Cannabigerol (CBG), a non-psychoactive cannabinoid found in cannabis, has emerged as a promising therapeutic agent with a diverse range of potential applications. Unlike its well-known counterpart tetrahydrocannabinol (THC), CBG does not induce intoxication, making it an attractive option in the clinic. Recent research has shed light on CBG’s intriguing molecular mechanisms, highlighting its potential to modulate multiple physiological processes. This review delves into the current understanding of CBG’s molecular interactions and explores its therapeutic power to alleviate various conditions, including cancer, metabolic, pain, and inflammatory disorders, amongst others. We discuss how CBG interacts with the endocannabinoid system and other key signaling pathways, such as CB1, CB2, TPR channels, and α2-adrenoceptor, potentially influencing inflammation, pain, neurodegeneration, and other ailments. Additionally, we highlight the ongoing research efforts aimed at elucidating the full spectrum of CBG’s therapeutic potential and its safety profile in clinical settings. Through this comprehensive analysis, we aim to provide a deeper understanding of CBG’s role in promoting human health and pave the way for future research endeavors.

Impaired angiogenesis in diabetes is a key process contributing to ischemic diseases such as peripheral arterial disease. Epigenetic mechanisms, including those mediated by long noncoding RNAs (lncRNAs), are crucial links connecting diabetes and the related chronic tissue ischemia. Here we identify the lncRNA that enhances endothelial nitric oxide synthase (eNOS) expression (LEENE) as a regulator of angiogenesis and ischemic response. LEENE expression was decreased in diabetic conditions in cultured endothelial cells (ECs), mouse hind limb muscles, and human arteries. Inhibition of LEENE in human microvascular ECs reduced their angiogenic capacity with a dysregulated angiogenic gene program. Diabetic mice deficient in Leene demonstrated impaired angiogenesis and perfusion following hind limb ischemia. Importantly, overexpression of human LEENE rescued the impaired ischemic response in Leene-knockout mice at tissue functional and single-cell transcriptomic levels. Mechanistically, LEENE RNA promoted transcription of proangiogenic genes in ECs, such as KDR (encoding VEGFR2) and NOS3 (encoding eNOS), potentially by interacting with LEO1, a key component of the RNA polymerase II–associated factor complex and MYC, a crucial transcription factor for angiogenesis. Taken together, our findings demonstrate an essential role for LEENE in the regulation of angiogenesis and tissue perfusion. Functional enhancement of LEENE to restore angiogenesis for tissue repair and regeneration may represent a potential strategy to tackle ischemic vascular diseases.

Therapeutic plasma exchange (TPE) is a blood purification technique which functions to remove pathological plasma constituents such as autoantibodies, inflammatory cytokines, immune complexes, and extracellular vesicles (EVs) that contribute to a range of disease states. In this review, we examine current and emerging indications for TPE across cardiovascular, metabolic, neurological, inflammatory, and oncological diseases. We cover emerging preclinical animal models and new applications, emphasizing the roles of cellular signaling and EV biology in mediating plasma functions, and discuss unique therapeutic “windows of opportunity” offered by TPE. We conclude that TPE is underutilized in both preventative and precision medicine, and that next generation TPE therapies will involve personalized plasma biomarker and modulation feedback, with synergistic plasma infusion therapies to mitigate age associated disease and promote tissue rejuvenation.

Angiogenic VEGF isoforms are upregulated in diabetic retinopathy (DR), driving pathological growth and fluid leakage. Serine-arginine-rich protein kinase-1 (SRPK1) regulates VEGF splicing, and its inhibition blocks angiogenesis. We tested the hypothesis that SRPK1 is activated in diabetes, and an SRPK1 inhibitor (SPHINX31) switches VEGF splicing in DR and prevents increased vascular permeability into the retina. SRPK1 was activated by high glucose (HG), in a PKC-dependent manner, and was blocked by SPHINX31. HG induced release of SRSF1 from the nuclear speckles, which was also SRPK1 dependent, and increased retinal pigment epithelial (RPE) monolayer admittance, which was reversed by SRPK1 inhibition (P < 0.05). Diabetes increased retinal permeability and thickness after 14 days which was blocked by treatment with SPHINX31 eye drops (P < 0.0001). These results show that SRPK1 inhibition, administered as an eye drop, protected the retinal barrier from hyperglycemia-associated loss of integrity in RPE cells in vitro and in diabetic rats in vivo. A clinical trial of another SRPK1 inhibitor has now been initiated in patients with diabetic macular edema. NEW & NOTEWORTHY VEGF-A₁₆₅b splicing is induced by hyperglycemia through PKC-mediated activation of SRPK1 in RPE cells, increasing their permeability and angiogenic capability. SRPK1 inhibitors can be given as eye drops to reduce retinal permeability and edema in diabetic retinopathy. Listen to this article’s corresponding podcast at https://ajpheart.podbean.com/e/srpk1-eye-drops-as-a-treatment-for-diabetic-retinopathy/.

Diabetes mellitus (DM) significantly accelerates vascular diseases like peripheral arterial disease (PAD). Endothelial cells (ECs) and macrophages (MΦs) singularly and synergistically are important contributors to DM-associated vascular dysfunction. Single-cell (sc) profiling technologies are revealing the true heterogeneity of ECs and MΦs, but how this cellular diversity translates to cell-cell interactions, and consequentially vascular function, remains unknown. We leveraged scRNA sequencing and spatial transcriptome (ST) profiling to analyze human mesenteric arteries from non-diabetic (ND) and type 2 diabetic (T2D) donors. We generated a transcriptome and interactome map encompassing the major arterial cells and highlighted Triggering Receptor Expressed on Myeloid Cells 2 ( TREM2 ) as a top T2D-induced gene in mononuclear phagocytes (MPs), with concomitant increases of TREM2 ligands in ECs. We verified DM-associated TREM2 induction in cell and mouse models, and found that TREM2 inhibition decreases pro-inflammatory responses in MPs and ECs, as well as increases EC migration in vitro . Furthermore, TREM2 inhibition using a neutralizing antibody enhanced ischemic recovery and flow reperfusion in DM mice subjected to hindlimb ischemia, suggesting that TREM2 promotes ischemic injury in DM. Finally, in human PAD, co-existing DM was associated with greater expression of TREM2 and its interaction with ECs, with a further increase in ischemic tissue compared to patient-matched non-ischemic tissue. Collectively, our study presents the first atlas of human diabetic vessels with single cell and spatial resolution, and identifies TREM2-EC interaction as a key driver of diabetic vasculopathies, the targeting of which may offer an opportunity to ameliorate vascular dysfunction associated with DM-PAD.

Peripheral arterial disease (PAD) represents a global health concern with a rising prevalence attributed to factors such as obesity, diabetes, aging, and smoking. Among patients with PAD, chronic limb-threatening ischemia (CLTI) is the most severe manifestation, associated with substantial morbidity and mortality. While revascularization remains the primary therapy for CLTI, not all patients are candidates for such interventions, highlighting the need for alternative approaches. Impaired angiogenesis, the growth of new blood vessels, is a central feature of PAD, and despite decades of research, effective clinical treatments remain elusive. Epigenetics, the study of heritable changes in gene expression, has gained prominence in understanding PAD pathogenesis. Here, we explore the role of epigenetic regulation in angiogenesis within the context of PAD, with a focus on long non-coding RNAs and fibroblast-endothelial cell transdifferentiation. Additionally, we discuss the interplay between metabolic control and epigenetic regulation, providing insights into potential novel therapeutic avenues for improving PAD treatments. This review aims to offer a concise update on the application of epigenetics in angiogenesis and PAD research, inspiring further investigations in this promising field.