A GIPR antagonist conjugated to GLP-1 analogues promotes weight loss with improved metabolic parameters in preclinical and phase 1 settings.

Obesity is a major public health crisis. Multi-specific peptides have emerged as promising therapeutic strategies for clinical weight loss. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are endogenous incretins that regulate weight through their receptors (R).

GIPR antagonist antibodies conjugated to GLP-1 peptide are bispecific molecules that decrease weight in obese mice and monkeys.

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) regulate glucose and energy homeostasis. Targeting both pathways with GIP receptor (GIPR) antagonist antibody (GIPR-Ab) and GLP-1 receptor (GLP-1R) agonist, by generating GIPR-Ab/GLP-1 bispecific molecules, is an approach for treating obesity and its comorbidities. In mice and monkeys, these molecules reduce body weight (BW) and improve many metabolic parameters.

Glucose-Dependent Insulinotropic Polypeptide Receptor Therapies for the Treatment of Obesity, Do Agonists = Antagonists?

Glucose-dependent insulinotropic polypeptide receptor (GIPR) is associated with obesity in human genome-wide association studies. Similarly, mouse genetic studies indicate that loss of function alleles and glucose-dependent insulinotropic polypeptide overexpression both protect from high-fat diet-induced weight gain. Together, these data provide compelling evidence to develop therapies targeting GIPR for the treatment of obesity.

Anti-obesity effects of GIPR antagonists alone and in combination with GLP-1R agonists in preclinical models.

Glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) has been identified in multiple genome-wide association studies (GWAS) as a contributor to obesity, and GIPR knockout mice are protected against diet-induced obesity (DIO). On the basis of this genetic evidence, we developed anti-GIPR antagonistic antibodies as a potential therapeutic strategy for the treatment of obesity and observed that a mouse anti-murine GIPR antibody (muGIPR-Ab) protected against body weight gain, improved multiple metabolic parameters, and was associated with reduced food intake and resting respiratory exchange ratio (RER) in DIO mice. We replicated these results in obese nonhuman primates (NHPs) using an anti-human GIPR antibody (hGIPR-Ab) and found that weight loss was more pronounced than in mice.

Au@CdSe heteroepitaxial nanorods: An example of metal nanorods fully covered by a semiconductor shell with strong photo-induced interfacial charge transfer effects.

Synthesis of metal@semiconductor heteroepitaxial nanorods fully covered by a semiconductor shell remains challenging due to the large lattice mismatch between the two components. Here, we prepared Au@CdSe heteroepitaxial nanorods by employing pre-growth of AgSe as an intermediate layer that favored the formation of a complete CdSe shell via a cation-exchange process. The optical properties of these hybrid nanostructures can be tailored by changing the shell thickness with thicker shells resulting in a redshift of the longitudinal surface plasmon resonance.

Value of surveillance computed tomography in the follow-up of diffuse large B-cell and follicular lymphomas.

Computed tomography (CT) as a routine follow-up has been a standard practice for patients with non-Hodgkin lymphoma although it is not recommended in most guidelines. We aimed to describe the value of surveillance CT in detection of disease relapse in patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma grade 3 (FL3) and to evaluate whether relapse detected by different methods influenced outcome. In this retrospective review of consecutive 341 patients with DLBCL or FL3 diagnosed between 2003 and 2009 in complete response (CR) or unconfirmed CR, 113 patients experienced relapses.

An apoA-I mimetic peptibody generates HDL-like particles and increases alpha-1 HDL subfraction in mice.

The aim of this study is to investigate the capability of an apoA-I mimetic with multiple amphipathic helices to form HDL-like particles in vitro and in vivo. To generate multivalent helices and to track the peptide mimetic, we have constructed a peptibody by fusing two tandem repeats of 4F peptide to the C terminus of a murine IgG Fc fragment. The resultant peptidbody, mFc-2X4F, dose-dependently promoted cholesterol efflux in vitro, and the efflux potency was superior to monomeric 4F peptide.

[The experiences of caregivers caring for children with cord blood transplantation].

Background: Advancing technology has greatly increased cord blood transplantation (CBT) success rates. However, transplant patient caregivers may encounter a great deal of stress related to knowledge deficits with regard to post-transplant care and lack of relevant care experience. Existing studies for CBT primarily focus on investigating the transplant process and survival rate.

[The enhancement of 1.5 microm near infrared luminescence in Er3+ and Yb3+ codoped Y2O3 nanocrystalline].

Y0.96 Er0.02 Yb0.

Strategy for the identification of GPR23/LPA4 receptor agonists and inverse agonists.

Lysophosphatidic acid (LPA) is a bioactive phospholipid that signals through G-protein-coupled receptors to produce a range of biological responses. A recently reported LPA receptor GPR23 (LPA4 receptor) has a low homology to the LPA(1-3) receptors identified previously. In Chinese hamster ovary cells expressing the human GPR23, LPA induced an increase in cellular cyclic adenosine monophosphate (cAMP) and calcium levels.

Resveratrol is not a direct activator of SIRT1 enzyme activity.

Resveratrol is a plant polyphenol capable of exerting beneficial metabolic effects which are thought to be mediated in large by the activation of the NAD(+)-dependent protein deacetylase SIRT1. Although resveratrol has been claimed to be a bona fide SIRT1 activator using a peptide substrate (Fluor de Lys-SIRT1 peptide substrate), recent reports indicate that this finding might be an experimental artifact and need to be clarified. Here, we show that: (i) the Fluor de Lys-SIRT1 peptide is an artificial SIRT1 substrate because in the absence of the covalently linked fluorophore the peptide itself is not a substrate of the enzyme, (ii) resveratrol does not activate SIRT1 in vitro in the presence of either a p53-derived peptide substrate or acetylated PGC-1alpha isolated from cells, and (iii) although SIRT1 deacetylates PGC-1alpha in both in vitro and cell-based assays, resveratrol did not activate SIRT1 under these conditions.

Acute glucose-lowering and insulin-sensitizing action of FGF21 in insulin-resistant mouse models--association with liver and adipose tissue effects.

Recombinant fibroblast growth factor (FGF)21 has antihyperglycemic, antihyperlipidemic, and antiobesity effects in diabetic rodent and monkey models. Previous studies were confined to measuring steady-state effects of FGF21 following subchronic or chronic administration. The present study focuses on the kinetics of biological actions of FGF21 following a single injection and on the associated physiological and cellular mechanisms underlying FGF21 actions.

An acyl-ghrelin-specific neutralizing antibody inhibits the acute ghrelin-mediated orexigenic effects in mice.

Ghrelin is a 28-amino acid peptide secreted mainly by the stomach. Acyl-ghrelin, which binds to and activates the growth hormone secretagogue receptor type 1a (GHS-R1a), is considered to be the active form for its orexigenic effects. It has been demonstrated that peripheral administration of ghrelin stimulates food intake and adiposity in rodents and humans.

[Preparation and luminescence of nanocrystalline ZrO2 : Pr3+ and ZrO2 : Pr3+, Sm3+].

The nanocrystalline ZrO2 : Pr3+ and ZrO2 : Pr3+, Sm3+ powders with room temperature sharp characteristic emissions were prepared by coprecipitation method. Luminescence properties of nanocrystalline ZrO2 : Pr3+ with different sintering temperatures and doping concentrations were studied. The energy transfer between the nanocrystalline ZrO2 host and the dopants was observed.

[Preparation and room temperature emission of nanocrystalline ZnO: Er3+].

The nanocrystalline ZnO:RE powders with room temperature sharp photoluminescence were prepared successfully by chemical precipitation method in the present work. This is a great progress in the study of rare earth doped ZnO. For the ZnO:Er3+ obtained in the present paper, the room temperature sharp characteristic emissions from the trivalent rare earth Er3+, including upconversion and near infrared emission, and the energy transfer between the nanocrystalline ZnO host and the dopants were observed.