Journal of pharmaceutical analysis最新文献

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Natural products (NPs) make a major contribution to drug development, offering a huge molecule pool for drug leads. Nevertheless, the pharmaceutical industry and academy have declined their enthusiasm to NPs research since the great challenges in elucidating the complex component and intricate mechanism of NPs. Here, we introduce an efficient fragment-based target research (FBTR) approach for pharmacology study and optimization of NPs. Focusing on the core fragment within the molecules of NPs, we screen the outstanding activity that be triggered, and corresponding target. Finally, drug optimization was carried out around the molecules that obtaining the activity-related core fragment and verified both in vitro and in vivo. With this approach, we obtained an optimized NPs named Erigeron breviscapus polyphenols (EBP) with definite target. After optimization, EBP plus (EBPP) not only trigger immunogenic cell death (ICD) of glioblastoma (GBM) cells effectively by targeting to Cys105 amino acid site of Fas-associating protein with a novel death domain (FADD) protein, but also prolong the survival of GBM mice by an average of 17.6 days. Significantly, our investigation presents an approach for addressing challenges in NPs development and opening up new opportunities for drug discovery. Our findings demonstrate the utility of FBTR in exploring the function of NPs, revealing the target, and advancing drug optimization for stronger clinical translation.

The nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome is downregulated in hepatocellular carcinoma (HCC), and its stability is regulated by ubiquitination. However, the regulatory mechanisms underlying NLRP3 deubiquitination and its role in HCC metastasis remains unclear. We demonstrated that ubiquitin-specific protease 50 (USP50) directly interacts with NLRP3, exhibiting deubiquitinase (DUB) activity through specific cleavage of K48-linked polyubiquitination chains to stabilize NLRP3 by preventing proteasomal degradation. Clinically, we observed that low NLRP3 and high β-catenin levels were negatively correlated in HCC specimens. Subsequent mechanistic exploration confirmed that NLRP3 exerts negative regulation on β-catenin by binding with glycogen synthase kinase 3 beta (GSK3β), reversing the downstream epithelial-mesenchymal transition (EMT) process, and inhibiting HCC metastasis. Notably, USP50 was found to activate NLRP3 inflammasome by promoting nuclear factor-kappa B (NF-κB) signaling, consequently enhancing proinflammatory cytokines. Furthermore, USP50 overexpression negatively regulated β-catenin, reversed EMT process and inhibited HCC metastasis in vivo. In conclusion, USP50 has emerged as a key player in regulating the NLRP3 inflammasome and inhibiting HCC metastasis by reversing the EMT process. As a result, it presents itself as a promising therapeutic target for HCC in the clinical setting. The intricacies of this regulatory mechanism, as revealed by our study, provide valuable insights into the understanding and potential interventions for HCC.

Dry eye (DE), a multifactorial ocular surface disease, is predominantly characterized by inflammation as a central pathological factor. Ursolic acid (UA), a pentacyclic triterpenoid with well-documented anti-inflammatory properties, was evaluated in this study for its therapeutic effects on ocular surface dysfunction associated with DE and its underlying mechanisms. A hyperosmotic stress model (500 mOsM) using human corneal epithelial cells (HCEs) and an animal model of DE was established to assess UA's protective effects on both cellular and organismal levels. Comprehensive assessments, including phenol-red cotton tests and slit-lamp examinations, were performed to evaluate ocular surface damage in the DE mouse model. Potential UA-related targets and their relevance to DE pathology were identified through database mining. Protein-protein interaction (PPI) network construction and pathway enrichment analysis using the Metascape platform highlighted core targets and signaling pathways. Molecular docking simulations using AutoDock and PyMOL further elucidated the interaction modes between UA and its targets. To validate the molecular mechanisms underlying UA's therapeutic effects, integrative analyses were conducted using single-cell sequencing data from the Single Cell Portal and RNA sequencing of tissue samples. The results demonstrated that UA eye drops significantly preserved ocular surface functional units and alleviated DE symptoms, through modulation of the epidermal growth factor receptor (EGFR)/rat sarcoma (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase (MAPK) kinase 1 (MAP2K1)/MAPK1 signaling pathway, as supported by network pharmacological analysis. Single-cell sequencing localized the distribution of key pathway proteins to the anterior ocular segment, particularly the cornea. In vivo experiments confirmed the therapeutic efficacy of UA eye drops via the EGFR/RAS/RAF/MAP2K1/MAPK1 pathway. Collectively, these findings underscore the potential of UA eye drops as a promising therapeutic approach for managing ocular surface disorders in DE.

Myocardial infarction (MI) is the leading cause of cardiovascular disease-related death worldwide. Nonetheless, existing therapeutic approaches for MI are hampered by issues such as reliance on pharmacological agents and suboptimal patient adherence. Caffeic acid (CA) is a bioactive polyphenolic compound with important anti-inflammatory, anti-bacterial and anti-oxidant functions. Still, its specific role and mechanism in treating cardiovascular disease remain to be further studied. In recent years, a large number of studies have shown that the kelch-like ECH-associated protein 1/nuclear factor erythroid 2 related factor 2 (Keap1/Nrf2) pathway is a key factor in the occurrence and development of cardiovascular diseases. In this study, H₂O₂-induced oxidative stress model of H9c2 cells and left anterior descending branch (LAD) conjunctival induced acute myocardial infarction reperfusion (AMI/R) model were used to evaluate the protective effect of CA on the heart. The interaction between CA and Keap1 was analyzed by CA-labeled fluorescence probe, target fishing, isothermal titration calorimetry (ITC), protein crystallography and surface plasmon resonance (SPR). Our results suggested that CA binds Keap1 and degrades Keap1 in a p62-dependent manner, further promoting nuclear transcription of Nrf2 and thus effectively reducing oxidative stress. In addition, based on the three-dimensional eutectic structure, it was confirmed that CA directly targets Keap1 protein by interacting with residues M550 and N532, inducing conformation changes in Keap1 protein. We also found that the CA analog chlorogenic acid (GCA) can bind Keap1. In conclusion, this study elucidates a novel molecular mechanism and structural basis for the protective effects of CA against oxidative damage via the Keap1-Nrf2 pathway.

In this comprehensive review, we delve into the evolution of drug delivery systems in reproductive medicine with a focus on the emerging role of exosomes, a class of extracellular vesicles. Exosomes offer unique advantages in overcoming these challenges due to their inherent biocompatibility, stability, and ability to facilitate targeted delivery. This review provides a detailed examination of exosome biogenesis and their function in cellular communication, setting the stage for understanding their potential as drug delivery vehicles. We explore the mechanisms through which exosomes can be loaded with small molecule drugs and the benefits they offer over synthetic nanoparticles. The review highlights groundbreaking case studies that illustrate the successful application of exosome-mediated drug delivery in reproductive health, including enhancing fertility treatments, supporting gamete and embryo development, and facilitating maternal-fetal communication. This study aims to provide a precise understanding of how exosomal drug delivery can revolutionize treatments for reproductive health disorders, paving the way for future therapeutic applications. Lastly, we touch upon the promising therapeutic implications of exosomal delivery for proteins and genes, offering a window into future treatments for reproductive health disorders.

Bipolar disorder (BD) affects 1% of the global population. BD is a group of chronic psychiatric disorders characterized by recurrent manic or hypomanic episodes that may alternate with depressive episodes. Given the current diagnostic modalities, accurately diagnosing BD, particularly distinguishing it from unipolar depression (UD), is challenging. Biomarkers have emerged as potent instruments for establishing objective diagnostic criteria for BD, and their identification, which reflects the pathophysiological processes of BD, can facilitate the precise diagnosis of the disorder. In this review, the search terms "BD" and "diagnosis" or "biomarker" were used as the key search syntax. In total, 110 studies were included. This review systematically examines the research in the field and summarizes current studies on biomarkers of BD in omics and neuroimaging. We hope that this review will benefit research aimed at establishing objective diagnostic criteria for BD and developing novel therapeutic interventions.

Iron is an essential trace element in the human body, crucial in maintaining normal physiological functions. Recent studies have identified iron ions as a significant factor in initiating the ferroptosis process, a novel mode of programmed cell death characterized by iron overload and lipid peroxide accumulation. The iron metabolism pathway is one of the primary mechanisms regulating ferroptosis, as it maintains iron homeostasis within the cell. Numerous studies have demonstrated that abnormalities in iron metabolism can trigger the Fenton reaction, exacerbating oxidative stress, and leading to cell membrane rupture, cellular dysfunction, and damage to tissue structures. Therefore, regulation of iron metabolism represents a key strategy for ameliorating ferroptosis and offers new insights for treating diseases associated with iron metabolism imbalances. This review first summarizes the mechanisms that regulate iron metabolic pathways in ferroptosis and discusses the connections between the pathogenesis of various diseases and iron metabolism. Next, we introduce natural and synthetic small molecule compounds, hormones, proteins, and new nanomaterials that can affect iron metabolism. Finally, we provide an overview of the challenges faced by iron regulators in clinical translation and a summary and outlook on iron metabolism in ferroptosis, aiming to pave the way for future exploration and optimization of iron metabolism regulation strategies.

The establishment of mouse models is critical for discovering the biological targets of tumorigenesis and cancer development, preclinical trials of targeted drugs, and formulation of personalized therapeutic regimens. Currently, the patient-derived xenograft (PDX) model is considered a reliable animal tumor model because of its ability to retain the characteristics of the primary tumor at the histopathological, molecular, and genetic levels, and to preserve the tumor microenvironment. The application of the PDX model has promoted in-depth research on tumors in recent years, focusing on drug development, tumor target discovery, and precise treatment of patients. However, there are still some common questions. This review introduces the latest research progress and common questions regarding tumors with high mortality rates, focusing on their application in targeted drug screening and the formulation of personalized medical strategies. The challenges faced, improvement methods, and future development of the PDX model in tumor treatment applications are also discussed. This article provides technical guidance and comprehensive expectations for anti-cancer drug screening and clinical personalized therapy.

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