Role of the endocannabinoid system in diabetes and diabetic complications

Increasing evidence suggests that an overactive endocannabinoid system (ECS) may contribute to the development of diabetes by promoting energy intake and storage, impairing both glucose and lipid metabolism, by exerting pro‐apoptotic effects in pancreatic beta cells and by facilitating inflammation in pancreatic islets. Furthermore, hyperglycaemia associated with diabetes has also been implicated in triggering perturbations of the ECS amplifying the pathological processes mentioned above, eventually culminating in a vicious circle. Compelling evidence from preclinical studies indicates that the ECS also influences diabetes‐induced oxidative stress, inflammation, fibrosis and subsequent tissue injury in target organs for diabetic complications. In this review, we provide an update on the contribution of the ECS to the pathogenesis of diabetes and diabetic microvascular (retinopathy, nephropathy and neuropathy) and cardiovascular complications. The therapeutic potential of targeting the ECS is also discussed. LINKED ARTICLES: This article is part of a themed section on Endocannabinoids. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.7/issueto

Pharmacological inhibition of CB1 cannabinoid receptor protects against doxorubicin-induced cardiotoxicity

OBJECTIVES: We aimed to explore the effects of pharmacologic inhibition of cannabinoid-1 (CB1) receptor in in vivo and in vitro models of doxorubicin (DOX)-induced cardiotoxicity. BACKGROUND: Doxorubicin is one of the most potent antitumor agents available; however, its clinical use is limited because of the risk of severe cardiotoxicity. Endocannabinoids mediate cardiodepressive effects through CB1 receptors in various pathophysiological conditions, and these effects can be reversed by CB1 antagonists. METHODS: Left ventricular function was measured by Millar pressure-volume system. Apoptosis markers, CB1/CB2 receptor expression, and endocannabinoid levels were determined by immunohistochemistry, Western blot, reverse transcription-polymerase chain reaction, real-time polymerase chain reaction, flow cytometry, fluorescent microscopy, and liquid chromatography/in-line mass spectrometry techniques. RESULTS: Five days after the administration of a single dose of DOX (20 mg/kg intraperitoneally) to mice, left ventricular systolic pressure, maximum first derivative of ventricular pressure with respect to time (+dP/dt), stroke work, ejection fraction, cardiac output, and load-independent indexes of contractility (end-systolic pressure-volume relation, preload-recruitable stroke work, dP/dt-end-diastolic volume relation) were significantly depressed, and the myocardial level of the endocannabinoid anandamide (but not CB1/CB2 receptor expression) was elevated compared with vehicle-treated control mice. Treatment with the CB1 antagonists rimonabant or AM281 markedly improved cardiac dysfunction and reduced DOX-induced apoptosis in the myocardium. Doxorubicin also decreased cell viability and induced apoptosis in the H9c2 myocardial cell line measured by flow cytometry and fluorescent microscopy, which were prevented by the preincubation of the cells with either CB1 antagonist, but not with CB1 and CB2 agonists and CB2 antagonists. CONCLUSIONS: These data suggest that CB1 antagonists may represent a new cardioprotective strategy against DOX-induced cardiotoxicity

Study of pathophysiology of Pompe disease and identification of novel therapeutic targets and biomarkers

Le basi molecolari e biochimiche della malattia di Pompe sono ormai ben note ma la fisiopatologia della malattia, ad oggi, resta ancora sconosciuta e la stessa terapia ha un’efficacia limitata nei pazienti. Il lavoro è focalizzato sullo studio delle interazioni proteiche dell’alfa glucosidasi acida (GAA), sulla presenza dello stress ossidativo nella malattia e nell’identificazione di nuovi biomarcatori per l’individuazione della diagnosi e per seguire la progressione della malattia. I risultati ottenuti offrono nuovi spunti per la comprensione dei meccanismi alla base della malattia e per l'individuazione di nuovi possibili target terapeutici

Cannabinoid receptors in GtoPdb v.2023.1

Cannabinoid receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Cannabinoid Receptors [119]) are activated by endogenous ligands that include N-arachidonoylethanolamine (anandamide), N-homo-γ-linolenoylethanolamine, N-docosatetra-7,10,13,16-enoylethanolamine and 2-arachidonoylglycerol. Potency determinations of endogenous agonists at these receptors are complicated by the possibility of differential susceptibility of endogenous ligands to enzymatic conversion [5].There are currently three licenced cannabinoid medicines each of which contains a compound that can activate CB1 and CB2 receptors [111]. Two of these medicines were developed to suppress nausea and vomiting produced by chemotherapy. These are nabilone (Cesamet®), a synthetic CB1/CB2 receptor agonist, and synthetic Δ9-tetrahydrocannabinol (Marinol®; dronabinol), which can also be used as an appetite stimulant. The third medicine, Sativex®, contains mainly Δ9-tetrahydrocannabinol and cannabidiol, both extracted from cannabis, and is used to treat multiple sclerosis and cancer pain

Expiratory flow rate, breath hold and anatomic dead space influence electronic nose ability to detect lung cancer

BACKGROUND: Electronic noses are composites of nanosensor arrays. Numerous studies showed their potential to detect lung cancer from breath samples by analysing exhaled volatile compound pattern ("breathprint"). Expiratory flow rate, breath hold and inclusion of anatomic dead space may influence the exhaled levels of some volatile compounds; however it has not been fully addressed how these factors affect electronic nose data. Therefore, the aim of the study was to investigate these effects. METHODS: 37 healthy subjects (44 +/- 14 years) and 27 patients with lung cancer (60 +/- 10 years) participated in the study. After deep inhalation through a volatile organic compound filter, subjects exhaled at two different flow rates (50 ml/sec and 75 ml/sec) into Teflon-coated bags. The effect of breath hold was analysed after 10 seconds of deep inhalation. We also studied the effect of anatomic dead space by excluding this fraction and comparing alveolar air to mixed (alveolar + anatomic dead space) air samples. Exhaled air samples were processed with Cyranose 320 electronic nose. RESULTS: Expiratory flow rate, breath hold and the inclusion of anatomic dead space significantly altered "breathprints" in healthy individuals (p 0.05). These factors also influenced the discrimination ability of the electronic nose to detect lung cancer significantly. CONCLUSIONS: We have shown that expiratory flow, breath hold and dead space influence exhaled volatile compound pattern assessed with electronic nose. These findings suggest critical methodological recommendations to standardise sample collections for electronic nose measurements

The value of diffusion-weighted imaging in assessing the ADC changes of tissues adjacent to breast carcinoma

<p>Abstract</p> <p>Background</p> <p>To define a threshold value of apparent diffusion coefficient (ADC) with which malignant breast lesions can be distinguished from benign lesions, and to evaluate the ADC change of peri-tumor tissue in breast carcinoma by echo planar-diffusion weighted imaging (EPI-DWI).</p> <p>Methods</p> <p>57 breast lesions were scanned by routine MRI and EPI-DWI. The ADC values were compared between malignant and benign lesions. The sensitivity and specificity of EPI-DWI and the threshold ADC value were evaluated by Receiver Operating Characteristic curve (ROC). The ADC values of malignant lesion and layered peri-tumor tissues (from innermost layer 1 to outermost layer 4 with 5 mm every layer) in different directions were compared and the ADC values among different layers were compared.</p> <p>Results</p> <p>The ADC value of 35 malignant lesions was statistically lower than that of 22 benign lesions (P < 0.05). In ROC curve, the threshold value was 1.24 +/- 0.25*10E-3 mm²/s (b = 500) or 1.20 +/- 0.25*10E-3 mm²/s (b = 1000). The ADC value of malignant lesions was statistically lower than that of peri-tumor tissues in different directions (P < 0.05). For peri-tumor tissues, the ADC values increased gradually from layer 1 to layer 4 and there was a significant difference between the ADC values of layer 1 and layer 2 (P < 0.05); while from layer 2 outwards, there was no statistical difference among different layers.</p> <p>Conclusion</p> <p>ADC value was a sensitive and specific parameter that could help to differentiate benign and malignant breast lesions. ADC changes in tissues adjacent to breast carcinoma could be detected by EPI-DWI, which made EPI-DWI a promising method for helping to determine surgical scope of breast carcinoma.</p

The Orexigenic Effect of Ghrelin Is Mediated through Central Activation of the Endogenous Cannabinoid System

INTRODUCTION Ghrelin and cannabinoids stimulate appetite, this effect possibly being mediated by the activation of hypothalamic AMP-activated protein kinase (AMPK), a key enzyme in appetite and metabolism regulation. The cannabinoid receptor type 1 (CB1) antagonist rimonabant can block the orexigenic effect of ghrelin. In this study, we have elucidated the mechanism of the putative ghrelin-cannabinoid interaction. METHODS The effects of ghrelin and CB1 antagonist rimonabant in wild-type mice, and the effect of ghrelin in CB1-knockout animals, were studied on food intake, hypothalamic AMPK activity and endogenous cannabinoid content. In patch-clamp electrophysiology experiments the effect of ghrelin was assessed on the synaptic inputs in parvocellular neurons of the hypothalamic paraventricular nucleus, with or without the pre-administration of a CB1 antagonist or of cannabinoid synthesis inhibitors. RESULTS AND CONCLUSIONS Ghrelin did not induce an orexigenic effect in CB1-knockout mice. Correspondingly, both the genetic lack of CB1 and the pharmacological blockade of CB1 inhibited the effect of ghrelin on AMPK activity. Ghrelin increased the endocannabinoid content of the hypothalamus in wild-type mice and this effect was abolished by rimonabant pre-treatment, while no effect was observed in CB1-KO animals. Electrophysiology studies showed that ghrelin can inhibit the excitatory inputs on the parvocellular neurons of the paraventricular nucleus, and that this effect is abolished by administration of a CB1 antagonist or an inhibitor of the DAG lipase, the enzyme responsible for 2-AG synthesis. The effect is also lost in the presence of BAPTA, an intracellular calcium chelator, which inhibits endocannabinoid synthesis in the recorded parvocellular neuron and therefore blocks the retrograde signaling exerted by endocannabinoids. In summary, an intact cannabinoid signaling pathway is necessary for the stimulatory effects of ghrelin on AMPK activity and food intake, and for the inhibitory effect of ghrelin on paraventricular neurons

Hepatitis C Virus Induces the Cannabinoid Receptor 1

BACKGROUND: Activation of hepatic CB(1) receptors (CB(1)) is associated with steatosis and fibrosis in experimental forms of liver disease. However, CB(1) expression has not been assessed in patients with chronic hepatitis C (CHC), a disease associated with insulin resistance, steatosis and metabolic disturbance. We aimed to determine the importance and explore the associations of CB(1) expression in CHC. METHODS: CB(1) receptor mRNA was measured by real time quantitative PCR on extracted liver tissue from 88 patients with CHC (genotypes 1 and 3), 12 controls and 10 patients with chronic hepatitis B (CHB). The Huh7/JFH1 Hepatitis C virus (HCV) cell culture model was used to validate results. PRINCIPAL FINDINGS: CB(1) was expressed in all patients with CHC and levels were 6-fold higher than in controls (P<0.001). CB(1) expression increased with fibrosis stage, with cirrhotics having up to a 2 fold up-regulation compared to those with low fibrosis stage (p<0.05). Even in mild CHC with no steatosis (F0-1), CB(1) levels remained substantially greater than in controls (p<0.001) and in those with mild CHB (F0-1; p<0.001). Huh7 cells infected with JFH-1 HCV showed an 8-fold upregulation of CB(1), and CB(1) expression directly correlated with the percentage of cells infected over time, suggesting that CB(1) is an HCV inducible gene. While HCV structural proteins appear essential for CB(1) induction, there was no core genotype specific difference in CB(1) expression. CB(1) significantly increased with steatosis grade, primarily driven by patients with genotype 3 CHC. In genotype 3 patients, CB(1) correlated with SREBP-1c and its downstream target FASN (SREBP-1c; R=0.37, FASN; R=0.39, p<0.05 for both). CONCLUSIONS/SIGNIFICANCE: CB(1) is up-regulated in CHC and is associated with increased steatosis in genotype 3. It is induced by the hepatitis C virus