A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.

Pathogenic BAG5 variants recently linked to dilated cardiomyopathy (DCM) prompt further investigation into phenotypic, mutational, and pathomechanistic aspects. We explored the clinical and molecular characteristics of DCM associated with BAG5 variants, uncovering the consistently severe manifestations of the disease and its impact on the endoplasmic reticulum (ER) stress response. The analysis involved three siblings affected by DCM and arrhythmia, along with their four unaffected siblings, their unaffected father, and their mother who exhibited arrhythmia.

Nine patients with KCNQ2-related neonatal seizures and functional studies of two missense variants.

Mutations in KCNQ2 encoding for voltage-gated K channel subunits underlying the neuronal M-current have been associated with infantile-onset epileptic disorders. The clinical spectrum ranges from self-limited neonatal seizures to epileptic encephalopathy and delayed development. Mutations in KCNQ2 could be either gain- or loss-of-function which require different therapeutic approaches.

Severe coarctation of the aorta, developmental delay, and multiple dysmorphic features in a child with SMAD6 and SMARCA4 variants.

Pathogenic variants in SMARCA4 cause Coffin-Siris syndrome (CSS) while those in SMAD6 lead to aortic valve disease and other dysmorphisms. We identified a 6-year-old Thai boy with features of CSS alongside unusual manifestations including, very severe coarctation of the aorta (CoA) requiring coarctectomy in the neonatal period and bilateral radioulnar synostoses. Trio exome sequencing revealed that the patient harbored two de novo variants, a missense c.

MBTPS2, a membrane bound protease, underlying several distinct skin and bone disorders.

The MBTPS2 gene on the X-chromosome encodes the membrane-bound transcription factor protease, site-2 (MBTPS2) or site-2 protease (S2P) which cleaves and activates several signaling and regulatory proteins from the membrane. The MBTPS2 is critical for a myriad of cellular processes, ranging from the regulation of cholesterol homeostasis to unfolded protein responses. While its functional role has become much clearer in the recent years, how mutations in the MBTPS2 gene lead to several human disorders with different phenotypes including Ichthyosis Follicularis, Atrichia and Photophobia syndrome (IFAP) with or without BRESHECK syndrome, Keratosis Follicularis Spinulosa Decalvans (KFSD), Olmsted syndrome, and Osteogenesis Imperfecta type XIX remains obscure.

Distinct phosphorylation sites in a prototypical GPCR differently orchestrate β-arrestin interaction, trafficking, and signaling.

Agonist-induced phosphorylation of G protein-coupled receptors (GPCRs) is a key determinant for their interaction with β-arrestins (βarrs) and subsequent functional responses. Therefore, it is important to decipher the contribution and interplay of different receptor phosphorylation sites in governing βarr interaction and functional outcomes. Here, we find that several phosphorylation sites in the human vasopressin receptor (VR), positioned either individually or in clusters, differentially contribute to βarr recruitment, trafficking, and ERK1/2 activation.

Internalization-Dependent Free Fatty Acid Receptor 2 Signaling Is Essential for Propionate-Induced Anorectic Gut Hormone Release.

The ability of propionate, a short-chain fatty acid produced from the fermentation of non-digestible carbohydrates in the colon, to stimulate the release of anorectic gut hormones, such as glucagon like peptide-1 (GLP-1), is an attractive approach to enhance appetite regulation, weight management, and glycemic control. Propionate induces GLP-1 release via its G protein-coupled receptor (GPCR), free fatty acid receptor 2 (FFA2), a GPCR that activates Gαi and Gαq/11. However, how pleiotropic GPCR signaling mechanisms in the gut regulates appetite is poorly understood.

Hardwiring wire-less networks: spatially encoded GPCR signaling in endocrine systems.

The pivotal and diverse roles G protein-coupled receptors (GPCRs) play in physiology are matched by the increasingly complex signal systems they activate. Over the past decade, our models of GPCR signaling systems also include a vital role of location in controlling GPCR signaling, whereby plasma membrane, clathrin-associated structures and a diverse endomembrane network provide highly specialized signal platforms for this superfamily of receptors. The aim of this review is to highlight the recent developments in this fast-evolving field, with particular emphasis on endocrine-relevant GPCRs.

The GPR120 agonist TUG-891 promotes metabolic health by stimulating mitochondrial respiration in brown fat.

Brown adipose tissue (BAT) activation stimulates energy expenditure in human adults, which makes it an attractive target to combat obesity and related disorders. Recent studies demonstrated a role for G protein-coupled receptor 120 (GPR120) in BAT thermogenesis. Here, we investigated the therapeutic potential of GPR120 agonism and addressed GPR120-mediated signaling in BAT We found that activation of GPR120 by the selective agonist TUG-891 acutely increases fat oxidation and reduces body weight and fat mass in C57Bl/6J mice.

Adherence to NICE guidelines on diabetes prevention in the UK: Effect on patient knowledge and perceived risk.

Background: NICE Guidelines for prevention of diabetes include identifying people at risk followed by cost-effective intervention if necessary. Based on assessment of risk via a questionnaire and/or blood test the intervention may comprise a brief discussion of risk factors and preventive advice or referral to intensive lifestyle intervention.

Design And Setting: In this cross-sectional study 59 subjects recruited from local GP practices were invited by letter to attend a screening for a diabetes prevention study.

Cultivar variations in antioxidant and antihyperlipidemic properties of pomelo pulp (Citrus grandis [L.] Osbeck) in Thailand.

Pomelo (Citrus grandis L. Osbeck) is a native fruit of great economic importance in Southeast Asia. To provide experimental evidence for the antioxidant and antihyperlipidemic properties of pomelo, 6 cultivars, including Kao-Yai (KY), Thong-dee (TD), Kao-Tangkwa (KT), Kao-Numpueng (KN), Ta-Koi (TK), and Tubtim Siam (TS) were evaluated.

The protective effects of pomelo extract (Citrus grandis L. Osbeck) against fructose-mediated protein oxidation and glycation.

Chronic hyperglycemia induces non-enzymatic protein glycation, which plays an important role in the development of diabetic complications. Immense efforts have been made to determine effective antiglycation compounds from natural products. Pomelo has shown beneficial effects for human health.