Long intergenic noncoding RNAs (lincRNAs) have a variety of properties that differ from those of messenger RNAs (mRNAs) encoding proteins. Long intergenic nonprotein coding RNA 667 (LINC00667) is a non-coding transcript located on chromosome 18p11.31. Recently, many studies have found that LINC00667 can enhance the progression of various cancers and play a key part in a lot of diseases, such as tumorigenesis. Therefore, LINC00667 can be recognized as a potential biomarker and therapeutic target. So, we reviewed the biological functions, relevant mechanisms, as well as clinical significance of LINC00667 in several human cancers in detail.

Endometrial cancer (EC) is a frequently diagnosed gynecologic cancer. Identifying reliable prognostic genes for predicting EC onset is crucial for reducing patient morbidity and mortality. Here, a comprehensive strategy with transcriptomic and proteomic data was performed to measure EC's characteristics. Based on the publicly available RNA-seq data, death-associated protein kinase 3, recombination signal-binding protein for the immunoglobulin kappa J region, and myosin light chain 9 were screened out as potential biomarkers that affect the EC patients' prognosis. A linear model was further constructed by multivariate Cox regression for the prediction of the risk of being malignant. From further integrative analysis, exosomes were found to have a highly enriched role that might participate in EC occurrence. The findings were validated by qRT-polymerase chain reaction (PCR) and western blotting. Collectively, we constructed a prognostic-gene-based model for EC prediction and found that exosomes participate in EC incidents, revealing significantly promising support for the diagnosis of EC.

Chemical labeling methods for proteins are highly researched. Herein, we introduced β-carbonyl sulfonium compounds for selective cysteine modification in proteins within biological systems. Structural tuning led to sulfonium-based probes with high reactivity and selectivity. These probes show excellent biocompatibility, cell uptake, and specificity towards cysteine profiling in live cells.

Due to their strong nucleophilicities, nucleophilic lysine and cysteine residues can be easily recognized and modified by electrophilic groups, thus, acting as the targets for covalent ligands or drugs. There-fore, the development of site-specific protein-modification chemistry for various nucleophilic residues has been explored to label proteins selectively for many biological and therapeutic applications. In this study, we constructed a series of sulfonium-based small molecules to react with the amine group of lysine residues by utilizing the strong electrophilicity of sulfonium, resulting in lysine-selective labeling via the formation of classical amide bonds under alkaline conditions (pH 9.0-11.0). After systematic optimization of the labeling conditions, this strategy was utilized for protein labeling across various bacteria's lysates. Finally, combined with the activity-based protein profiling (ABPP)strategy, we successfully identified and analyzed hundreds of labeled lysine residues in the bacterial proteome.

Herein, we report a versatile reaction platform for tracelessly cleavable cysteine-selective peptide/protein modification. This platform offers highly tunable and predictable conjugation and cleavage by rationally estimating the electron effect on the nucleophilic halopyridiniums. Cleavable peptide stapling, antibody conjugation, enzyme masking/de-masking, and proteome labeling were achieved based on this facile pyridinium-thiol-exchange protocol.

Kidney stone disease (KSD) is a common urological disease entailing the formation of minerals and salts that form inside the urinary tract, caused by diabetes, high blood pressure, hypertension, and monogenetic components in most patients.

Protein active states are dynamically regulated by various modifications; thus, endogenous protein modification is an important tool for understanding protein functions and networks in complicated biological systems. Here we developed a new pyridinium-based approach to label lysine residues under physiological conditions that is low-toxicity, efficient, and lysine-selective. Furthermore, we performed a large-scale analysis of the ∼70% lysine-selective proteome in MCF-7 cells using activity-based protein profiling (ABPP). We quantifically assessed 1216 lysine-labeled peptides in cell lysates and identified 386 modified lysine sites including 43 mitochondrial-localized proteins in live MCF-7 cells. Labeled proteins significantly preferred the mitochondria. This pyridinium-based methodology demonstrates the importance of analyzing endogenous proteins under native conditions and provides a robust chemical strategy utilizing either lysine-selective protein labeling or spatiotemporal profiling in a living system.

The enzyme FabH plays a critical role in the initial step of fatty acid biosynthesis, which is vital for the survival of bacteria. As a result, FabH has emerged as an appealing target for the development of novel antibacterial agents. In this study, employing the chemical proteomics method, we validated the previously identified skeleton amide derivatives bearing dioxygenated rings, potentially formed through metabolic processes. Building upon the proteomics findings, we then synthesized and evaluated 32 compounds containing N-heterocyclic amides for their antimicrobial activity for future optimizing the deoxygenated amides. Several compounds demonstrated potent antimicrobial properties with low toxicity, particularly compound 25, which exhibited remarkable potential as an agent with an MIC range of 1.25-3.13 mu g/mL against the tested bacterial strains and an IC50 of 2.0 mu M against E. coli-derived FabH. Furthermore, we evaluated nine analogues with relatively low MIC values through cytotoxicity and hemolytic activity assessments, Lipinski's rule-of-five criteria, and in silico ADMET predictions to ascertain their druggability potential. Notably, a detailed docking simulation was performed to investigate the binding interactions of compound 25 within the binding pocket of E. coli FabH, which encouragingly revealed strong binding interactions. Based on our findings, compound 25 emerges as the optimal candidate for in vivo therapy aimed at treating infected skin defects. Remarkably, the application of compound 25 demonstrated a significant reduction in the duration of wound infection and notably accelerated the healing process of infected wounds, achieving an impressive 94 % healing rate by day 10.

The copper-free azide-alkyne cycloaddition wasbroadly appliedin numerous research fields. Herein, we report a facile Cu-free clickreaction utilizing fluoride-responsive azide and alkynyl pyridiniumcycloaddition at ambient temperatures in aqueous media. The reactivityof alkynyl pyridinium was successfully masked by a silyl-protectinggroup at the alkyne group, and the deprotection could be readily achievedwith the addition of F-, which renders the reactivity.The substrates were readily synthesized and proven to be stable atthe bench. This bioorthogonal fluoride-responsive click reaction wasthen successfully employed in peptide modification, protein labeling,and cell imaging, suggesting its potential in various applications.

Covalent proteolysis-targeting chimeras (PROTACs) offer enhanced selectivity, prolonged action, and increased efficacy against challenging target proteins.

Tyrosine sulfation is an important post-translational modification that enhances the inhibitory activity of hirudin. Herein, we developed a facile synthetic strategy to afford the sulfated hirudins with up to three modifications and in multi-milligram scales, after a single HPLC purification step. Through these synthetic proteins, a novel type of modulation mechanism exhibited by tyrosine sulfation was proposed, which would help to delineate the structure–function relationships in other sulfated proteins and more importantly, to serve as a basis for the development of related antithrombotic agents.

Selenium-enriched polysaccharides from Pyracantha fortuneana (SePFP) has many beneficial physiological activities, but how it improves the aging associated abnormal lipid metabolism is still unclear. Therefore, we explored the mechanisms of the regulatory role of SePFP on liver lipid accumulation in aging mice. Methods: 60 naturally aged C57BL/6J male mice were divided into 6 groups: adult group, aging group (21-month-old mice), aging mice treated with low-, medium- and high-doses of SePFP (SePFP-L, SePFP-M, SePFP-H), and aging mice treated with resveratrol (RSV). SePFP and RSV were administrated daily via oral gavage from 16 to 21 months old. The parameters of energy metabolism were measured in all mice before sacrifice, and liver tissues were collected to determine the levels of metabolism-related enzymes by real-time PCR and Western blot. Results: We found that SePFP significantly reduced the body weight, liver to bodyweight ratio, and white fat to body weight ratio in aging mice. SePFP also down-regulated the triglycerides and cholesterol levels in liver and serum, and decreased respiratory quotient in aging mice. The mechanism of SePFP regulating lipid metabolism was mainly through promoting fatty acid transportation to mitochondria and enhancing mitochondrial β-oxidation and ketone body production. Conclusion: SePFP attenuates liver lipid deposition in aging mice by enhancing hepatic mitochondrial β-oxidation.

Over the past 20 years, great efforts have been invested in developing site-specific approaches to protein modification to dissect protein functions directly and accurately. Here, we report a proximity-triggered group transfer strategy from a sulfonium warhead to a Cysteine (Cys) residue of the target protein. With a guiding ligand, cargoes could be transferred selectively from a sulfonium center onto the Cys residue in the vicinity of their binding interface. The successful thalidomide transfer of sulfonium 1-X could be applied intracellularly for epidermal growth factor receptor degradation, highlighting the potential of group transfer strategy as a suite of chemical biology studies, including cell imaging, protein profiling, and protein degradation by simply employing different transferrable groups. [GRAPHICS] .

UBE2C (Ubiquitin conjugating enzyme E2 C), a key regulator of cell cycle progression, is a promising target for discovery of antitumor agents. However, it is challenging to develop inhibitors of UBE2C owing to its lack of "druggable" pockets. BioPROTACs (biological proteolysis targeting chimeras) are a kind of protein-based degraders by fusing an adaptor to a subunit of E3 ligase for ubiquitination and subsequent proteasome-dependent degradation of target protein. We report herein the design and biological evaluation of a UBE2C-targeting bioPROTAC based on the NEL (novel E3 ligase) domain of bacterial E3 ligase IpaH9.8 and the UBE2C-binding WHB (winged-helix B) domain of APC2 (anaphase promoting complex subunit 2). The in vitro ubiquitination test and Mass Spectrometry analysis showed that the bioPROTAC could transfer ubiquitin to surface exposed lysines on UBE2C and catalyzed the formation of polyubiquitin chains. In addition, the transient co-expression experiment showed that the bioPROTAC could promote proteasomal degradation of heterologous UBE2C and rescue its downstream substrates in mammalian cells.

Despite being a low-abundance amino acid, cysteine plays an essential role in regulating protein function and serves as a satisfactory target of post-translational modifications and drug developments. To comprehensively assess reactive-cysteine-containing proteins, the development of chemical proteomic probes to label cysteine residues in human cells is an important objective. Cysteine modification using sulfonium-based probes is a novel method to identify reactive cysteine residues in proteins. Herein, we reported a set of "cysteine-reactive sulfonium-based (C-Sul)" probes to label the reactive cysteine sites in cellular proteins. Notably, water-soluble C-Sul probes have a significantly enhanced stability and cellular uptakes, displaying a high specificity toward reactive cysteines and compatibility with quantitative proteomic profiling. In comparison to the conventional iodoacetamide-based probe, C-Sul particularly has no inhibitory effects on cell viability, enabling its application in proteomic profiling of reactive cysteine residues under biorelevant conditions. We propose C-Sul probes as optimal tools of cysteine profiling for further broadly basic research.

Visible-light-mediated methods were heavily studied as a useful tool for cysteine-selective bio-conjugation; however, many current methods suffer from bio-incompatible reaction conditions and slow kinetics. To address these challenges, herein, we report a transition metal-free thiol-sulfoxonium ylide photo-click reaction that enables bioconjugation under bio-compatible conditions. The reaction is highly cysteine-selective and generally finished within minutes with naturally occurring riboflavin derivatives as organic photocatalysts. The catalysts and substrates are readily accessible and bench stable and have satisfactory water solubility. As a proof-of-concept study, the reaction was smoothly applied in chemo-proteomic analysis, which provides efficient tools to explore the druggable content of the human proteome.

The ligand-directed (LD) chemistry provides powerful tools for site-specific modification of proteins. We utilized a peptide with an appended methionine (Met) as a ligand; then, the Met thioether was modified into sulfonium which enabled a proximity induced group transfer onto protein cysteine in the vicinity upon peptide-target binding. The sulfonium warhead could be easily constructed with unprotected peptides, and the transferable group scope was conducted on model protein PDZ and its ligand peptides. In addition, a living cell labeling was successfully achieved.

A biomimetic method has been established for the chemo-selective desulfurization of cysteinyl peptides and proteins in aqueous media. The derivatives of biocatalytic cofactors, flavins, were found to be efficient photosensitizers in a thiyl-radical-mediated desulfurization of Cys. The reaction was conducted in an ultrafast manner with both polypeptides and proteins.

B cells and immunoglobulins are implicated in the pathogenesis of chronic diseases, including coronary artery disease (CAD). However, it remains elusive how the humoral immunity is incriminated in the disease progression of CAD. Using serum samples of chronic coronary syndrome (CCS) and acute myocardial infarction (AMI), we conducted a quantitative profiling of the proteomic landscape recognized by immunoglobulins, which we term immunoglobulin-associated proteome (IgAP). Intriguingly, CCS and AMI patients displayed distinctive IgAP profiles that enriched proteins in the pathways of blood coagulation regulation and lipoprotein transport, suggesting that CCS-AMI transition involves changes of these pathways that are associated with immunoglobulins. Furthermore, we identified immunoglobulin-bound coagulation factor X (F10) as a potential biomarker and validated it with an independent cohort of CCS, AMI and healthy individuals. Our study indicates that IgAP proteins may serve as novel diagnostic biomarkers for CCS and AMI. Significance: Our work it demonstrates a clear implication of immunoglobulin-associated proteome IgAP), the immunoglobulins, in the pathogenesis of CAD. In addition, it reports for the first time that immunoglobulin-bound F10 is implicated in CAD.

Histidine (His, H) undergoes various post-translational modifications (PTMs) and plays multiple roles in protein interactions and enzyme catalyzed reactions. However, compared with other amino acids such as Lys or Cys, His modification is much less explored. Herein we describe a novel visible-light-driven thioacetal activation reaction which enables facile modification on histidine residues. An efficient addition to histidine imidazole N3 under biocompatible conditions was achieved with an electrophilic thionium intermediate. This method allows chemo-selective modification on peptides and proteins with good conversions and efficient histidine-proteome profiling with cell lysates. 78 histidine containing proteins were for the first time found with significant enrichment, most functioning in metal accumulation in brain related diseases. This facile His modification method greatly expands the chemo-selective toolbox for histidine-targeted protein conjugation and helps to reveal histidine's role in protein functions.