Structural pharmacology and mechanisms of GLP-1R signaling.

Glucagon-like peptide-1 receptor (GLP-1R), a class B1 G protein-coupled receptor, plays critical roles in glucose homeostasis. Recent structural pharmacology studies using cryogenic electron microscopy, X-ray crystallography, mass spectrometry, and functional analyses, have provided valuable insights into its activation by endogenous hormones and mono- or dual agonists like semaglutide and tirzepatide, highly effective in treating type 2 diabetes and obesity. They highlight significant conformational changes in the extracellular and transmembrane domains of GLP-1R that drive receptor activation and downstream signal transduction.

Molecular features of the ligand-free GLP-1R, GCGR and GIPR in complex with G proteins.

Class B1 G protein-coupled receptors (GPCRs) are important regulators of many physiological functions such as glucose homeostasis, which is mainly mediated by three peptide hormones, i.e., glucagon-like peptide-1 (GLP-1), glucagon (GCG), and glucose-dependent insulinotropic polypeptide (GIP).

Molecular basis of signal transduction mediated by the human GIPR splice variants.

Glucose-dependent insulinotropic polypeptide receptor (GIPR) is a potential drug target for metabolic disorders. It works with glucagon-like peptide-1 receptor and glucagon receptor in humans to maintain glucose homeostasis. Unlike the other two receptors, GIPR has at least 13 reported splice variants (SVs), more than half of which have sequence variations at either C or N terminus.

Structural analysis of the dual agonism at GLP-1R and GCGR.

Glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR), two members of class B1 G protein-coupled receptors, play important roles in glucose homeostasis and energy metabolism. They share a high degree of sequence homology but have different functionalities. Unimolecular dual agonists of both receptors developed recently displayed better clinical efficacies than that of monotherapy.

GPCR activation and GRK2 assembly by a biased intracellular agonist.

Phosphorylation of G-protein-coupled receptors (GPCRs) by GPCR kinases (GRKs) desensitizes G-protein signalling and promotes arrestin signalling, which is also modulated by biased ligands. The molecular assembly of GRKs on GPCRs and the basis of GRK-mediated biased signalling remain largely unknown owing to the weak GPCR-GRK interactions. Here we report the complex structure of neurotensin receptor 1 (NTSR1) bound to GRK2, Gα and the arrestin-biased ligand SBI-553.

Structural insights into ligand recognition and subtype selectivity of the human melanocortin-3 and melanocortin-5 receptors.

Members of the melanocortin receptor (MCR) family that recognize different melanocortin peptides mediate a broad spectrum of cellular processes including energy homeostasis, inflammation and skin pigmentation through five MCR subtypes (MC1R-MC5R). The structural basis of subtype selectivity of the endogenous agonist γ-MSH and non-selectivity of agonist α-MSH remains elusive, as the two agonists are highly similar with a conserved HFRW motif. Here, we report three cryo-electron microscopy structures of MC3R-G in complex with γ-MSH and MC5R-G in the presence of α-MSH or a potent synthetic agonist PG-901.

Primary Ovarian Small Cell Carcinoma of Pulmonary Type: Analysis of 6 Cases and Review of 31 Cases in the Literatures.

Objective Primary ovarian small cell carcinoma of pulmonary type (SCCOPT) is a rare ovarian tumor with a poor prognosis. The platinum-based chemotherapy is the standard treatment. However, there is little research on the clinical characteristics of SCCOPT and the potential benefits of other treatments due to its low incidence.

Ligand recognition mechanism of the human relaxin family peptide receptor 4 (RXFP4).

Members of the insulin superfamily regulate pleiotropic biological processes through two types of target-specific but structurally conserved peptides, insulin/insulin-like growth factors and relaxin/insulin-like peptides. The latter bind to the human relaxin family peptide receptors (RXFPs). Here, we report three cryo-electron microscopy structures of RXFP4-G protein complexes in the presence of the endogenous ligand insulin-like peptide 5 (INSL5) or one of the two small molecule agonists, compound 4 and DC591053.

Role of iodine density value on dual-energy CT for detection of high tumor cell proportion region in lung cancer during CT-guided transthoracic biopsy.

Objective: This study aimed to identify regions with at least 20% tumor cell content in lung cancer tumors by using spectral parameters from dual-layer spectral detector computed tomography (SDCT) to design the puncture path for transthoracic lung biopsy (TTLB).

Materials And Methods: This prospective study recruited patients with suspected lung cancer. Forty-one patients were enrolled to identify the high tumor cell proportion region (HTPR) and then another 15 patients to validate the accuracy of the HTPR.

Dual Role of Wnt5a in the Progression of Inflammatory Diseases.

Wnt5a is a secreted Wnt ligand that plays a critical role in cellular pathways and inflammatory diseases. The gene encodes two protein isoforms, Wnt5a-long and Wnt5a-short, which differ based on different promoter methylation and have distinct functions. However, the mechanisms of the promoter methylation are unclear.

Targeted metabolomic profiles of serum amino acids and acylcarnitines related to gastric cancer.

Background: Early diagnosis and treatment are imperative for improving survival in gastric cancer (GC). This work aimed to assess the ability of human serum amino acid and acylcarnitine profiles in distinguishing GC cases from atrophic gastritis (AG) and control superficial gastritis (SG) patients.

Methods: Sixty-nine GC, seventy-four AG and seventy-two SG control patients treated from May 2018 to May 2019 in Gansu Provincial Hospitalwere included.

Establishment of Reference Values for Pepsinogens in Healthy Subjects of the Gansu Province: a Cross-Sectional Study.

Background: At present, the pepsinogen reference values applicable to subjects from Gansu province have not been established. Therefore, the current study aimed to establish reference values for PGI, PGII, and the PGI/ PGII ratio in Gansu Province, Northwest China.

Methods: The present study was a cross-sectional study.

A distinctive ligand recognition mechanism by the human vasoactive intestinal polypeptide receptor 2.

Class B1 of G protein-coupled receptors (GPCRs) comprises 15 members activated by physiologically important peptide hormones. Among them, vasoactive intestinal polypeptide receptor 2 (VIP2R) is expressed in the central and peripheral nervous systems and involved in a number of pathophysiological conditions, including pulmonary arterial hypertension, autoimmune and psychiatric disorders, in which it is thus a valuable drug target. Here, we report the cryo-electron microscopy structure of the human VIP2R bound to its endogenous ligand PACAP27 and the stimulatory G protein.

Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors.

Glucose homeostasis, regulated by glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon (GCG) is critical to human health. Several multi-targeting agonists at GIPR, GLP-1R or GCGR, developed to maximize metabolic benefits with reduced side-effects, are in clinical trials to treat type 2 diabetes and obesity. To elucidate the molecular mechanisms by which tirzepatide, a GIPR/GLP-1R dual agonist, and peptide 20, a GIPR/GLP-1R/GCGR triagonist, manifest their multiplexed pharmacological actions over monoagonists such as semaglutide, we determine cryo-electron microscopy structures of tirzepatide-bound GIPR and GLP-1R as well as peptide 20-bound GIPR, GLP-1R and GCGR.

Structural perspective of class B1 GPCR signaling.

Class B1 G protein-coupled receptors (GPCRs) play important roles in human physiology and disease pathology. Using cryo-electron microscopy (cryo-EM) and X-ray crystallography, the 3D structures of all 15 members of this receptor subfamily have been determined in recent years at the near-atomic level. Although they share many structural commonalities, they show distinct features in terms of ligand recognition and receptor activation.

Insights into agonist-elicited activation of the human glucose-dependent insulinotropic polypeptide receptor.

Glucose-dependent insulinotropic polypeptide (GIP) and its receptor (GIPR) are part of the incretin system that regulates glucose homeostasis. A series of GIPR residues putatively important for ligand binding and receptor activation were mutated and pharmacologically evaluated using GIPR selective agonists in cAMP accumulation, ERK1/2 phosphorylation (pERK1/2) and β-arrestin 2 recruitment assays. The impact of mutation on ligand efficacy was determined by operational modelling of experimental data for each mutant, with results mapped onto the full-length, active-state GIPR structure.

Structural insights into hormone recognition by the human glucose-dependent insulinotropic polypeptide receptor.

Glucose-dependent insulinotropic polypeptide (GIP) is a peptide hormone that exerts crucial metabolic functions by binding and activating its cognate receptor, GIPR. As an important therapeutic target, GIPR has been subjected to intensive structural studies without success. Here, we report the cryo-EM structure of the human GIPR in complex with GIP and a G heterotrimer at a global resolution of 2.

A unique hormonal recognition feature of the human glucagon-like peptide-2 receptor.

Glucagon-like peptides (GLP-1 and GLP-2) are two proglucagon-derived intestinal hormones that mediate distinct physiological functions through two related receptors (GLP-1R and GLP-2R) which are important drug targets for metabolic disorders and Crohn's disease, respectively. Despite great progress in GLP-1R structure determination, our understanding on the differences of peptide binding and signal transduction between these two receptors remains elusive. Here we report the electron microscopy structure of the human GLP-2R in complex with GLP-2 and a G heterotrimer.

Structural basis for activation of the growth hormone-releasing hormone receptor.

Growth hormone-releasing hormone (GHRH) regulates the secretion of growth hormone that virtually controls metabolism and growth of every tissue through its binding to the cognate receptor (GHRHR). Malfunction in GHRHR signaling is associated with abnormal growth, making GHRHR an attractive therapeutic target against dwarfism (e.g.

[Pilot Study on Start-up and Stable Operation at Low Temperature Based on Denitrifying Phosphorus Removal].

In order to understand the denitrifying and phosphorus removal characteristics of denitrifying phosphate-accumulating organisms (DPAOs), a pilot scale (20 m) denitrifying and phosphorus removal experiment was carried out using a modified University of Cape Town (UCT) process at low temperatures of (6-16)℃. The test results show that at such temperatures, the hydraulic retention time (HRT) is 20 h and the solids retention time (SRT) is 35 days, and the modified UCT process can start up successfully and run steadily. When running steadily, the system can maintain nitrogen and phosphorus removal rates of 60%±5% and 80%±5%, respectively.

The influence of titanium dioxide nanoparticles on their cellular response to macrophage cells.

As the most widely application of nanomaterials in biology and medicine, their interaction with biological system and the afterwards cellular responses would be addressed. Here, the agglomerate states of two kinds of TiO NPs in culture medium were characterized and the cluster specific cellular responses in RAW264.7 cells were investigated.

Developmental neurotoxicity and immunotoxicity induced by graphene oxide in zebrafish embryos.

Graphene oxide (GO) has emerged as the worldwide promising candidate for biomedical application, such as for drug delivery, bio-sensing and anti-cancer therapy. This study was focused on the zebrafish and RAW264.7 cell line as in vivo and in vitro models to assess the potential developmental neurotoxicity and immunotoxicity of GO.