Binding kinetics, bias, receptor internalization and effects on insulin secretion in vitro and in vivo of a novel GLP-1R/GIPR dual agonist, HISHS-2001.

Aims: The use of incretin analogues has emerged as an effective approach to achieve both enhanced insulin secretion and weight loss in Type 2 diabetes (T2D) patients. Agonists which bind and stimulate multiple receptors have shown particular promise. However, off-target effects remain a complication of using these agents, and modified versions with optimised pharmacological profiles and/or biased signalling are sought.

Therapeutic combination of L-ascorbic acid, N-acetylcysteine, and dimethyl fumarate in Friedreich's ataxia: insights from in vitro models.

Friedreich's Ataxia (FRDA) is a rare neurological disorder caused by an abnormal expansion of Guanine-Adenine-Adenine (GAA) repeat in intron 1 of the gene, which encodes frataxin, leading to reduced expression of frataxin, a mitochondrial protein essential for cellular homeostasis. Frataxin deficiency results in oxidative stress and mitochondrial dysfunction and impaired redox balance. Currently, there is no cure for FRDA.

Galleria mellonella as a drug discovery model to study oxidative stress.

Biological systems are equipped with endogenous antioxidant defence mechanisms against reactive oxygen species (ROS). Accumulation of ROS usually overwhelms this, creating pathologic effects. Oxidative toxicity has been reported as a causative factor in neurodegenerative diseases, cancer and diabetes mellitus (DM).

Binding Kinetics, Bias, Receptor Internalization and Effects on Insulin Secretion and of a Novel GLP-1R/GIPR Dual Agonist, HISHS-2001.

The use of incretin analogues has emerged in recent years as an effective approach to achieve both enhanced insulin secretion and weight loss in type 2 diabetes (T2D) patients. Agonists which bind and stimulate multiple receptors have shown particular promise. However, off target effects, including nausea and diarrhoea, remain a complication of using these agents, and modified versions with optimized pharmacological profiles and/or biased signaling at the cognate receptors are increasingly sought.

Engineered mini-G proteins block the internalization of cognate GPCRs and disrupt downstream intracellular signaling.

Mini-G proteins are engineered, thermostable variants of Gα subunits designed to stabilize G protein-coupled receptors (GPCRs) in their active conformations. Because of their small size and ease of use, they are popular tools for assessing GPCR behaviors in cells, both as reporters of receptor coupling to Gα subtypes and for cellular assays to quantify compartmentalized signaling at various subcellular locations. Here, we report that overexpression of mini-G proteins with their cognate GPCRs disrupted GPCR endocytic trafficking and associated intracellular signaling.

Emerging antioxidant therapies in Friedreich's ataxia.

Friedreich's ataxia (FRDA) is a rare childhood neurologic disorder, affecting 1 in 50,000 Caucasians. The disease is caused by the abnormal expansion of the GAA repeat sequence in intron 1 of the gene, leading to the reduced expression of the mitochondrial protein frataxin. The disease is characterised by progressive neurodegeneration, hypertrophic cardiomyopathy, diabetes mellitus and musculoskeletal deformities.

In vivo and in vitro characterization of GL0034, a novel long-acting glucagon-like peptide-1 receptor agonist.

Aims: To describe the in vitro characteristics and antidiabetic in vivo efficacy of the novel glucagon-like peptide-1 receptor agonist (GLP-1RA) GL0034.

Materials And Methods: Glucagon-like peptide-1 receptor (GLP-1R) kinetic binding parameters, cyclic adenosine monophosphate (cAMP) signalling, endocytosis and recycling were measured using HEK293 and INS-1832/3 cells expressing human GLP-1R. Insulin secretion was measured in vitro using INS-1832/3 cells, mouse islets and human islets.