Search Results (119)

Lymphoma continues to pose a serious challenge to global health, underscoring the urgent need for new therapeutic strategies. Recently, the gut microbiome has been shown to play a potential role in regulating immune responses and influencing cancer progression. However, its molecular mechanisms of action in lymphoma remain poorly understood. This study investigates the antiproliferative and apoptotic activities of gut microbiota-derived metabolites, specifically nisin (N) and urolithin B (UB), individually and in combination 7:3 (5750 μM), against the human lymphoma cell line HKB-11. Comprehensive evaluations were performed using Alamar Blue viability assays, combination index (CI) analyses, reactive oxygen species (ROS) quantification, flow cytometry for apoptosis detection, and advanced bottom-up proteomics analyses. N and UB exhibited potent antiproliferative activity, with the 7:3 combination demonstrating strong synergistic effects (CI < 1), significantly enhancing apoptosis (p < 0.01) and ROS production (p < 0.0001) compared to the untreated control. Proteomics analyses revealed substantial alterations in proteins crucial to ribosomal biogenesis, mitochondrial function, cell cycle control, and apoptosis regulation, including a marked downregulation of ribosomal proteins (RPS27; Log₂FC = −3.47) and UBE2N (Log₂FC = −0.60). These findings highlight the potential of N and UB combinations as a novel and practical therapeutic approach for lymphoma treatment, warranting further in vivo exploration and clinical validation. Full article

The histone H2A variant H2AZ plays pivotal roles in shaping chromatin architecture and regulating gene expression. We recently identified H2AZ.2 in histone H2A lysine 119 ubiquitination (H2AK119ub)-enriched nucleosomes, but it is not known whether its highly related isoform H2AZ.1 also regulates this modification. In this study, we employed isoform-specific epitope-tagged knock-in mouse embryonic stem cell (ESC) lines to dissect the roles of each isoform in Polycomb Repressive Complex 1 (PRC1)-mediated H2AK119ub. Our results show that H2AZ.1 and H2AZ.2 share highly overlapping genomic binding profiles, both co-localizing extensively with H2AK119ub-enriched loci. The knockdown of either isoform led to reduced H2AK119ub levels; however, the two isoforms appear to function through distinct mechanisms. H2AZ.1 facilitates the recruitment of Ring1B, the catalytic subunit of PRC1, thereby promoting the deposition of H2AK119ub. In contrast, H2AZ.2 does not significantly affect Ring1B recruitment but instead functions as a structural component that stabilizes H2AK119ub-modified nucleosomes. In vitro ubiquitination assays indicate that H2AZ.1-containing nucleosomes serve as more efficient substrates for PRC1-mediated ubiquitination compared to those containing H2AZ.2. Thus, these findings define the distinct mechanisms of the two H2AZ variants in regulated PRC1-mediated H2AK119 ubiquitination and highlight a functional division of labor in epigenetic regulation. Full article

Lymphoma continues to pose a significant global health burden, highlighting the urgent need for novel therapeutic strategies. Recent advances in microbiome research have identified gut-microbiota-derived metabolites, or postbiotics, as promising candidates in cancer therapy. This study investigates the antiproliferative and mechanistic effects of two postbiotics, Nisin (N) and Urolithin B (UB), individually and in combination, against the human lymphoma cell line HKB-11. Moreover, this study evaluated cytotoxic efficacy and underlying molecular pathways using a comprehensive experimental approach, including the Alamar Blue assay, combination index (CI) analysis, flow cytometry, reactive oxygen species (ROS) quantification, and bottom-up proteomics. N and UB displayed notable antiproliferative effects, with IC₅₀ values of 1467 µM and 87.56 µM, respectively. Importantly, their combination at a 4:6 ratio demonstrated strong synergy (CI = 0.09 at IC₉₅), significantly enhancing apoptosis (p ≤ 0.0001) and modulating oxidative stress. Proteomic profiling revealed significant regulation of key proteins related to lipid metabolism, mitochondrial function, cell cycle control, and apoptosis, including upregulation of COX6C (Log₂FC = 2.07) and downregulation of CDK4 (Log₂FC = −1.26). These findings provide mechanistic insights and underscore the translational potential of postbiotics in lymphoma treatment. Further preclinical and clinical investigations are warranted to explore their role in therapeutic regimens. Full article

This study identified 13 endoplasmic reticulum stress (ERS)-related biomarkers associated with multiple sclerosis (MS) through integrated bioinformatics analysis (including weighted gene co-expression network analysis and machine learning algorithms) and single-cell sequencing, combined with validation in an experimental autoimmune encephalomyelitis (EAE) mouse model. Among them, GPX1, RCN1, and UBE2D3 exhibited high diagnostic value (AUC > 0.7, p < 0.05), and the diagnostic potential of GPX1 and RCN1 was confirmed in the animal model. The study found that memory B cells, plasma cells, neutrophils, and M1 macrophages were significantly increased in MS patients, while naive B cells and activated NK cells decreased. Consensus clustering based on key ERS-related genes divided MS patients into two subtypes. Single-cell sequencing showed that microglia and pericytes were the cell types with the highest expression of key ERS-related genes, and the APP-CD74 pathway was enhanced in the brain tissue of MS patients. Mendelian randomization analysis suggested that GPX1 plays a protective role in MS. These findings reveal the mechanisms of ERS-related biomarkers in MS and provide potential targets for diagnosis and treatment. Full article

This study analyzes publicly available RNA-seq data to comprehensively include the complex heterogeneity of prostate cancer (PCa) etiology. It combines prostate and prostate cancer (PCa) cell lines, representing primary PCa cells, Gleason scores, ages, and PCa of different racial origins. Additionally, some cell lines were exposed to endocrine-disrupting chemicals (EDCs). The research aims to identify hub genes and transcription factors (TFs) of the prostate carcinogenesis pathway as molecular targets for clinical investigations to elucidate EDC-induced aggressiveness and to develop potential biomarkers for their exposure risk assessments. PCa cells rely on androgen receptor (AR)-mediated signaling to survive, develop, and function. Fifteen various RNA-seq datasets were normalized for distribution, and the significance (p-value < 0.05) threshold of differentially expressed genes (DEGs) was set based on |log2FC| ≥ 2 change. Through integrated bioinformatics, we applied cBioPortal, UCSC-Xena, TIMER2.0, and TRRUST platforms, among others, to associate hub genes and their TFs based on their biologically meaningful roles in aggressive prostate carcinogenesis. Among all RNA-Seq datasets, we found 75 overlapping DEGs, with BUB1B (32%) and CCNB1 (29%) genes exhibiting the highest degree of mutation, amplification, and deletion. EDC-associated CCNB1, BUB1B, and CCNA2 in PCa cells exposed to EDCs were consistently shown to be associated with high Gleason scores (≥4 + 3) and in the >60 age group of patients. Selected TFs (E2F4, MYC, and YBX1) were also significantly associated with DEGs (NCAPG, MKI67, CCNA2, CCNB1, CDK1, CCNB2, AURKA, UBE2C, BUB1B) and influenced the overall survival (p-value < 0.05) of PCa cases. This is one of the first comprehensive studies combining 15 publicly available RNA-seq datasets to demonstrate the association of EDC-associated hub genes and their TFs aligning with the aggressive carcinogenic pathways in the higher age group (>60 years) of patients. The findings highlight the potential of these hub genes as candidates for further studies to develop molecular biomarkers for assessing the EDC-related PCa risk, diagnosing PCa aggressiveness, and identifying therapeutic targets. Full article

DNA damage repair (DDR) plays a key role in maintaining genomic stability and developing inflammatory bowel disease (IBD). However, no report about the causal association between DDR and IBD exists. Whether DDR-related genes are the precise causal association to IBD in etiology remains unclear. Herein, we employed a multi-omics summary data-based Mendelian randomization (SMR) approach to ascertain the potential causal effects of DDR-related genes in IBD. Methods: Summary statistics from expression quantitative trait loci (eQTL), DNA methylation QTL (mQTL), and protein QTL (pQTL) on European descent were included. The GWAS summarized data for IBD and its two subtypes, Crohn’s disease (CD) and ulcerative colitis (UC), were acquired from the FinnGen study. We elected from genetic variants located within or near 2000 DDR-related genes in cis, which are closely associated with DDR-related gene changes. Variants were selected as instrumental variables (IVs) and assessed for causality with IBD and its subtypes using both SMR and two-sample MR (TSMR) approaches. Colocalization analysis was employed to evaluate whether a single genetic variant simultaneously influences two traits, thereby validating the pleiotropy hypothesis. Results: We identified seven DDR-related genes (Arid5b, Cox5a, Erbb2, Ube2l3, Gpx1, H2bcl2, and Mapk3), 33 DNA methylation genes, and two DDR-related proteins (CD274 and FCGR2A) which were all causally associated with IBD and its subtypes. Beyond causality, we integrated the multi-omics data between mQTL-eQTL and conducted druggability values. We found that DNA methylation of Erbb2 and Gpx1 significantly impacted their gene expression levels offering insights into the potential regulatory mechanisms of risk variants on IBD. Meanwhile, CD247 and FCGR2A could serve as targets for potential pharmacological interventions in IBD. Conclusions: Our study demonstrates the causal role of DDR in IBD based on the data-driven MR. Moreover, we found potential regulatory mechanisms of risk variants on IBD and potential pharmacological targets. Full article

To reduce the risk of syncope, trained breath-hold divers (BHDs) use a specialized breathing technique after surfacing called “hook breathing” (HB). It consists of a full inspiration followed by a Valsalva-like maneuver and with subsequent exhalation performed against resistance to generate continuous positive airway pressure during exhalation. This study analyzed the influence of HB on oxygen saturation recovery after a −40 m depth apnea dive in trained BHDs. Thirteen BHDs performed two dives to −40 m at different days, one followed by HB after a dive and the other using usual breathing (UB). To detect signs of lung edema, ultrasound B-line measurements were conducted before, 10 min after the dive, and within 1 h after the dive. To detect oxygen saturation recovery, pulse oximetry was recorded before and immediately after surfacing. Both groups exhibited significant increases in SpO₂ over time (UB: F (2.25, 24.7) = 22.1, p < 0.001, ηg2 = 0.612; HB: F (2.11, 23.2) = 29.0, p < 0.001, ηg2 = 0.688). Significant differences in SpO₂ were observed between the HB and UB groups at 30–45 s post-apnea, with higher SpO₂ values in the HB group; between 1.64 and 5.08% of SpO₂ in favor of the HB intervention. Four participants showed ultrasound B-lines within ten minutes post-dive. After a 40 m apnea dive, the results revealed significant SpO₂ recovery from 30 s to 45 s, with the HB recovering more rapidly. No differences were found at earlier (10–25 s) or later time points (50–60 s). Full article

Chickens possess a well-developed vision that allows them to perceive a wide range of the color spectrum. In addition, they display an inherent sensitivity toward specific light spectra, which suggests that coloring feed could influence feed preference, feed intake and growth performance. This trial assessed the effect of feed coloring on broiler feed color preferences. A total of 216 day-old Cobb by-product males were randomly distributed into 18 battery cages, each containing 12 chicks and subjected to three dietary treatments from 1 to 21 days, resulting in six replicates per dietary treatment. Feed color treatments consisted of a common corn–soybean meal-based undyed basal (UB) broiler starter diet, which was dyed to obtain blue-colored (B) and purple-colored (P) diets, resulting in a total of three diets used to create the feed combinations. Two feed troughs were affixed to each cage, allowing for the assignment of dietary treatments as follows: UB-B, UB-P, and B-P. The birds had ad libitum access to feed and water throughout the study. Feed consumption data were collected at 7-day intervals. Additionally, bird weights were measured at 1 and 21 days. The data were analyzed as a completely randomized design using the SAS GLIMMIX and TTEST procedures. Overall, broilers exhibited a preference for the UB diet compared to the B and P diets. Broilers had a 27.5 and 29.2% higher (p < 0.05) feed consumption of UB feed compared to P feed from 1 to 14 and 1 to 21 days, respectively. In addition, broilers tended to have a higher (p = 0.098) consumption of UB feed compared to B feed from 1 to 14 days. No differences were observed in feed consumption between B and P diets during the experimental period. Based on feed consumption data, broilers displayed a preference towards the UB feed when paired with B or P diets. Feed coloring did not impact the mortality of broilers and did not result in adverse growth. Overall, broilers preferred the UB diet over the B and P diets and showed no preference between B and P diets. Based on the results of this trial, diets that appear more conventional, compared to dyed diets, can promote consumption. Special care must be taken to avoid ingredients that could alter the diet’s coloration. Full article

Semen quality and persistence are critical for evaluating the usability of individual boars in AI, a standard practice in pig breeding. We conducted GWASs on various semen traits of Duroc boars, including MOT, DEN, ABN, MMP, AIR, and ROS levels. These traits were assessed using FCM and CASA. A total of 1183 Duroc boars were genotyped using the GeneSeek GGP Porcine 50 K SNP BeadChip. The GWAS was performed using three different models: GLM, MLM, and FarmCPU. Additionally, trait heritability was estimated using single- and multiple-trait PBLUP models, yielding 0.19, 0.29, 0.13, 0.18, 0.11, and 0.14 heritability for MOT, DEN, ABN, MMP, AIR, and ROS, respectively. All semen traits exhibited low heritability except ABN, which demonstrated medium heritability. Nine candidate genes (GPX5, AWN, PSP-II, CCDC62, TMEM65, SLC8B1, TRPV4, UBE3B, and SIRT5) were potentially associated with semen traits. These genes are associated with antioxidant and mitochondrial functions in porcine sperm. Our findings provide insight into the genetic architecture of semen traits in Duroc boars, and the identified SNPs and candidate genes may enhance economic outcomes in the pig breeding industry while improving sperm quality through targeted breeding strategies. Full article

Endohedral metallo-borospherenes M@B₄₀ have received considerable attention since the discovery of B₄₀ in 2014. However, the coordination bonding nature of most of actinide-doped endohedral An@B₄₀ still remains in dispute or unexplored. Extensive and systematic first-principles theory calculations performed herein unveil the ground states of triplet U@B₄₀ (1, C_2v, ³A₂), quartet U@B₄₀⁻ (2, C_2v, ⁴B₁), quintet Np@B₄₀⁺ (3, C_2v, ⁵A₁), sextet Np@B₄₀ (4, C₂, ⁶A), septet Pu@B₄₀ (5, C_2v, ⁷A₂), octet Am@B₄₀ (6, C_2v, ⁸A₂), and octet Cm@B₄₀⁺ (7, C_2v, ⁸A₂) at the coupled-cluster with triple excitations CCSD(T) level. Detailed principal interacting spin orbital (PISO) and adaptive natural density partitioning (AdNDP) analyses reveal their coordination bonding patterns and show that, with the numbers of unpaired α-electrons in parallel spins varying from n_α = 2, 3, 4, 5, 6, 7, to 7 in these complexes, the percentage contribution of the An 5f-involved PISO pairs to overall coordination bonding interactions decreases monotonously from 41% to 1%, and the contribution of An 6d-involved PISO pairs increases monotonously from 47% to 72%, while the marginal contribution of An 7s-involved PISO pairs remains basically unchanged (4~7%). The IR, Raman, and photoelectron spectra of the most concerned species are computationally simulated to facilitate their characterizations in future experiments. Full article

The aromatic boron cluster B₈^2– (D_7h) has similar π bonding to C₆H₆, which is named “borozene”. The B₈^2– ligand has been observed to stabilize monovalent Ln(+I) in C_7v-LnB₈⁻ (Ln = La, Pr, Tb, Tm, and Yb) borozene complexes. Low-valency actinide complexes have been reported more rarely, and B₈^2– may be one of the potential ligands. Here, we report a theoretical study on a series of actinide metal-doping octa-boron clusters AnB₈ (An = Pa, U, Np, and Pu). It was found that each species has both half-sandwich and chair-like structures. Except for PaB₈, the half-sandwich structures of UB₈, NpB₈, and PuB₈ are more energetically stable than the chair-like structures, and the half-sandwich clusters of AnB₈ are found to be actinide(II) borozene complexes with the M^II[B₈²⁻] type. For each of the half-sandwich clusters, the B₈²⁻ ligand has σ and π double aromaticity. Various bonding analyses of AnB₈ confirm the covalent interactions between the doped actinide metals and the octa-boron clusters, which further stabilize the complexes and determine the relative stability of AnB₈. As expected, these complexes show high bond dissociation energies, especially PaB₈ with stronger Pa-B covalent bonds. These results demonstrate that the B₈²⁻ doubly aromatic ligand is able to stabilize divalent actinides. Full article

Endometriosis (EMT) is a common gynecological disease with a strong genetic component, while its precise etiology remains elusive. This study aims to integrate transcriptome-wide association study (TWAS), Mendelian randomization (MR), and bioinformatics analyses to reveal novel putatively causal genes and potential mechanisms. We obtained summary-level data of the Genotype-Tissue Expression Project (GTEx), v8 expression quantitative loci (eQTL) data, and the genome-wide association study (GWAS) data of EMT and its subtypes from the R11 release results of the FinnGen consortium for analysis. GWAS data of modifiable risk factors were collected from IEU Open GWAS. Cross-tissue TWAS analyses were performed using the unified test for molecular signature (UTMOST), while functional summary-based imputation (FUSION) was employed for single-tissue TWAS analyses. Furthermore, we also conducted multi-marker analysis of genomic annotation (MAGMA) analyses to validate the significant associations. Subsequent Mendelian randomization (MR) and colocalization analysis elucidated the causal associations between the identified genes across various tissues and EMT. To further delve into mechanisms, two-sample network MR analyses were conducted. At last, bioinformatics analyses were employed to enhance our understanding of the functional implications and expression patterns of these identified genes. For EMT, 22 significant gene signals were identified by UTMOST, 615 by FUSION, and 354 by MAGMA. Ultimately, six genes, including CISD2, EFRB, GREB1, IMMT, SULT1E1, and UBE2D3, were identified as candidate susceptibility genes for EMT. Through similar procedures, we identified GREB1, IL1A, and SULT1E1 for EMT of the ovary, and we identified GREB1 for EMT of the pelvic peritoneum, EMT of rectovaginal septum and vagina, and deep EMT. In MR analyses, the expression of IMMT in 21 tissues, EFR3B in the adrenal gland, CISD2 in 17 tissues, and UBE2D3 in 7 tissues demonstrated causal relationships with EMT risk. In addition, CISD2, IMMT, and UBE2D3, across different tissues, exhibited strong colocalization with EMT (PPH4 > 0.7). Two-sample network MR analyses revealed that CISD2, EFR3B, and UBE2D3 could potentially regulate the levels of blood lipids and hip circumference so as to influence the risk of EMT. Furthermore, bioinformatics analyses confirmed our findings and delved into the biological functions of the identified genes. Our study unveiled seven novel candidate genes whose predicted expression was associated with the risk of EMT, providing new insights into the underlying genetic framework of EMT. These findings will facilitate a deeper comprehension of the tissue-specific transcriptional regulatory mechanisms associated with EMT, paving the way for optimizing the management and treatment of EMT. Full article

Background: The ubiquitination process plays a crucial role in neuronal differentiation and function. Numerous studies have focused on the expression and functions of E3 ligases during these different stages, far fewer on E2 conjugating enzymes. In mice, as in humans, these E2s belong to 17 conjugating enzyme families. Objectives: We analyzed by real-time PCR the expression dynamics of all known E2 genes during an in vitro differentiation of mouse hippocampal neuronal cultures, and after, we analyzed their stimulation with N-methyl-D-aspartate (NMDA). Results: We found that 36 of the 38 E2 genes were expressed in hippocampal neurons. Many were up-regulated during neuritogenesis and/or synaptogenesis stages, such as Ube2h, Ube2b, and Aktip. Rapid and delayed responses to NMDA stimulation were associated with the increased expression of several E2 genes, such as Ube2i, the SUMO-conjugating E2 enzyme. We also observed similar expression profiles within the same E2 gene family, consistent with the presence of similar transcription factor binding sites in their respective promoter sequences. Conclusions: Our study indicates that specific expression profiles of E2 genes are correlated with changes in neuronal differentiation and activity. A better understanding of the regulation and function of E2s is needed to better understand the role played by the ubiquitination process in physiological mechanisms and pathophysiological alterations involved in neurodevelopmental or neurodegenerative diseases. Full article

Background: Positron emission tomography (PET) with ¹⁸F-FDG is being used more frequently to evaluate primary pelvic tumors (PTs). However, a standardized hydration protocol is essential for an optimal diuretic effect and constant results. Methods: We reviewed 109 patients with PTs who had undergone ¹⁸F-FDG PET/CT examinations between November 2006 and April 2013. Four different protocols were used: (a) no hydration (group 1); (b) oral hydration (800 mL) after an early scan (group 2); (c) intravenous (IV) hydration (500 mL) during an early scan followed by oral hydration (800 mL) and IV furosemide (20 mg) after an early scan (group 3); and (d) oral hydration (800 mL) before an FDG injection followed by the protocol from group 3 (group 4). The maximum standardized uptake (SUV_max) of the urinary bladder (UB) and PTs and the PT/UB SUV_max ratios were examined. Results: The UB SUV_max of group 4 was significantly lower in the early scan compared to that in the other three groups. Group 4 had a significantly higher PT/UB SUV_max ratio in the early scan than the other three groups, and it also had a 52.5% positivity rate for PTs. Conclusions: The pre-hydration plus forced diuresis protocol yielded the optimal effect of UB radiotracer washout and had the best PT/UB SUV_max ratio in both scans. Full article

Backgroud: Rett syndrome is a neurodevelopmental disorder that affects 1 in 10,000 females. Various treatments have been explored; however, no effective treatments have been reported to date, except for trofinetide, a synthetic analog of glycine-proline-glutamic acid, which was approved by the FDA in 2023. Serological biomarkers that correlate with the disease status of RTT are needed to promote early diagnosis and to develop novel agents. Methods: In this study, we performed a high-depth proteomic analysis of extracellular vesicles containing preparations extracted from patient plasma samples to identify novel biomarkers. Results: We identified 33 upregulated and 17 downregulated candidate proteins among a total of 4273 proteins in RTT compared to the healthy controls. Among these, UBE3B was predominantly increased in patients with Rett syndrome and exhibited a strong correlation with the clinical severity score, indicating the severity of the disease. Conclusions: We demonstrated that the proteomics of high-depth extracellular vesicles containing preparations in rare diseases could be valuable in identifying new disease biomarkers and understanding their pathophysiology. Full article