Search Results (569)

Lysine succinylation is a recently discovered post-translational protein modification, the process of which requires the participation of various enzymes. The close association between cancer and protein post-translational modifications (PTMs), such as acetylation and phosphorylation, has been extensively investigated and well-established. In recent years, growing attention has been directed toward the role of succinylation in cancer progression. Accumulating evidence demonstrates that protein succinylation and desuccinylation play critical roles in promoting the development of various cancers, including lung, prostate, and renal cancers. Notably, the primary substrates undergoing succinylation are non-histone proteins. Therefore, elucidating the functions of cancer-related succinylated proteins is essential for identifying novel therapeutic targets. This review comprehensively summarizes current research advances regarding protein succinylation in common cancers and discusses the progress in developing succinylation-targeting drugs. Specifically, we focus on the molecular mechanisms by which succinylation regulates cancer progression, along with the identification of key succinylation sites. Our discussion aims to provide valuable insights for future research and the development of innovative cancer treatments. Full article

Proteins serve as crucial functional components in food processing, with their unique physicochemical properties directly influencing the texture and stability of food products. Proteins exhibit a range of functional properties, including emulsification, foaming, gelation, and hydration. These properties arise from the structural differences in protein molecules. To equip proteins with enhanced and diversified biological functions, researchers have developed a variety of protein modification techniques. Recent breakthroughs in artificial intelligence technologies have opened new opportunities for research on protein chemical modifications. Novel algorithms based on advanced techniques, such as deep learning, image recognition, and natural language processing, have been developed for intelligent prediction of protein modification sites. The application of these AI technologies provides innovative research tools and methodological support for rational design and targeted engineering of protein functions. This review delves into the applications of chemical modification methods aimed at improving protein solubility, emulsifying capabilities, gelation capacity, antioxidant activity, antimicrobial properties, and nutritional value. These modifications alter the structural and functional attributes of proteins, significantly enhancing their performance within food systems and expanding their application prospects in such domains as medicine and biomaterials. Full article

Bone metastasis remains a significant cause of morbidity and diminished quality of life in patients with advanced breast, prostate, and lung cancers. Emerging research highlights the pivotal role of reversible epigenetic alterations, including DNA methylation, histone modifications, chromatin remodeling complex dysregulation, and non-coding RNA networks, in orchestrating each phase of skeletal colonization. Site-specific promoter hypermethylation of tumor suppressor genes such as HIN-1 and RASSF1A, alongside global DNA hypomethylation that activates metastasis-associated genes, contributes to cancer cell plasticity and facilitates epithelial-to-mesenchymal transition (EMT). Key histone modifiers, including KLF5, EZH2, and the demethylases KDM4/6, regulate osteoclastogenic signaling pathways and the transition between metastatic dormancy and reactivation. Simultaneously, SWI/SNF chromatin remodelers such as BRG1 and BRM reconfigure enhancer–promoter interactions that promote bone tropism. Non-coding RNAs, including miRNAs, lncRNAs, and circRNAs (e.g., miR-34a, NORAD, circIKBKB), circulate via exosomes to modulate the RANKL/OPG axis, thereby conditioning the bone microenvironment and fostering the formation of a pre-metastatic niche. These mechanistic insights have accelerated the development of epigenetic therapies. DNA methyltransferase inhibitors (e.g., decitabine, guadecitabine) have shown promise in attenuating osteoclast differentiation, while histone deacetylase inhibitors display context-dependent effects on tumor progression and bone remodeling. Inhibitors targeting EZH2, BET proteins, and KDM1A are now advancing through early-phase clinical trials, often in combination with bisphosphonates or immune checkpoint inhibitors. Moreover, novel approaches such as CRISPR/dCas9-based epigenome editing and RNA-targeted therapies offer locus-specific reprogramming potential. Together, these advances position epigenetic modulation as a promising axis in precision oncology aimed at interrupting the pathological crosstalk between tumor cells and the bone microenvironment. This review synthesizes current mechanistic understanding, evaluates the therapeutic landscape, and outlines the translational challenges ahead in leveraging epigenetic science to prevent and treat bone metastases. Full article

Multivalent lectin–glycan interactions (MLGIs) are vital for viral infection, cell-cell communication and regulation of immune responses. Their structural and biophysical data are thus important, not only for providing insights into their underlying mechanisms but also for designing potent glycoconjugate therapeutics against target MLGIs. However, such information remains to be limited for some important MLGIs, significantly restricting the research progress. We have recently demonstrated that functional nanoparticles, including ∼4 nm quantum dots and varying sized gold nanoparticles (GNPs), densely glycosylated with various natural mono- and oligo- saccharides, are powerful biophysical probes for MLGIs. Using two important viral receptors, DC-SIGN and DC-SIGNR (together denoted as DC-SIGN/R hereafter), as model multimeric lectins, we have shown that α-mannose and α-manno-α-1,2-biose (abbreviated as Man and DiMan, respectively) coated GNPs not only can provide sensitive measurement of MLGI affinities but also reveal critical structural information (e.g., binding site orientation and mode) which are important for MLGI targeting. In this study, we produced mannuronic acid (ManA) coated GNPs (GNP-ManA) of two different sizes to probe the effect of glycan modification on their MLGI affinity and antiviral property. Using our recently developed GNP fluorescence quenching assay, we find that GNP-ManA binds effectively to both DC-SIGN/R and increasing the size of GNP significantly enhances their MLGI affinity. Consistent with this, increasing the GNP size also significantly enhances their ability to block DC-SIGN/R-augmented virus entry into host cells. Particularly, ManA coated 13 nm GNP potently block Ebola virus glycoprotein-driven entry into DC-SIGN/R-expressing cells with sub-nM levels of EC₅₀. Our findings suggest that GNP-ManA probes can act as a useful tool to quantify the characteristics of MLGIs, where increasing the GNP scaffold size substantially enhances their MLGI affinity and antiviral potency. Full article

100 nm thick TiO₂/TiN bilayers with varying thickness ratios were deposited via reactive sputtering of a Ti target in controlled oxygen and nitrogen atmospheres. Post-deposition annealing in air at 600 °C was performed to induce nitrogen diffusion through the oxygen-deficient TiO₂ layer. The resulting changes in morphology and chemical environment were investigated in detail using transmission electron microscopy (TEM), scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and UV-Vis spectroscopy. Detailed TEM and XPS analyses have confirmed nitrogen diffusion across the TiO₂ layer, with surface nitrogen concentration and the ratio of interstitial to substitutional nitrogen dependent on the TiO₂/TiN mass ratio. Optical studies demonstrated modifications in optical constants and a reduction of the effective bandgap from 3.2 eV to 2.6 eV due to new energy states introduced by nitrogen doping. Changes in surface free energy induced by nitrogen incorporation showed a correlation to nitrogen doping sites on the surface, which had positive effects on overall photocatalytic activity. Photocatalytic activity, assessed through methylene blue degradation, showed enhancement attributed to nitrogen doping. Additionally, deposition of a 5 nm gold layer on the annealed sample enabled investigation of synergistic effects between nitrogen doping and gold incorporation, resulting in further improved photocatalytic performance. These findings establish the TiO₂/TiN bilayer as a versatile platform for supporting thin gold films with enhanced photocatalytic properties. Full article

CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats-associated protein 9)-mediated genome editing has emerged as a transformative tool in medicine, offering significant potential for cancer therapy because of its capacity to precisely target and alter the genetic modifications associated with the disease. However, a major challenge for its clinical translation is the safe and efficient in vivo delivery of CRISPR/Cas9 components to target cells. Nanotechnology is a promising solution to this problem. Nanocarriers, owing to their tunable physicochemical properties, can encapsulate and protect CRISPR/Cas9 components, enabling targeted delivery and enhanced cellular uptake. This review provides a comprehensive examination of the synergistic potential of CRISPR/Cas9 and nanotechnology in cancer therapy and explores their integrated therapeutic applications in gene editing and immunotherapy. A critical aspect of in vivo CRISPR/Cas9 application is to achieve effective localization at the tumor site while minimizing off-target effects. Nanocarriers can be engineered to overcome biological barriers, thereby augmenting tumor-specific delivery and facilitating intracellular uptake. Furthermore, their design allows for controlled release of the therapeutic payload, ensuring sustained efficacy and reduced systemic toxicity. The optimization of nanocarrier attributes, including size, shape, surface charge, and composition, is crucial for improving the cellular internalization, endosomal escape, and nuclear localization of CRISPR/Cas9. Moreover, surface functionalization with targeting ligands can enhance the specificity of cancer cells, leading to improved gene-editing accuracy. This review thoroughly discusses the challenges associated with in vivo CRISPR/Cas9 delivery and the innovative nanotechnological strategies employed to overcome them, highlighting their combined potential for advancing cancer treatment for clinical application. Full article

The interaction between epigenetic mechanisms and the gut microbiome is potentially crucial for the development and maintenance of intestinal health. Lysine acetylation, an important post-translational modification, plays a complex and critical role in the epigenetic regulation of the host by the gut microbiota. However, there are currently no reports on how gut microbiota dysbiosis affects host physiology in early life through global lysine acetylation. In this study, we constructed a mouse model of gut microbiota dysbiosis using antibiotic cocktail therapy (ABX). Using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the cecum, we analyzed the cecal lysine acetylome and proteome. As a result, we profiled the lysine acetylation landscape of the cecum and identified a total of 16,579 acetylation sites from 5218 proteins. Differentially acetylated proteins (DAPs) are involved in various metabolic pathways, including the citrate cycle (TCA cycle), butanoate metabolism, pyruvate metabolism, glycolysis/gluconeogenesis, and fatty acid biosynthesis. Moreover, both glycolysis and gluconeogenesis are significantly enriched in acetylation and protein modifications. This study aimed to provide valuable insights into the epigenetic molecular mechanisms associated with host protein acetylation as influenced by early-life gut microbiota disturbances. It reveals potential therapeutic targets for metabolic disorders linked to gut microbiota dysbiosis, thereby establishing a theoretical foundation for the clinical prevention and treatment of diseases arising from such dysbiosis. Full article

Study design: Trends in the utilization of Mandibulo-Maxillary Fixation (MMF) are shifting nowadays from tooth-borne devices over specialized screws to hybrid MMF devices. Hybrid MMF devices come in self-made Erich arch bar modifications and commercial hybrid MMF systems (CHMMFSs). Objective: We survey the available technical/clinical data. Hypothetically, the risk of tooth root damage by transalveolar screws is diminished by a targeting function of the screw holes/slots. Methods: We utilize a literature review and graphic displays to disclose parallels and dissimilarities in design and functionality with an in-depth look at the targeting properties. Results: Self-made hybrid arch bars have limitations to meet low-risk interradicular screw insertion sites. Technical/clinical information on CHMMFSs is unevenly distributed in favor of the SMARTLock System: positive outcome variables are increased speed of application/removal, the possibility to eliminate wiring and stick injuries and screw fixation with standoff of the embodiment along the attached gingiva. Inferred from the SMARTLock System, all four CHMMFs possess potential to effectively prevent tooth root injuries but are subject to their design features and targeting with the screw-receiving holes. The height profile and geometry shape of a CHMMFS may restrict three-dimensional spatial orientation and reach during placement. To bridge between interradicular spaces and tooth equators, where hooks or tie-up-cleats for intermaxillary cerclages should be ideally positioned under biomechanical aspects, can be problematic. The movability of their screw-receiving holes according to all six degrees of freedom differs. Conclusion: CHMMFSs allow simple immobilization of facial fractures involving dental occlusion. The performance in avoiding tooth root damage is a matter of design subtleties. Full article

Selective water withdrawals (SWWs) are frequently used to minimize the downstream effects of dams by blending water from different depths to achieve a desired temperature regime in the river. In 2010, an SWW was installed on the outlet structure of the primary hydropower reservoir on the Deschutes River (Oregon, USA) to increase spring temperatures by releasing a combination of surface water and bottom waters from a dam that formerly only had a hypolimnetic outlet. The objective of increasing spring river temperatures was to recreate pre-dam river temperatures and optimize conditions for the spawning and rearing of anadromous fish. The operation of the SWW achieved the target temperature regime, but the release of surface water from a hypereutrophic impoundment resulted in a number of unintended consequences. These changes included significant increases in river pH and dissolved oxygen saturation. Inorganic nitrogen releases decreased in spring but increased in summer. The release of surface water from the reservoir increased levels of plankton in the river resulting in changes to the macroinvertebrates such as increases in filter feeders and a greater percentage of taxa tolerant to reduced water quality. No significant increase in anadromous fish was observed. The presence of large irrigation diversions upstream of the reservoir was not accounted for in the temperature analysis that led to the construction of the SWW. This complicating factor would have reduced flow in the river leading to increased river temperatures at the hydropower site during the measurement period used to develop representations of historical temperature. The analysis supports the use of numerical models to assist in forecast changes associated with SWWs, but the results from this project illustrate the need for greater consideration of complex responses of aquatic communities caused by structural modifications to dams. Full article

Background/Objectives: Effective and targeted delivery of doxorubicin (DOX) remains a significant challenge due to its dose-limiting cardiotoxicity and systemic side effects. Liposomal formulations like Doxil^® have improved tumor targeting and reduced toxicity, but issues such as limited stability, poor release control, and insufficient site-specific delivery persist. As a result, there is a growing interest in advanced drug delivery systems, particularly polymeric nanocarriers, which offer biocompatibility, tunable properties, and ease of fabrication. Methods: This review is organized into two key sections. The first section provides a comprehensive overview of DOX, including its mechanism of action, clinical challenges, and the limitations of current chemotherapy approaches. The second section highlights recent advances in polymeric nanocarriers for DOX delivery, focusing on polymeric micelles as well as other promising systems like hydrogels, dendrimers, polymersomes, and polymer–drug conjugates. Results: Initial discussions explore current strategies enhancing DOX’s clinical translation, including methods to address cardiotoxicity and multidrug resistance. The latter part presents recent studies that report improved drug loading efficiency in polymeric nanocarriers through techniques such as core/shell modifications, enhanced hydrophobic interactions, and polymer–drug conjugation. Conclusions: Despite notable progress in polymeric nanocarrier-based DOX delivery, challenges like limited circulation time, immunogenicity, and manufacturing scalability continue to hinder clinical application. Continued innovation in this field is crucial for the development of safe, effective, and clinically translatable polymeric nanocarriers for cancer therapy. Full article

Fatty liver is a major metabolic disease in periparturient dairy goats. Protein ubiquitination, a type of dynamic and multifaceted post-translational modification, plays an important role in metabolism by regulating the stability and function of target proteins. However, the hepatic protein ubiquitination profile in dairy goats with fatty liver is yet to be elucidated. In this study, we collected liver and blood samples from healthy dairy goats (Con, n = 3) and dairy goats with fatty liver (FL, n = 3). Then, we analyzed the overall ubiquitination of hepatic proteins in dairy goats with fatty liver through quantitative ubiquitin label-free proteomics and bioinformatics. Proteins showing significantly altered levels of ubiquitination were identified via bioinformatics, and related regulatory pathways were screened. The results showed that the blood levels of beta-hydroxybutyric acid and non-esterified fatty acids were significantly upregulated in dairy goats with fatty liver, and a total of 238 ubiquitination sites across 921 proteins were found to be differentially altered in the fatty liver group. Among them, ubiquitination was upregulated at 351 sites across 93 proteins and downregulated at 570 sites across 145 proteins. In addition, GO and KEGG pathway analysis revealed that the differentially ubiquitinated proteins were enriched in pathways regulating lipid metabolism, such as the PPAR signaling pathway, fatty acid degradation, and peroxisome activity. Notably, by observing the overlap among these three sub-networks, we found that proteins with downregulated ubiquitination—such as ACSL1, ACSL5, EHHADH, and ACAA1—were transcriptionally upregulated in dairy goats with fatty liver. This study reveals the key ubiquitinated proteins in dairy goats with fatty liver and provides a more comprehensive understanding of the pathogenesis of fatty liver in dairy goats. Full article

The aim of this study is to investigate the physiological characteristics and regulatory mechanisms of porcine intramuscular fat (IMF), subcutaneous fat (take back fat (BF), for example), and visceral fat (take perienteric fat (PF), for example) to address the challenge of optimizing meat quality without excessive fat deposition. Many improved breed pigs have fast growth rates, high lean meat rates, and low subcutaneous fat deposits, but they also have low IMF content, resulting in poor meat quality. There is usually a positive correlation between intramuscular fat and subcutaneous fat deposits. This study selected eight-month-old female Tibetan pigs as experimental subjects. After slaughter, fat samples were collected. Histological differences in adipocyte morphology were observed via hematoxylin–eosin (HE) staining of tissue sections, and phenotypic characteristics of different adipose tissues were analyzed through fatty acid composition determination. Transcriptome sequencing and untargeted metabolomics were employed to perform pairwise comparisons between different fatty tissues to identify differentially expressed genes and metabolites. A siRNA interference model was constructed and combined with Oil Red O staining and lipid droplet optical density measurement to investigate the regulatory role of WNT16 in adipocyte differentiation. Comparative analysis of phenotypic and fatty acid composition differences in adipocytes from different locations revealed that IMF adipocytes have significantly smaller areas and diameters compared to other fat depots and contain higher levels of monounsaturated fatty acids. Integrated transcriptomic and metabolomic analyses identified differential expression of WNT16 and L-tyrosine, both of which are involved in the melanogenesis pathway. Functional validation showed that inhibiting WNT16 in porcine preadipocytes downregulated adipogenic regulators and reduced lipid droplet accumulation. This cross-level regulatory mechanism of “phenotype detection–multi-omics analysis–gene function research” highlighted WNT16 as a potential key regulator of site-specific fat deposition, providing new molecular targets for optimizing meat quality through nutritional regulation and genetic modification. Full article

Glycans on the surface of all immune cells are the product of diverse post-translational modifications (glycosylation) that affect almost all proteins and possess enormous structural heterogeneity. Their bioinformational content is decoded by glycan-binding proteins (lectins, GBPs), such as C-type lectins, including selectins, galectins, and Siglecs. Glycans located on the surface of immune cells are involved in many immunological processes through interactions with GBPs. Lectins recognize changes in the glycan epitopes; distinguish among host (self), microbial (non-self), and tumor (modified self) antigens; and consequently regulate immune responses. Understanding GBP–glycan interactions accelerates the development of glycan-targeted therapeutics in severe diseases, including inflammatory and autoimmune diseases and cancer. This review will discuss N- and O-glycosylations and glycosyltransferases involved in the biosynthesis of carbohydrate epitopes and address how interactions between glycan epitopes and GBPs are crucial in immune responses. The pivotal role of the glycan antigen tetrasaccharide sialyl Lewis x in mediating immune and tumor cell trafficking into the extravascular site will be discussed. Next, the role of glycans in modulating bacterial, fungal, viral, and parasitic infections and cancer will be surveyed. Finally, the role of glycosylation in antibodies and carbohydrate vaccines will be analyzed. Full article

TRPA1 (Transient Receptor Potential Ankyrin 1), a cation channel predominantly expressed in sensory neurons, plays a critical role in detecting noxious stimuli and mediating pain signal transmission. As a key player in nociceptive signaling pathways, TRPA1 has emerged as a promising therapeutic target for the development of novel analgesics. Crotalphine (CRP), a 14-amino acid peptide, has been demonstrated to specifically activate TRPA1 and elicit potent analgesic effects. Previous cryo-EM (cryo-electron microscopy) studies have elucidated the structural mechanisms of TRPA1 activation by small-molecule agonists, such as iodoacetamide (IA), through covalent modification of N-terminal cysteine residues. However, the molecular interactions between TRPA1 and peptide ligands, including crotalphine, remain unclear. Here, we present the cryo-EM structure of ligand-free human TRPA1 consistent with the literature, as well as TRPA1 complexed with crotalphine, with resolutions of 3.1 Å and 3.8 Å, respectively. Through a combination of single-particle cryo-EM studies, patch-clamp electrophysiology, and microscale thermophoresis (MST), we have identified the cysteine residue at position 621 (Cys621) within the TRPA1 ion channel as the primary binding site for crotalphine. Upon binding to the reactive pocket containing C621, crotalphine induces rotational and translational movements of the transmembrane domain. This allosteric modulation coordinately dilates both the upper and lower gates, facilitating ion permeation. Full article

Mesoporous silica nanoparticles (MSNs) are gaining popularity in nanomedicine due to their large surface area, variable pore size, great biocompatibility, and chemical adaptability. In recent years, the combination of smart polymeric materials with MSNs has transformed the area of regulated drug administration, particularly under stimuli-responsive settings. Polymer-modified MSNs provide increased stability, longer circulation times, and, most crucially, the capacity to respond to diverse internal (pH, redox potential, enzymes, and temperature) and external (light, magnetic field, and ultrasonic) stimuli. These systems allow for the site-specific, on-demand release of therapeutic molecules, increasing treatment effectiveness while decreasing off-target effects. This review presents a comprehensive analysis of recent advancements in the development and application of polymer-functionalized MSNs for stimuli-triggered drug delivery. Key polymeric modifications, including thermoresponsive, pH-sensitive, redox-responsive, and enzyme-degradable systems, are discussed in terms of their design strategies and therapeutic outcomes. The synergistic use of dual or multiple stimuli-responsive polymers is also highlighted as a promising avenue to enhance precision and control in complex biological environments. Moreover, the integration of targeting ligands and stealth polymers such as PEG further enables selective tumor targeting and immune evasion, broadening the potential clinical applications of these nanocarriers. Recent progress in stimuli-triggered MSNs for combination therapies such as chemo-photothermal and chemo-photodynamic therapy is also covered, emphasizing how polymer modifications enhance responsiveness and therapeutic synergy. Finally, the review discusses current challenges, including scalability, biosafety, and regulatory considerations, and provides perspectives on future directions to bridge the gap between laboratory research and clinical translation. Full article