Search

G protein-coupled receptors (GPCRs) are important, potential drug targets for the treatment of metabolic disorders, such as obesity. GPCRs crosstalk with several transducers, including heterotrimeric G proteins, GPCR kinases (GRKs), and β-arrestins. GPCR-biased agonism has raised the potential of novel drug development to preferentially activate therapeutic signaling pathways over pathways that lead to unwanted side effects. The obesity epidemic and its metabolic complications continue to be a major global public health threat but effective treatments are limited. The accelerated development of structural techniques, like X-ray crystallography and cryo-electron microscopy, has paved the way to understanding how biased agonism measured at GPCRs results in specific downstream physiologic responses. Herein some well-validated GPCR targets are briefly summarized and several new and promising receptors for obesity treatment are outlined. This review highlights the significance of deciphering the role of GPCRs in obesity pathology and biased signaling for drug development. We anticipate the review will facilitate the development of novel GPCR-targeted anti-obesity drugs that lead to heightened therapeutic efficacy with decreased side effect profiles.

Abstract Malaria continues to pose a serious global health threat, and artemisinin remains the core drug for global malaria control. However, the situation of malaria resistance has become increasingly severe due to the emergence and spread of artemisinin resistance. In recent years, significant progress has been made in understanding the mechanism of action (MoA) of artemisinin. Prior research on the MoA of artemisinin mainly focused on covalently bound targets that are alkylated by artemisinin‐free radicals. However, less attention has been given to the reversible noncovalent binding targets, and there is a paucity of information regarding artemisinin targets at different life cycle stages of the parasite. In this study, we identified the protein targets of artemisinin at different stages of the parasite's intraerythrocytic developmental cycle using a photoaffinity probe. Our findings demonstrate that artemisinin interacts with parasite proteins in vivo through both covalent and noncovalent modes. Extensive mechanistic studies were then conducted by integrating target validation, phenotypic studies, and untargeted metabolomics. The results suggest that protein synthesis, glycolysis, and oxidative homeostasis are critically involved in the antimalarial activities of artemisinin. In summary, this study provides fresh insights into the mechanisms underlying artemisinin's antimalarial effects and its protein targets.

The composition of serum is extremely complex, which complicates the discovery of new pharmacodynamic biomarkers via serum proteome for disease prediction and diagnosis. Recently, nanoparticles have been reported to efficiently reduce the proportion of high-abundance proteins and enrich low-abundance proteins in serum. Here, we synthesized a silica-coated iron oxide nanoparticle and developed a highly efficient and reproducible protein corona (PC)-based proteomic analysis strategy to improve the range of serum proteomic analysis. We identified 1,070 proteins with a median coefficient of variation of 12.56% using PC-based proteomic analysis, which was twice the number of proteins identified by direct digestion. There were also more biological processes enriched with these proteins. We applied this strategy to identify more pharmacodynamic biomarkers on collagen-induced arthritis (CIA) rat model treated with methotrexate (MTX). The bioinformatic results indicated that 485 differentially expressed proteins (DEPs) were found in CIA rats, of which 323 DEPs recovered to near normal levels after treatment with MTX. This strategy can not only help enhance our understanding of the mechanisms of disease and drug action through serum proteomics studies, but also provide more pharmacodynamic biomarkers for disease prediction, diagnosis, and treatment.

In the present paper, a modified Fourier series approach is developed for new precise flexural analysis of three different types of concrete plates in a rectangular sewage tank. The bending problems of the bottom plate, side-plate, and the fluid-guiding plate are not easily solved via using the traditional analytic approaches. Based on the Fourier series theory, the present approach provides a unified semi-inverse solving procedure for the above plates by means of choosing three different kinds of Fourier series as the trial functions. Although all the trial functions are quite similar to the classical Navier-form solution, new, precise analytic flexural solutions for plates without Navier-type edge conditions (all edges simply-supported) are achieved, which is mainly attributed to employing the Stoke’s transform technique. For each case, the plate-bending problems are finally altered to deal with linear algebra equations. Furthermore, owing to the orthogonality and completeness of the Fourier series, the obtained solutions perfectly satisfy both the edge conditions and the governing partial differential equation of plates, which paves an easily implemented and rational way for engineers and researchers to provide new, exact designs of plate structures. The main contribution of this study lies in the provision of a unified solution procedure for addressing complex plate-bending problems across diverse boundary conditions. By employing a range of Fourier series types, this approach offers a comprehensive solution framework that accommodates the complexities inherent in plate analysis. The correctness of the present analytic solutions is verified against precise finite element method (FEM) results and ones available in the literature. Finally, the influences of foundation, edge conditions, and aspect ratio on flexural behaviors of plates are discussed in detail.

Nanocarriers have therapeutic potential to facilitate drug delivery, including biological agents, small-molecule drugs, and nucleic acids. However, their efficiency is limited by several factors; among which, endosomal/lysosomal degradation after endocytosis is the most important. This review summarizes advanced strategies for overcoming endosomal/lysosomal barriers to efficient nanodrug delivery based on the perspective of cellular uptake and intracellular transport mechanisms. These strategies include promoting endosomal/lysosomal escape, using non-endocytic methods of delivery to directly cross the cell membrane to evade endosomes/lysosomes and making a detour pathway to evade endosomes/lysosomes. On the basis of the findings of this review, we proposed several promising strategies for overcoming endosomal/lysosomal barriers through the smarter and more efficient design of nanodrug delivery systems for future clinical applications.

Calcium phosphate nanoparticles represent promising materials for drug delivery because of its favorable properties, including biocompatibility, biodegradability and strong affinity for binding to nucleic acids (pDNA, siRNA, miRNA, etc.) and therapeutic drugs (cisplatin, carboplatin, paclitaxel, gefitinib, doxorubicin, etc.). Various strategies to prepare the size-controllable, stable, targeting and pH-responsive CaP nanocarriers have been extensively developed as the potential candidates in clinic. This review discusses the mostly recent developments in the design of calcium phosphate nanocarriers as drug delivery systems and therapeutic agents. Additionally, the advantage is unquestionably demonstrated and the obstacles are thoroughly examined in order to overcome future clinical issues.

Background: Glycyrrhizic acid (GA) has been reported to be liver protective; however, the characters and underlying mechanisms of GA against tripterygium glycoside tablet (TGT)-induced acute liver injury remain unelucidated.Hypothesis/Purpose: We assumed that GA could relieve TGT-induced acute liver injury by regulating liver function-related genes and lipid metabolites.Study Design: TGT-induced acute liver injury models were constructed in vivo and in vitro. Then the liver protective effect and mechanisms of GA were investigated by a combination of transcriptome, lipid metabolomics, and experimental validation.Methods: Intraperitoneal injection of GA was given in advance for six successive days. Then, the TGT-induced acute liver injury model was constructed by a single oral administration of TGT at 270 mg/kg, except for the normal group. All animals were sacrificed 18 h later. The serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin (TBIL), glutathione peroxidase (GSH-PX), and superoxide dismutase (SOD) were quantified. Liver tissues were used to observe pathological changes through hematoxylin–eosin (HE) staining and selected for transcriptome and metabolome sequencing. The underlying mechanisms were analyzed and further validated both in vivo and in vitro.Results: Pre-administration of GA markedly decreased the serum concentrations of AST, ALT, ALP, and TBIL but increased those of SOD and GSH-Px, improving the liver morphology of mice with TGT-induced acute liver injury. In addition, GA significantly increased the gene levels of Cyp2b13, Cyp2c69, Cyp3a16, Cyp3a44, Fmo3, and Nipal1. Differentially accumulated metabolites were screened and classified as phosphatidylcholine (PC) and phosphatidylethanolamine (PE). The in vitro results indicated that pre-administration of GA markedly alleviated the inhibitory effect of TGT on BRL-3A activity.Conclusion: This study combined transcriptome, lipid metabolomics, and experimental validation to offer convincing evidence that GA alleviates TGT-induced acute liver injury partially by regulating the activities of CYP and the metabolism of PC and PE.

A rapid and sensitive method was established for arsenic (As) speciation based on high performance liquid chromatography coupled to inductively coupled plasma mass spectrometry (HPLC-ICP-MS). This method was validated for the quantification of four arsenic species, including arsenite (AsIII), arsenate (AsV), monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV) in cynomolgus macaque plasma. Separation was achieved in just 3.7 min with an alkyl reverse phase column and highly aqueous mobile phase containing 20 mM citric acid and 5 mM sodium hexanesulfonate (pH = 4.3). The calibration curves were linear over the range of 5–500 ng·mL−1 (measured as As), with r > 0.99. The above method was validated for selectivity, precision, accuracy, matrix effect, recovery, carryover effect and stability, and applied in a comparative pharmacokinetic study of arsenic species in cynomolgus macaque samples following intravenous and intragastrical administration of arsenic trioxide solution (0.80 mg·kg−1; 0.61 mg·kg−1 of arsenic); in addition, the absolute oral bioavailability of the active ingredient AsIII of arsenic trioxide in cynomolgus macaque samples was derived as 60.9 ± 16.1%.

There are rarely new therapeutic breakthroughs present for neurodegenerative diseases in the last decades. Thus, new effective drugs are urgently needed for millions of patients with neurodegenerative diseases. Celastrol, a pentacyclic triterpenoid compound, is one of the main active ingredients isolated from Tripterygium wilfordii Hook. f. that has multiple biological activities. Recently, amount evidence indicates that celastrol exerts neuroprotective effects and holds therapeutic potential to serve as a novel agent for neurodegenerative diseases. This review focuses on the therapeutic efficacy and major regulatory mechanisms of celastrol to rescue damaged neurons, restore normal cognitive and sensory motor functions in neurodegenerative diseases. Importantly, we highlight recent progress regarding identification of the drug targets of celastrol by using advanced quantitative chemical proteomics technology. Overall, this review provides novel insights into the pharmacological activities and therapeutic potential of celastrol for incurable neurodegenerative diseases. [ABSTRACT FROM AUTHOR]