Search Results (5)

Recent advances in cannabinoid-based therapies identified the natural CB2 receptor agonist β-caryophyllene (BCP) as a promising anti-inflammatory and neuroprotective agent. To further explore its therapeutic potential on the management of neurodegenerative disorders, in the present study we investigated the ability of BCP to prevent neuroinflammation and promote neuroprotection by using both in vitro and ex vivo models of β-amyloid induced neurotoxicity. Our data showed that BCP significantly protected human microglial HMC3 cells from Aβ_25-35-induced cytotoxicity, reducing the release of pro-inflammatory cytokines (TNF-α, IL-6) while enhancing IL-10 secretion. These effects were associated with a reduced activation of the NF-κB pathway, which emerged as a central mediator of BCP action. Notably, the use of CB2R- or PPARγ-selective antagonists revealed that the observed NF-κB inhibition by BCP may involve the coordinated activation of both canonical (e.g., CB2R) and non-canonical (e.g., PPARγ) receptors. Moreover, BCP restored the expression of SIRT1, PGC-1α, and BDNF, indicating the involvement of neurotrophic pathways. Clear neuroprotective properties for BCP have been highlighted in Aβ_1-42-treated brain slice preparations, where BCP demonstrated the rescue of both the amyloid-dependent depression of BDNF expression and long-term synaptic potentiation (LTP) impairment. Overall, our results suggest that BCP constitutes an attractive natural molecule for the treatment of Aβ-induced neuroinflammation and synaptic dysfunction, warranting further exploration for its clinical application. Full article

Inflammation and oxidative stress are interlinked and interdependent processes involved in many chronic diseases, including neurodegeneration, diabetes, cardiovascular diseases, and cancer. Therefore, targeting inflammatory pathways may represent a potential therapeutic strategy. Emerging evidence indicates that many phytochemicals extracted from edible plants have the potential to ameliorate the disease phenotypes. In this scenario, ß-caryophyllene (BCP), a bicyclic sesquiterpene, and carnosic acid (CA), an ortho-diphenolic diterpene, were demonstrated to exhibit anti-inflammatory, and antioxidant activities, as well as neuroprotective and mitoprotective effects in different in vitro and in vivo models. BCP essentially promotes its effects by acting as a selective agonist and allosteric modulator of cannabinoid type-2 receptor (CB2R). CA is a pro-electrophilic compound that, in response to oxidation, is converted to its electrophilic form. This can interact and activate the Keap1/Nrf2/ARE transcription pathway, triggering the synthesis of endogenous antioxidant “phase 2” enzymes. However, given the nature of its chemical structure, CA also exhibits direct antioxidant effects. BCP and CA can readily cross the BBB and accumulate in brain regions, giving rise to neuroprotective effects by preventing mitochondrial dysfunction and inhibiting activated microglia, substantially through the activation of pro-survival signalling pathways, including regulation of apoptosis and autophagy, and molecular mechanisms related to mitochondrial quality control. Findings from different in vitro/in vivo experimental models of Parkinson’s disease and Alzheimer’s disease reported the beneficial effects of both compounds, suggesting that their use in treatments may be a promising strategy in the management of neurodegenerative diseases aimed at maintaining mitochondrial homeostasis and ameliorating glia-mediated neuroinflammation. Full article

Renal fibrosis is a hallmark event in the pathogenesis of diabetic nephropathy. Considerable evidence now supports that multiple intracellular signaling pathways are critically involved in renal fibrosis. Previously, our studies have shown that dysregulation of the MicroRNA 29a (miR-29a)- or cannabinoid type 1 receptor (CB1R)-mediated signaling cascade in renal glomeruli substantially contributes to diabetic renal fibrosis. The purpose of the current study was to explore whether curcumin, a natural polyphenolic compound with potential renoprotective activity, could modulate the miR-29a/CB1R signaling axis to attenuate renal fibrosis. In this study, rat renal mesangial cells cultured in high glucose (HG) and the diabetic db/db mice were used as an in vitro and in vivo model of diabetes, respectively. Our results showed that in rat renal mesangial cells, curcumin treatment substantially counteracted HG-induced changes in the expressions of miR-29a, CB1R, peroxisome proliferator-activated receptor gamma (PPAR-γ), and a profibrotic marker type IV collagen (collagen IV), as assessed by quantitative Real-Time Polymerase chain reaction (RT-PCR). Furthermore, in the db/db mouse model, administration of curcumin markedly lowered urinary albumin excretion, and reduced deposition of extracellular matrices including collagen IV in renal tissues. Importantly, quantitative RT-PCR, in situ hybridization, and immunohistochemical analysis revealed that curcumin treatment consistently blocked diabetes-induced downregulation of miR-29a and upregulation of CB1R in renal glomeruli. Collectively, our study provides novel evidence showing that curcumin can rescue the dysregulated miR-29a/CB1R signaling pathway in glomerular mesangium to ameliorate diabetic renal fibrosis. Full article

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. Full article

Diabetic nephropathy often leads to end-stage renal disease and life-threatening morbidities. Simple control of risk factors is insufficient to prevent the progression of diabetic nephropathy, hence the need for discovering new treatments is of paramount importance. Recently, the dysregulation of microRNAs or the cannabinoid signaling pathway has been implicated in the pathogenesis of various renal tubulointerstitial fibrotic damages and thus novel therapeutic targets for chronic kidney diseases have emerged; however, the role of microRNAs or cannabinoid receptors on diabetes-induced glomerular injuries remains to be elucidated. In high-glucose-stressed renal mesangial cells, transfection of a miR-29a precursor sufficiently suppressed the mRNA and protein expressions of cannabinoid type 1 receptor (CB1R). Our data also revealed upregulated CB1R, interleukin-1β, interleukin-6, tumor necrosis factor-α, c-Jun, and type 4 collagen in the glomeruli of streptozotocin (STZ)-induced diabetic mice, whereas the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ) was decreased. Importantly, using gain-of-function transgenic mice, we demonstrated that miR-29a acts as a negative regulator of CB1R, blocks the expressions of these proinflammatory and profibrogenic mediators, and attenuates renal hypertrophy. We also showed that overexpression of miR-29a restored PPAR-γ signaling in the renal glomeruli of diabetic animals. Collectively, our findings indicate that the interaction between miR-29a, CB1R, and PPAR-γ may play an important role in protecting diabetic renal glomeruli from fibrotic injuries. Full article