Role of CB2 cannabinoid receptor in the development of food addiction in male mice.

The endocannabinoid system plays an important role in multiple behavioral responses due to its wide distribution in the central nervous system. The cannabinoid CB1 receptor was associated to the loss of behavioral control over food intake occurring during food addiction. The cannabinoid CB2 receptor (CB2R) is expressed in brain areas canonically associated with addictive-like behavior and was linked to drug-addictive properties. In this study, we evaluated for the first time the specific role of the CB2R in food addiction by using a well-validated operant mouse model of long-term training to obtain highly palatable food. We have compared in this model the behavioral responses of wild-type mice, mutant mice constitutively lacking CB2R, and transgenic mice overexpressing CB2R. The lack of CB2R constitutes a protective factor for the development of food addiction and the impulsive and depressive-like behavior associated. In contrast, the overexpression of CB2R induces a vulnerable phenotype toward food addiction after long-term exposure to highly palatable chocolate pellets. Relevant transcriptomic changes were associated to resilience and vulnerability to food addiction depending on the genotype, which provides a mechanistic explanation for these behavioral changes. Therefore, CB2R may constitute a potential therapeutic target for the loss of eating control and the comorbid emotional effects associated to food addiction.

Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group.

The neuro-anatomical substrates of major depressive disorder (MDD) are still not well understood, despite many neuroimaging studies over the past few decades. Here we present the largest ever worldwide study by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Major Depressive Disorder Working Group on cortical structural alterations in MDD. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2148 MDD patients and 7957 healthy controls were analysed with harmonized protocols at 20 sites around the world. To detect consistent effects of MDD and its modulators on cortical thickness and surface area estimates derived from MRI, statistical effects from sites were meta-analysed separately for adults and adolescents. Adults with MDD had thinner cortical gray matter than controls in the orbitofrontal cortex (OFC), anterior and posterior cingulate, insula and temporal lobes (Cohen's d effect sizes: -0.10 to -0.14). These effects were most pronounced in first episode and adult-onset patients (>21 years). Compared to matched controls, adolescents with MDD had lower total surface area (but no differences in cortical thickness) and regional reductions in frontal regions (medial OFC and superior frontal gyrus) and primary and higher-order visual, somatosensory and motor areas (d: -0.26 to -0.57). The strongest effects were found in recurrent adolescent patients. This highly powered global effort to identify consistent brain abnormalities showed widespread cortical alterations in MDD patients as compared to controls and suggests that MDD may impact brain structure in a highly dynamic way, with different patterns of alterations at different stages of life.

Pasture, multi-enzymes, benzoic acid and essential oils positively influence performance, intestinal organ weight and egg quality in free-range laying hens.

1. The objective of this study was to investigate the effect of range type, multi-enzyme applications, and a combination of benzoic acid (BA) and essential oils (EO) on the productive performance, organ weight and egg quality of free-range laying hens. 2. Three hundred laying hens were evaluated for the short-term (6 weeks) and long-term (12 weeks) effects of range type (G = no pasture, P = pasture) and feed additives (T1 = control; T2 = betaglucanase/pectinase/protease; T3 = BA/EO). Body weight, feed intake (FI), feed conversion ratio (FCR), egg production (EP), digestive organ weight, and egg quality (EQ) were evaluated. Data were analysed using SPSS 2.2 in a 2×2×3 factorial arrangement. 3. Hens that ranged on pasture were significantly heavier (2043 g vs. 1996 g; p < 0.001), laid heavier eggs (61.9 g vs. 60.3 g; p < 0.001) and produced darker yolk colour (4.3 vs. 7.0; p < 0.001) compared to hens ranged on gravel. Hens fed T2 were significantly heavier (2050 g) compared to hens fed T1 (2005 g) or T3 (2008 g). Organ weights (gizzard, liver and pancreas) were significantly heavier in hens ranged on pasture (16.8 g/kg BW, 22.3 g/kg BW and 1.89 g/kg BW, respectively) compared to hens ranged on gravel (14.2 g/kg BW, 21.7 g/kg BW and 1.83 g/kg BW, respectively). Over time, body weight (1970-2070 g; p < 0.001) and egg weight (59.5-62.8 g; p < 0.001) increased, FI (123-120 g; p = 0.024) was reduced and FCR (2.36-2.10; p = 0.002) improved 4. In conclusion, hens housed on pasture and fed multi-enzyme supplemented diets had significantly heavier body weight and produced heavier eggs with darker yolk colour. Pasture intake and enzyme supplementation increased digestive organ weight significantly.

Supplementation of broiler diets with high levels of microbial protease and phytase enables partial replacement of commercial soybean meal with raw, full-fat soybean.

A 3 × 3 + 1 factorial, involving three levels of protease (0, 15,000 or 30,000 PROT/kg) and three levels of phytase (1,000, 2,000 or 3,000 FYT/kg), was used to evaluate the effect of replacing commercial soybean meal (SBM) with raw, full-fat soybean (RFSB) at 75 g/kg of diet for broilers. A control diet was used for comparison. Each treatment was replicated six times, with nine birds per replicate. The concentration of trypsin inhibitors (TIs) in the test diets was approximately 10,193.4 TIU/kg. Regardless of enzyme supplementation, feed intake (FI) and body weight gain (BWG) of birds in the control group were superior to those on the test diets. Birds that received the protease-free test diets had reduced FI and BWG, but when supplemented with protease, were similar to the control diet in BWG, FI (except 0-35 days) and feed conversion ratio (FCR). When the test diet was supplemented with elevated levels (extradose) of protease and phytase, the BWG was improved during 0-10 days (p = .05) and 0-24 days (p < .01). Regardless of protease supplementation, the weight of thighs was lower for birds fed the test diets. Birds that received the control diet had smaller weight of pancreas. Increasing the level of phytase supplementation reduced (p < .05) the weight of the pancreas. The apparent ileal digestibility (AID) of CP and AA was higher in birds on the control diets, but this was also improved in test diets by protease supplementation. The activities of trypsin (7%), general proteolytic (11%) and lipase (12%) were slightly increased because of protease supplementation. Mucosal depth and apparent villus surface areas were increased by about 2.9% and 20%, respectively, due to supplementation of elevated level of phytase. It can be concluded that RFSB could partially replace SBM in broiler diets, provided the diets are supplemented with elevated levels of protease and phytase.

Physiological and health-related response of broiler chickens fed diets containing raw, full-fat soya bean meal supplemented with microbial protease.

A 2 × 3 factorial study (protease: 0 or 1,5000 PROT/kg and raw full-fat soya bean meal [RSBM] replacing the commercial SBM at 0, 45 and 75 g/kg of diet) was conducted to examine the performance of broilers. Phytase (2000 FYT/kg) was uniformly added to each diet, each also replicated six times, with eight birds per replicate. Birds were raised in climate-controlled rooms using sawdust as the bedding material and offered starter, grower and finisher diets. Feed intake (FI) and body weight gain (BWG) were reduced (p < .05) due to increasing levels of RSBM, but feed conversion ratio (FCR; 0-35 days) was unaffected. Over the first 24 days, neither RSBM nor protease supplementation affected (p > .05) mortality, footpad dermatitis or intestinal lesions in birds. At day 24, the weight, length, width and strength of tibia bone were reduced in chickens that received an elevated level of RSBM (75 g/kg of diet), but this was not significant at day 35. At day 24 (p < .05) and 35 (p < .01), Ca concentration in the litter was reduced when the RSBM level was increased in the diet, but P content was not affected. On days 24 (p < .05) and 35 (p < .01), the N content in litter was also increased with increase in dietary RSBM. Protease supplementation increased (p < .05) the uric acid concentration in the litter (at day 35), but the reverse was the case for ammonia concentration. Overall, the results of this study indicate that there are no major health-related risks, associated with the replacement of commercial SBM with RSBM (≤25%) in broiler diets.

Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder working group.

The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen's d=-0.14, % difference=-1.24). This effect was driven by patients with recurrent MDD (Cohen's d=-0.17, % difference=-1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen's d=-0.20, % difference=-1.85) and a trend toward smaller amygdala (Cohen's d=-0.11, % difference=-1.23) and larger lateral ventricles (Cohen's d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.

Quantitative PCR: an alternative approach to detect common copy number alterations in multiple myeloma.

Chromosome 1q gains and 13q deletions are common cytogenetic aberrations in multiple myeloma (MM) that confer a poor prognosis. There are several techniques for the targeted study of these alterations, but interphase fluorescence in situ hybridization (FISH) is the current gold standard. The aim of the present study was to validate quantitative PCR (qPCR) as an alternative to FISH studies in CD138+-enriched plasma cells (PCs) from MM patients at diagnosis. We analyzed 1q gains and 13q deletions by qPCR in 57 and 60 MM patients, respectively. qPCR applicability was 84 and 88% for 1q and 13q, respectively. The qPCR and FISH methods had a sensitivity and specificity of 88 and 71% for 1q gains, and 79 and 100% for 13q deletions. A second qPCR assay for each region was carried out to confirm the previous results. Paired qPCR (two assays) and FISH results were available from 53 MM patients: 26 for 1q amplification and 27 for 13q deletion. qPCR assays gave concordant results (qPCR-consistent) in 20 of the 26 (77%) 1q gains and 25 of the 27 (93%) 13q deletions. Considering only the consistent data, the overall concordance among qPCR and FISH was 85 and 100% for 1q gains and 13q deletions, respectively. Our results show a substantial agreement between qPCR and the gold standard FISH technique, indicating the potential of qPCR as an alternative approach, particularly when the starting material is too scarce or cells are too damaged to obtain accurate results from FISH studies.

Pancreatic polypeptide regulates glucagon release through PPYR1 receptors expressed in mouse and human alpha-cells.

BACKGROUND: Plasma levels of pancreatic polypeptide (PP) rise upon food intake. Although other pancreatic islet hormones, such as insulin and glucagon, have been extensively investigated, PP secretion and actions are still poorly understood. METHODS: The release of PP upon glucose stimulation and the effects of PP on glucagon and insulin secretion were analyzed in isolated pancreatic islets. Expression of PP receptor (PPYR1) was investigated by immunoblotting, quantitative RT-PCR on sorted pancreatic islet cells, and immunohistochemistry. RESULTS: In isolated mouse pancreatic islets, glucose stimulation increased PP release, while insulin secretion was up and glucagon release was down. Direct exposure of islets to PP inhibited glucagon release. In mouse islets, PPYR1 protein was observed by immunoblotting and quantitative RT-PCR revealed PPYR1 expression in the FACS-enriched glucagon alpha-cell fraction. Immunohistochemistry on pancreatic sections showed the presence of PPYR1 in alpha-cells of both mouse and human islets, while the receptor was absent in other islet cell types and exocrine pancreas. CONCLUSIONS: Glucose stimulates PP secretion and PP inhibits glucagon release in mouse pancreatic islets. PP receptors are present in alpha-cells of mouse and human pancreatic islets. GENERAL SIGNIFICANCE: These data demonstrate glucose-regulated secretion of PP and its effects on glucagon release through PPYR1 receptors expressed by alpha-cells.

The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbens.

Tonically active cholinergic interneurons (TANs) from the nucleus accumbens (NAc) are centrally involved in reward behavior. TANs express a vesicular glutamate transporter referred to as VGLUT3 and thus use both acetylcholine and glutamate as neurotransmitters. The respective roles of each transmitter in the regulation of reward and addiction are still unknown. In this study, we showed that disruption of the gene that encodes VGLUT3 (Slc17a8) markedly increased cocaine self-administration in mice. Concomitantly, the amount of dopamine (DA) release was strongly augmented in the NAc of VGLUT3(-/-) mice because of a lack of signaling by metabotropic glutamate receptors. Furthermore, dendritic spines and glutamatergic synaptic transmission on medium spiny neurons were increased in the NAc of VGLUT3(-/-) mice. Increased DA and glutamate signaling in the NAc are hallmarks of addiction. Our study shows that TANs use glutamate to reduce DA release and decrease reinforcing properties of cocaine in mice. Interestingly, we also observed an increased frequency of rare variations in SLC17A8 in a cohort of severe drug abusers compared with controls. Our findings identify VGLUT3 as an unexpected regulator of drug abuse.

Effect of pH on technological parameters and physicochemical and texture characteristics of the pasta filata cheese Telita.

The objective of this study was to determine the effect of stretching pH on technological parameters and physicochemical and texture characteristics of the pasta filata cheese Telita. A no-brine cheese-making method was used to control both melting and stretching temperatures. Six vats of cheese, each with a different stretching pH (5.2, 5.3, 5.4, 5.5, 5.6, and 5.7), were made in 2h. Cheese-making was replicated using 2 different lots of milk. Differences in stretching pH significantly affected all variables evaluated; stretching temperature and pH were positively correlated. Technological parameters showed an inverse relationship between pH and acidity and a direct relationship between melting and stretching temperature. The yield was highest as the pH increased and ranged from 11.4 to 12.9 kg of cheese/100 kg of milk. Physicochemical characteristics showed the following: moisture 48.1 to 53.5% (soft and semi-hard cheese), fat 46.3 to 54.9% (dry basis, full-fat cheese), minerals 2.8 to 3.5% (dry basis), calcium content 0.5 to 1.0% (dry basis), sodium 0.38 to 0.78% (dry basis), and whiteness index 77.2 to 84.5. Texture parameters showed that as the stretching pH increased, hardness increased, adhesiveness decreased, cohesiveness decreased, springiness increased, and chewiness increased. Samples were grouped based on principal component analysis. Group 1 contained cheeses at pH 5.2 and 5.3 and were better in terms of retention of components. Group 2 contained cheeses at pH 5.6 and 5.7. These cheeses attained the highest yields, were whitest, and presented the highest values for texture parameters except for adhesiveness and cohesiveness. The third group of cheeses at pH 5.4 and 5.5 were considered the best because they showed a good balance among all variables evaluated.

Mice deficient for delta- and mu-opioid receptors exhibit opposing alterations of emotional responses.

The role of the opioid system in controlling pain, reward and addiction is well established, but its role in regulating other emotional responses is poorly documented in pharmacology. The mu-, delta- and kappa- opioid receptors (encoded by Oprm, Oprd1 and Oprk1, respectively) mediate the biological activity of opioids. We have generated Oprd1-deficient mice and compared the behavioural responses of mice lacking Oprd1, Oprm (ref. 6) and Oprk1 (ref. 7) in several models of anxiety and depression. Our data show no detectable phenotype in Oprk1-/- mutants, suggesting that kappa-receptors do not have a role in this aspect of opioid function; opposing phenotypes in Oprm-/- and Oprd1-/- mutants which contrasts with the classical notion of similar activities of mu- and delta-receptors; and consistent anxiogenic- and depressive-like responses in Oprd1-/- mice, indicating that delta-receptor activity contributes to improvement of mood states. We conclude that the Oprd1-encoded receptor, which has been proposed to be a promising target for the clinical management of pain, should also be considered in the treatment of drug addiction and other mood-related disorders.

A retrospective study of cane toad (Rhinella marina) toxicity in 190 domestic cats in Southeastern Queensland: Clinical presentations, treatments, and outcomes.

OBJECTIVE: To report the clinical presentations, treatments and outcomes of toad toxicity in domestic cats in Southeastern Queensland, Australia. METHODS: This report describes a retrospective study of 190 cases of cane toad (Rhinella marina) toxicity in cats in south-eastern Queensland, Australia. All cases were presented for veterinary treatment between 2011 and 2020 at four specialist veterinary emergency centres in Southeast Queensland, Australia. Cane toad toxicity was diagnosed based on a history of exposure and clinical signs. RESULTS: Domestic short-hair breeds accounted for 53.6% of the cases. Presentation was seasonal with the highest incidence over the warmer months of the year (November - March). Hypersalivation was described in 96.3% (183/190), tachypnoea in 34.2% (65/190) and altered behaviour in 18.4% (35/190) of cases. Seizures occurred in 1% of cases. Of the 190 cases, 6.3% (12/190) were hospitalised and 0.5% (1/190) were euthanised and overall 99.5% (189/190) survived hospital discharge. CLINICAL SIGNIFICANCE: Cane toad toxicity is relatively common in cats in Southeast Queensland and following buccal lavage the prognosis for recovery was excellent.

Hub and spoke framework for study of surgical centralization within United States health systems.

BACKGROUND: Hospital consolidation into health systems has mixed effects on surgical quality, potentially related to degree of surgical centralization at high-volume (hub) sites. We developed a novel measure of centralization and evaluated a hub and spoke framework. METHODS: Surgical centralization within health systems was measured using hospital surgical volumes (American Hospital Association) and health system data (Agency for Healthcare Research and Quality). Hub and spoke hospitals were compared using mixed effects logistic regression and system characteristics associated with surgical centralization were identified using a linear model. RESULTS: Within 382 health systems containing 3022 hospitals, system hubs perform 63% of cases (IQR 40-84%). Hubs are larger, in metropolitan and urban areas, and more often academically affiliated. Degree of surgical centralization varies ten-fold. Larger, multistate, and investor-owned systems are less centralized. Adjusting for these factors, there is less centralization among teaching systems (p â€‹< â€‹0.001). CONCLUSIONS: A hub-spoke framework applies to most health systems but centralization varies significantly. Future studies of health system surgical care should assess the contributions of surgical centralization and teaching status on differential quality.

The neural correlates of negative prediction error signaling in human fear conditioning.

In a temporal difference (TD) learning approach to classical conditioning, a prediction error (PE) signal shifts from outcome deliverance to the onset of the conditioned stimulus. Omission of an expected outcome results in a negative PE signal, which is the initial step towards successful extinction. In order to visualize negative PE signaling during fear conditioning, we employed combined functional magnetic resonance (fMRI) and skin conductance response (SCR) measurements in a conditioning task with visual stimuli and mild electrical shocks. Positive PE signaling was associated with increased activation in the bilateral insula, supplementary motor area, brainstem, and visual cortices. Negative PE signaling was associated with increased activation in the ventromedial and dorsolateral prefrontal cortices, the left lateral orbital gyrus, the middle temporal gyri, angular gyri, and visual cortices. The involvement of the ventromedial prefrontal and orbitofrontal cortex in extinction learning has been well documented, and this study provides evidence for the notion that these regions are already involved in negative PE signaling during fear conditioning.

Cytotoxic effects of Kingella kingae outer membrane vesicles on human cells.

Kingella kingae is an emerging pathogen causing osteoarticular infections in pediatric patients. Electron microscopy of K. kingae clinical isolates revealed the heterogeneously-sized membranous structures blebbing from the outer membrane that were classified as outer membrane vesicles (OMVs). OMVs purified from the secreted fraction of a septic arthritis K. kingae isolate were characterized. Among several major proteins, K. kingae OMVs contained virulence factors RtxA toxin and PilC2 pilus adhesin. RtxA was also found secreted as a soluble protein in the extracellular environment indicating that the bacterium may utilize different mechanisms for the toxin delivery. OMVs were shown to be hemolytic and possess some leukotoxic activity while high leukotoxicity was detected in the non-hemolytic OMV-free component of the secreted fraction. OMVs were internalized by human osteoblasts and synovial cells. Upon interaction with OMVs, the cells produced increased levels of human granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 6 (IL-6) suggesting that these cytokines might be involved in the signaling response of infected joint and bone tissues during natural K. kingae infection. This study is the first report of OMV production by K. kingae and demonstrates that OMVs are a complex virulence factor of the organism causing cytolytic and inflammatory effects on host cells.

Vulnerability to addiction.

Addiction is a chronic brain disease that has dramatic health and socioeconomic consequences worldwide. Multiple approaches have been used for decades to clarify the neurobiological basis of this disease and to identify novel potential treatments. This review summarizes the main brain networks involved in the vulnerability to addiction and specific innovative technological approaches to investigate these neural circuits. First, the evolution of the definition of addiction across the Diagnostic and Statistical Manual of Mental Disorders (DSM) is revised. We next discuss several innovative experimental techniques that, combined with behavioral approaches, have allowed recent critical advances in understanding the neural circuits involved in addiction, including DREADDs, calcium imaging, and electrophysiology. All these techniques have been used to investigate specific neural circuits involved in vulnerability to addiction and have been extremely useful to clarify the neurobiological basis of each specific component of the addictive process. These novel tools targeting specific brain regions are of great interest to further understand the different aspects of this complex disease. This article is part of the special issue on 'Vulnerabilities to Substance Abuse.'.

Mutations in the John Cunningham virus VP1 gene could predispose to the development of progressive multifocal leukoencephalopathy in multiple sclerosis patients undergoing treatment with natalizumab.

BACKGROUND: Patients with Multiple Sclerosis (MS) undergoing treatment with natalizumab (NTZ) are at risk of developing progressive multifocal leukoencephalopathy (PML) due to the reactivation of John Cunningham (JC) virus. A relevant characteristic among PML cases is the development of single nucleotide mutations in the VP1 gene of the causal JC virus. The identification of such mutations in timely manner can provide valuable information for MS management. OBJECTIVE: To identify mutations along the JC virus VP1 gene in MS patients undergoing treatment with NTZ, and correlate them with anti-JC virus antibody index. METHODS: Eighty-eight MS patients, one hundred twenty controls, and six patients with diagnosis of Human Immunodeficiency Virus (HIV) with and without secondary PML were included. JC virus was identified in peripheral blood mononuclear cells and cerebrospinal fluid by PCR. Amplification and sequencing of the entire length of the VP1 gene were performed in all positive clinical samples. RESULTS: In MS cases no mutations were observed in the JC virus VP1 gene, but it was positive in HIV controls with PML. Interestingly, the JC virus VP1 gene sequence derived from the HIV patients exhibited a non-silent substitution in position 186 (G â†’ C), leading to an amino acid change (Lys â†’ Asp). We did not find correlation between anti-JC virus antibody index and DNA viral detection. CONCLUSIONS: . The identification of single nucleotide mutants in the JC virus VP1 gene might be an early predictive marker to PML for efficient patient treatment and follow-up.

Use of coumarins as complementary medicine with an integrative approach against cervical cancer: background and mechanisms of action.

Cervical cancer is characterized by the cellular transformation caused by Human Papillomavirus (HPV), favoring cell proliferation, migration, invasion, and metastasis. Cervical cancer is conventionally treated with radiation therapy, and chemotherapy focused on the destruction of tumor cells. However, chemoresistance and low selectivity between tumor and non-tumor cells have been reported, causing side effects in patients. Metabolites of natural origin have shown selectivity against tumor cells, suggesting their use for reducing the side effects caused by drugs used in conventional therapy. Among these compounds, several natural coumarins stand out, such as auraptene, scopoletin, osthole, and praeruptorin, of which antiproliferative, anti-migratory, and anti-invasive activity have been reported. Auraptene, scopoletin, osthole, and praeruptorin show a cytotoxic or antiproliferative effect on cervical tumor cells, arresting the cell cycle by inducing the overexpression of negative regulators of the cell cycle, or inducing cell death by increasing the expression of pro-apoptotic proteins and decreasing that of anti-apoptotic proteins. On the other hand, auraptene, scopoletin, and praeruptorin inhibit the capacity for migration, invasion, and metastasis of cervical tumor cells, mainly by inhibiting the expression and activity of matrix metalloproteinase-2 and -9. The PI3K/Akt signal pathway appears to be central to the anti-tumor activity of the coumarins analyzed in this review. In addition, auraptene, osthole, and praeruptorin are useful in sensitizing tumor cells to radiotherapy or chemotherapeutic molecules, such as FOLFOX, cisplatin, or DOX. Coumarins offer an excellent possibility for developing new drugs as complementary medicine with an integrative approach against cervical cancer.

Deficiency of CB2 cannabinoid receptor in mice improves insulin sensitivity but increases food intake and obesity with age.

AIMS/HYPOTHESIS: The endocannabinoid system has a key role in energy storage and metabolic disorders. The endocannabinoid receptor 2 (CB2R), which was first detected in immune cells, is present in the main peripheral organs responsible for metabolic control. During obesity, CB2R is involved in the development of adipose tissue inflammation and fatty liver. We examined the long-term effects of CB2R deficiency in glucose metabolism. METHODS: Mice deficient in CB2R (Cb2 ( -/- ) [also known as Cnr2]) were studied at different ages (2-12 months). Two-month-old Cb2 (-/-) and wild-type mice were treated with a selective CB2R antagonist or fed a high-fat diet. RESULTS: The lack of CB2R in Cb2 (-/-) mice led to greater increases in food intake and body weight with age than in Cb2 (+/+) mice. However, 12-month-old obese Cb2 (-/-) mice did not develop insulin resistance and showed enhanced insulin-stimulated glucose uptake in skeletal muscle. In agreement, adipose tissue hypertrophy was not associated with inflammation. Similarly, treatment of wild-type mice with CB2R antagonist resulted in improved insulin sensitivity. Moreover, when 2-month-old Cb2 (-/-) mice were fed a high-fat diet, reduced body weight gain and normal insulin sensitivity were observed. CONCLUSIONS/INTERPRETATION: These results indicate that the lack of CB2R-mediated responses protected mice from both age-related and diet-induced insulin resistance, suggesting that these receptors may be a potential therapeutic target in obesity and insulin resistance.