This study investigates the effects of SR141716, a selective CB 1 receptor antagonist that reduces food intake and body weight of rodents, on Acrp30 mRNA expression in adipose tissue. Acrp30, a plasma protein exclusively expressed and secreted by adipose tissue, has been shown to induce free fatty acid oxidation, hyperglycemia and hyperinsulinemia decrease, and body weight reduction. We report that N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR141716) treatment once daily (10 mg/kg/d, i.p.) from 2 to 14 days reduced body weight and stimulated Acrp30 mRNA expression in adipose tissue of obese Zucker (fa/fa) rats. In parallel, the hyperinsulinemia associated with this animal model was reduced by SR141716 treatment. In cultured mouse adipocytes (3T3 F442A), SR141716 (25 to 100 nM) also induced an overexpression of Acrp30 mRNA and protein. In addition, in adipose tissue of CB 1 -receptor knockout mice, SR141716 had no effect on Acrp30 mRNA expression, demonstrating a CB 1 receptor mediating effect. Furthermore, RT-PCR analysis revealed that rat adipose tissue and 3T3 F442A adipocytes expressed CB 1 receptor mRNA. Relative quantification of this expression revealed an up-regulation (3-to 4-fold) of CB 1 receptor mRNA expression in adipose tissue of obese (fa/fa) rats and in differentiated 3T3 F442A adipocytes compared with lean rats and undifferentiated adipocytes, respectively. Western blot analysis revealed the presence of CB 1 receptors in 3T3 F442A adipocytes, and their expression was up-regulated in differentiated cells. These results show that SR141716 stimulated Acrp30 mRNA expression in adipose tissue by an effect on adipocytes, and reduced hyperinsulinemia in obese (fa/fa) rats. These hormonal regulations may participate in the body weight reduction induced by SR141716 and suggest a role of metabolic regulation in the antiobesity effect of SR141716.

This study investigated the effects of rimonabant (SR141716), an antagonist of the cannabinoid receptor type 1 (CB1), on obesity-associated hepatic steatosis and related features of metabolic syndrome: inflammation (elevated plasma levels of tumor necrosis factor alpha [TNFalpha]), dyslipidemia, and reduced plasma levels of adiponectin. We report that oral treatment of obese (fa/fa) rats with rimonabant (30 mg/kg) daily for 8 weeks abolished hepatic steatosis. This treatment reduced hepatomegaly, reduced elevation of plasma levels of enzyme markers of hepatic damage (alanine aminotransferase, gamma glutamyltransferase, and alkaline phosphatase) and decreased the high level of local hepatic TNFalpha currently associated with steatohepatitis. In parallel, treatment of obese (fa/fa) rats with rimonabant reduced the high plasma level of the proinflammatory cytokine TNFalpha and increased the reduced plasma level of the anti-inflammatory hormone adiponectin. Finally, rimonabant treatment also improved dyslipidemia by both decreasing plasma levels of triglycerides, free fatty acids, and total cholesterol and increasing the HDLc/LDLc ratio. All the effects of rimonabant found in this study were not or only slightly observed in pair-fed obese animals, highlighting the additional beneficial effects of treatment with rimonabant compared to diet. These results demonstrate that rimonabant plays a hepatoprotective role and suggest that this CB1 receptor antagonist potentially has clinical applications in the treatment of obesity-associated liver diseases and related features of metabolic syndrome.

Functionalisation of MSN with mannose for PDT applications dramatically improved the efficiency of PDT on breast cancer cells.

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The cation-independent mannose 6-phosphate receptor is a multifunctional protein which binds at the cell surface to two distinct classes of ligands, the mannose 6-phosphate (M6P) bearing proteins and IGF-II. Its major function is to bind and transport M6P-enzymes to lysosomes, but it can also modulate the activity of a variety of extracellular M6P-glycoproteins (i.e., latent TGFbeta precursor, urokinase-type plasminogen activator receptor, Granzyme B, growth factors, Herpes virus). The purpose of this review is to highlight the synthesis and potential use of high affinity M6P analogues able to target this receptor. Several M6P analogues with phosphonate, carboxylate or malonate groups display a higher affinity and a stronger stability in human serum than M6P itself. These derivatives could be used to favour the delivery of specific therapeutic compounds to lysosomes, notably in enzyme replacement therapies of lysosomal diseases or in neoplastic drug targeting. In addition, their potential applications in preventing clinical disorders, which are associated with the activities of other M6P-proteins involved in wound healing, cell growth or viral infection, will be discussed.

Adipocyte cell proliferation is an important process in body fat mass development in obesity. Adiponectin or Acrp30 is an adipocytokine exclusively expressed and secreted by adipose tissue that regulates lipid and glucose metabolism and plays a key role in body weight regulation and homeostasis. Adiponectin mRNA expression in adipose tissue and plasma level of adiponectin are decreased in obesity and type 2 diabetes. In obese rodents, the selective CB 1 receptor antagonist rimonabant reduces food intake and body weight and improves lipid and glucose parameters. We have reported previously that rimonabant stimulated adiponectin mRNA expression in adipose tissue of obese fa/fa rats, by a direct effect on adipocytes. We report here that rimonabant (10 -400 nM) inhibits cell proliferation of cultured mouse 3T3 F442A preadipocytes in a concentration-dependent manner. In parallel to this inhibitory effect on preadipocyte cell proliferation, rimonabant (25-100 nM) stimulates mRNA expression and protein levels of two late markers of adipocyte differentiation (adiponectin and glyceraldehyde-3-phosphate dehydrogenase) with a maximal effect at 100 nM, without inducing the accumulation of lipid droplets. Furthermore, treatment of mouse 3T3 F442A preadipocytes with rimonabant (100 nM) inhibits basal and serum-induced p42/44 mitogen-activated protein (MAP) kinase activity. These results suggest that inhibition of MAP kinase activity by rimonabant may be one of mechanisms involved in the inhibition of 3T3 F442A preadipocyte cell proliferation and stimulation of adiponectin and GAPDH expression. The inhibition of preadipocyte cell proliferation and the induction of adipocyte late "maturation" may participate in rimonabant-induced antiobesity effects, particularly the reduction of body fat mass.Obesity is a complex metabolic disorder resulting from an imbalance between energy intake and expenditure. This dysregulation may have a genetic and/or behavioral origin, involving the quality and quantity of food intake as well as lifestyle (Carpino, 2000). Obesity is characterized by an increase in body weight and adipose tissue hyperplasia and hypertrophy with excessive fat storage (Hausman et al., 2001;Spiegelman and Flier, 2001). Adipose tissue is now considered an active endocrine organ that produces and secretes various hormones and biologically active proteins called adipocytokines, including leptin, adipsin, resistin, tumor necrosis factor ␣, interleukin 6, transforming growth factor ␤, angiotensinogen, plasminogen activator inhibitor-1, and adiponectin (Trayhurn and Beattie, 2001;Fain et al., 2004;Trayhurn and Wood, 2004). Through autocrine, paracrine, and endocrine mechanisms, these adipocytokines play multiple and crucial roles in several pathophysiological processe, such as obesity, and associated chronic diseases, including diabetes, dyslipidemia, cardiovascular disorders (atherosclerosis, hypertension, myocardial infarction, coronary diseases), and inflammation (Trayhurn and Beattie, 2001;Fortuno et al., 2003;Lyon e...

the systems described so far require UV-Vis light which limits their applications. Two-Photon Excitation (TPE) in the near-infrared region is a promising alternative to UV-vis light due to the many advantages TPE provides such as three dimensional spatial resolution, lower scattering losses, and deeper penetration in tissues.[ 16 ] Very few TPE-triggered MSN-based drug delivery systems have been described in the literature, [ 17,18 ] and only two very recent examples were reported with cytotoxic drug delivery in cancer cells. The fi rst example is based on coumarin cleavage and needed very high material concentration (1 mg mL −1 ) in cells and long time of irradiation (1 h) to observe a cancer cell killing effect.[ 19 ] The second was described by us and concerned nanoimpellers reconfi gured for TPE.[ 20 ] The system was effi cient in inducing cancer cell death under TPE. In this communication, we report an alternative MSN-azobenzene-based system with a high specifi c surface area and pore volume for TPE-triggered drug delivery in cancer cells. Furthermore, two-photon fl uorescence imaging in vitro was also performed (see Scheme 1 ). First of all, a novel two-photon paracyclophane-based fl uorophore (CF) possessing a high two-photon absorption cross-section was designed and fully characterized. (see the Supporting Information). The maximum emission of the fl uorophore was 415 nm in THF, with a quantum yield of 68% suitable for FRET with azobenzene ( Figure 1 ).The silylated fl uorophore (CF) was co-condensed with tetraethoxysilane (TEOS) and cetyltrimethylammonium bromide (CTAB) in basic media to lead to the two-photon fl uorescent MSN (MCF NPs). Mono-triethoxysilylated azobenzene was then grafted on the surface of the nanoparticles (MCF-AZO NPs). Then, the cargo was loaded in the pores of the MCF-AZO NPs. The supramolecular complexation of β-cyclodextrin was performed in ice-cooled conditions, in order to cap the porous surface to lead to the nanovalve (MCF-AZO@βCD NPs). As a control MCM-41 type MSN NPs were functionalized with azobenzene (MSN-AZO NPs) and β-cyclodextrin MSN-AZO@βCD NPs using the same procedure.The characterizations of the MCF NPs after surfactant removal confi rmed the monodispersity and mesoporosity of Drug Delivery

Porous silicon nanoparticles (pSiNPs) act as a sensitizer for the 2-photon excitation of a pendant porphyrin using NIR laser light, for imaging and photodynamic therapy. Mannose-functionalized pSiNPs can be vectorized to MCF-7 human breast cancer cells through a mannose receptor-mediated endocytosis mechanism to provide a 3-fold enhancement of the 2-photon PDT effect.