GLP-1R Signaling and Functional Molecules in Incretin Therapy.

Glucagon-like peptide-1 receptor (GLP-1R) is a critical therapeutic target for type 2 diabetes mellitus (T2DM). The GLP-1R cellular signaling mechanism relevant to insulin secretion and blood glucose regulation has been extensively studied. Numerous drugs targeting GLP-1R have entered clinical treatment. However, novel functional molecules with reduced side effects and enhanced therapeutic efficacy are still in high demand. In this review, we summarize the basis of GLP-1R cellular signaling, and how it is involved in the treatment of T2DM. We review the functional molecules of incretin therapy in various stages of clinical trials. We also outline the current strategies and emerging techniques that are furthering the development of novel therapeutic drugs for T2DM and other metabolic diseases.

Partial Fourier reconstruction of complex MR images using complex-valued convolutional neural networks.

PURPOSE: To provide a complex-valued deep learning approach for partial Fourier (PF) reconstruction of complex MR images. METHODS: Conventional PF reconstruction methods, such as projection onto convex sets (POCS), uses low-resolution image phase information from the central symmetrically sampled k-space for image reconstruction. However, this smooth phase constraint undermines the phase estimation accuracy in presence of rapid local phase variations, causing image artifacts and limiting the extent of PF reconstruction. Using both magnitude and phase characteristics in big complex image datasets, we propose a complex-valued deep learning approach with an unrolled network architecture for PF reconstruction that iteratively reconstructs PF sampled data and enforces data consistency. We evaluate our approach for reconstructing both spin-echo and gradient-echo data. RESULTS: The proposed method outperformed the iterative POCS PF reconstruction method. It produced better artifact suppression and recovery of both image magnitude and phase details in presence of local phase changes. No noise amplification was observed even for highly PF reconstruction. Moreover, the network trained on axial brain data could reconstruct sagittal and coronal brain and knee data. This method could be extended to 2D PF reconstruction and joint multi-slice PF reconstruction. CONCLUSION: Our proposed method can effectively reconstruct MR data even at low PF fractions, yielding high-fidelity magnitude and phase images. It presents a valuable alternative to conventional PF reconstruction, especially for phase-sensitive 2D or 3D MRI applications.

Two-Dimensional Detergent Expansion Strategy for Membrane Protein Studies.

Detergents are the most frequently applied reagents in membrane protein (MP) studies. The limited diversity of one-head-one-tailed traditional detergents, however, is far from sufficient for structurally distinct MPs. Expansion of detergent repertoire has a continuous momentum. In line with the speculation that detergent pre-assembly exerts superiority, herein we report for the first time cross-conjugation of two series of monomeric detergents for constructing a two-dimensional library of dimeric detergents. Optimum detergents stood out with unique preferences in the systematic evaluation of individual MPs. Furthermore, unprecedented hybrid detergents 14M8G and 14M9G enabled high-quality EM study of transporter MsbA and NMR study of G protein-coupled receptor A2A AR, respectively. Given the abundance of cross-coupling chemistries, comprehensive diversity could be readily covered that would facilitate the finding of new detergents for the manipulation of thorny MPs and innovation of the functional and structural study in future.

Spatial transcriptomics reveals heterogeneity of histological subtypes between lepidic and acinar lung adenocarcinoma.

BACKGROUND: Patients who possess various histological subtypes of early-stage lung adenocarcinoma (LUAD) have considerably diverse prognoses. The simultaneous existence of several histological subtypes reduces the clinical accuracy of the diagnosis and prognosis of early-stage LUAD due to intratumour intricacy. METHODS: We included 11 postoperative LUAD patients pathologically confirmed to be stage IA. Single-cell RNA sequencing (scRNA-seq) was carried out on matched tumour and normal tissue. Three formalin-fixed and paraffin-embedded cases were randomly selected for 10× Genomics Visium analysis, one of which was analysed by digital spatial profiler (DSP). RESULTS: Using DSP and 10× Genomics Visium analysis, signature gene profiles for lepidic and acinar histological subtypes were acquired. The percentage of histological subtypes predicted for the patients from samples of 11 LUAD fresh tissues by scRNA-seq showed a degree of concordance with the clinicopathologic findings assessed by visual examination. DSP proteomics and 10× Genomics Visium transcriptomics analyses revealed that a negative correlation (Spearman correlation analysis: r = -.886; p = .033) between the expression levels of CD8 and the expression trend of programmed cell death 1(PD-L1) on tumour endothelial cells. The percentage of CD8+ T cells in the acinar region was lower than in the lepidic region. CONCLUSIONS: These findings illustrate that assessing patient histological subtypes at the single-cell level is feasible. Additionally, tumour endothelial cells that express PD-L1 in stage IA LUAD suppress immune-responsive CD8+ T cells.

Ketogenic diet-induced bile acids protect against obesity through reduced calorie absorption.

The low-carbohydrate ketogenic diet (KD) has long been practiced for weight loss, but the underlying mechanisms remain elusive. Gut microbiota and metabolites have been suggested to mediate the metabolic changes caused by KD consumption, although the particular gut microbes or metabolites involved are unclear. Here, we show that KD consumption enhances serum levels of taurodeoxycholic acid (TDCA) and tauroursodeoxycholic acid (TUDCA) in mice to decrease body weight and fasting glucose levels. Mechanistically, KD feeding decreases the abundance of a bile salt hydrolase (BSH)-coding gut bacterium, Lactobacillus murinus ASF361. The reduction of L. murinus ASF361 or inhibition of BSH activity increases the circulating levels of TDCA and TUDCA, thereby reducing energy absorption by inhibiting intestinal carbonic anhydrase 1 expression, which leads to weight loss. TDCA and TUDCA treatments have been found to protect against obesity and its complications in multiple mouse models. Additionally, the associations among the abovementioned bile acids, microbial BSH and metabolic traits were consistently observed both in an observational study of healthy human participants (n = 416) and in a low-carbohydrate KD interventional study of participants who were either overweight or with obesity (n = 25). In summary, we uncover a unique host-gut microbiota metabolic interaction mechanism for KD consumption to decrease body weight and fasting glucose levels. Our findings support TDCA and TUDCA as two promising drug candidates for obesity and its complications in addition to a KD.

Ginger supplement significantly reduced length of hospital stay in individuals with COVID-19.

BACKGROUND: Evidence from previous studies has suggested that ginger extract exhibits the potential as an alternative treatment for Coronavirus disease 2019 (COVID-19). Here, we want to investigate whether ginger supplement improves the clinical manifestation of hospitalized COVID-19 individuals. METHODS: A total of 227 hospitalized individuals with COVID-19 were randomized to either the control (n = 132) or intervention group (n = 95). The intervention group took ginger supplement orally at the dosage of 1.5 g twice daily, until they were discharged from the hospital. Both groups received the same standard of general medical care during hospitalization, and the length of stay was recorded and compared between groups. RESULTS: Among all participants, a significant reduction in hospitalization time (the difference between the treatment and control groups was 2.4 d, 95% CI 1.6-3.2) was detected in response to the ginger supplement. This effect was more pronounced in men, participants aged 60 years or older, and participants with pre-existing medical conditions, relative to their counterparts (P-interactions < 0.05 for all). CONCLUSION: Ginger supplement significantly shortened the length of stay of hospitalized individuals with COVID-19. TRIAL REGISTRATION: The trial was registered on the Chinese Clinical Trial Registry (ChiCTR2200059824).

G protein-coupled receptors: structure- and function-based drug discovery.

As one of the most successful therapeutic target families, G protein-coupled receptors (GPCRs) have experienced a transformation from random ligand screening to knowledge-driven drug design. We are eye-witnessing tremendous progresses made recently in the understanding of their structure-function relationships that facilitated drug development at an unprecedented pace. This article intends to provide a comprehensive overview of this important field to a broader readership that shares some common interests in drug discovery.

Rational Remodeling of Atypical Scaffolds for the Design of Photoswitchable Cannabinoid Receptor Tools.

Azobenzene-embedded photoswitchable ligands are the widely used chemical tools in photopharmacological studies. Current approaches to azobenzene introduction rely mainly on the isosteric replacement of typical azologable groups. However, atypical scaffolds may offer more opportunities for photoswitch remodeling, which are chemically in an overwhelming majority. Herein, we investigate the rational remodeling of atypical scaffolds for azobenzene introduction, as exemplified in the development of photoswitchable ligands for the cannabinoid receptor 2 (CB2). Based on the analysis of residue-type clusters surrounding the binding pocket, we conclude that among the three representative atypical arms of the CB2 antagonist, AM10257, the adamantyl arm is the most appropriate for azobenzene remodeling. The optimizing spacer length and attachment position revealed AzoLig 9 with excellent thermal bistability, decent photopharmacological switchability between its two configurations, and high subtype selectivity. This structure-guided approach gave new impetus in the extension of new chemical spaces for tool customization for increasingly diversified photo-pharmacological studies and beyond.