by the selective agonist AM1241 can overrun cognitive deficits in OVC/D-gal rats through modulation of TLR4/ NFκB p65 signaling, mediated by modulating CREB/BDNF pathway, thereby can be applied as a potential therapeutic strategy in AD treatment.

doi: 10.1371/journal.pone.0265961. PMID: 35349580; PMCID: PMC8963558.

Cannabidiol improves glucose utilization and modulates glucose-induced dysmetabolic activities in isolated rats' peripheral adipose tissues.

Erukainure OL, Matsabisa MG, Salau VF, Olofinsan KA, Oyedemi SO, Chukwuma CI, Nde AL, Islam MS. 

Biomed Pharmacother. 2022 Mar 30;149:112863. 

Reduced glucose uptake and utilization, with concomitant lipolysis in adipose tissues has been linked to the pathogenesis of obesity and its complications. The present study investigated the effect of cannabinoid-stimulated glucose uptake on redox imbalance, glucose and lipid metabolisms, as well as cholinergic and purinergic dysfunctions in isolated rats' adipose tissues. Freshly Isolated rats' adipose tissues were incubated with glucose and different concentrations of cannabidiol for 2 h at 37 °C. The negative control consisted of incubation without cannabidiol, while normal control consisted of incubations without glucose and/or cannabidiol and Metformin served as the standard drug. Cannabidiol caused an increase in adipose-glucose uptake, with concomitant elevation of glutathione, triglyceride level, superoxide dismutase, catalase and 5'nucleoidase activities. It also caused suppression in malondialdehyde and cholesterol levels, acetylcholinesterase, ENTPDase, fructose-1,6-biphosphatase, glucose 6-phosphatase, glycogen phosphorylase, and lipase activities. In silico studies revealed a strong molecular interaction of cannabidiol with adipose triglyceride lipase, hormone-sensitive lipase, and monoglyceride lipase. These results indicate that cannabidiol-enhanced glucose uptake in adipose tissues is associated with enhanced antioxidative activities, concomitant modulation of cholinergic and purinergic dysfunctions, and improved glucose - lipid homeostasis.

doi: 10.1016/j.biopha.2022.112863. Epub ahead of print. PMID: 35358799.

Interplay between the Cannabinoid System and microRNAs in Cancer. 

Salamat JM, Abbott KL, Flannery PC, Ledbetter EL, Pondugula SR.

ACS Omega. 2022 Mar 14;7(12):9995-10000. 

Cancer patients often use cannabinoids for alleviating symptoms induced by cancer pathogenesis and cancer treatment. This use of cannabinoids can have unexpected effects in cancer patients depending on the cancer type, resulting in either beneficial (e.g., anticancer) or adverse (e.g., oncogenic) effects. While cannabinoids can enhance the growth and progression of some cancers, they can also suppress the growth and progression of other cancers. However, the underlying mechanisms of such differential effects are poorly understood. miRNAs have been shown to be involved in driving the hallmarks of cancer, affecting cancer growth and progression as well as cancer therapy response. Although the understanding of the effects of cannabinoids and miRNAs as they relate to cancer continues to improve, the interplay between cannabinoid system and miRNAs in cancer pathogenesis and cancer treatment response is poorly understood. Investigation of such interactions between the cannabinoid system and miRNAs could provide novel insights into the underlying mechanisms of the differential effects of cannabinoids in cancer and can help predict and improve the prognosis of cancer patients.

doi: 10.1021/acsomega.2c00635. PMID: 35382335; PMCID: PMC8973111.

A Low Dose of Pure Cannabidiol Is Sufficient to Stimulate the Cytotoxic Function of CIK Cells without Exerting the Downstream Mediators in Pancreatic Cancer Cells. 

Garofano F, Sharma A, Abken H, Gonzalez-Carmona MA, Schmidt-Wolf IGH. 

Int J Mol Sci. 2022 Mar 29;23(7):3783.

Despite numerous studies conducted over the past decade, the exact role of the cannabinoid system in cancer development remains unclear. Though research has focused on two cannabinoid receptors (CB1, CB2) activated by most cannabinoids, CB2 holds greater attention due to its expression in cells of the immune system. In particular, cytokine-induced killer cells (CIKs), which are pivotal cytotoxic immunological effector cells, express a high-level of CB2 receptors. Herein, we sought to investigate whether inducing CIK cells with cannabidiol can enhance their cytotoxicity and if there are any possible counter effects in its downstream cascade of phosphorylated p38 and CREB using a pancreatic ductal adenocarcinoma cell line (PANC-1). Our results showed that IL-2 modulates primarily the expression of the CB2 receptor on CIK cells used during ex vivo CIK expansion. The autophagosomal-associated scaffold protein p62 was found to co-localize with CB2 receptors in CIK cells and the PANC-1 cell line. CIK cells showed a low level of intracellular phospho-p38 and, when stimulated with cannabidiol (CBD), a donor specific variability in phospho-CREB. CBD significantly decreases the viability of PANC-1 cells presumably by increasing the cytotoxicity of CIK cells. Taken together, in our preclinical in vitro study, we propose that a low effective dose of CBD is sufficient to stimulate the cytotoxic function of CIK without exerting any associated mediator. Thus, the combinatorial approach of non-psychoactive CBD and CIK cells appears to be safe and can be considered for a clinical perspective in pancreatic cancer.

doi: 10.3390/ijms23073783. PMID: 35409142; PMCID: PMC8998663.