Association of Molecular Markers in Plasmodium Falciparum Crt and Mdr1 with in Vitro Chloroquine Resistance: a Philippine Study

Parasitology International. Jun, 2009  |  Pubmed ID: 19567229

Specific mutations in the pfcrt and pfmdr1 genes have been reported to be associated with chloroquine-resistant falciparum malaria parasites worldwide. These genetic markers are considered to be useful tools for the elucidation of several aspects of the epidemiology of drug resistant malaria. In this study, Plasmodium falciparum isolates from three distinct areas of the Philippines were analyzed for drug-resistance-associated genetic mutations, and their association with the in vitro chloroquine (CQ) response. Two novel pfcrt 72-76 allelic types, CVMDT and SVMDT, were detected. The frequency of the pfcrt K76T mutation in the isolates that were successfully tested for in vitro CQ susceptibility was found to be 100% in Kalinga, 80% in Palawan, and 87% in Mindanao. The frequency of the pfmdr1 N86Y mutation was 39% in Kalinga, 35% in Palawan, and 93% in Mindanao isolates. No mutations were found at positions 1042 and 1246 of pfmdr1. However, there were no significant associations found between polymorphisms in these genes and in vitro CQ susceptibility. The results of this study indicate that mutations in pfcrt and pfmdr1 are not predictive of in vitro CQ resistance in Philippine isolates and may therefore not be suitable as molecular markers for surveillance.

Disruption of the Neurogenic Niche in the Subventricular Zone of Postnatal Hydrocephalic Hyh Mice

Journal of Neuropathology and Experimental Neurology. Sep, 2009  |  Pubmed ID: 19680142

Neural stem cells persist after embryonic development in the subventricular zone (SVZ) niche and produce new neural cells during postnatal life; ependymal cells are a key component associated with this neurogenic niche. In the animal model of human hydrocephalus, the hyh mouse, the ependyma of the lateral ventricles is progressively lost during late embryonic and early postnatal life and disappears from most of the ventricular surface throughout its life span. To determine the potential consequences of this loss on the SVZ, we characterized the abnormalities in this neurogenic niche in hyh mice. There was overall disorganization and a marked reduction of proliferative cells in the SVZ of both newborn and adult hyh hydrocephalic mice in vivo; neuroblasts were displaced to the ventricular surface, and their migration through the rostral migratory stream was reduced. The numbers of resident neural progenitor cells in hyh mice were also markedly reduced, but they were capable of proliferating, forming neurospheres, and differentiating into neurons and glia in vitro in a manner indistinguishable from that of wild-type progenitor cells. These findings suggest that the reduction of proliferative activity observed in vivo is not caused by a cell autonomous defect of SVZ progenitors but is a consequence of a reduced number of these cells. Furthermore, the overall tissue disorganization of the SVZ and displacement of neuroblasts imply alterations in the neurogenic niche of postnatal hyh mice.

Mammary Tumor Development in Dogs is Associated with BRCA1 and BRCA2

Cancer Research. Nov, 2009  |  Pubmed ID: 19887619

Breast cancer is a major contributor to overall morbidity and mortality in women. Several genes predisposing to breast cancer have been identified, but the majority of risk factors remain unknown. Even less is known about the inherited risk factors underlying canine mammary tumors (CMT). Clear breed predispositions exist, with 36% of English springer spaniels (ESS) in Sweden being affected. Here, we evaluate 10 human breast cancer genes (BRCA1, BRCA2, CHEK2, ERBB2, FGFR2, LSP1, MAP3K1, RCAS1, TOX3, and TP53) for association with CMTs. Sixty-three single-nucleotide polymorphisms (SNPs; four to nine SNPs per gene) were genotyped by iPLEX in female ESS dogs, 212 CMT cases and 143 controls. Two genes, BRCA1 and BRCA2, were significantly associated with CMT (Bonferroni corrected P = 0.005 and P = 0.0001, respectively). Borderline association was seen for FGFR2. Benign and malignant cases were also analyzed separately. Those findings supported the association to BRCA1 and BRCA2 but with a stronger association to BRCA1 in malignant cases. Both BRCA1 and BRCA2 showed odds ratios of approximately 4. In conclusion, this study indicates that BRCA1 and BRCA2 contribute to the risk of CMT in ESS, suggesting that dogs may serve as a good model for human breast cancer.

A Diagnostic Oligonucleotide Microarray for Simultaneous Detection of Grapevine Viruses

Journal of Virological Methods. Feb, 2010  |  Pubmed ID: 19914293

At least 58 viruses have been reported to infect grapevines causing economic damage globally. Conventional detection strategies based on serological assays, biological indexing and RT-PCR targeting one or few viruses in each assay are widely used. Grapevines are prone to contain mixed infections of several viruses, making the use of these techniques time-consuming. A 70-mer oligonucleotide microarray able to detect simultaneously a broad spectrum of known viruses as well as new viruses by cross-hybridization to highly conserved probes is reported in the present study. The array contains 570 unique probes designed against highly conserved and species-specific regions of 44 plant viral genomes. In addition probes designed against plant housekeeping genes are also included. By using a random primed RT-PCR amplification strategy of grapevine double stranded RNA-enriched samples, viral agents were detected in single and mixed infections. The microarray accuracy to detect 10 grapevine viruses was compared with RT-PCR yielding consistent results. For this purpose, grapevine samples containing single or mixed infections of Grapevine leafroll-associated virus-1, -2, -3, -4, -7, -9, Grapevine fanleaf virus, Grapevine rupestris stem pitting-associated virus, Grapevine virus A, and Grapevine virus B were used. Genomic libraries containing complete viral genomes were also used as part of the validation process. The specific probe hybridization pattern obtained from each virus makes this approach a powerful tool for high throughput plant certification purposes and also for virus discovery if the new viral genomic sequences have partial similarity with the microarray probes. Three Closteroviridae members (Grapevine leafroll-associated virus -4, -7 and -9) were detected for the first time in Chilean grapevines using the microarray.

Endocannabinoid System in the Adult Rat Circumventricular Areas: an Immunohistochemical Study

The Journal of Comparative Neurology. Aug, 2010  |  Pubmed ID: 20533360

Endocannabinoids (ECs) are important neuromodulators involved in a plethora of physiological processes such as modulation of synaptic transmission, neuroprotection, immune function, and neurodevelopment, among others. However, still lacking is a detailed study on the presence of this system in the circumventricular areas, brain structures controlling the interaction between cerebrospinal fluid and brain parenchyma. The aim of this work was to provide the anatomical basis supporting a functional role of ECs in the activity of circumventricular areas. To this end, an immunohistochemical study of the EC system in rat brain was performed. Receptors and synthesizing and degrading enzymes for ECs were widely distributed in rat ependyma and subependyma, marginal glia, and circumventricular organs (CVOs) such as the choroid plexus, subfornical organ, subcommissural organ, median eminence, and area postrema. These zones constitute barrier systems between the brain parenchyma and the ventricular or subarachnoid cerebrospinal fluid (CSF) and between the extracellular hemal milieu of CVOs and the brain parenchyma or the CSF. By immunohistochemistry and real-time polymerase chain reaction we found DAGLalpha, DAGLbeta, NAPE-PLD, MAGL, and FAAH in the ependyma. These finding suggest that the ependyma can release and clear ECs from the ventricular CSF. Subependymal astrocytes and tanycytes displayed DAGLalpha immunoreactivity but parenchymal astrocytes did not express EC-synthesizing enzymes, thus establishing a sharp distinction between these two astrocyte populations. CB1 was located in fibers innervating discrete subventricular zones such as the neurogenic striatal subventricular zone and the fourth ventricle. CB1 fibers also innervated some CVOs.

Early Maternal Deprivation Induces Changes on the Expression of 2-AG Biosynthesis and Degradation Enzymes in Neonatal Rat Hippocampus

Brain Research. Aug, 2010  |  Pubmed ID: 20599824

Early maternal deprivation (MD) in rats (24h, PND 9-10) is a model for neurodevelopmental stress. Our previous data showed that MD altered the hippocampal levels of the endocannabinoid 2-AG and the expression of hippocampal cannabinoid receptors in 13-day-old rats, with males being more markedly affected. The aim of this study was to analyze the impact of MD on the enzymes involved in 2-AG biosynthesis (DAGLalpha and DAGLbeta) and degradation (MAGL) in relevant areas (DG, CA1, CA3) of the hippocampus in 13-day-old neonatal rats. The expression of the enzymes was evaluated by quantitative RT-PCR, immunohistochemistry, and densitometry. MD induced a significant increase in DAGLalpha immunoreactivity in both males and females, which was mainly associated with fibers in the polymorphic cell layer of the dentate gyrus and in the stratum pyramidale of CA3. In contrast, the molecular layer of the dentate gyrus showed a significant decrease in DAGLalpha immunoreactivity in MD males and females. No changes were observed in DAGLbeta immunoreactivity. MD induced a significant decrease in MAGL immunoreactivity in hippocampal CA3 and CA1 areas, more marked in males than in females, and that was mainly associated with fibers in all strata of CA3 and CA1. The results also showed a significant decrease of MAGL mRNA levels in MD males. These data support a clear association between neurodevelopmental stress and dysregulation of the endocannabinoid system. This association may be relevant for schizophrenia and other neurodevelopmental psychiatric disorders.

Presence of Rose Spring Dwarf-associated Virus in Chile: Partial Genome Sequence and Detection in Roses and Their Colonizing Aphids

Virus Genes. Oct, 2010  |  Pubmed ID: 20607379

Rose is one of the most important cut flowers produced in the world. It is also grown in landscape plantings and public gardens for ornamental purposes. However, there is no detailed information available about viruses infecting roses in Chile. In order to gain insight about the viruses that could be present, a plant showing yellow vein chlorosis in its leaves was collected from a garden in Santiago. Double-stranded RNA (dsRNA) was isolated and after a random primed RT-PCR amplification procedure followed by sequencing, Rose spring dwarf-associated virus (RSDaV) presence was established. In order to widen the survey, several additional symptomatic and asymptomatic plants as well as aphids were screened by RT-PCR using two different pairs of virus-specific primers. RSDaV was detected in 24% of the analyzed samples. To our knowledge, this is the first report of RSDaV in Chilean rose plants and Rhodobium porosum (Sanderson) aphids.

Notch1 is Required for Maintenance of the Reservoir of Adult Hippocampal Stem Cells

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Aug, 2010  |  Pubmed ID: 20685991

Notch1 regulates neural stem cell (NSC) number during development, but its role in adult neurogenesis is unclear. We generated nestin-CreER(T2)/R26R-YFP/Notch1(loxP/loxP) [Notch1inducible knock-out (iKO)] mice to allow tamoxifen (TAM)-inducible elimination of Notch1 and concomitant expression of yellow fluorescent protein (YFP) in nestin-expressing Type-1 NSCs and their progeny in the adult hippocampal subgranular zone (SGZ). Consistent with previous research, YFP+ cells in all stages of neurogenesis were evident in the subgranular zone (SGZ) of wild-type (WT) mice (nestin-CreER(T2)/R26R-YFP/Notch1(w/w)) after tamoxifen (post-TAM), producing adult-generated YFP+ dentate gyrus neurons. Compared with WT littermates, Notch1 iKO mice had similar numbers of total SGZ YFP+ cells 13 and 30 d post-TAM but had significantly fewer SGZ YFP+ cells 60 and 90 d post-TAM. Significantly fewer YFP+ Type-1 NSCs and transiently amplifying progenitors (TAPs) resulted in generation of fewer YFP+ granule neurons in Notch1 iKO mice. Strikingly, 30 d of running rescued this deficit, as the total YFP+ cell number in Notch iKO mice was equivalent to WT levels. This was even more notable given the persistent deficits in the Type-1 NSC and TAP reservoirs. Our data show that Notch1 signaling is required to maintain a reservoir of undifferentiated cells and ensure continuity of adult hippocampal neurogenesis, but that alternative Notch- and Type-1 NSC-independent pathways compensate in response to physical activity. These data shed light on the complex relationship between Type-1 NSCs, adult neurogenesis, the neurogenic niche, and environmental stimuli.

[Partial Jejunal Volvulus Due to a Mesenteric Cystic Lymphangioma]

Anales Del Sistema Sanitario De Navarra. Sep-Dec, 2010  |  Pubmed ID: 21233869

Mesenteric cysts are unusual benign tumours that include lymphangioma. Their clinical presentation is variable and acute symptoms can be produced due to complications. This tumour appears especially in childhood, and its prognosis after surgical removal is excellent. We present the case of a 15 year old female patient with symptoms of postprandial abdominal pain and palpation of smooth mass in hypogastrium. Radiological studies showed a big polilobular mass of cystic substance that included a portion of jejune with incomplete volvulus. The treatment was the removal of the cyst and a jejunal portion and the pathological diagnosis was mesenteric cyst lymphangioma. The patient is asymptomatic more than three years after the intervention.

Rho Kinase Inhibition Activates the Homologous Angiotensin-converting Enzyme-angiotensin-(1-9) Axis in Experimental Hypertension

Journal of Hypertension. Apr, 2011  |  Pubmed ID: 21330937

Angiotensin II (Ang II) levels depend on renin, angiotensin-converting enzyme (ACE), and on the homologous angiotensin-converting enzyme (ACE2). Increased ACE and Ang II levels are associated with higher Rho kinase activity. However, the relationship between Rho kinase activation and ACE2 in hypertension is unknown.

Obesity-dependent Cannabinoid Modulation of Proliferation in Adult Neurogenic Regions

The European Journal of Neuroscience. May, 2011  |  Pubmed ID: 21395869

Endocannabinoid signalling participates in the control of neurogenesis, especially after brain insults. Obesity may explain alterations in physiology affecting neurogenesis, although it is unclear whether cannabinoid signalling may modulate neural proliferation in obese animals. Here we analyse the impact of obesity by using two approaches, a high-fat diet (HFD, 60% fat) and a standard/low-fat diet (STD, 10% fat), and the response to a subchronic treatment with the cannabinoid receptor type 1 (CB1) inverse agonist AM251 (3 mg/kg) on cell proliferation of two relevant neurogenic regions, namely the subventricular zone in the striatal wall of the lateral ventricle (SVZ) and the subgranular zone of the dentate gyrus (SGZ), and also in the hypothalamus given its role in energy metabolism. We found evidence of an interaction between diet-induced obesity and CB1 signalling in the regulation of cell proliferation. AM251 reduced caloric intake and body weight in obese rats, as well as corrected plasma levels of cholesterol and triglycerides. AM251 is shown, for the first time, to modulate cell proliferation in HFD-obese rats only. We observed an increase in the number of 5-bromo-2-deoxyuridine-labelled (BrdU+) cells in the SGZ, but a decrease in the number of BrdU+ cells in the SVZ and the hypothalamus of AM251-treated HFD rats. These BrdU+ cells expressed the neuron-specific βIII-tubulin. These results suggest that obesity may impact cell proliferation in the brain selectively, and provide support for a role of CB1 signalling regulation of neurogenesis in response to obesity.

Reduction of Body Weight, Liver Steatosis and Expression of Stearoyl-CoA Desaturase 1 by the Isoflavone Daidzein in Diet-induced Obesity

British Journal of Pharmacology. Dec, 2011  |  Pubmed ID: 21557739

The lack of safe and effective treatments for obesity has increased interest in natural products that may serve as alternative therapies. From this perspective, we have analysed the effects of daidzein, one of the main soy isoflavones, on diet-induced obesity in rats.

A Comparative Analysis of Intraperitoneal Versus Intracerebroventricular Administration of Bromodeoxyuridine for the Study of Cell Proliferation in the Adult Rat Brain

Journal of Neuroscience Methods. Oct, 2011  |  Pubmed ID: 21864575

Bromodeoxyuridine (BrdU) is the most widely used marker to detect proliferative cells in the adult brain. Here we analyse whether the route of administration of the tracer influences the number of labelled cells. For the intraperitoneal (ip) administration of BrdU, we performed two daily injections during 7 days, and for an intracerebroventricular (icv) delivery, it was continuously infused into one lateral ventricle for a 7 days period as well. After ip administration, cells labelled with BrdU were seen in the subventricular zone of the striatal wall of the lateral ventricle, the hippocampus and the neurohemal circumventricular organs. Also, the habenula and large myelinated tracts, such as the fornix and the corpus callosum, showed many BrdU-positive nuclei. Labelled nuclei were scarce in the parenchymal regions of the rest of the brain. In contrast, a significant increase in the number of BrdU-positive nuclei was observed in the parenchyma of the periventricular zones after icv administration of the marker, thus showing a greater availability of the tracer when it was administered directly into the ventricular cerebrospinal fluid. We suggest that the availability of BrdU in the vicinity of proliferating cells may depend on the permeability of the brain vessels to nucleosides in each location. By using double immunocytochemistry we found that neurons, astrocytes, oligodendrocytes, tanycytes and microglia had incorporated the tracer, demonstrating their proliferation capacity.

Species Delimitation in the Continental Forms of the Genus Epicrates (Serpentes, Boidae) Integrating Phylogenetics and Environmental Niche Models

PloS One. 2011  |  Pubmed ID: 21912634

Until recently, the genus Epicrates (Boidae) presented only one continental species, Epicrates cenchria, distributed in Central and South America, but after a taxonomic revision using morphologic characters five species were recognized: E. cenchria, E. crassus, E. maurus, E. assisi, and E. alvarezi. We analyzed two independent data sets, environmental niche models and phylogeny based on molecular information, to explore species delimitation in the continental species of this genus. Our results indicated that the environmental requirements of the species are different; therefore there are not evidences of ecological interchangeability among them. There is a clear correlation between species distributions and the major biogeographic regions of Central and South America. Their overall distribution reveals that allopatry or parapatry is the general pattern. These evidences suggest that habitat isolation prevents or limits gene exchange among them. The phylogenetic reconstruction showed that the continental Epicrates are monophyletic, being E. alvarezi the sister species for the remaining two clades: E. crassus-E. assisi, and E. maurus-E. cenchria. The clade grouping the continental Epicrates is the sister taxon of the genus Eunectes and not of the Caribbean Epicrates clade, indicating that the genus is paraphyletic. There is a non-consistent pattern in niche evolution among continental Epicrates. On the contrary, a high variation and abrupt shifts in environmental variables are shown when ancestral character states were reconstructed on the sequence-based tree. The degree of genetic and ecological divergence among continental Epicrates and the phylogenetic analyses support the elevation to full species of E. cenchria, E. crassus, E. maurus, E. assisi, and E. alvarezi.

Ambulatory Information Systems: the Last Frontier

Healthcare Informatics : the Business Magazine for Information and Communication Systems. Oct, 2011  |  Pubmed ID: 22043741

Expression of the Cannabinoid System in Muscle: Effects of a High-fat Diet and CB1 Receptor Blockade

The Biochemical Journal. Jan, 2011  |  Pubmed ID: 20955176

The ECS (endocannabinoid system) plays an important role in the onset of obesity and metabolic disorders, implicating central and peripheral mechanisms predominantly via CB1 (cannabinoid type 1) receptors. CB1 receptor antagonist/inverse agonist treatment improves cardiometabolic risk factors and insulin resistance. However, the relative contribution of peripheral organs to the net beneficial metabolic effects remains unclear. In the present study, we have identified the presence of the endocannabinoid signalling machinery in skeletal muscle and also investigated the impact of an HFD (high-fat diet) on lipid-metabolism-related genes and endocannabinoid-related proteins. Finally, we tested whether administration of the CB1 inverse agonist AM251 restored the alterations induced by the HFD. Rats were fed on either an STD (standard/low-fat diet) or an HFD for 10 weeks and then treated with AM251 (3 mg/kg of body weight per day) for 14 days. The accumulated caloric intake was progressively higher in rats fed on the HFD than the STD, resulting in a divergence in body weight gain. AM251 treatment reduced accumulated food/caloric intake and body weight gain, being more marked in rats fed on the HFD. CB2 (cannabinoid type 2) receptor and PPARα (peroxisome-proliferator-activated receptor α) gene expression was decreased in HFD-fed rats, whereas MAGL (monoglyceride lipase) gene expression was up-regulated. These data suggest an altered endocannabinoid signalling as a result of the HFD. AM251 treatment reduced CB2 receptor, PPARγ and AdipoR1 (adiponectin receptor 1) gene expression in STD-fed rats, but only partially normalized the CB2 receptor in HFD-fed rats. Protein levels corroborated gene expression results, but also showed a decrease in DAGL (diacylglycerol) β and DAGLα after AM251 treatment in STD- and HFD-fed rats respectively. In conclusion, the results of the present study indicate a diet-sensitive ECS in skeletal muscle, suggesting that blockade of CB1 receptors could work towards restoration of the metabolic adaption imposed by diet.

Molecular Biological Aspects on Canine and Human Mammary Tumors

Veterinary Pathology. Jan, 2011  |  Pubmed ID: 21147766

The high incidence of mammary tumor disease reported in certain canine breeds suggests a significant genetic component, as has already been described in human familial breast cancer-in BRCA1- and BRCA2-associated breast cancer in particular. The identification of genetic risk factors is critical to improvements in the prevention, diagnosis, and treatment of these tumors. In recent years, there has been significant progress in developing the tools and reagents necessary to analyze the canine genome. This work has culminated in a high-quality draft genome sequence, as well as a single-nucleotide polymorphism map and single-nucleotide polymorphism arrays for genomewide association analysis. These tools provide an unprecedented opportunity to characterize the genetic influences in canine diseases such as cancer, eventually allowing for exploration of more effective therapies. Given the high homology between the canine genome sequence and its human counterpart--as well as the many similarities regarding the morphology, biological behavior, and clinical course of mammary tumors in both species--the dog has proven to be an excellent comparative model. This review highlights the comparative aspects regarding certain areas within molecular biology, and it discusses future perspectives. The findings in larger genomewide association analyses and cDNA expression arrays are described, and the BRCA1/BRCA2 complex is compared in detail between the 2 species.

Differential Effects of Single Versus Repeated Alcohol Withdrawal on the Expression of Endocannabinoid System-Related Genes in the Rat Amygdala

Alcoholism, Clinical and Experimental Research. Dec, 2011  |  Pubmed ID: 22141465

Background:  Endogenous cannabinoids such as anandamide and 2-arachidonoylglycerol (2-AG) exert important regulatory influences on neuronal signaling, participate in short- and long-term forms of neuroplasticity, and modulate stress responses and affective behavior in part through the modulation of neurotransmission in the amygdala. Alcohol consumption alters brain endocannabinoid levels, and alcohol dependence is associated with dysregulated amygdalar function, stress responsivity, and affective control. Methods:  The consequence of long-term alcohol consumption on the expression of genes related to endocannabinoid signaling was investigated using quantitative RT-PCR analyses of amygdala tissue. Two groups of ethanol (EtOH)-exposed rats were generated by maintenance on an EtOH liquid diet (10%): the first group received continuous access to EtOH for 15 days, whereas the second group was given intermittent access to the EtOH diet (5 d/wk for 3 weeks). Control subjects were maintained on an isocaloric EtOH-free liquid diet. To provide an initial profile of acute withdrawal, amygdala tissue was harvested following either 6 or 24 hours of EtOH withdrawal. Results:  Acute EtOH withdrawal was associated with significant changes in mRNA expression for various components of the endogenous cannabinoid system in the amygdala. Specifically, reductions in mRNA expression for the primary clearance routes for anandamide and 2-AG (fatty acid amide hydrolase [FAAH] and monoacylglycerol lipase [MAGL], respectively) were evident, as were reductions in mRNA expression for CB(1) , CB(2) , and GPR55 receptors. Although similar alterations in FAAH mRNA were evident following either continuous or intermittent EtOH exposure, alterations in MAGL and cannabinoid receptor-related mRNA (e.g., CB(1) , CB(2) , GPR55) were more pronounced following intermittent exposure. In general, greater withdrawal-associated deficits in mRNA expression were evident following 24 versus 6 hours of withdrawal. No significant changes in mRNA expression for enzymes involved in 2-AG biosynthesis (e.g., diacylglicerol lipase-α/β) were found in any condition. Conclusions:  These findings suggest that EtOH dependence and withdrawal are associated with dysregulated endocannabinoid signaling in the amygdala. These alterations may contribute to withdrawal-related dysregulation of amygdalar neurotransmission.

ADIPONECTIN PROMOTER ACTIVATOR NP-1 REDUCES BODY WEIGHT AND HEPATIC STEATOSIS IN HIGH-FAT DIET-FED ANIMALS

American Journal of Physiology. Endocrinology and Metabolism. Jan, 2012  |  Pubmed ID: 22297300

Enhancement of adiponectin level has been shown to have beneficial effects, including anti-obesity, anti-diabetic and hepatoprotective effects. This evidence supports the therapeutic utility of adiponectin in complicated obesity. The present study characterized the in vivo effects of sustained adiponectin release by NP-1, a new class of thiazol-derivative that increases adiponectin levels. Acute administration of NP-1 reduces feeding, increases plasma adiponectin and improved insulin sensitivity without inducing malaise as revealed by conditioned taste aversion studies. Short-term (7 days) treatment with NP-1 also reduced feeding and body weight gain, and increased phosphorylation of AMPK in muscle, a main intracellular effector of adiponectin. NP-1 was also evaluated in diet-induced obesity, and adult male Wistar rats were fed two different types of diet: a standard high-carbohydrate/low-fat diet (SD) and a high-fat diet (HFD). Once obesity was established, animals were daily treated with NP-1 (5 mg kg-1) for 14 consecutive days. Chronic NP-1 induced body weight loss, reduction of food intake and resulted in both a marked decrease in liver steatosis and in an improvement of biochemical indexes of liver damage in HFD-fed rats. However, a marked induction of tolerance in adiponectin gene transcription and release was observed after chronic NP-1 with respect to the acute actions of this drug. The present results support the role of adiponectin signaling in diet-induced obesity and set in place a potential use of compounds able to induce adiponectin release for the treatment of obesity and non-alcoholic fatty liver with the limits imposed by the induction of pharmacological tolerance.

Effects of the Anandamide Uptake Blocker AM404 on Food Intake Depend on Feeding Status and Route of Administration

Pharmacology, Biochemistry, and Behavior. Mar, 2012  |  Pubmed ID: 22133635

Endocannabinoids (anandamide and 2-AG) are relevant modulators of appetite and energy expenditure through their action on cannabinoid CB(1) receptors. The actions of anandamide on feeding behavior are dependent both, on the anatomical location of CB(1) receptors (central nervous system versus peripheral tissues) and the feeding status. Anandamide uptake into cells, prior to its degradation by specific enzymatic systems, is a necessary step for the regulation of its extracellular levels. The present study explores the route and feeding stimulus dependency of the effects of the anandamide uptake blocker AM404. Peripherally, AM404 reduced feeding in partially satiated animals through a PPARα-independent mechanism, but not in food deprived ones. When AM404 was injected into the cerebral ventricles of food deprived rats, it resulted in hyperphagia that was antagonized by the cannabinoid receptor inverse agonist SR141716A. These results support the multimodal action of endocannabinoid signaling in feeding regulation, which depends on the anatomical site and the feeding status of the animal.