Synthesis and antitumor effects of novel betulinic acid derivatives bearing electrophilic moieties.

Betulinic acid (BA) is a kind of naturally occurring lupane pentacyclic triterpenoid, possessing various biological activities including antiviral, anti-inflammatory and antitumor activity. Covalent inhibitors, characterized by electrophilic warheads that form covalent bonds with specific amino acid residues of target proteins, have garnered enormous attention in anticancer agent discovery over the past decade owing to their exceptional selectivity and efficacy. In this study, BA was structurally modified with electrophilic groups, and 23 derivatives of BA were synthesized.

DEWNA: dynamic entropy weight network analysis and its application to the DNA-binding proteome in A549 cells with cisplatin-induced damage.

Cisplatin is one of the most commonly used chemotherapy drugs for treating solid tumors. As a genotoxic agent, cisplatin binds to DNA and forms platinum-DNA adducts that cause DNA damage and activate a series of signaling pathways mediated by various DNA-binding proteins (DBPs), ultimately leading to cell death. Therefore, DBPs play crucial roles in the cellular response to cisplatin and in determining cell fate.

An Extensive Atlas of Proteome and Phosphoproteome Turnover Across Mouse Tissues and Brain Regions.

Understanding how proteins in different mammalian tissues are regulated is central to biology. Protein abundance, turnover, and post-translational modifications like phosphorylation, are key factors that determine tissue-specific proteome properties. However, these properties are challenging to study across tissues and remain poorly understood.

Discovery of Daclatasvir as a potential PD-L1 inhibitor from drug repurposing.

This study employed a drug repositioning strategy to discover novel PD-L1 small molecule inhibitors. 3D-QSAR pharmacophore models were establishedand subsequently validated through various means to select a robust model, Hypo-1, suitable for virtual screening. Hypo1 was used toscreen a library of 7,475 compounds from the Drugbank database, leading to the identification of 283 molecules following molecular docking with PD-L1.

Benzvalene-like Carboranes: Genuine Rule Breakers and Good Kinetic Stability.

Substituents are widespread in chemistry, but it has remained quite difficult to reliably determine the thermodynamic and kinetic stabilities of substituted compounds, though they are key to helping establish a structural rule and synthetic viability, respectively. As an important class of valence isomers in the benzene family, benzvalene-like structures have been extensively studied in systems associated with electron-neutral (i.e.

Distribution, sources, and contamination evaluation of heavy metals in surface sediments of the Qizhou Island sea area in Hainan, China.

Coastal areas are regions of active interaction between the sea and land and are highly sensitive to changes in heavy metal contamination caused by natural and anthropogenic activities. The contents of heavy metals in 80 surface sediments in the Qizhou Island sea area in the northeast of Hainan Island were determined to assess the contamination status, spatial distribution, sources, and ecological risks. The results indicate that the main factors influencing the distribution patterns and contents of heavy metals are hydrodynamic conditions and sources of materials.

PTMoreR-enabled cross-species PTM mapping and comparative phosphoproteomics across mammals.

To support PTM proteomic analysis and annotation in different species, we developed PTMoreR, a user-friendly tool that considers the surrounding amino acid sequences of PTM sites during BLAST, enabling a motif-centric analysis across species. By controlling sequence window similarity, PTMoreR can map phosphoproteomic results between any two species, perform site-level functional enrichment analysis, and generate kinase-substrate networks. We demonstrate that the majority of real P-sites in mice can be inferred from experimentally derived human P-sites with PTMoreR mapping.

Inhibition of xanthine oxidase alleviated pancreatic necrosis HIF-1-regulated LDHA and NLRP3 signaling pathway in acute pancreatitis.

Acute pancreatitis (AP) is a potentially fatal condition with no targeted treatment options. Although inhibiting xanthine oxidase (XO) in the treatment of AP has been studied in several experimental models and clinical trials, whether XO is a target of AP and what its the main mechanism of action is remains unclear. Here, we aimed to re-evaluate whether XO is a target aggravating AP other than merely generating reactive oxygen species that trigger AP.

Platelet-derived growth factor receptor β-targeted positron emission tomography imaging for the noninvasive monitoring of liver fibrosis.

Purpose: Noninvasive quantifying activated hepatic stellate cells (aHSCs) by molecular imaging is helpful for assessing disease progression and therapeutic responses of liver fibrosis. Our purpose is to develop platelet-derived growth factor receptor β (PDGFRβ)-targeted radioactive tracer for assessing liver fibrosis by positron emission tomography (PET) imaging of aHSCs.

Methods: Comparative transcriptomics, immunofluorescence staining and flow cytometry were used to evaluate PDGFRβ as biomarker for human aHSCs and determine the correlation of PDGFRβ with the severity of liver fibrosis.

A basic phosphoproteomic-DIA workflow integrating precise quantification of phosphosites in systems biology.

Phosphorylation is one of the most important post-translational modifications (PTMs) of proteins, governing critical protein functions. Most human proteins have been shown to undergo phosphorylation, and phosphoproteomic studies have been widely applied due to recent advancements in high-resolution mass spectrometry technology. Although the experimental workflow for phosphoproteomics has been well-established, it would be useful to optimize and summarize a detailed, feasible protocol that combines phosphoproteomics and data-independent acquisition (DIA), along with follow-up data analysis procedures due to the recent instrumental and bioinformatic advances in measuring and understanding tens of thousands of site-specific phosphorylation events in a single experiment.

Characterization of site-specific -glycosylation signatures of isolated uromodulin from human urine.

Uromodulin (Umod, Tamm-Horsfall protein) is the most abundant urinary -glycoprotein produced exclusively by the kidney. It can form filaments to antagonize the adhesion of uropathogens. However, the site-specific -glycosylation signatures of Umod in healthy individuals and patients with IgA nephropathy (IgAN) remain poorly understood due to the lack of suitable isolation and analytical methods.

Multi-dimensional metabolomic profiling reveals dysregulated ornithine metabolism hallmarks associated with a severe acute pancreatitis phenotype.

To reveal dysregulated metabolism hallmark that was associated with a severe acute pancreatitis (SAP) phenotype. In this study, LC-MS/MS-based targeted metabolomics was used to analyze plasma samples from 106 acute pancreatitis (AP) patients (34 mild, 38 moderate, and 34 severe) admitted within 48 hours from abdominal pain onset and 41 healthy controls. Temporal metabolic profiling was performed on days 1, 3, and 7 after admission.

Proteomics of adjacent-to-tumor samples uncovers clinically relevant biological events in hepatocellular carcinoma.

Normal adjacent tissues (NATs) of hepatocellular carcinoma (HCC) differ from healthy liver tissues and their heterogeneity may contain biological information associated with disease occurrence and clinical outcome that has yet to be fully evaluated at the proteomic level. This study provides a detailed description of the heterogeneity of NATs and the differences between NATs and healthy livers and revealed that molecular features of tumor subgroups in HCC were partially reflected in their respective NATs. Proteomic data classified HCC NATs into two subtypes (Subtypes 1 and 2), and Subtype 2 was associated with poor prognosis and high-risk recurrence.

An optogenetic-phosphoproteomic study reveals dynamic Akt1 signaling profiles in endothelial cells.

The serine/threonine kinase AKT is a central node in cell signaling. While aberrant AKT activation underlies the development of a variety of human diseases, how different patterns of AKT-dependent phosphorylation dictate downstream signaling and phenotypic outcomes remains largely enigmatic. Herein, we perform a systems-level analysis that integrates methodological advances in optogenetics, mass spectrometry-based phosphoproteomics, and bioinformatics to elucidate how different intensity, duration, and pattern of Akt1 stimulation lead to distinct temporal phosphorylation profiles in vascular endothelial cells.

Evaluating the sustainability of demand oriented biogas supply programs under different flexible hierarchies: A suggested approach based on the triple bottom line principle.

In this paper, a decision-making approach based on the triple bottom line concept is presented for evaluating the sustainability of demand-oriented biogas supply (DOBS) programs with regard to their environmental, economic, and social impacts. For the assessment, an indicator system was developed, whose main parameters were quantified by integrating emergy analysis, economic benefit assessment, and a proposed social risk accounting method. The Charnes-Cooper-Wei-Huang (CCWH) model with constrained cone was adopted to calculate the comprehensive sustainability via the synthesis of the economic, environmental, and social indicators, in which eight scenarios were set according to the flexibility hierarchy of biogas supplied for load demand, biogas production mode, and feeding substrates.

Synthesis and biological evaluation of oleanolic acid derivatives with electrophilic warheads as antitumor agents.

The oleanolic acid derivatives containing electrophilic warheads were synthesized, and their antitumor activities were investigated. The cytotoxicity of compounds against tumor cells were determined by the MTT method. The antitumor effects of compounds , and were evaluated through a wound-healing assay, apoptosis and cell circle analysis, and cellular reactive oxide species determination.

Association of serum PCSK9 levels with platelet function in patients with acute coronary syndromes.

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates low-density lipoprotein (LDL) homeostasis and plays a key role in acute coronary syndrome (ACS). The cardioprotective effect of PCSK9 inhibition extends beyond LDL cholesterol reduction, involving regulation of platelet function by not yet unraveled mechanisms. Oxidized-LDL (ox-LDL) is increased during ACS and induces platelet activation via binding to platelet surface.

Temporal Proteomic and Lipidomic Profiles of Cerulein-Induced Acute Pancreatitis Reveal Novel Insights for Metabolic Alterations in the Disease Pathogenesis.

The pathophysiological mechanisms of acute pancreatitis (AP) are complex and have remained a mystery to date, but metabolism is gradually recognized as an important driver of AP onset and development. We used a cerulein-induced AP mouse model to conduct liquid chromatography-mass spectrometry (LC-MS/MS)-based time-course proteomics and lipidomics in order to better understand the underlying metabolic alterations linked with AP. Results showed that a series of significant changes in proteins over time with a boost in expression were enriched in lipase activity, lipoprotein, and lipids absorption and transport regulation.

Phosphoproteomic analysis of metformin signaling in colorectal cancer cells elucidates mechanism of action and potential therapeutic opportunities.

Background: The biguanide drug metformin is a safe and widely prescribed drug for type 2 diabetes. Interestingly, hundreds of clinical trials have been set to evaluate the potential role of metformin in the prevention and treatment of cancer including colorectal cancer (CRC). However, the "metformin signaling" remains controversial.

Molecular superglue-mediated higher-order assembly of TRAIL variants with superior apoptosis induction and antitumor activity.

Prompting higher-order death receptor (DR) clustering by increasing the valency of DR agonist is efficient to induce apoptosis of tumor cells. As an attractive DR agonist with superior biosafety, the trimeric tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) exerts limited antitumor effect in patients, which is predominantly attributed to its low DR clustering ability and short serum half-life. Previous antibody scaffolds-based engineering strategies to increase the valency and/or prolong the serum half-life of TRAIL improve apoptosis induction, however, often produce large proteins with poor tumor penetration.

Proteomic Landscape of Human Spermatozoa: Optimized Extraction Method and Application.

Human spermatozoa proteomics exposed to some physical, biological or chemical stressors is being explored. However, there is a lack of optimized sample preparation methods to achieve in-depth protein coverage for sperm cells. Meanwhile, it is not clear whether antibiotics can regulate proteins to affect sperm quality.

Proteome and phosphoproteome profiling of non-small cell lung cancer cell line A549 treated with TRAIL.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is recognized for its promising therapeutic effects against cancer. However, mechanisms underlying the effect of TRAIL on protein expression, signal transduction, and apoptosis induction remain unclear. We surmised that a systematic analysis of the proteome and phosphoproteome associated with TRAIL signaling may help elucidate the mechanisms involved and facilitate the development of therapeutics.

Proteotype coevolution and quantitative diversity across 11 mammalian species.

Evolutionary profiling has been largely limited to the nucleotide level. Using consistent proteomic methods, we quantified proteomic and phosphoproteomic layers in fibroblasts from 11 common mammalian species, with transcriptomes as reference. Covariation analysis indicates that transcript and protein expression levels and variabilities across mammals remarkably follow functional role, with extracellular matrix-associated expression being the most variable, demonstrating strong transcriptome-proteome coevolution.