Effect of oral cannabis administration on the fat depots of obese and streptozotocin-induced diabetic rats.

The prevalence of obesity and insulin-resistance is on the rise, globally. Cannabis have been shown to have anti-diabetic/obesity properties, however, the effect mediated at various fat depots remains to be clarified. The aim of this study was to (1) investigate the anti-diabetic property of an oral cannabis administration in an obese and streptozotocin-induced diabetic rat model and (2) to determine and compare the effect mediated at the peritoneal and intramuscular fat level. Cannabis concentration of 1.25 mg/kg body weight (relative to THC content) was effective in reversing insulin-resistance in the rat model, unlike the other higher cannabinoid concentrations. At the peritoneal fat level, gene expression of fat beigeing markers, namely Cidea and UCP1, were significantly increased compared to the untreated control. At the intramuscular fat level, on the other hand, CE1.25 treatment did not promote fat beigeing but instead significantly increased mitochondrial activity, relative to the untreated control. Therefore, these findings indicate that the mechanism of action of oral cannabis administration, where glucose and lipid homeostasis is restored, is not only dependent on the dosage but also on the type of fat depot investigated.

Comparative detection method of early onset cytokine-induced stress in ß-cells (INS-1E).

ß-Cells contain a prominent endoplasmic reticulum (ER), disrupting ER homeostasis and function, activating the unfolded protein response (UPR). Currently, no direct protocols measure the UPR initiation. Current methods to measure ER stress include the quantification of nitric oxide (NO) (indirect method), Western blotting, and qRT-PCR of downstream components. However, these methods do not account for the overlap with mitochondrial dysfunction. In this study, INS-1E cells were exposed to proinflammatory cytokines to induce ER stress, as determined using NO, thioflavin T (ThT) binding, and ß-cell functionality (insulin production). ER stress was confirmed through the upregulation of CHOP. Cell viability was monitored using MTT, sulforhodamine B, and the xCELLigence system. Morphological changes were monitored using electron microscopy. IL-1ß exposure-induced ß-cell stress after 4 H, decreased insulin levels, and increased thioflavin binding were noted. Increased NO production was only detected after 10 H, highlighting its lack of sensitivity, and the need for a continuous, selective, rapid, convenient, and economical detection method for early onset of ER stress. Standard methods (MTT and NO) failed to detect early ER stress. The xCELLigence coupled with a functional assay such as the detection of insulin levels or ThT are better predictors of ER stress in INS-1E cells.

Cannabis and metformin on diabetic male Wistar rat sperm and reproductive organ parameters.

Purpose: Cannabis use has reportedly increased in type 2 diabetic users as a possible co-treatment for associated pain and inflammation. Both cannabis and metformin (an anti-diabetic drug) have a limited number of studies completed on their effect on male reproductive parameters in a diabetic model. This study determined if cannabis and metformin administration alter various reproductive parameters in diabetic male rats. Methods: Male Wistar rats (n = 35) were fed on a high fat diet and injected with streptozotocin (30 mg/kg rat) to induce a type-2 diabetic model. Treatment groups received cannabis based on Delta-9-Tetrahydrocannabinol (THC) concentrations of 1.25, 2.5 and 5 mg/kg per rat and metformin (50 mg/kg) every alternate day for 10 weeks. Organ weight; serum testosterone levels and sperm count, motility, lipid peroxidation, citrate synthase and lactate dehydrogenase activities were measured. Results: Cannabis treatment induced a significant concentration dependent decrease in sperm motility at 5 mg/kg rat THC (P = 0.009) administration. Metformin significantly (P = 0.035) increased sperm counts and lactate dehydrogenase activity (P = 0.002). Both cannabis and metformin negatively affected testosterone concentrations. Conclusions: Cannabis needs to be used cautiously as an alternative treatment in diabetic males based on the negative effects observed for the various reproductive parameters in this diabetic rat model.

Selected terpenoids from medicinal plants modulate endoplasmic reticulum stress in metabolic disorders.

OBJECTIVES: The majority of research performed on cellular stress and apoptosis focuses on mitochondrial dysfunction; however, the importance of the endoplasmic reticulum dysfunction and the link to metabolic diseases has gained a substantial interest. This review focuses on the potential of terpenoids to influence endoplasmic reticulum stress and the possible role terpenoids play as the treatment of metabolic diseases. KEY FINDINGS: Metabolic diseases develop as a result of a cascade of cellular pathways. In most cases, cells are able to compensate for the disruption of the cellular homeostasis although the initiation of response pathways; however, chronic stress initiates apoptotic pathways. This reviewed (1) showed the importance of phytoterpenoids to influence endoplasmic reticulum (ER) stress and homeostasis, (2) showed how regulating ER stress affect the cell survival and death, and (3) highlighted some examples of how the progression of metabolic diseases can be influenced by ER. SUMMARY: Due to the substantial number of terpenoids that have been identified in literature, this review gave examples of 21 terpenoids that have been documented to have an effect on the different proteins associated with ER stress, how these plant terpenoids influence ER dysfunction and metabolic diseases such as diabetes, cancer, liver, and neurological diseases and parasitic infections.

The cardioprotective effects of marrubiin, a diterpenoid found in Leonotis leonurus extracts.

ETHNOPHARMACOLOGICAL RELEVANCE: Leonotis leonurus L. (Lamiaceae) is used as a traditional medicine for a variety of ailments in South Africa. The diterpene marrubiin is the major product constituent in specimens of this plant occurring in South Africa. MATERIALS AND METHODS: Marrubiin isolated from South African specimens of L. leonurus in addition to an organic extract of L. leonurus were tested in vivo, ex vivo and in vitro for their anticoagulant, antiplatelet and anti-inflammatory activities. RESULTS: Marrubiin and the organic extract suppressed coagulation, platelet aggregation and inflammatory markers. For the coagulation markers it was found that the organic extract and marrubiin significantly prolonged activated partial thromboplastin time (APTT). Fibrin and D-dimer formation were drastically decreased. These findings were observed in an ex vivo model and an obese rat model. Chemokines enhance leukocyte recruitment to inflammatory sites. TNF-α and RANTES secretion were significantly reduced by the extract and marrubiin when determined in the obese rat model relative to the controls. Calcium mobilization and TXB(2) synthesis were suppressed by the extract and marrubiin. An in vitro model was used to elucidate the antiplatelet mechanism and it was found that the extract and marrubiin inhibited platelet aggregation by inhibiting the binding of fibrinogen to glycoprotein (GP) IIb/IIIa receptor in a concentration dependent manner. CONCLUSION: The findings reflect that marrubiin largely contributes to the extract's anticoagulant, antiplatelet and anti-inflammatory effects observed.