The synthetic cannabinoid 5F-MDMB-PICA enhances the metabolic activity and angiogenesis in human brain microvascular endothelial cells by upregulation of VEGF, ANG-1, and ANG-2.

Brain angiogenesis, the formation of new blood vessels from existing brain vasculature, has been previously associated with neural plasticity and addictive behaviors related to substances. Synthetic cannabinoids (SCs) have become increasingly popular due to their ability to mimic the effects of cannabis, offering high potency and easy accessibility. In the current study, we reveal that the SC 5F-MDMB-PICA, the most common SC in the United States in 2019, increases cell metabolic activity and promotes angiogenesis in human brain microvascular endothelial cells (HBMECs). First, we performed an MTT assay to evaluate the effects of 5F-MDMB-PICA treatment at various concentrations (0.0001 µM, 0.001 µM, 0.01 µM, 0.1 µM, and 1 µM) on HBMECs metabolic activity. The results demonstrated higher concentrations of the SC improved cell metabolic activity. Furthermore, 5F-MDMB-PICA treatment enhanced tube formation and migration of HBMECs in a dosage-dependent manner. Additionally, the mRNA, secreted protein, and intracellular protein levels of vascular endothelial growth factor, angiopoietin-1, and angiopoietin-2, which are involved in the regulation of angiogenesis, as well as the protein levels of cannabinoid receptor type-1, were all increased following treatment with 5F-MDMB-PICA. Notably, the phosphorylation levels at Serine 9 residue of glycogen synthase kinase-3ß were also increased in the 5F-MDMB-PICA treated HBMECs. Collectively, our findings demonstrate that 5F-MDMB-PICA can enhance angiogenesis in HBMECs, suggesting the significant role of angiogenesis in the response to SCs. Manipulating this interaction may pave the way for innovative treatments targeting SC addiction and angiogenesis-related conditions.

The expression analyses of GSK3B, VEGF, ANG1, and ANG2 in human brain microvascular endothelial cells treated with the synthetic cannabinoid XLR-11.

The endocannabinoid system receptors, cannabinoid receptors type-1 (CBR-1) and -2 (CBR-2), are implicated in several behavioral and cognitive processes. Many studies have indicated a correlation between cannabinoid receptors and angiogenesis. The current study aims to reveal the possible molecular signaling involved in brain angiogenesis induced by the activation of CBR-1 and CBR-2. We investigated whether the synthetic cannabinoid XLR-11, an agonist of CBR-1 and CBR-2, influences the mRNA and protein expression of vascular endothelial growth factor (VEGF), angiopoietin-1 (ANG1) and -2 (ANG2) in human brain microvascular endothelial cells (hBMVEs). Furthermore, we determined the phosphorylation of glycogen synthase kinase 3 beta (GSK3B) expression. Treatment of hBMVEs cells with XLR-11 elevated the mRNA levels of VEGF, ANG1, and ANG2. The secretion of these proangiogenic factors was increased in the media. Furthermore, the intracellular expression of VEGF, ANG1, ANG2, and GSK3B was significantly increased. This current research provides a new possible approach by targeting the cannabinoid receptors to control and regulate brain angiogenesis for treating a variety of angiogenesis-related diseases. This could be achived by using different agonists or antagonists of the cannabinoid receptors based on the nature of the diseases.

Pharmacogenomics of genetic polymorphism within the genes responsible for SARS-CoV-2 susceptibility and the drug-metabolising genes used in treatment.

The ongoing outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represents a significant challenge to international health. Pharmacogenomics aims to identify the different genetic variations that exist between individuals and populations in order to determine appropriate treatment protocols to enhance the efficacy of drugs and reduce their side-effects. This literature review provides an overview of recent studies of genetic polymorphisms in genes that mediate the SARS-CoV-2 infection mechanism (ACE1, ACE2, TMPRSS2 and CD26). In addition, genetic variations in the drug-metabolising enzyme genes of several selected drugs used in the treatment of COVID-19 are summarised. This may help construct an effective health protocol based on genetic biomarkers to optimise response to treatment. Potentially, pharmacogenomics could contribute to the development of effective high-throughput assays to improve patient evaluation, but their use will also create ethical, medical, regulatory, and legal issues, which should now be considered in the era of personalised medicine.

Effects of the synthetic cannabinoid XLR-11 on the viability and migration rates of human brain microvascular endothelial cells in a clinically-relevant model.

BACKGROUND: Synthetic cannabinoids (SCs) are a group of newly-developed drugs that bind and activate endocannabinoid system receptors. Angiogenesis is a biological process in which new blood vessels are formed from preexistent blood vessels. It plays a vital role in tissue growth, wound healing, and embryogenesis. This study aims to investigate the effects of the synthetic cannabinoid XLR-11 on specific cellular functions such as viability and angiogenesis in vitro. METHODS: Human brain microvascular endothelial cells (HBMECs) were cultured in DMEM/F12 medium supplemented with an endothelial cell growth kit. The MTT assay was used to investigate the viability of endothelial cells. An endothelial cell migration assay was used to investigate migration ability, while a tube formation assay was used to investigate the angiogenic capacity of the endothelial cells. RESULTS: XLR-11 was found to enhance the viability of HBMECs. Moreover, the migration rate and angiogenic capacity significantly increased in the presence of various concentrations of XLR-11 compared to the control. CONCLUSION: The current study shows that XLR-11 increases the viability of human brain microvascular endothelial cells and enhances angiogenesis in the brain in vitro, suggesting that XLR-11 could potentially be used as a therapeutic angiogenic drug in human brain injury treatment.