Identification of Structurally Novel KRAS Inhibitors through Covalent DNA-Encoded Library Screening.

Covalent inhibition of the KRAS oncoprotein has emerged as a promising therapeutic approach for the treatment of nonsmall cell lung cancer (NSCLC). The identification of KRAS inhibitors has typically relied on the high-throughput screening (HTS) of libraries of cysteine-reactive small molecules or on the attachment of cysteine-reactive warheads to noncovalent binders of KRAS. Such screening approaches have historically been limited in the size and diversity of molecules that could be effectively screened.

The 5-Aminolevulinic Acid (5-ALA) Supplement Enhances PSII Photochemical Activity and Antioxidant Activity in the Late Growth Promotion of .

This study focused on the physiological regulation and mechanism of exogenous 5-aminolevulinic acid (5-ALA) in the late growth of . In the middle of May, different concentrations of 5-ALA (0, 10, 20, 50 mg·L) were sprayed on the leaves. The effects of 5-ALA on tuberous root growth, antioxidant enzyme system, gas exchange, photosynthetic pigment contents and photosynthetic characteristics were measured from 23 May to 13 June.

Diagnostic Value of Multimodal Magnetic Resonance Imaging in Discriminating Between Metastatic and Non-Metastatic Pelvic Lymph Nodes in Cervical Cancer.

Background: The status of pelvic lymph node (PLN) metastasis affects treatment and prognosis plans in patients with cervical cancer. However, it is hard to be diagnosed in clinical practice.

Purpose: The present study aimed to evaluate the diagnostic value of multimodal magnetic resonance imaging (MRI) in discriminating between metastatic and non-metastatic pelvic lymph nodes (PLNs) in cervical cancer.

LncRNA NEAT1/microRNA-124 regulates cell viability, inflammation and fibrosis in high-glucose-treated mesangial cells.

Long non-coding RNA (lncRNA) nuclear enriched abundant transcript 1 (NEAT1) has been frequently found to be dysregulated, which contributes to diabetes-related complications. The present study aimed to explore the effect of knockdown on mouse mesangial cell (MMC) viability, apoptosis, inflammation and fibrosis in an model of diabetic nephropathy (DN). The SV40 MES13 MMC cell line was first cultured with high glucose to establish an MMC DN cell model.

Observation on the Efficacy of Ketone Ester Drop Pill in Improving Hypertension Combined with Carotid Atherosclerotic Plaque.

Purpose: To observe and analyze the efficacy of ketone ester drop pill intervention in patients with hypertension combined with carotid atherosclerotic plaque.

Methods: The subjects were 300 patients with hypertension complicated with carotid atherosclerotic plaque treated in our hospital from January 2019 to September 2021. The grouping was done by the random number table method and 300 patients were divided equally into 2 groups.

Structural insights into ligand recognition and selectivity of somatostatin receptors.

Somatostatin receptors (SSTRs) play versatile roles in inhibiting the secretion of multiple hormones such as growth hormone and thyroid-stimulating hormone, and thus are considered as targets for treating multiple tumors. Despite great progress made in therapeutic development against this diverse receptor family, drugs that target SSTRs still show limited efficacy with preferential binding affinity and conspicuous side-effects. Here, we report five structures of SSTR2 and SSTR4 in different states, including two crystal structures of SSTR2 in complex with a selective peptide antagonist and a non-peptide agonist, respectively, a cryo-electron microscopy (cryo-EM) structure of G-bound SSTR2 in the presence of the endogenous ligand SST-14, as well as two cryo-EM structures of G-bound SSTR4 in complex with SST-14 and a small-molecule agonist J-2156, respectively.

APLNR Regulates IFN-γ signaling via β-arrestin 1 mediated JAK-STAT1 pathway in melanoma cells.

The apelin receptor (APLNR) regulates many biological processes including metabolism, angiogenesis, circulating blood volume and cardiovascular function. Additionally, APLNR is overexpressed in various types of cancer and influences cancer progression. APLNR is reported to regulate tumor recognition during immune surveillance by modulating the IFN-γ response.

Optimization of Taxol Extraction Process Using Response Surface Methodology and Investigation of Temporal and Spatial Distribution of Taxol in .

is an important source for industrial extraction of taxol in China. However, the standard and steps of extraction are currently not uniform, which seriously affects the taxol yield. In the present study, the influence of four factors (methanol concentration, solid-liquid ratio, ultrasonic extraction temperature, and ultrasonic extraction time) on the taxol yield was successively explored in .

A self-reported Frailty Index predicts long-term mortality in hospitalized patients with cirrhosis.

Background: Frailty is a syndrome that diminishes the potential for functional recovery in liver cirrhosis (LC). However, its utility is limited due to sole reliance on physical performance, especially in hospitalized patients. We investigate the predictive value of a modified self-reported Frailty Index in cirrhotics, and identify which health deficits play more important roles.

Chlorophyll a Fluorescence Transient and 2-Dimensional Electrophoresis Analyses Reveal Response Characteristics of Photosynthesis to Heat Stress in . 'Prairifire'.

Flowering crabapples are a series of precious ornamental woody plants. However, their growth and development are inhibited in the subtropical regions due to the weak photosynthesis under high-temperature environment in the summer. Chlorophyll a fluorescence transient and 2-dimensional electrophoresis (2-DE) analyses were conducted to investigate the response characteristics of photosynthesis under simulated 38 °C heat stress in leaves of .

Loss of APJ mediated β-arrestin signalling improves high-fat diet induced metabolic dysfunction but does not alter cardiac function in mice.

Apelin receptor (APJ) is a G protein-coupled receptor that contributes to many physiological processes and is emerging as a therapeutic target to treat a variety of diseases. For most disease indications the role of G protein vs β-arrestin signalling in mitigating disease pathophysiology remains poorly understood. This hinders the development of G protein biased APJ agonists, which have been proposed to have several advantages over balanced APJ signalling agonists.

Function-based high-throughput screening for antibody antagonists and agonists against G protein-coupled receptors.

Hybridoma and phage display are two powerful technologies for isolating target-specific monoclonal antibodies based on the binding. However, for complex membrane proteins, such as G protein-coupled receptors (GPCRs), binding-based screening rarely results in functional antibodies. Here we describe a function-based high-throughput screening method for quickly identifying antibody antagonists and agonists against GPCRs by combining glycosylphosphatidylinositol-anchored antibody cell display with β-arrestin recruitment-based cell sorting and screening.

Author Correction: Cryo-EM structures of PAC1 receptor reveal ligand binding mechanism.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Cryo-EM structures of PAC1 receptor reveal ligand binding mechanism.

The pituitary adenylate cyclase-activating polypeptide type I receptor (PAC1R) belongs to the secretin receptor family and is widely distributed in the central neural system and peripheral organs. Abnormal activation of the receptor mediates trigeminovascular activation and sensitization, which is highly related to migraine, making PAC1R a potential therapeutic target. Elucidation of PAC1R activation mechanism would benefit discovery of therapeutic drugs for neuronal disorders.

Structure-guided discovery of a single-domain antibody agonist against human apelin receptor.

Developing antibody agonists targeting the human apelin receptor (APJ) is a promising therapeutic approach for the treatment of chronic heart failure. Here, we report the structure-guided discovery of a single-domain antibody (sdAb) agonist JN241-9, based on the cocrystal structure of APJ with an sdAb antagonist JN241, the first cocrystal structure of a class A G protein-coupled receptor (GPCR) with a functional antibody. As revealed by the structure, JN241 binds to the extracellular side of APJ, makes critical contacts with the second extracellular loop, and inserts the CDR3 into the ligand-binding pocket.

Facile fabrication of nanosheet-assembled MnCoO hollow flower-like microspheres as highly effective catalysts for the low-temperature selective catalytic reduction of NO by NH.

A series of MnCoO flower-like hollow microspheres with various molecular proportions of reactant were prepared through simple solvothermal method for the ammonia selective catalytic reduction (SCR) at low temperatures. The as-prepared samples have been applied by various characterization techniques to explore the formation process of the morphology and physicochemical properties. The Mn(1)Co(1)O presented the optimal intrinsic catalytic performance (95% NO conversion at 75 °C), favorable thermal stability, and strong SO resistance.

Fragment-Based Computational Method for Designing GPCR Ligands.

G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors, which is arguably the most important family of drug target. With the technology breakthroughs in X-ray crystallography and cryo-electron microscopy, more than 300 GPCR-ligand complex structures have been publicly reported since 2007, covering about 60 unique GPCRs. Such abundant structural information certainly will facilitate the structure-based drug design by targeting GPCRs.

Fe-modified Ce-MnO/ACF catalysts for selective catalytic reduction of NO by NH at low-middle temperature.

A series of MnO/ACF, Ce-MnO/ACF, and Fe-Ce-MnO/ACF catalysts on selective catalytic reduction (SCR) of NO with NH at low-middle temperature had been successfully prepared through ultrasonic impregnation method, and the catalysts were characterized by SEM, XRD, BET, H-TPR, NH-TPD, XPS, and FT-IR spectroscopy, respectively. The results demonstrated that the 15 wt% Fe-Ce-MnO/ACF catalyst achieved 90% NO conversion (100~300 °C), good water resistance, and stability (175 °C). The excellent catalytic performance of the Fe-Ce-MnO/ACF catalyst was mainly attributed to the interaction among Mn, Ce, and Fe.

Network Pharmacology and Reverse Molecular Docking-Based Prediction of the Molecular Targets and Pathways for Avicularin Against Cancer.

Aim And Objective: Avicularin has been found to inhibit the proliferation of HepG-2 cells in vitro in the screening of our laboratory. We intended to explain the molecular mechanism of this effect. Therefore, the combined methods of reverse molecular docking and network pharmacology were used in order to illuminate the molecular mechanisms for Avicularin against cancer.

GPCR structure and function relationship: identification of a biased apelin receptor mutant.

Biased ligands of G protein-coupled receptors (GPCRs) may have improved therapeutic benefits and safety profiles. However, the molecular mechanism of GPCR biased signaling remains largely unknown. Using apelin receptor (APJ) as a model, we systematically investigated the potential effects of amino acid residues around the orthosteric binding site on biased signaling.

Effects of cadmium stress on the antioxidant system and chlorophyll fluorescence characteristics of two Taxodium clones.

The T.118 and T.406 seedlings showed strong adaptability under Cd concentrations ≤ 50 µM.

From RORγt Agonist to Two Types of RORγt Inverse Agonists.

Biaryl amides as new RORγt modulators were discovered. The crystal structure of biaryl amide agonist in complex with RORγt ligand binding domain (LBD) was resolved, and both "short" and "long" inverse agonists were obtained by removing from or adding to a proper structural moiety. While "short" inverse agonist () recruits a corepressor peptide and dispels a coactivator peptide, "long" inverse agonist () dispels both.

Structural Basis for Apelin Control of the Human Apelin Receptor.

Apelin receptor (APJR) is a key regulator of human cardiovascular function and is activated by two different endogenous peptide ligands, apelin and Elabela, each with different isoforms diversified by length and amino acid sequence. Here we report the 2.6-Å resolution crystal structure of human APJR in complex with a designed 17-amino-acid apelin mimetic peptide agonist.

Discovery of N-(4-aryl-5-aryloxy-thiazol-2-yl)-amides as potent RORγt inverse agonists.

A novel series of N-(4-aryl-5-aryloxy-thiazol-2-yl)-amides as RORγt inverse agonists was discovered. Binding mode analysis of a RORγt partial agonist (2c) revealed by co-crystal structure in RORγt LBD suggests that the inverse agonists do not directly interfere with the interaction between H12 and the RORγt LBD. Detailed SAR exploration led to identification of potent RORγt inverse agonists such as 3m with a pIC50 of 8.

Preparation, Physicochemical Characterization and I n - vitro Dissolution Studies of Diosmin-cyclodextrin Inclusion Complexes.

Diosmin, a vascular-protecting agent, is practically insoluble in water, and its oral absorption is limited by its extremely low dissolution rate. In this study, β-cyclodextrin (βCD) and 2-hydroxypropyl-β-cyclodextrin (HPβCD) were obtained to improve the solubility and dissolution rate of diosmin. Phase solubility studies of diosmin with βCD and HPβCD in distilled water were conducted to characterize the complexes in liquid state.