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Background and Purpose: Glucagon-like peptide-2 (GLP-2) is secreted postprandially from enteroendocrine Lcells and has anabolic action on gut and bone. Short-acting teduglutide is the only approved GLP-2 analog for the treatment of short-bowel syndrome (SBS). To improve the therapeutic effect, we created a series of lipidated GLP-2R agonists. Experimental Approach: Six GLP-2 analogs were studied in vitro for cAMP accumulation, β-arrestin 1 and 2 recruitment, affinity, and internalization. The trophic actions on intestine and bone were examined in vivo in rodents. Key Results: Lipidations at lysines introduced at position 12, 16, and 20 of hGLP-2(1−33) were well-tolerated with less than 2.2-fold impaired potency and full efficacy at the hGLP-2R in cAMP accumulation. In contrast, N- and C-terminal (His1 and Lys30) lipidations impaired potency by 4.2- and 45-fold and lowered efficacy to 77% and 85% of hGLP-2, respectively. All variants were similarly active on the rat and mouse GLP-2Rs and the three most active variants displayed increased selectivity for hGLP-2R over hGLP-1R activation, compared to native hGLP-2. Impact on arrestin recruitment and receptor internalization followed that of Gαs-coupling, except for lipidation in position 20, where internalization was more impaired, suggesting desensitization protection. A highly active variant (C16 at position 20) with low internalization and a half-life of 9.5 h in rats showed improved gut and bone tropism with increased weight of small intestine in mice and decreased CTX levels in rats. Conclusion and implication: We present novel hGLP-2 agonists suitable for in vivo studies of the GLP-2 system to uncover its pharmacological potential.

Objectives: To investigate the effect of glucagon-like peptide-1 (GLP-1) receptor and glucose dependent insulinotrophic polypeptide (GIP) receptor dual agonist DA-JC4 on alleviating Parkinson's disease (PD) and unveil related cellular mechanisms., Methods: Rotenone was injected to generate a rat PD model, on which the effect of DA-JC4 on motor functions was evaluated by rotational behavioral assay and open field test. The survival of dopaminergic neurons was analyzed, in addition to assays for mitochondrial stress and quantification of neurotransmitter levels using high performance liquid chromatography (HPLC). In cultured hippocampal neurons, the effect of DA-JC4 on mitochondrial stress and related cellular mechanism was analyzed by Flow cytometry, western blotting and reactive oxygen species (ROS)., Results: DA-JC4 significantly improved motor functions in PD rats, and elevated levels of major neurotransmitters. By histological analysis, DA-JC4 protected dopaminergic neurons from rotenone-induced cell death, which was associated with reduced mitochondrial stress. Experiments in cultured rat hippocampal neurons validated the neuroprotective role of DA-JC4 against cell apoptosis and mitochondrial stress induced by rotenone. The protective effect of DA-JC4 was later found to be dependent on AKT/JNK signal pathway, as treatment using AKT inhibitor or JNK activator abolished such effects., Conclusion: Our results showed that the dual agonist of GLP-1/GIP receptor could ameliorate motor dysfunctions of PD by protecting dopaminergic neurons which was mediated by relieved mitochondrial stress and apoptosis via AKT/JNK signal pathway., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Retinoic Acid Receptor-Related Orphan Receptor γt (RORγt) is a dual-functional therapeutic target. The agonists and inhibitors of RORγt are potential agents for tumor immunotherapy and autoimmune diseases, respectively, and sometimes share similar scaffolds. Although the widely distributed triterpenoid ursolic acid (UA) has been identified as a RORγt inhibitor, the report of a triterpenoid RORγt agonist is still absent. By screening an in-house triterpenoid library, we uncovered a novel RORγt agonist, betulinaldehyde (1), together with an inhibitor (2, 3β, 28-Dihydroxy-lupan-29-oic acid). Compound 1 showed a good RORγt activating effect with the EC 50 of 11.4 μM in Alpha Screen assay, and altered the thermal stability of RORγt by directly binding to the protein in vitro. Combined with the SPR assay, the Kd value of compound 1 was examined as 2.99 μM. The modulation mechanism of triterpenoid agonists and inhibitors were discussed by molecular docking. Herein, we firstly discovered compound 1 as a triterpenoid agonist of RORγt. The co-distribution of triterpenoid RORγt agonist and inhibitors in the same plant, might be related to the anti-inflammatory and anti-cancerous bioactivity of the plant extract., (Copyright © 2019. Published by Elsevier B.V.)