![]() ![]() (B) Gipr fl/fl and Gipr βCell−/− male littermates were fed HFD for 12 weeks and then IP dosed with the vehicle or mGIPR-Ab/P1 (0.5 mg/kg or 2.5 mg/kg) every 6 days for 18 days. Two-way repeated-measures ANOVA with Dunnett’s multiple comparisons for BW analysis and one-way ANOVA with Sidak’s test for multiple comparisons were done for glucose, insulin, triglycerides, and total cholesterol #p < 0.05, #p < 0.0001 vehicle versus mGIPR-Ab (2.5 mg/kg) ++++p < 0.0001 vehicle versus control-Ab/P1 ˆˆp < 0.001, ˆˆˆp < 0.001, ˆˆˆˆp < 0.0001 vehicle versus mGIPR-Ab/P1 (0.5 mg/kg) or ∗∗p < 0.01, ∗∗∗∗p < 0.0001 vehicle versus mGIPR-Ab/P1 (2.5 mg/kg) ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001, ∗∗∗∗p < 0.0001 treatment versus vehicle or between different groups as indicated in the graph with a bracket. n = 7 mice/group for lean and 7–8 mice/group for DIO, not all lean mice produced enough plasma for analysis (n = 4–6 mice/group for insulin, and n = 4–7 mice/group for triglycerides and cholesterol). MGIPR-Ab/P1 dose-dependently reduced BW and showed greater effects on BW loss than mGIPR-Ab or control-Ab/P1 administered alone in lean and DIO mice, and the effects are independent of pancreatic β cells (A) BW percentage change was measured over time and terminal plasma insulin, triglycerides, and total cholesterol were measured in lean or DIO mice dosed with vehicle, mGIPR-Ab (2.5 mg/kg), control-Ab/P1 (2 mg/kg), and mGIPR-Ab/P1 (0.5 mg/kg and 2.5 mg/kg). Overall, our GIPR-Ab/GLP-1 molecules promote BW loss, and they may be used for treating obesity.Ĭyclic adenosine monophosphate antibody cAMP diet-induced obese mice glucagon-like peptide-1 glucose-dependent insulinotropic polypeptide monkeys obesity weight loss. This may explain the efficacy of the bispecific molecules. Simultaneous receptor binding and rapid receptor internalization by GIPR-Ab/GLP-1 amplify endosomal cAMP production in recombinant cells expressing both receptors. GIPR-Ab/GLP-1 also reduces the respiratory exchange ratio in DIO mice. BW loss is greater with GIPR-Ab/GLP-1 than with GIPR-Ab or a control antibody conjugate, suggesting synergistic effects. In mice and monkeys, these molecules reduce body weight (BW) and improve many metabolic parameters. 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. It is suggested that the observed antiviral activity of both Iris RIPs relies on their RNA N-glycohydrolase activity towards TMV RNA and plant rRNA.Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) regulate glucose and energy homeostasis. The antiviral activity of both RIPs was not accompanied by an induction of pathogenesis-related proteins. Hence our results demonstrate that expression of the type-1 and type-2 RIPs from Iris confers tobacco plants local protection against two unrelated viruses. In spite of the strong local antiviral effect of IRIP and IRAb the RIPs could not provide systemic protection against TEV. To verify whether IRIP or IRAb can also confer systemic protection against viruses, transgenic RIP-expressing scions were grafted onto control rootstocks and leaves of the rootstocks challenged with tobacco etch virus (TEV). Transgenic tobacco lines expressing IRAb showed a dose-dependent enhanced resistance against TMV infection but the level of protection was markedly lower than in plants expressing IRIP, the type-1 RIP from Iris that closely resembles the A-chain of IRAb. Although constitutive expression of IRAb resulted in an aberrant phenotype, the plants were fertile. Samsun NN) plants and challenging the transgenic plants with tobacco mosaic virus (TMV). ![]() The antiviral activity of the type-2 ribosome-inactivating protein (RIP) IRAb from Iris was analyzed by expressing IRAb in tobacco (Nicotiana tabacum L.
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