Search Results (3,556)

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID-19 syndrome (LC) show substantial clinical overlap, but direct comparative microbiome studies remain limited. Methods: In this cross-sectional study, we compared the fecal gut microbiome of patients with ME/CFS, LC, and healthy controls (HC) within a unified analytical framework using 16S rRNA profiling, differential abundance testing, and multivariate modeling. We also examined associations between microbiome variation and questionnaire-derived symptom-domain scores. Results: Alpha-diversity did not differ significantly among groups, whereas beta-diversity analyses showed small but significant disease-associated community differences with broad overlap between cohorts. Differential abundance analysis identified stronger signals in disease-versus-control contrasts than in the direct ME/CFS vs. LC contrast. Both ME/CFS and LC shared enrichment of Sutterella and depletion of Terrisporobacter and Lachnospiraceae relative to HC. Predicted functional profiling showed shared disease-versus-control changes in pathways related to anaerobic acetate/H₂ carbon flow, inositol/polyol degradation, phosphonate/C1-related metabolism, and lysine-derived fermentation. Regression analyses showed the strongest microbiome associations with fatigue-related and physiosomatic domains, while affective, cognitive, and gastrointestinal outcomes showed weaker signals. Conclusions: Overall, these findings support the presence of overlapping but non-identical gut microbiome alterations in ME/CFS and LC. The results provide a basis for future longitudinal and multi-omics studies aimed at clarifying the stability, functional relevance, and clinical utility of these microbial patterns. Full article

A total of 192 weaned piglets (Topigs TN70), 26 days of age, with an initial body weight of 7.2 ± 0.5 kg, were used to determine the standardized ileal digestible (SID) histidine (His) to lysine (Lys) ratio required to maximize growth performance. Six dietary treatments with graded SID His to Lys ratios ranging from 0.2 to 0.38 were generated with the supplementation of L-His to a grain-based basal diet deficient in His. At the end of the trial (day 41 post weaning), 72 male piglets were euthanized for the analysis of histidine-containing dipeptides, particularly carnosine, in the M. longissimus dorsi. In addition, blood samples were collected from 72 piglets to determine plasma urea-nitrogen and hematological parameters. Piglets fed low dietary His (SID His to Lys < 0.27) exhibited hemoglobin concentrations below the reference value, indicating anemia. Muscle carnosine content increased linearly with increasing dietary His and did not reach a plateau within the tested range. Based on growth performance responses, the SID His to Lys ratio required to achieve maximum growth performance in fast-growing piglets is 0.34. These findings emphasize the importance of supervising the SID His to Lys ratio, particularly in practical piglet feed formulations. Full article

Prostate-specific membrane antigen (PSMA) ligands are currently one of the popular platforms for creating drugs targeted at prostate cancer tumor cells. In this review, we have collected and systematized current approaches to the synthesis of PSMA ligands based on N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-(S)-L-lysine (DCL), the most widely used scaffold in the design of such ligands. The main approaches to each stage of the synthesis of PSMA inhibitors with various structures are considered in detail, and the existing synthetic techniques are compiled and analyzed. We also review examples of using different synthetic pathways for diagnostic and therapeutic drugs based on PSMA ligands. We propose an algorithm for selecting a synthetic route based on the structure of the target ligand. Full article

Background/Objective: With rising per capita sugar consumption, skin glycation-related issues including dullness, homeostasis disruption and accelerated wrinkling have gained widespread attention. However, globally standardized and rigorous evaluation criteria for anti-glycation efficacy remain lacking. This study aimed to establish stage-specific glycation injury cell models and elucidate the stage-dependent molecular mechanisms of glycation-induced fibroblast damage, providing a standardized reference for anti-glycation efficacy assessment. Methods: Three glycation injury models were constructed in human foreskin fibroblasts (HFF-1): early-stage (glucose-induced), intermediate-stage (glyoxal-induced), and late-stage (advanced glycation end products (AGEs)-induced). Core biomarkers including Nε-(carboxymethyl)lysine (CML), collagen type I (Col I) and elastin (ELN) were used to optimize modeling conditions via Cell Counting Kit-8 (CCK-8) and enzyme-linked immunosorbent assay (ELISA). Untargeted metabolomics based on ultra-high-performance liquid chromatography (UHPLC)-Q Exactive Orbitrap was applied to identify differential metabolites and perturbed pathways, following Metabolomics Standards Initiative (MSI) Level 2 identification criteria. Results: Optimal conditions were determined as 50 mmol/L glucose for 48 h, 0.5 mmol/L glyoxal for 48 h, and 200 μg/mL AGEs for 24 h. A total of 319, 34 and 148 differential metabolites were identified in the three groups, respectively. Six key pathways were significantly perturbed. Early and intermediate models shared similar mechanisms (purine metabolism disturbance), while the late model showed distinct alterations in pyrimidine, nicotinate, arachidonic acid and steroid hormone metabolism. Conclusions: Three stable stage-specific glycation models were successfully established in HFF-1 cells. Significant differences in metabolic profiles and mechanisms exist across the three stages, providing a rational basis for model selection and theoretical support for anti-glycation efficacy evaluation. Full article

Sialic acids are a diverse class of widely distributed monosaccharides that are engaged in a wide range of biological processes. Sialin, a sialic acid/proton symporter, transports sialic acid across membranes between the lysosomal lumen and cytosol, playing a critical role in sialin metabolism. Taking advantage of recently published experimental structures of sialin, we report here the first computational study that probes the molecular mechanism of ligand transport through sialin, which is yet to be fully understood. In particular, we carry out steered molecular dynamics simulations of the transport of N-acetylneuraminic acid, the most widely spread natural derivative of sialic acids, through sialin with two key glutamate residues (E171 and E175) in various protonation states. The previously proposed model is refined with enriched atomistic details from this study for the cotransport of sialic acid and proton. With additional quantum calculations, our data suggest a possible explanation for why mutation R168A retains most of the transport activities, but R168K does not. Full article

High lactate concentration is a hallmark of the tumor microenvironment (TME). Regulatory T cells (Tregs) exhibit unique metabolic adaptability to this lactate-rich environment, yet the underlying mechanisms remain incompletely understood. Here, we demonstrate that the monocarboxylate transporter MCT4 is upregulated in tumor-infiltrating Tregs and mediates direct lactate uptake. Using Treg-specific conditional knockout (cKO) mice, we show that MCT4 deficiency does not affect basal Treg development but abrogates lactate-induced Foxp3 stabilization and impairs Treg suppressive function. Mechanistically, MCT4-mediated lactate uptake promotes the lactylation of Foxp3 at lysine 277 (K277), which competitively inhibits its ubiquitination, thereby enhancing Foxp3 protein stability and nuclear localization. Nuclear Foxp3 subsequently interacts with IRF3 to promote IL-10 transcription and secretion. In the B16 melanoma model, MCT4-deficient Tregs display compromised stability and reduced tumor infiltration, leading to enhanced CD8⁺ T cell effector function and attenuated tumor growth. Collectively, our findings reveal that MCT4-mediated lactate uptake sustains Treg stability and function through Foxp3 lactylation, identifying MCT4 as a potential therapeutic target for modulating Treg activity in cancer. Full article

The objective of this study was to evaluate the effects of dietary Allium mongolicum Regel essential oil (AMO) supplementation on growth performance, carcass traits, meat quality, and muscle amino acid profile in finishing lambs. A total of twenty male Dorper × Han crossbred lambs (body weight = 32.5 ± 2.5 kg, 4–4.5 months old) were randomly allocated into two dietary treatments (n = 10 per group): a control group fed a basal diet (roughage to concentrate ratio of 45:55) or an AMO group supplemented with 56 mg/d of AMO per lamb. The trial consisted of a 15-day adaptation period followed by a 60-day experimental period. At the end of the trial, six lambs were randomly selected from each group for slaughter. Samples of the longissimus thoracis (LT) muscle were collected to determine meat quality traits, proximate composition, and amino acid profiles. Supplementation increased average daily gain by 6.6% and improved feed conversion ratio by 4.6% (p < 0.05), whereas feed intake and final body weight were not affected (p > 0.05). In LT, GR tissue depth and loin muscle area were increased (p < 0.05). Drip loss was reduced (p < 0.05), whereas proximate composition, cooking loss, and shear force remained unchanged (p > 0.05). The hydrolyzed amino acid composition and protein nutritional value of LT were not affected (p > 0.05). However, total free amino acid (FAA), total essential FAA, and the concentrations of free leucine, isoleucine, lysine, valine, phenylalanine, tyrosine, alanine, glutamic acid, glycine, and cysteine were increased by supplementation (p < 0.05). Moreover, flavor-related FAA, including umami-, sweet-, and bitter/sweet/sulfurous-related FAA were also increased by supplementation (p < 0.05). These results indicate that AMO improves growth efficiency and enhances LT meat quality, particularly by increasing flavor-related FAA, without altering protein nutritional characteristics. Full article

Breast cancer is prevalent and deadly, affecting women worldwide. Increasing research suggests that lysine lactylation (KLA) and DNA damage repair (DDR) play critical roles in tumor progression and that KLA and DDR are interconnected, as KLA can modulate DDR protein function, thereby influencing genome stability and drug response, while DDR signaling can reciprocally reshape lactate metabolism and KLA activity. In this study, we developed a novel prognostic gene signature (KLA and DDR index, KLDRI) based on KLA- and DDR-related genes. Model genes (PGK1, MORF4L2, RAD54B, RPA3, CCND2) were generated via LASSO-Cox regression. Patients were stratified into high- and low-risk groups according to KLDRI, the robust prognostic value of which was demonstrated via survival and validation analyses in the TCGA cohort and the METABRIC and GSE96058 cohorts, respectively. Tumor microenvironment analysis indicated an immunologically suppressed phenotype in high-risk patients, whereas low-risk patients exhibited an immune-inflamed microenvironment. Drug sensitivity analysis indicated reduced sensitivity to multiple chemotherapy and targeted therapy drugs in the high-risk group. Single-cell transcriptomic analysis revealed differential gene expression patterns between risk groups. A prognostic nomogram based on KLDRI was developed to predict overall survival. Furthermore, functional experiments demonstrated that RPA3 knockdown suppressed cancer cell proliferation and migration, sensitized cells to cisplatin treatment, and reduced global lactylation, which may serve as a novel biomarker and potential therapeutic target. These findings enhance our understanding of the interplay between KLA, DDR, and breast cancer progression, facilitating the development of personalized therapeutic strategies. Full article

The literature collected from various search engines and high-quality scientific databases reveals that amino acid (AA)-functionalized nanoparticles have emerged as a promising field for selective detection and remediation of heavy metals (HMs). Among the various nanoparticles (NPs), gold nanoparticles (AuNPs) and silver nanoparticles (AgNPs) have drawn considerable attention, attributed to their unique optical, catalytic, and surface plasmon resonance properties. Functionalization with amino acids significantly enhances nanoparticle stability, biocompatibility, and metal-binding affinity through diverse functional groups. AA-functionalized AuNPs, including glycine, cystine, leucine, methionine, tyrosine, aspartic acid, histidine, and lysine-capped systems, exhibit tunable selectivity toward heavy metal ions. Bifunctionalization strategies further enhance sensitivity by inducing nanoparticle aggregation or signal amplification. Beyond single amino acids, polypeptides and protein-functionalized AuNPs offer enhanced molecular recognition and multivalent binding, expanding their applicability in complex matrices. Similarly, amino acid-functionalized AgNPs, such as those capped with similar amino acids stated above, exhibit strong interactions with heavy metals, AA bifunctionalization, and bimetallic nanoparticles (BNPs), particularly amino acid-functionalized Au–Ag systems, which combine the advantages of both metals, leading to improved sensitivity, selectivity, and signal strength. Although these advances have been made, a major gap remains in the systematic comparison of different amino acids, peptides, and bimetallic systems under real-world conditions. This gap can be addressed by standardized testing methods, clearer structure–function relationships and combined experimentation to guide the rational design of more efficient AA-functionalized nanoparticles. Full article

Cyclin-dependent kinase 1 (CDK1) is frequently upregulated in multiple cancers and plays a central role in cell cycle progression and tumorigenesis. However, whether CDK1 directly regulates the histone acetyltransferase KAT8 (also known as MOF) in non-small cell lung cancer (NSCLC) remains unclear. Here, we identify CDK1 as a kinase that directly interacts with and phosphorylates KAT8 at serine 348 (S348) and threonine 418 (T418). Mechanistically, CDK1-mediated phosphorylation, particularly at S348, enhances the interaction between KAT8 and MSL1, thereby stabilizing the MSL complex and promoting KAT8-dependent acetylation of histone H4 at lysine 16 (H4K16). Functionally, the phosphorylation-deficient mutant KAT8-S348A exhibits impaired MSL complex assembly, reduced H4K16 acetylation, and decreased NSCLC cell proliferation both in vitro and in vivo. Pharmacological inhibition of CDK1 using RO-3306 suppresses KAT8 phosphorylation and H4K16 acetylation, leading to significant tumor growth inhibition. Notably, this effect is partially rescued by re-expression of wild-type KAT8 but not by the S348A mutant, supporting a phosphorylation-dependent mechanism. Collectively, these findings define a CDK1–KAT8 signaling axis that promotes NSCLC proliferation through epigenetic regulation and suggest that targeting CDK1-dependent KAT8 phosphorylation may represent a potential therapeutic strategy for lung cancer. Full article

Background and objectives: The PWWP domain of lens epithelium-derived growth factor p75 (LEDGF/p75) mediates chromatin engagement through recognition of histone H3 lysine 36 di- and trimethylation (H3K36me2/3) and nucleosomal DNA. LEDGF/p75 plays a role in multiple human diseases. In particular, its interaction with HIV-1 integrase enables viral genome integration. However, the LEDGF PWWP domain remains difficult to target with small molecules as it lacks optimally shaped binding pockets. Here, we report the generation of high-affinity nanobodies (Nbs) to investigate the structure and function of this domain. Methods: Camelids were immunized with recombinant LEDGF PWWP domain, and immune phage display libraries were screened for affinity. Selected Nbs were recombinantly expressed in E. coli and purified. Their interaction with the PWWP domain of LEDGF and its close homolog HRP-2 was characterized using size-exclusion chromatography and surface plasmon resonance. Structural characterization of the Nbs was performed using X-ray crystallography. Functional effects on chromatin engagement were evaluated using an AlphaScreen assay. Results: Nine sequence-distinct Nbs were identified, seven of which were confirmed to bind the LEDGF PWWP domain with nanomolar affinities. Five Nbs also bound the HRP-2 domain, consistent with conserved functional surfaces, while two showed reduced affinity. The crystal structures of two Nbs (NbC03 and NbH10) confirmed there were canonical immunoglobulin folds, while the latter additionally revealed a domain-swapped dimer. Moreover, NbH10 dose-dependently inhibited the interaction between full-length LEDGF/p75 and H3K36me3-modified nucleosomes in vitro. Conclusions: This work establishes a validated panel of Nbs targeting the LEDGF PWWP domain and identifies one Nb capable of functionally disrupting the LEDGF–chromatin interaction. These Nbs serve as valuable tools for functional studies and structure-based drug design. Full article

Once written off as nothing more than a waste product of glycolysis, lactic acid is now seen as a key signaling molecule that operates across a wide range of physiological and pathological processes, from immune regulation and tumor metabolism to neural function. But its role goes beyond energy metabolism and cell signaling. Recent studies have uncovered a new type of post-translational modification called histone lactylation, in which lactate itself provides the lactoyl group attached to lysine residues on histones. This modification directly ties a cell’s metabolic state to the epigenetic control of gene expression. For example, histone lactylation helps shift macrophages from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype by fine-tuning gene transcription. In this review, we walk through the discovery and biochemical foundation of histone lactylation; discuss the likely writer and eraser enzymes that manage its dynamic changes; and highlight recent advances in understanding the role of this modification in inflammation, tumorigenesis, neurological disorders, and interactions with gut microbes. We also lay out key unanswered questions and consider why targeting protein lactylation might open up new therapeutic possibilities. Full article

Background: The first 1000 days of a child’s life, from a woman’s pregnancy to her child’s second birthday, represent a critical window during which nutritional and environmental exposures shape long-term health. Gut microbiota play an important role in metabolic and overall health. Although pet exposure during pregnancy affects neonatal microbiota, immunity, and development, its effects on maternal health remain unclear. This study investigated the associations of pet exposure with gestational health, maternal and infant microbiota, and breast milk composition in overweight/obese pregnant women. Methods: Fecal samples and breast milk samples were collected from pet-exposed participants (n = 22) and non-exposed controls (n = 32) for 16S rRNA sequencing. Breast milk lipids and proteins were also quantified. Results: Pet exposure before conception, during pregnancy, and postpartum was not associated with gestational diabetes mellitus or gestational weight gain. In the maternal gut, the relative abundances of Proteobacteria, Verrucomicrobia, Sutterellaceae, Enterobacteriaceae, Akkermansia muciniphila, and Parabacteroides were higher, whereas that of Ruminococcus was lower, in the pet-exposed group. In breast milk, the relative abundance of Escherichia-Shigella and the concentrations of phosphatidylinositol 36:2, phosphatidylethanolamine 38:3, lysine, and β-casein were higher, whereas the abundance of Rothia was lower, in the pet-exposed group. The relative abundance of Escherichia-Shigella was also lower in the infant gut of the pet-exposed group. Conclusions: In overweight/obese pregnant women, pet exposure was associated with differences in maternal gut and breast milk microbiota, higher concentrations of selected breast milk phospholipids and β-casein, and lower Escherichia-Shigella abundance in the infant gut. Full article

This study evaluated the nutritional composition, nutrient digestibility, and effects on small intestinal morphology of feather meal (100% feather meal) and a mixed meal consisting of 90% feather meal and 10% offal meal. A total of 300 twenty-two-day-old male Ross 308 broilers were randomly allocated into two dietary treatment groups (93% feather meal- or mixed meal-based diets). Each treatment had six replicates of 25 birds in each replication, and the experiment lasted 7 days using a direct feeding approach for nutrient digestibility evaluation. Data were analyzed using the General Linear Model (GLM) of the Statistical Analysis System (SAS), and treatment means were compared using a two-sample t-test (5%). Results showed that feather meal had higher crude protein and gross energy, while mixed meal contained greater ash, crude fiber, and unsaturated fatty acids. Feather meal was rich in methionine and lysine, whereas mixed meal had higher levels of valine, leucine, and serine. Standardized ileal digestibility was higher for fiber and most amino acids in the mixed meal, while protein digestibility and metabolizable energy were similar (p > 0.05) between treatments. Additionally, birds fed the mixed meal exhibited improved intestinal morphology, with greater jejunum and ileum villus height. In summary, the mixed meal showed better digestibility and gut morphology, indicating greater potential as a sustainable protein source. Full article

Here, the proximate composition, total amino acid content and antioxidant activity of Agria, Désirée and Kennebec potato varieties cultivated on the Matese plateau (Campania region, Southern Italy) were evaluated. Significant differences were observed among varieties in terms of proteins (1.98–3.07 g/100 g FW), carbohydrates (12.05–15.78 g/100 g FW) and moisture (78.42–84.68 g/100 g FW), while lipids were consistently low (~0.1 g/100 g FW), ~2.6-fold lower than ‘gold’ potatoes, used as a reference. Ashes were relatively high (1.10–1.39 g/100 g FW), ~1.4-fold higher than ‘gold’ potatoes. Total amino acid profiles were similar, although statistically significant differences were observed for Glx (glutamic acid + glutamine) and Asx (aspartic acid + asparagine), which are the most abundant amino acids, followed by valine, arginine and lysine. The chemical score of essential amino acids highlights that Matese potato varieties have a high nutritional content of phenylalanine + tyrosine and threonine, with average chemical scores of ~99.8% and 91.6%, respectively, while leucine is the limiting amino acid. The free amino acid profile does not show statistically significant differences. The total phenolic content (TPC) of analysed varieties (57.85–123.27 mg GAE/100 g of FW) was higher than those reported in the literature and directly correlated with the evaluated antioxidant activity (ABTS and DPPH). Finally, Matese potatoes are rich in potassium, phosphorus, calcium and magnesium, with minor minerals (~1.6%) and selenium traces (~0.53 µg/100 g FW). Overall, these findings highlight the potential of Matese potatoes to enhance local consumption, preserve culinary heritage and support gastronomic tourism growth. Full article