Diabetes mellitus (DM), a metabolic disorder is one of the most prevalent chronic diseases worldwide across developed as well as developing nations. Hyperglycemia is the core feature of the type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), following insulin deficiency and impaired insulin secretion or sensitivity leads insulin resistance (IR), respectively. Genetic and environmental factors attributed to the pathogenesis of DM and various therapeutic strategies are available for the prevention and treatment of T2DM. Among the numerous therapeutic approaches, the health effects of dietary/nutraceutical approach due to the presence of bioactive constituents, popularly termed phytochemicals are receiving special interest for pharmacological effects and therapeutic benefits. The phytochemicals classes, in particular sesquiterpenes received attention because of potent antioxidant, anti-inflammatory, and antihyperglycemic effects and health benefits mediating modulation of enzymes, receptors, and signaling pathways deranged in DM and its complications. One of the terpene compounds, β-caryophyllene (BCP), received enormous attention because of its abundant occurrence, non-psychoactive nature, and dietary availability through consumption of edible plants including spices. BCP exhibit selective full agonism on cannabinoid receptor type 2 (CB2R), an important component of endocannabinoid system, and plays a role in glucose and lipid metabolism and represents the newest drug target for chronic inflammatory diseases. BCP also showed agonist action on peroxisome proliferated activated receptor subtypes, PPAR-α and PPAR-γ, the main target of currently used fibrates and imidazolidinones for dyslipidemia and IR, respectively. Many studies demonstrated its antioxidant, anti-inflammatory, organoprotective, and antihyperglycemic properties. In the present review, the plausible therapeutic potential of BCP in diabetes and associated complications has been comprehensively elaborated based on experimental and a few clinical studies available. Further, the pharmacological and molecular mechanisms of BCP in diabetes and its complications have been represented using synoptic tables and schemes. Given the safe status, abundant natural occurrence, oral bioavailability, dietary use and pleiotropic properties modulating receptors and enzymes, BCP appears as a promising molecule for diabetes and its complications.

ID 14617 Poster Board 303 Chronic hyperglycemia-induced advanced glycation end products-receptor for advanced glycation end products (AGE-RAGE) following activation results in the oxidative stress, inflammasome activation, and tissue fibrosis and plays important role in the development and progression of diabetic cardiomyopathy (DCM). Provided the emerging role of cannabinoid type 2 receptors (CB2) in diabetes and its complications, the present study aimed to investigate the role of CB2 receptor activation in murine model of DCM by its agonist β-caryophyllene (BCP), a dietary phytocannabinoid. The study also investigated underlying signaling pathways. The experimental murine model of DCM was induced by feeding high fat diet (45% fat) for four weeks in addition to single intraperitoneal injection of streptozotocin (100 mg/kg/body weight). Following the development of diabetes, animals were orally treated with BCP (50 mg/kg/body weight) for 12 weeks. In one group to demonstrate CB2 receptor specific properties of BCP, AM630 (1.5 mg/kg), a specific CB2 receptor antagonist, was given 30 min prior to BCP treatment. At the end of the experiments, metabolic, histopathological, immunohistochemical, electron microscopic and western blotting were performed to evaluate efficacy and demonstrate mechanism. The results revealed that treatment with BCP significantly improved glucose tolerance, enhanced serum insulin level along with reducing insulin resistance. BCP restored phosphorylation of cardiac contractile protein troponin I. BCP was observed to enhance PI3K/AKT phosphorylation, reduce expression of Keap1 which upregulated antioxidant enzymes (HO1, SOD2) mediated by stimulation of Nrf2 signaling. The AGE-RAGE signaling pathway in the heart of DCM mice was significantly mitigated by BCP treatment evidenced by reduced expression of AGEs, RAGE and NOX4. Additionally, NLRP3 inflammasome activation was downregulated and expression of ASC, pro-caspase1 was significantly reduced which further decreased IL-1β and IL-18 expression. The H&E, Masson’s trichome, and transmission electron microscopy results further supported the finding that BCP mitigated cardiac hypertrophy, collagen deposition, myofilament disarrangement, mitochondrial disruption, thickened capillary basement membrane, and increased nuclear membrane invaginations. Furthermore, BCP suppressed endothelial-to-mesenchymal transition (EndMT) in DCM mice hearts revealed by decreased expression levels of fibroblast markers (α-SMA, vimentin, and collagen I) and increased expression levels of endothelial markers (CD31 and VE-cadherin). Interestingly, pre-administration of AM630 abrogated the positive effects of BCP in DCM mice. Collectively, these results demonstrate that inhibition of AGE/RAGE by BCP treatment to DCM mice rescues against diabetes associated complications by reducing oxidative damage, fibrosis, and inflammasome activation attributed to upregulation of PI3K/AKT/Nrf2 signaling, repression of EndMT transition, and inhibition of NLRP3 inflammasome activation in a CB2 receptor dependent mechanism. The study results suggest that CB2 receptors activation may be a vital therapeutic avenue for diabetic cardiomyopathy and BCP could be a novel agent of natural origin with a rationale based on pharmacological and molecular mechanisms for its use as therapeutic and nutraceutical agent.