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Whey protein ingestion during recovery from exercise increases myofibrillar but not muscle connective protein synthesis rates. It has been speculated that whey protein does not provide sufficient glycine to maximize postexercise muscle connective protein synthesis rates. In the present study, we assessed the impact of coingesting different amounts of collagen with whey protein as a nutritional strategy to increase plasma glycine availability during recovery from exercise. In a randomized, double-blind, crossover design, 14 recreationally active men (age: 26 ± 5 years; body mass index: 23.8 ± 2.1 kg·m−2) ingested in total 30 g protein, provided as whey protein with 0 g (WHEY), 5 g (WC05); 10 g (WC10), and 15 g (WC15) of collagen protein immediately after a single bout of resistance exercise. Blood samples were collected frequently over 6 hr of postexercise recovery to assess postprandial plasma amino acid kinetics and availability. Protein ingestion strongly increased plasma amino acid concentrations (p <.001) with no differences in plasma total amino acid availability between treatments (p >.05). The postprandial rise in plasma leucine and essential amino acid availability was greater in WHEY compared with the WC10 and WC15 treatments (p <.05). Plasma glycine and nonessential amino acid concentrations declined following whey protein ingestion but increased following collagen coingestion (p <.05). Postprandial plasma glycine availability averaged −8.9 ± 5.8, 9.2 ± 3.7, 23.1 ± 6.5, and 39.8 ± 11.0 mmol·360 min/L in WHEY, WC05, WC10, and WC15, respectively (incremental area under curve values, p <.05). Coingestion of a small amount of collagen (5 g) with whey protein (25 g) is sufficient to prevent the decline in plasma glycine availability during recovery from lower body resistance-type exercise in recreationally active men. [ABSTRACT FROM AUTHOR]

The objective of this meta-analysis was to develop and evaluate models for predicting nitrogen (N) excretion in feces, urine, and manure in beef cattle in South America. The study incorporated a total of 1,116 individual observations of N excretion in feces and 939 individual observations of N excretion in feces and in urine (g/d), representing a diverse range of diets, animal genotypes, and management conditions in South America. The dataset also included data on dry matter intake (DMI; kg/d) and nitrogen intake (NI; g/d), concentrations of dietary components, as well as average daily gain (ADG; g/d) and average body weight (BW; kg). Models were derived using linear mixed-effects regression with a random intercept for the study. Fecal N excretion was positively associated with DMI, NI, nonfibrous carbohydrates, average BW, and ADG and negatively associated with EE and CP concentration in the diet. The univariate model predicting fecal N excretion based on DMI (model 1) performed slightly better than the univariate model, which used NI as a predictor variable (model 2) with a root mean square error (RMSE) of 38.0 vs. 39.2%, the RMSE-observations SD ratio (RSR) of 0.81 vs. 0.84, and concordance correlation coefficient (CCC) of 0.53 vs. 0.50, respectively. Models predicting urinary N excretion were less accurate than those derived to predict fecal N excretion, with an average RMSE of 43.7% vs. 37.0%, respectively. Urinary and manure N excretion were positively associated with DMI, NI, CP, average BW, and ADG and negatively associated with neutral detergent fiber concentration in the diet. As opposed to fecal N excretion, the univariate model predicting urinary N excretion using NI (model 10) performed slightly better than the univariate model using DMI (model 9) as predictor variable with an RMSE of 36.0% vs. 39.7%, RSR 0.85 vs. 0.93, and CCC of 0.43 vs. 0.29, respectively. The models developed in this study are applicable for predicting N excretion in beef cattle across a broad spectrum of dietary compositions and animal genotypes in South America. The univariate model using DMI as a predictor is recommended for fecal N prediction, while the univariate model using NI is recommended for predicting urinary and manure N excretion because the use of more complex models resulted in little to no benefits. However, it may be more useful to consider more complex models that incorporate nutrient intakes and diet composition for decision-making when N excretion is a factor to be considered. Three extant equations evaluated in this study have the potential to be used in tropical conditions typical of South America to predict fecal N excretion with good precision and accuracy. However, none of the extant equations are recommended for predicting urine or manure N excretion because of their high RMSE, and low precision and accuracy.

Introduction: Sex‐determining region Y‐related high‐mobility group box 17 protein (SOX17), a proangiogenic transcription factor, is specifically expressed in tumor endothelial cells (TECs) of implanted Lewis lung carcinoma. However, the expression profile of SOX17 is largely unknown in human lung cancer. We aimed to elucidate SOX17 expression in cancer cells and the tumor microenvironment of lung adenocarcinoma. Methods: In the present study, we examined SOX17 expression in whole‐tissue specimens of 83 lung adenocarcinomas by immunohistochemistry. Results: SOX17 immunoreactivity was minimal in lung adenocarcinoma cells, except in five non‐mucinous adenocarcinomas in situ. SOX17 was also expressed in cultured A549 lung adenocarcinoma cells, which is widely used as a model of malignant alveolar type II epithelial cells. Notably, SOX17 immunoreactivity was found in endothelial cells of tumor‐penetrating vessels in 19 of 83 lung adenocarcinoma tissue specimens, with statistical significance to stromal infiltration of CD8+ T cells (p < 0.01) but was not associated with the number of tertiary lymph nodes. Although not statistically significant, SOX17 immunoreactivity was related to favorable patient outcomes. Conclusion: Our findings indicate that SOX17 might play a pleiotropic role in lung adenocarcinoma in cancer cells and stromal niches. SOX17‐mediated CD8+ T‐cell‐rich tumor microenvironment might attract interest in improving the effect of cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Starvation of Escherichia coli thyA auxotrophs for the required thymine or thymidine leads to the cessation of DNA synthesis and, unexpectedly, to thymineless death (TLD). Previously, TLD-alleviating defects were identified by the candidate gene approach, for their contribution to replication initiation, fork repair, or SOS induction. However, no TLD-blocking mutations were ever found, suggesting a multifactorial nature of TLD. Since (until recently) no unbiased isolation of TLD suppressors was reported, we used enrichment after insertional mutagenesis to systematically isolate TLD suppressors. Our approach was validated by isolation of known TLD-alleviating mutants in recombinational repair. At the same time, and unexpectedly for the current TLD models, most of the isolated suppressors affected general metabolism, while the strongest suppressors impacted the central metabolism. Several temperature-sensitive (Ts) mutants in important/essential functions, like nadA , ribB , or coa A, almost completely suppressed TLD at 42°C. Since blocking protein synthesis completely by chloramphenicol prevents TLD, while reducing protein synthesis to 10% alleviates TLD only slightly, we measured the level of protein synthesis in these mutants at 42°C and found it to be 20–70% of the WT, not enough reduction to explain TLD prevention. We conclude that the isolated central metabolism mutants prevent TLD by affecting specific TLD-promoting functions. [ABSTRACT FROM AUTHOR]

Simple Summary: Engagement of an advanced immunofluorescence technology demonstrated, for the first time, the cell cycle-dependent control of TRBP2 protein, a major component of the RNAi machinery. TRBP2 expression is lost during mitosis and restored in the cell nucleus upon interphase entry. None of the post-translational modifications, such as ubiquitination or phosphorylation, herein examined proved able to play an essential role in TRBP2 loss from the nucleus of mitotic cells. Different types of cancer cells, with diverse tissue origin, malignancy grade, metastatic potential, and mutational load, are shown to lack TRBP2 nuclear compartmentalization during mitosis, thereby opening new diagnostic and therapeutic windows for human malignancies in the clinic. Background: Transactivation Response Element RNA-binding Protein (TRBP2) is a double-stranded RNA-binding protein widely known for its critical contribution to RNA interference (RNAi), a conserved mechanism of gene-expression regulation mediated through small non-coding RNA moieties (ncRNAs). Nevertheless, TRBP2 has also proved to be involved in other molecular pathways and biological processes, such as cell growth, organism development, spermatogenesis, and stress response. Mutations or aberrant expression of TRBP2 have been previously associated with diverse human pathologies, including Alzheimer's disease, cardiomyopathy, and cancer, with TRBP2 playing an essential role(s) in proliferation, invasion, and metastasis of tumor cells. Methods: Hence, the present study aims to investigate, via employment of advanced flow cytometry, immunofluorescence, cell transgenesis and bioinformatics technologies, new, still elusive, functions and properties of TRBP2, particularly regarding its cell cycle-specific control during cancer cell division. Results: We have identified a novel, mitosis-dependent regulation of TRBP2 protein expression, as clearly evidenced by the lack of its immunofluorescence-facilitated detection during mitotic phases, in several human cancer cell lines of different tissue origin. Notably, the obtained TRBP2-downregulation patterns seem to derive from molecular mechanisms that act independently of oncogenic activities (e.g., malignancy grade), metastatic capacities (e.g., low versus high), and mutational signatures (e.g., p53−/− or p53ΔΥ126) of cancer cells. Conclusions: Taken together, we herein propose that TRBP2 serves as a novel cell cycle-dependent regulator, likely exerting mitosis-suppression functions, and, thus, its mitosis-specific downregulation can hold strong promise to be exploited for the efficient and successful prognosis, diagnosis, and (radio-/chemo-)therapy of diverse human malignancies, in the clinic. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigates the role of three specific proteins—FGF8, ALK, and EML4—in predicting the prognosis of patients with esophageal squamous cell carcinoma (ESCC), a common type of esophageal cancer. The aim of the study was to assess whether the presence and levels of these proteins could indicate which patients are at a higher risk of poor survival following surgery. By analyzing tissue samples from 122 patients, who underwent surgical removal of their cancer, the study discovered that an increase in FGF8 protein levels is associated with a reduced chance of survival. Additionally, the study found a significant correlation between FGF8 and alterations in the ALK and EML4 proteins. These results suggest that FGF8 could serve as a valuable marker for predicting patient outcomes and might also become a target for future therapies aimed at improving survival rates in ESCC patients. FGF8, ALK, and EML4 have been identified as promising biomarkers in a number of malignancies. The aim of this study was to examine the prognostic role of FGF8, ALK, and EML4 in esophageal squamous cell carcinoma (ESCC). Methods: Consecutive patients with ESCC who underwent upfront resection were included in this study. ALK and EML4 gene status was evaluated by fluorescence in situ hybridization (FISH) using a triple-color break-apart single-fusion probe and a probe against 2p11. FGF8, ALK, and EML4 protein expression was determined by immunohistochemistry. Results: A total of 122 patients were included in this study. Multivariate analysis revealed that FGF8 overexpression is an independent negative prognostic factor for patients' overall survival (OS) (p = 0.04). Furthermore, a significant correlation between the expression of FGF8, and ALK (p = 0.04) and EML4 (p = 0.01) alteration was found. Conclusions: FGF8 overexpression is an adverse independent prognostic factor in patients with upfront resected ESCC. Furthermore, FGF8 expression significantly correlates with ALK and EML4 amplification and may therefore qualify as a future therapeutic target. [ABSTRACT FROM AUTHOR]

Simple Summary: A pseudogene, by definition, is a segment of DNA that structurally resembles an established gene but has undergone mutation drift or genomic translocation where it no longer codes for an active protein. An example of this type of relationship is seen with the oncofetal protein Cripto-1 (CR1) and its pseudogene homolog Cripto-3 (CR3). The CR1 gene is expressed on chromosome 3 and CR3 on the X chromosome. They both code for a 188AA protein but differ by six AAs. Given the closeness of their protein structure, commercially available antibodies cannot differentiate CR1 from CR3. Hence, CR3 remains a pseudogene in human biology and its relationship with tumor malignancies underdetermined. Our newly generated discriminatory anti-CR1/anti-CR3 monoclonal antibodies have now proven that CR3 is a translated protein found in diverse human cancers, tracking with disease severity, involved with cell signaling and expressed as a cell-tethered or soluble entity, thus negating its pseudogene status. Background/Objectives: Cripto-1 (CR1) is a plurifunctional embryonic protein required for implantation and re-expressed in the adult during wound repair, inflammation, and tumorigenesis. CR1 and its predicted CR1 pseudogene product Cripto-3/CR3 are highly homologous proteins, and given this physical attribute, commercially available antibodies cannot discriminate between CR1 and CR3. Methods: A series of mouse monoclonal antibodies [MoAbs] were developed with a high-affinity binding that can differentiate human CR1/CR3 proteins and showed no measurable cross-reactivity. Results: Using these reagents, we confirm that CR3 is a bona fide translated protein found in human tumor tissue, cancer cell lysates, and in normal/cancer patient donor sera. We also reveal that CR1 and CR3 compete for binding to signal transduction protein Nodal, glucose-regulated protein 78Da (GRP78), and activin receptor-like kinase 4 (Alk4). Our discriminatory MoAbs provide new reagents to help clarify current CR1/CR3 protein expression vagaries in the Cripto field of study, challenging established CR1 conventions. In addition, our data validate CR3 involvement in human carcinogenesis and cell signaling pathways, with potential clinical relevance in determining cancer patient prognosis and disease severity. [ABSTRACT FROM AUTHOR]

Human sepsis is characterized by increased protein breakdown and changes in arginine and citrulline metabolism. However, it is unclear whether this is caused by changes in transorgan metabolism. We therefore studied the changes in protein and arginine-related metabolism on the whole body (Wb) and transorgan levels in a Pseudomonas aeruginosa-induced pig sepsis model. We studied 22 conscious pigs for 18 h during sepsis induced by infusing live bacteria (Pseudomonas aeruginosa) or after placebo infusion (Control). We used stable isotope tracers to measure Wb and skeletal muscle protein synthesis and breakdown, as well as Wb, splanchnic, skeletal muscle, hepatic, and portal-drained viscera (PDV) arginine and citrulline disposal and production rates. During sepsis, arginine Wb production (P = 0.0146), skeletal muscle release (P = 0.0035), and liver arginine uptake were elevated (P = 0.0031). Wb de novo arginine synthesis, citrulline production, and transorgan PDV release of citrulline, glutamine, and arginine did not differ between Sepsis and Control pigs. However, Wb (P < 0.0001) and muscle (P < 0.001) protein breakdown were increased, suggesting that the enhanced arginine production is predominantly derived from muscle breakdown in sepsis. In conclusion, live bacterium sepsis increases muscle arginine release and liver uptake, mirroring previous pig endotoxemia studies. In contrast to observations in humans, acute live bacterium sepsis in pigs does not change citrulline production or arterial arginine concentration. We therefore conclude that the arginine dysregulation observed in human sepsis is possibly initiated by enhanced protein catabolism and splanchnic arginine catabolism, whereas decreased arterial arginine concentration and citrulline metabolism may require more time to fully manifest in patients. NEW & NOTEWORTHY: Our work highlights that arginine availability may be largely determined by muscle breakdown and hepatic extraction in early sepsis, while citrulline production appears maintained. Additionally, our work highlights a novel ANCOVA approach for transorgan analysis to control for inherent variation in transorgan data and increase statistical sensitivity. [ABSTRACT FROM AUTHOR]

Aim: Sex‐determining region Y‐related high‐mobility group box 4 (SOX4) has been reported to play a carcinogenic role in endometrial cancer (EC). However, the biological function and regulatory mechanisms of SOX4 in ferroptosis during the progression of EC are still unknown. Methods: The mRNA and protein levels were scrutinized by quantitative reverse‐transcription polymerase chain reaction and western blot, respectively. The cell viability and proliferative capability were determined by cell counting kit‐8 assay and 5‐ethynyl‐2′‐deoxyuridine (EdU) assay. Transcriptional regulation of gene expression was investigated by dual‐luciferase reporter assay and chromatin immunoprecipitation. Ferroptosis was evaluated by detection of reactive oxygen species, malondialdehyde, Fe2+, and ferroptosis‐related proteins. The mice test was implemented to confirm the influence of SOX4 on EC tumor growth and ferroptosis in vivo. Results: We here discovered the elevation of SOX4 in EC tissues and cells. Functionally, SOX4 knockdown hampered proliferation and promoted ferroptosis of EC cells. Mechanistically, SOX4 bound to p53 promoter and inhibited its transcriptional activity in EC cells. In addition, p53 transcriptionally suppressed SLC7A11 expression in EC cells. Downregulation of p53 reverses the effect of SOX4 knockdown on proliferation and ferroptosis of EC cells. Finally, in vivo experiments demonstrated that SOX4 depletion hindered tumor growth and triggered ferroptosis in EC. Conclusions: These findings collectively suggested that SOX4 inhibited ferroptosis and promoted proliferation of EC cells via the p53/SLC7A11 signaling. Our research unveiled a novel regulatory mechanism of ferroptosis in EC, offering promising perspectives for the development of EC therapies. [ABSTRACT FROM AUTHOR]

Maternal exercise is beneficial for offspring brain development. Amyloid precursor protein (APP) influences neurogenesis and synaptic plasticity. Cleavage products of APP are implicated in the proliferation of neural progenitor cells and neuronal network development. Our study aimed to investigate differences in APP processing in active or sedentary offspring of dams who were exposed to voluntary wheel running with and without a western diet throughout gestation. Female Wistar rats (7–8 weeks old) were fed a normal chow or western diet and randomized into voluntary wheel run or sedentary conditions. Dams returned to sedentary conditions post-parturition. The pups were weaned at 6 weeks after which point half of the samples were collected, while the rest of the pups remained on a normal diet, separated into sedentary or voluntary wheel run groups, and collected 12 weeks later. In utero exposure to maternal exercise was associated with higher neuronal nuclear protein, higher soluble APPα and lower soluble APPβ in offspring prefrontal cortex tissue at 6, but not 18 weeks of age. Neuronal nuclear protein is exclusive to mature neurons implying that offspring of mothers who exercised could have more neuron maturation potentially influenced by the higher APPα content at this early developmental stage. The voluntary wheel run offspring groups had a higher mature/pro brain derived neurotrophic factor ratio compared to the sedentary counterparts. The maternal effects were isolated to the juvenile 6-week-old pups, while the differences in the adult offspring were caused by their own exercise status. [ABSTRACT FROM AUTHOR]

Transthyretin (TTR), a homotetrameric protein found in plasma, cerebrospinal fluid, and the eye, plays a pivotal role in the onset of several amyloid diseases with high morbidity and mortality. Protein aggregation and fibril formation by wild-type TTR and its natural more amyloidogenic variants are hallmarks of ATTRwt and ATTRv amyloidosis, respectively. The formation of soluble amyloid aggregates and the accumulation of insoluble amyloid fibrils and deposits in multiple tissues can lead to organ dysfunction and cell death. The most frequent manifestations of ATTR are polyneuropathies and cardiomyopathies. However, clinical manifestations such as carpal tunnel syndrome, leptomeningeal, and ocular amyloidosis, among several others may also occur. This review provides an up-to-date listing of all single amino-acid mutations in TTR known to date. Of approximately 220 single-point mutations, 93% are considered pathogenic. Aspartic acid is the residue mutated with the highest frequency, whereas tryptophan is highly conserved. "Hot spot" mutation regions are mainly assigned to β-strands B, C, and D. This manuscript also reviews the protein aggregation models that have been proposed for TTR amyloid fibril formation and the transient conformational states that convert native TTR into aggregation-prone molecular species. Finally, it compiles the various in vitro TTR aggregation protocols currently in use for research and drug development purposes. In short, this article reviews and discusses TTR mutagenesis and amyloidogenesis, and their implications in disease onset. [ABSTRACT FROM AUTHOR]

Silkworm, Bombyx mori, an economically significant insect, plays a crucial role in silk production. However, silkworm breeding is highly susceptible to various pathogens, particularly the Bombyx mori nucleopolyhedrovirus (BmNPV), which poses a serious threat. Recent metabonomic studies have provided insights into the metabolic changes associated with BmNPV infection. BmNPV infection has obvious temporal characteristics. However, few studies have investigated the silkworms infected in different periods. This study employed gas chromatography–mass spectrometry (GC–MS) to perform a comprehensive analysis of haemolymph metabolites in silkworms at 48, 72, 96 and 120 h post‐infection (h.p.i.). Through the integration of time‐course analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, the study revealed distinct four‐stage metabolic characteristics in the silkworm's response to BmNPV infection. At Stage 1 (48 h.p.i.), silkworms activate antioxidant defence mechanisms, with significant enrichment in metabolic pathways involving key antioxidants such as glutathione, to mitigate oxidative stress induced by viral invasion. By Stage 2 (72 h.p.i.), pathways related to amino acid metabolism and protein synthesis become active, indicating an increase in protein synthesis. In Stage 3 (96 h.p.i.), energy metabolism and substance transport pathways are significantly upregulated to support the rapid viral replication and the enhanced locomotor behaviour of silkworm. Finally, at Stage 4 (120 h.p.i.), there is a further enhancement of pathways related to energy metabolism, nucleic acid synthesis, and substance transport, which align with peak viral assembly and release. These findings contribute to an in‐depth understanding of the biochemical basis of silkworm resistance to NPV. [ABSTRACT FROM AUTHOR]

Benign prostatic hyperplasia (BPH) is a condition commonly observed in aging males. Inflammatory and metabolic factors are pivotal in the development and progression of BPH. The degree to which the effects of 91 inflammation-related proteins on BPH are mediated by 1400 plasma metabolites remains ambiguous. Our research analyzed the impact of these traits utilizing genetic evidence.Two-sample Mendelian randomization (MR) and multivariable MR (MVMR) were utilized in our study to infer the genetic causal effect of inflammation-related proteins on BPH, with metabolites serving as mediators. Increased levels of IL-2 were linked to a heightened incidence of BPH (β = 0.071, OR:1.074, 95% CI [1.002–1.152], p = 0.045), whereas lower concentrations of N6,N6-dimethyllysine were associated with decreased risk (β1=-0.127, p = 0.02; β2=-0.039, p = 0.008). The mediation effect was 0.005 (95% CI [0.0004, 0.012], OR: 1.005, 95% CI [1.000, 1.012]), accounting for 7.04% of the total effect. subsequently, we examined the phenotypic co-localization of the two pairings independently, revealing that the posterior probability of rs145516501 associated with IL-2 and BPH was 80.7%, whereas the posterior likelihood of rs4917820 linked to N6,N6-dimethyllysine levels and BPH was 95.9%. The research indicated that N6,N6-dimethyllysine levels seem to influence the causative relationship between IL-2 and BPH. These results elucidate the complex interplay between inflammation-related proteins and metabolism in the context of BPH, offering novel diagnostic and therapeutic avenues and enhancing our comprehension of the disease's etiology for prospective research. [ABSTRACT FROM AUTHOR]

Background:BRCA1 gene dysfunction seen in epithelial ovarian carcinomas often results from germline mutations, somatic mutations, and promoter methylation. Identification of tumors with loss of BRCA1 protein expression has shown to have therapeutic and prognostic implications. The aim of this study was to determine the expression of BRCA1 protein in epithelial ovarian cancer (EOC) and the associated clinicopathological characteristics. Methods and Results: This was a cross‐sectional laboratory‐based study that used paraffin‐embedded tissue blocks of patients histologically diagnosed with EOC from January 2010 to August 2018. Tissue sections were stained with hematoxylin and eosin (H&E) for histological confirmation and with immunohistochemistry (IHC) using a mouse‐derived monoclonal antibody MS110 for BRCA1 protein expression. The association between BRCA1 protein expression and independent variables was determined using Pearson's Chi‐square test. A total of 104 tissue blocks from patients with EOC were included in the study with a mean age of 48.7 ± 12.8 years. Serous tumors were the most common which comprised 74.0% (77/104) of all the tumors and majority of them 75.3% (58/77) were high grade. Loss of expression of BRCA1 protein expression was found in 33.7% (33/98) of all the cases. There was no statistically significant association between BRCA1 expression and age of patients, tumor grade, and histological subtype. Conclusion: There is a high expression of altered BRCA1 expression in tissues of EOC. Although it has not shown association with age of patients, histology types, and tumor grade, further studies need to assess its influence of the survival of cancer patients with EOC. [ABSTRACT FROM AUTHOR]

Background: Osteoarthritis (OA) is marked by the progressive degradation of joint cartilage and subchondral bone. The precise molecular mechanisms driving meniscus deterioration in OA, especially at the single-cell level, remain poorly understood. Method: We analyzed two datasets from the GEO database, GSE220243 and GSE98918, focusing on meniscus tissue sequencing data from OA and non-OA patients. The standard Seurat procedure was employed to process single-cell data and identify differentially expressed genes (DEGs). Immune cell infiltration was assessed using the Microenvironment Cell Populations (MCP) counter and CIBERSORT algorithms. For the microarray data, DEGs were identified with the limma package, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using ClusterProfiler. The overlapping DEGs from both datasets were imported into Cytoscape to generate protein-protein interaction (PPI) networks and identify hub genes. Transcription factor (TF) and miRNA interaction networks were analyzed using NetworkAnalyst, and gene-related predictive drugs were enriched through the DSigDB platform. Result: After quality control, 34,763 cells from the OA patients and 34,145 cells from the healthy controls were analyzed. UMAP identified and SingleR annotated 14 cell clusters. The 10 largest cell clusters were selected for further analysis. The OA group exhibited a notable increase in macrophages and a reduction in cytotoxic lymphocytes and endothelial cells in the meniscus. In GSE98918, 220 DEGs were identified, and the MCODE plug-in in Cytoscape pinpointed a key module containing 12 candidate genes. The MCC methodfiltered the top 20 DEGs in each GSE220243 cluster. Overlapping DEGs from GSE220243 and GSE98918 identified COL1A1, COL3A1, COL5A2, COL6A3, LOX, and VEGFA as significantly decreased in OA, with COL3A1, COL5A2, LOX, and VEGFA upregulated in meniscal chondrocytes. The interaction network highlighted 3 key miRNAs and 13 shared TFs. Ten gene-related predictive drug molecules were identified. Conclusion: This research highlights crucial genes in the OA meniscus and uncovers their differing regulatory patterns between chondrocytes and non-chondrocytes. These findings enhance our understanding of the molecular mechanisms driving OA pathogenesis and aid in identifying potential drug targets. [ABSTRACT FROM AUTHOR]

Energy content has long been proposed as a fundamental, integrated, and reliable indicator of the condition of individuals as it reflects past bioenergetics and influences future life‐history traits. There is a direct biochemical link between energy density and body composition described by four main compounds in fish (protein, lipid, ash, and water), with proteins and lipids being the sources of energy. If relationships between water content, or lipid content, and energy density have been well described in relative terms, the absolute mass variations in the proximate composition have been overlooked and thus their interpretation is often equivocal. In our study, based on a large and unique dataset on the proximate composition and energy density of anchovy (Engraulis encrasicolus) and sardine (Sardina pilchardus) from sampling in the Bay of Biscay and the English Channel, we aimed to better explain the patterns between water content and other proximate components or energy density, based on the dynamics of proteins, lipids, and water absolute masses. For the first time, we defined good, intermediate, and poor condition states in wild fish, based on water content, corresponding to the different dynamics of lipids and proteins in the metabolism of individuals. Anchovy and sardine exhibited remarkably similar patterns of variation in the compounds and in the limits between the condition states with respect to water content. Those patterns revealed that water mass remained constant for a given fish size whatever its condition state, and that variability in water content only resulted from the variation in lipid and protein masses. Furthermore, the differential dynamics of proteins and lipids, with only lipids mobilized in the good condition state, only proteins in the poor condition state, and both proteins and lipids in the intermediate condition state, elucidates the nonlinear pattern observed in the relationship between energy density and water content. Overall, our results highlight the importance of monitoring the intraspecific variations in water content to predict the proximate composition and energy content in small pelagic fish and better assess individual and population conditions in changing ecosystems as well as to better parameterize bioenergetic models. [ABSTRACT FROM AUTHOR]

Aim Method Results Interpretation To evaluate whether serum metabolomics differ between ambulatory individuals with cerebral palsy (CP) compared with individuals with typical development and whether functional capacity is associated with metabolite abundance.Thirty‐eight adolescents and young adults were enrolled (CP: n = 19; typical development: n = 19). After functional capacity testing (10‐meter walk, sit‐to‐stand, and peak knee flexion/extension torques), blood was drawn. Targeted serum metabolomics on hydrophilic metabolites were performed by high‐performance liquid chromatography coupled with high‐resolution and tandem mass spectrometry. Metabolite dimensionality reduction, pathway analysis, fold change, and t‐tests evaluated changes in metabolite abundance. Associations were tested between functional measures and metabolite abundance.Individuals with CP had a significant increase in the abundance of essential amino acids, catabolic products of protein metabolism, and tricarboxylic acid cycle substrates, such as valine, tryptophan, kynurenic acid, and pyruvate (p < 0.05). Importantly, the abundance of numerous metabolites was only highly associated with functional capacity in individuals with CP such that greater abundance was associated with greater capacity, but not in those with typical development.Our findings show clear increases in serum metabolites in individuals with CP, which are associated with functional capacity for movement. The altered metabolite profile measured after exercise might reflect increased energy production needed for movement. Appropriate nutritional intake during exercise might be needed given increased energy requirements. [ABSTRACT FROM AUTHOR]

Simple Summary: Mortalin is a heat shock protein 70 stress chaperone family member with variable subcellular localization in normal and cancer cells. It is an essential protein with multiple functions that support and promote proliferation, endorsed by its enriched expression in various cancers. Due to its prime involvement in stress adaptation and carcinogenesis, regulating Mortalin expression and function is a viable therapeutic avenue. Upregulation of stress chaperone Mortalin has been closely linked to the malignant transformation of cells, tumorigenesis, the progression of tumors to highly aggressive stages, metastasis, drug resistance, and relapse. Various in vitro and in vivo assays have provided evidence of the critical role of Mortalin upregulation in promoting cancer cell characteristics, including proliferation, migration, invasion, and the inhibition of apoptosis, a consistent feature of most cancers. Given its critical role in several steps in oncogenesis and multi-modes of action, Mortalin presents a promising target for cancer therapy. Consequently, Mortalin inhibitors are emerging as potential anti-cancer drugs. In this review, we discuss various inhibitors of Mortalin (peptides, small RNAs, natural and synthetic compounds, and antibodies), elucidating their anti-cancer potentials. [ABSTRACT FROM AUTHOR]

Simple Summary: This article herein presented explores the role of the epigenetic marker H3K27me3 in tumors of the Central Nervous System, highlighting its importance for diagnosis, prognosis, and treatment. H3K27me3 involves the trimethylation of lysine 27 on the histone H3 protein, which is essential for regulating gene activity and maintaining chromatin structure. A reduction in H3K27me3 levels is commonly seen in CNS tumors such as diffuse midline gliomas and meningiomas and is associated with more aggressive tumor behavior and a worse prognosis. This article emphasizes the utility of H3K27me3 loss in tumor diagnosis, prognosis, and the advancement of targeted therapies. Central nervous system (CNS) tumors represent a formidable clinical challenge due to their molecular complexity and varied prognostic outcomes. This review delves into the pivotal role of the epigenetic marker H3K27me3 in the development and treatment of CNS tumors. H3K27me3, specifically the trimethylation of lysine 27 on the histone H3 protein, plays a crucial role in regulating gene expression and maintaining chromatin architecture (e.g., in X-chromosome inactivation). Notably, a reduction in H3K27me3 levels, frequently tied to mutations in the H3 gene family such as H3F3A and HIST1H3B, is evident in diverse brain tumor variants, including the diffuse midline glioma characterized by the H3K27M mutation and certain pediatric high-grade gliomas. The loss of H3K27me3 has been linked to more aggressive behavior in meningiomas, with the trimethylation loss associated with significantly shorter recurrence-free survival (RFS) among grade 2 meningiomas, albeit not within grade 1 tumors. Pediatric posterior fossa ependymomas characterized by a lowered H3K27me3 and DNA hypomethylation exhibit poor prognosis, underscoring the prognostic significance of these epigenetic alterations in CNS tumors. Comprehending the role of H3K27me3 in CNS tumors is vital for advancing diagnostic tools and therapeutic interventions, with the goal of enhancing patient outcomes and quality of life. This review underscores the importance of ongoing investigations into H3K27me to refine and optimize management strategies for CNS tumors, paving the way for improved personalized medicine practices in oncology. [ABSTRACT FROM AUTHOR]

p57Kip2 is a member of the cyclin-dependent kinase (CDK) Interacting Protein/Kinase Inhibitory Protein (CIP/Kip) family that also includes p21Cip1/WAF1 and p27Kip1. Different from its siblings, few data are available about the p57Kip2 protein, especially in humans. Structurally, p57Kip2 is an intrinsically unstructured protein, a characteristic that confers functional flexibility with multiple transient interactions influencing the metabolism and roles of the protein. Being an IUP, its localization, stability, and binding to functional partners might be strongly modulated by post-translational modifications, especially phosphorylation. In this work, we investigated by two-dimensional analysis the phosphorylation pattern of p57Kip2 in different cellular models, revealing how the human protein appears to be extensively phosphorylated, compared to p21Cip1/WAF1 and p27Kip1. We further observed clear differences in the phosphoisoforms distributed in the cytosolic and nuclear compartments in asynchronous and synchronized cells. Particularly, the unmodified form is detectable only in the nucleus, while the more acidic forms are present in the cytoplasm. Most importantly, we found that the phosphorylation state of p57Kip2 influences the binding with some p57Kip2 partners, such as CDKs, LIMK1 and CRM1. Thus, it is necessary to completely identify the phosphorylated residues of the protein to fully unravel the roles of this CIP/Kip protein, which are still partially identified. [ABSTRACT FROM AUTHOR]

Objective: In this study, we examined the effectiveness of hyperbaric oxygen (HBO) therapy in ameliorating cognitive deficits in mice with Alzheimer's disease (AD), while also assessing its impact on the autophagic pathway within the context of AD. Methods: 20 double-transgenic mice expressing the amyloid precursor protein and presenilin 1 (APP/PS1) were purposefully selected and randomly assigned to groups A and B. Concurrently, 20 C57BL/6 mice were chosen and randomly categorized into groups C and D, each consisting of 10 mice. Mice in groups B and D received HBO treatment. The Morris water maze assay was used to assess changes in mouse behavior. Immunohistochemistry techniques were used to quantify the expression levels of amyloid-beta 42 (Ab42) and microtubuleassociated protein 1A/1B-light chain 3 (LC3) in hippocampal tissues, while western blot analysis was used to investigate the levels of LC3-II, p62, phosphoinositide 3-kinase (PI3K), and mammalian target of rapamycin (mTOR) proteins within hippocampal tissues. Results: Mice allocated to group B exhibited reduced escape latency and prolonged dwell time in the target quadrant compared to other groups. Histological examination revealed conspicuous plaque-like deposits of Ab42 in the hippocampal tissues of mice in groups A and B. Group B displayed diminished Ab42-positive reactants and augmented microtubule-associated protein 1A/1B-LC3-positive reactants compared to group A. LC3-positive reactants were also detected in the hippocampal tissues of mice in groups C and D, surpassing the levels observed in groups A and B. Furthermore, group B demonstrated significantly lower expression of mTOR protein and markedly higher expression of LC3-II protein in mouse hippocampal tissues when compared to group A (P < 0.05). Conversely, there were no significant disparities noted in PI3K and p62 protein expression between groups B and A. Notably, no discernible discrepancies were observed in the expression levels of mTOR, PI3K, LC3-II, and p62 proteins between groups C and D within mouse hippocampal tissues. Conclusion: HBO treatment demonstrates efficacy in enhancing cognitive function in mice with AD and holds promise as a potential therapeutic intervention for AD by facilitating the activation of the mTOR pathwaymediated autophagy. [ABSTRACT FROM AUTHOR]

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Background: Clausena harmandiana (CH), commonly known as song fa dong, was a medicinal plant traditionally used to treat illnesses and as a health tonic. CH root extract (CHRE) exhibited various bioactivities, including neuroprotective, antioxidant, antimicrobial, antifungal, anti-inflammatory, and anti-cancer effects. However, CHRE data on neuroprotective in AD-like animal models were still scarce. Objectives: This study aimed to investigate the effects of CHRE on Aβ1-42-induced cognitive deficits, free radical damage, and neuronal death in rats. Methods: Forty-eight adult male Sprague-Dawley rats (250–300 g) were classified as sham control (SC), V+Aβ, Vit C+Aβ, CHRE125+Aβ, CHRE250+Aβ, and CHRE500+Aβ (n = 8 in each group). Animals were orally administered with 0.5% sodium carboxymethylcellulose, vitamin C (200 mg/kg BW), or CHRE (125, 250, and 500 mg/kg BW) and were untreated for 35 days. On day 21, all treated rats were injected with 1 µl of aggregated Aβ1-42 (1 µg/µl) into the lateral ventricles, bilaterally, whereas untreated rats were injected with sterilized normal saline (NS). The Morris water maze test estimated the rat's learning and memory one week later. At the end of the treatment, all rats were sacrificed, and their brains were removed and divided into two hemispheres. On the left, morphological changes and neuronal density were observed in hippocampal CA1 and CA3 regions. While, on the right, changes in free radical damage markers (SOD, CAT, GPx, MDA, and Nrf2) and protein expression of active caspase-3 were evaluated in the hippocampus. Results: Pretreatment with CHRE at all doses could alleviate spatial learning and memory defects. CHRE also improved morphological changes and a decrease in neuronal density in CA1 and CA3 regions. Additionally, CHRE significantly increased the activities of antioxidant enzymes (SOD, CAT, GPx) and Nrf2 expression. This was coupled with significantly decreased MDA levels and active caspase-3 expression in the hippocampus of Aβ1-42-induced rats, which was similar to vitamin C exposure. Conclusions: Our findings suggested that CHRE ameliorated cognitive deficits and exhibited neuroprotective effects by reducing free radical damage and mitigating neuronal abnormality and neuronal death. [ABSTRACT FROM AUTHOR]

Poly(ADP-ribose) (PAR), a non-canonical nucleic acid, is essential for DNA/RNA metabolism and protein condensation, and its dysregulation is linked to cancer and neurodegeneration. However, key structural insights into PAR's functions remain largely uncharacterized, hindered by the challenges in synthesizing and characterizing PAR, which are attributed to its length heterogeneity. A central issue is how PAR, comprised solely of ADP-ribose units, attains specificity in its binding and condensing proteins based on chain length. Here, we integrate molecular dynamics simulations with small-angle X-ray scattering to analyze PAR structures. We identify diverse structural ensembles of PAR that fall into distinct subclasses and reveal distinct compaction of two different lengths of PAR upon the addition of small amounts of Mg2+ ions. Unlike PAR15, PAR22 forms ADP-ribose bundles via local intramolecular coil-to-globule transitions. Understanding these length-dependent structural changes could be central to deciphering the specific biological functions of PAR. This study reveals the 3D structures of poly(ADP-ribose) (PAR) using small-angle X-ray scattering and molecular dynamics simulations. It demonstrates how cation concentration and polymer length influence PAR's structure, providing insights into how a homopolymer can have specific functional roles. [ABSTRACT FROM AUTHOR]

Phoenix barb (Spinibarbus denticulatus denticulatus) is a notable fish species in South China and is valued for its ecological and economic importance. To elucidate the molecular basis underlying its growth, we collected transcriptome profiles from the brains and livers of individual fish with different growth rates and compared differentially expressed genes (DEGs) at 3 and 9 months after hatching (MAH). Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that the pathways associated with growth were predominantly enriched in fatty acid biosynthesis, AMPK signaling, PI3K-Akt signaling, estrogen signaling, and protein metabolism. Notably, a greater number of DEGs from the fast-growing group were associated with these pathways at the early growth stage (3 MAH) than at the later stage (9 MAH). Real-time quantitative PCR results further validated that the genes involved in these pathways exhibited higher expression levels in fast-growing samples. This study enhances our understanding of the genetic mechanisms underlying growth rate differences and provides valuable genetic resources for future growth-related molecular breeding programs of phoenix barbs. [ABSTRACT FROM AUTHOR]

Microsporidia are unfriendly microorganisms, and their infections cause considerable damage to economically or environmentally important insects like silkworms and honeybees. Thus, the identification of measures to improve host resistance to microsporidia infections is critically needed. Here, an overexpressed miR-6498-5p transgenic silkworm line was constructed. Importantly, the survival rates and median lethal doses of the transgenic line were clearly higher after infection with Nosema bombycis. H&E staining and RT-qPCR analyses revealed an inhibitory effect on the proliferation of N. bombycis in the transgenic larvae. Metabolomics analysis further revealed the presence of 56 differential metabolites between the two lines. KEGG analysis of these 56 metabolites found that they were involved in various amino acid and vitamin metabolism pathways. Notably, VB6 metabolism was enriched among the metabolites, and the pathway was well known for its involvement in the synthesis, interconversion, and degradation of amino acids. These suggest that miR-6498-5p modifies parasitic environments to inhibit the proliferation of N. bombycis by affect ing the host amino acid metabolism. These results demonstrate the potential of microRNAs as biomolecules that can promote resistance to microsporidia and provide new insights and a new approach to generate microsporidia-resistant biological materials. IMPORTANCE Microsporidia have an extremely wide host range and are capable of infecting a wide variety of insects and vertebrates, including humans, and their lethality to multiple species often poses significant environmental management challenge. Here, we successfully constructed a microsporidium-resistant line in the silkworm, based on the overexpression of miR-6498-5p. Our results strongly support the hypothesis that miR-6498-5p efficiently suppresses the proliferation of Nosema bombycis by regulating the host VB6 metabolism, a key pathway for enzymes involved in amino acid transport and protein metabolism. Our study provides new insights for understanding host anti-pathogen defenses toward microsporidia. [ABSTRACT FROM AUTHOR]

Simple Summary: Epithelial-to-mesenchymal transition (EMT) plays a critical role in cancer progression, contributing to the invasive and migratory abilities of tumor cells. In this study, we show that FBXO11 promotes the degradation of ZEB1, a key EMT regulator, via ubiquitination. Loss of FBXO11 increases ZEB1 levels, enhancing the invasiveness of lung cancer cells, while its overexpression reduces ZEB1 and suppresses invasion. Importantly, higher FBXO11 expression is associated with better prognosis in non-small cell lung cancer (NSCLC), highlighting its potential role as a therapeutic target for controlling EMT and cancer metastasis. Epithelial-to-mesenchymal transition (EMT) affects the invasion and migration of cancer cells. Here, we show that FBXO11 recognizes and promotes ubiquitin-mediated degradation of ZEB1. There is a strong association between FBXO11 and ZEB1 in non-small cell lung cancer (NSLC) in a clinical database. FBXO11 interacts with ZEB1, a core inducer of EMT. FBXO11 leads to increased ubiquitination and proteasomal degradation of ZEB1. Depletion of endogenous FBXO11 causes ZEB1 protein accumulation and EMT in A549 and H1299 cells, while overexpression of FBXO11 reduces ZEB1 protein abundance and cellular invasiveness. Importantly, the depletion of ZEB1 suppresses the increased migration and invasion of A549 and H1299 cells promoted by the depletion of FBXO11. The same results are shown in xenograft tumors. High FBXO11 expression is associated with a favorable prognosis in NSLC. Collectively, our study demonstrates that FBXO11 modulates EMT by mediating the stability of ZEB1 in lung cancer cells. [ABSTRACT FROM AUTHOR]

Germline cells produce gametes, which are specialized cells essential for sexual reproduction. Germline cells first amplify through several rounds of mitosis before switching to the meiotic program, which requires specific sets of proteins for DNA recombination, chromosome pairing, and segregation. Surprisingly, we previously found that some proteins of the synaptonemal complex, a prophase I meiotic structure, are already expressed and required in the mitotic region of Drosophila females. Here, to assess if additional meiotic genes were expressed earlier than expected, we isolated mitotic and meiotic cell populations to compare their RNA content. Our transcriptomic analysis reveals that all known meiosis I genes are already expressed in the mitotic region; however, only some of them are translated. As a case study, we focused on mei-W68 , the Drosophila homolog of Spo11 , to assess its expression at both the mRNA and protein levels and used different mutant alleles to assay for a premeiotic function. We could not detect any functional role for Mei-W68 during homologous chromosome pairing in dividing germ cells. Our study paves the way for further functional analysis of meiotic genes expressed in the mitotic region. [ABSTRACT FROM AUTHOR]

Cohesins promote proper chromosome segregation, gene transcription, genomic architecture, DNA condensation, and DNA damage repair. Mutations in either cohesin subunits or regulatory genes can give rise to severe developmental abnormalities (such as Robert Syndrome and Cornelia de Lange Syndrome) and also are highly correlated with cancer. Despite this, little is known about cohesin regulation. Eco1 (ESCO2/EFO2 in humans) and Rad61 (WAPL in humans) represent two such regulators but perform opposing roles. Eco1 acetylation of cohesin during S phase, for instance, stabilizes cohesin-DNA binding to promote sister chromatid cohesion. On the other hand, Rad61 promotes the dissociation of cohesin from DNA. While Eco1 is essential, ECO1 and RAD61 co-deletion results in yeast cell viability, but only within a limited temperature range. Here, we report that eco1 rad61 cell lethality is due to reduced levels of the cohesin subunit Mcd1. Results from a suppressor screen further reveals that FDO1 deletion rescues the temperature-sensitive (ts) growth defects exhibited by eco1 rad61 double mutant cells by increasing Mcd1 levels. Regulation of MCD1 expression, however, appears more complex. Elevated expression of MBP1 , which encodes a subunit of the MBF transcription complex, also rescues eco1 rad61 cell growth defects. Elevated expression of SWI6 , however, which encodes the Mbp1 -binding partner of MBF, exacerbates eco1 rad61 cell growth and also abrogates the Mpb1-dependent rescue. Finally, we identify two additional transcription factors, Fkh1 and Fkh2 , that impact MCD1 expression. In combination, these findings provide new insights into the nuanced and multi-faceted transcriptional pathways that impact MCD1 expression. [ABSTRACT FROM AUTHOR]

RNA-binding proteins (RBPs) play essential roles in coordinating germline gene expression and development in all organisms. Here, we report that loss of ADR-2, a member of the adenosine deaminase acting on RNA family of RBPs and the sole adenosine-to-inosine RNA-editing enzyme in Caenorhabditis elegans , can improve fertility in multiple genetic backgrounds. First, we show that loss of RNA editing by ADR-2 restores normal embryo production to subfertile animals that transgenically express a vitellogenin (yolk protein) fusion to green fluorescent protein. Using this phenotype, a high-throughput screen was designed to identify RBPs that when depleted yield synthetic phenotypes with loss of adr-2. The screen uncovered a genetic interaction between ADR-2 and SQD-1, a member of the heterogeneous nuclear ribonucleoprotein family of RBPs. Microscopy, reproductive assays, and high-throughput sequencing reveal that sqd-1 is essential for the onset of oogenesis and oogenic gene expression in young adult animals and that loss of adr-2 can counteract the effects of loss of sqd-1 on gene expression and rescue the switch from spermatogenesis to oogenesis. Together, these data demonstrate that ADR-2 can contribute to the suppression of fertility and suggest novel roles for both RNA editing–dependent and RNA editing–independent mechanisms in regulating embryogenesis. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to clarify the difference in Fusobacterium nucleatum (F. nucleatum) induced inflammatory cytokines and nod‐like receptor protein 3 (NLRP3) inflammasomes dysregulation among three periodontal cells. Methods: Oral epithelial cells (HIOECs), THP‐1 macrophages, and human gingival fibroblasts (HGFs) were exposed to F. nucleatum with/without adenosine triphosphate (ATP) and nigericin (Nig). Cell morphology was assessed by scanning electron microscopy. qRT‐PCR, protein microarrays, and bioinformatic methods were used to evaluate the cytokines and their complex interplay. NLRP3 inflammasomes activation was detected by western blotting and ELISA. Results: F. nucleatum adhered to and invaded cells. In HIOECs, F. nucleatum enhanced interleukin (IL)‐1α/1β/6/10/13, TNF‐α, and interferon (IFN)‐γ expression. In THP‐1 macrophages, F. nucleatum up‐regulated IL‐1α/1β/6/10 and TNF‐α levels. In HGFs, F. nucleatum increased IL‐6 levels. F. nucleatum and ATP synergistically boosted IFN‐γ level in THP‐1 macrophages and IL‐13 level in HGFs. IL‐1α/1β/6, and TNF‐α served as epicenters of the inflammatory response. Additionally, F. nucleatum activated NLRP3 inflammasomes in HIOECs, and ATP/Nig boosted the activation. F. nucleatum also triggered NLRP3 inflammasomes in THP‐1 macrophages, but in HGFs, only NLRP3 and caspase‐1 levels were elevated. Conclusion: F. nucleatum infiltrated periodontal supporting cells and dysregulated inflammatory cytokines and NLRP3 inflammasomes. [ABSTRACT FROM AUTHOR]

Objective: To explore the biological function and mechanisms of CEBPB and NAT10‐mediated N4‐acetylcytidine (ac4c) modification in salivary adenoid cystic carcinoma (SACC). Materials and Methods: CEBPB and NAT10 were knocked down in SACC–LM cells by siRNA transfection and overexpressed in SACC‐83 cells by plasmid transfection. Malignant phenotypes were evaluated using CCK‐8, Transwell migration and colony formation assays. Real‐time PCR, western blotting, ChIP and acRIP were used to investigate the molecular mechanisms involved. Results: We found that CEBPB was highly expressed in SACC tissues and correlated with lung metastasis and unfavourable prognosis. Gain‐ and loss‐of‐function experiments revealed that CEBPB promoted SACC malignant phenotypes. Mechanistically, CEBPB exerted its oncogenic effect by binding to the vimentin gene promoter region to enhance its expression. Moreover, NAT10‐mediated ac4c modification led to stabilization and overexpression of CEBPB in SACC cells. We also found that NAT10, the only known human enzyme responsible for ac4C modification, promoted SACC cell migration, proliferation and colony formation. Moreover, CEBPB overexpression restored the inhibitory effect of NAT10 knockdown on malignant phenotypes. Conclusions: Our study reveals the critical role of the newly identified NAT10/CEBPB/vimentin axis in SACC malignant progression, and the findings may be applied to improve treatment for SACC. [ABSTRACT FROM AUTHOR]

Objective: Anterior disc displacement (ADD) is a common clinical issue and may cause osteoarthritis (OA). However, the research of protein changes in synovial fluid as disease development marker and potential treatment clue is still insufficient. Materials and Methods: We conducted the high‐resolution mass spectrometry (MS) of synovial fluid collected from 60 patients with normal disk position to ADD and ADD with osteoarthritis (OA). The proteins with significant changes among the 3 groups were analyzed by biological information and further validated by in primary rat condyle chondrocytes and OA animal model. Results: FGL2, THBS4, TNC, FN1, OMD etc. were significantly increased in ADD without OA (p < 0.05), which reflected the active extracellular matrix and collagen metabolism. FGFR1, FBLN2, GRB2 etc. were significantly increased in ADD with OA group (p < 0.05), which revealed an association with apoptosis and ferroptosis. Proteins such as P4HB, CBLN4, FHL1, VIM continuously increase in the whole disease progress (p < 0.05). Both the in vitro and in vivo results are consistent with protein changes detected in MS profile. Conclusion: This study firstly provides the expression changes of proteins from normal disc condyle relationship toward ADD with OA, which can be selected and studied further as disease progress marker and potential treatment targets. [ABSTRACT FROM AUTHOR]

Objectives: The World Health Organization's definition of oral epithelial dysplasia includes differentiated dysplasia, which is defined by purely architectural abnormalities of oral mucosa without cytological changes. We analysed differentiated dysplasia's frequency, progression risk and correlation with oral brush cytology. Materials and Methods: Cytoarchitectural criteria and expression patterns of keratin 13/17 and ki67 were studied in oral biopsies clinically diagnosed with leukoplakia. Biopsies were assessed for dysplasia and its grade. Available brush cytology findings were obtained from clinical records. Results: We included 159 biopsies from 112 patients (33% differentiated dysplasia; 27% keratosis without dysplasia; oral epithelial dysplasia with atypia of mild, moderate and severe degree including invasive cancers in 9%, 8% and 7%, respectively). Keratin 13 loss and keratin 17 gain were higher in differentiated‐dysplasia cases (p < 0.0001), which had the highest hypergranulosis frequency. Keratin 17 expression was associated with higher malignant‐transformation rates (p = 0.0028). The transformation rate and time were comparable between dysplasia with atypia and differentiated‐dysplasia cases, which had higher progression rates and shorter time periods than keratosis cases without dysplasia (p = 0.08). Cytology prior to differentiated dysplasia all indicated normal oral mucosa. Conclusions: Keratin 17 but not oral brush cytology can help identify patients with differentiated dysplasia with higher risk for malignant transformation. [ABSTRACT FROM AUTHOR]

[Display omitted] • Lipidomics identified 23 lipid classes low in glycolipids in tick salivary glands. • Phosphatidylcholine (PC; 26.66%) was the lipid class with the highest representation. • Tick salivary glycolipids were mostly represented by diacylglycerol (DG; 0.48%). • Individuals bitten by ticks produced more phosphatidylcholine-IgG antibodies. • DG levels were higher in tick salivary glands than in tick saliva. Ticks, as hematophagous ectoparasites, can manipulate host immune and metabolic processes, causing tick-borne allergies such as α-Gal syndrome (AGS). Glycolipids with bound galactose-alpha-1–3-galactose (α-Gal) are potential allergenic molecules associated with AGS. Nevertheless, proteins and lipids lacking α-Gal modifications may contribute to tick salivary allergies and be linked to AGS. In this study, we characterized the effect of deglycosylated tick salivary proteins without lipids on treated zebrafish fed with dog food formulated with mammalian (beef, lamb, pork) meat by quantitative proteomics analysis of intestinal samples. The characterization and functional annotations of tick salivary lipids with low representation of glycolipids was conducted using a lipidomics approach. Results showed a significant effect of treatment with saliva and saliva deglycosylated protein fraction on zebrafish abnormal or no feeding (p < 0.005). Treatment with this fraction affected multiple metabolic pathways, defense responses to pathogens and protein metabolism, which correlated with abnormal or no feeding. Lipidomics analysis identified 23 lipid classes with low representation of glycolipids (0.70% of identified lipids). The lipid class with highest representation was phosphatidylcholine (PC; 26.66%) and for glycolipids it corresponded to diacylglycerol (DG; 0.48%). Qualitative analysis of PC antibodies revealed that individuals bitten by ticks were more likely to produce PC-IgG antibodies (p < 0.001). DG levels were significantly higher in tick salivary glands (p < 0.05) compared with tick saliva and salivary fractions. The α-Gal content was higher in tick saliva than in deglycosylated saliva and lipid fractions. These results support a possible role for tick salivary proteins and lipids without α-Gal modifications in AGS. [ABSTRACT FROM AUTHOR]

Antiretroviral treatment of HIV infected individuals cannot eliminate the HIV reservoir and immune control of HIV is rarely seen upon treatment interruption. In long-term non-progressors (LTNP), an effective CD8 T cell response is thought to contribute to be immune control of HIV. Here we studied the transcriptional profile of virus specific CD8 T cells during the asymptomatic phase of disease, to gain molecular insights in CD8 T cell functionality in HIV progressors and different groups of LTNP: HLA-B*57 LTNP, non-HLA-B*57 LTNP and individuals carrying the MAVS minor genotype (rs7262903/rs7269320). Principal component analysis revealed distinct overall transcriptional profiles between the groups. The transcription profile of HIV-specific CD8 T cells of LTNP groups was associated with increased cytokine/IL-12 signaling and protein/RNA metabolism pathways, indicating an increased CD8 T cell functionality. Although the transcription profile of CMV-specific CD8 T cells differed from that of HIV-specific CD8 T cells, with mainly an upregulation of gene expression in progressors, similar affected pathways were identified. Moreover, CMV-specific CD8 T cells from progressors showed increased expression of genes related to effector functions and suggests recent antigen exposure. Our data shows that changes in cytokine signaling and the energy demanding RNA and protein metabolism are related to CD8 T cell dysfunction, which may indicate that mitochondrial dysfunction is an important driver of T cell dysfunctionality during chronic HIV infection. Indeed, improvement of mitochondrial function by IL-12 and mitoTempo treatment, enhanced in vitro IFNγ release by PBMC from PWH upon HIV gag and CMV pp65 peptide stimulation. Our study provides new insights into the molecular pathways associated with CD8 T cell mediated immune control of chronic HIV infection which is important for the design of novel treatment strategies to restore or improve the HIV-specific immune response. [ABSTRACT FROM AUTHOR]

Objective: TNFAIP8 and TIPE2 belong to TNFa-induced protein 8 (TNFAIP8/TIPE) family. They control apoptosis and direct leukocyte migration. Nucleus pulposus cell loss is a hallmark of intervertebral disc degeneration in response to injury, and inflammation may cause pain. Here, we examined the effects of TNFAIP8/TIPE2 deficiency on the intervertebral discs in mice with these genes deleted. Design: Tail intervertebral discs in Tnfaip8 or Tipe2 single and double knockout mice (Tnfaip8−/− , Tipe2−/− , and Tnfaip8/Tipe2 dko), and wild-type controls were injured. The spine motion segments were stained with safranin O to reveal proteoglycans. Macrophages were identified by immunostaining, and selected inflammatory marker and collagen gene expression was examined by Real Time PCR. Results: The injured tail intervertebral discs of Tnfaip−/− , Tipe2−/− , and Tnfaip8/Tipe2 dko mice all displayed higher levels of proteoglycans than wild-type controls. Fewer macrophages were found in the injured intervertebral discs of Tipe2−/− and Tnfaip8/Tipe2 dko mice than wild type. Il6, Adam8, and Col1 gene expression was downregulated in the injured intervertebral discs of Tnfip8/Tipe2 dko mice. Conclusions: TNFAIP8 and TIPE2 loss of function ameliorated proteoglycan loss and inflammation in the injured intervertebral discs. They may serve as molecular targets to preserve disc structure and reduce inflammation. [ABSTRACT FROM AUTHOR]

Introduction: The human immunodeficiency virus (HIV) and tuberculosis (TB) co-infection presents significant challenges due to the complex interplay between these diseases, leading to exacerbated metabolic disturbances. Understanding these metabolic profiles is crucial for improving diagnostic and therapeutic approaches. Objective: This study aimed to characterise the urinary acylcarnitine and amino acid profiles, including 5-hydroxyindoleacetic acid (5-HIAA), in patients co-infected with HIV and TB using targeted liquid chromatography mass spectrometry (LC–MS) metabolomics. Methods: Urine samples, categorised into HIV, TB, HIV/TB co-infected, and healthy controls, were analysed using HPLC–MS/MS. Statistical analyses included one-way ANOVA and a Kruskal-Wallis test to determine significant differences in the acylcarnitine and amino acid profiles between groups. Results: The study revealed significant metabolic alterations, especially in TB and co-infected groups. Elevated levels of medium-chain acylcarnitines indicated increased fatty acid oxidation, commonly associated with cachexia in TB. Altered amino acid profiles suggested disruptions in protein and glucose metabolism, indicating a shift towards diabetes-like metabolic states. Notably, TB was identified as a primary driver of these changes, affecting protein turnover, and impacting energy metabolism in co-infected patients. Conclusion: The metabolic profiling of HIV/TB co-infection highlights the profound impact of TB on metabolic pathways, which may exacerbate the clinical complexities of co-infection. Understanding these metabolic disruptions can guide the development of targeted treatments and improve management strategies, ultimately enhancing the clinical outcomes for these patients. Further research is required to validate these findings and explore their implications in larger, diverse populations. [ABSTRACT FROM AUTHOR]

Pathobionts associated with periodontitis, such as Treponema denticola, must possess numerous sensory transduction systems to adapt to the highly dynamic subgingival environment. To date, the signaling pathways utilized by T. denticola to rapidly sense and respond to environmental stimuli are mainly unknown. Bis‐(3′–5′) cyclic diadenosine monophosphate (c‐di‐AMP) is a nucleotide secondary messenger that regulates osmolyte transport, central metabolism, biofilm development, and pathogenicity in many bacteria but is uncharacterized in T. denticola. Here, we studied c‐di‐AMP signaling in T. denticola to understand how it contributes to T. denticola physiology. We demonstrated that T. denticola produces c‐di‐AMP and identified enzymes that function in the synthesis (TDE1909) and hydrolysis (TDE0027) of c‐di‐AMP. To investigate how c‐di‐AMP may impact T. denticola cellular processes, a screening assay was performed to identify putative c‐di‐AMP receptor proteins. This approach identified TDE0087, annotated as a potassium uptake protein, as the first T. denticola c‐di‐AMP binding protein. As potassium homeostasis is critical for maintaining turgor pressure, we demonstrated that T. denticola c‐di‐AMP concentrations are impacted by osmolarity, suggesting that c‐di‐AMP negatively regulates potassium uptake in hypoosmotic solutions. Collectively, this study demonstrates T. denticola utilizes c‐di‐AMP signaling, identifies c‐di‐AMP metabolism proteins, identifies putative receptor proteins, and correlates c‐di‐AMP signaling to osmoregulation. [ABSTRACT FROM AUTHOR]

In the present study, we evaluated the physicochemical properties, free amino acids concentration, metabolomics, and the relationship between main metabolites and volatile compounds of Jinhua ham prepared using Taihu black pigs during a ripening period of 210 days to elucidate the distinguishing features and formation process of the quality of this ham. During the eight timepoints, the color parameters redness and yellowness exhibited significant changes. Water activity gradually decreased. The tastes of saltiness, sourness and umami were main taste characteristics of Jinhua ham. Carnosine and glutamic acid were the main umami taste compounds and their contents reached to 1785 ± 92.2 and 699 ± 65.1 mg/100 g respectively. Metabolomics-based analysis showed that the dominant biochemical reaction was the metabolism of carboxylic acids and their derivatives. Total 153 significantly differential metabolites were identified. The main metabolic pathways were different in the three different periods respectively. Lipid metabolism was the predominant pathway in low–temperature stage, while amino acid formation and protein metabolism were the predominant pathways in the moderate–temperature and high–temperature stage. The dominant flavor compounds were closely related to the key differential metabolites. Our study findings revealed the quality, significantly differential metabolites, and formation process of Jinhua ham prepared using Taihu black pigs. [ABSTRACT FROM AUTHOR]

In recent years, systemic inflammation has emerged as a pivotal player in the development and progression of various degenerative diseases. This complex, chronic inflammatory state, often undetected, can have far‐reaching consequences for the body's physiology. At the molecular level, markers such as C‐reactive protein, cytokines and other inflammatory mediators serve as indicators of systemic inflammation and often act as predictors of numerous musculoskeletal diseases and even certain forms of cancer. The concept of 'meta‐inflammation', specifically referring to metabolically triggered inflammation, allows healthcare professionals to understand inflammatory responses in patients with metabolic syndrome. Driven by nutrient excess and the expansion of adipose tissue, meta‐inflammation is closely associated with insulin resistance, further propagating the metabolic dysfunction observed in many Western societies. Wound persistence, on the other hand, exacerbates the detrimental effects of prolonged inflammation at the local level. Acute inflammation is a beneficial and essential process for wound healing and infection control. However, when inflammation fails to resolve, it can impede the healing process, leading to chronic wounds, excessive scarring and even the activation of fibrotic pathways. This approach significantly reduces the efficacy of regenerative biological therapies. Our review focuses on the vital role of proteins, vitamins and minerals in collagen synthesis and cell proliferation for tissue healing. We also examine hormonal influences on regeneration, noting the negative effects of imbalances, and emphasize glucose regulation's importance in creating a stable environment for chronic wound healing. [ABSTRACT FROM AUTHOR]

Background: Idiopathic pulmonary fibrosis (IPF) is the result of multiple cycles of epithelial cell injury and fibroblast activation; currently, there is no clear etiology. Increasing evidence suggests that protein metabolism and amino acids play a crucial role in IPF, but the role of D-amino acids is not yet clear. The aim of this study was to identify novel mediators in order to test the hypothesis that D-amino acid oxidase (DAO) plays a significant role in the pathogenesis of IPF. Methods: We analyzed DAO gene expression in patients with IPF and mice with bleomycin (BLM)-induced lung fibrosis. We performed in vitro and in vivo assays to determine the effect of DAO on primary type II alveolar epithelial cells from mice and A549 cells. Results: DAO expression was downregulated in the lungs of IPF patients and BLM-induced fibrotic mice. Treatment with D-serine (D-Ser) or drug inhibition of DAO promoted cell senescence through the p53/p21 pathway. Dao-/- mice showed an intensified fibrotic response, and the anti-fibrotic role of T3 was abolished. Conclusion: We concluded that the DAO-p53/p21 axis might be a key antifibrotic pathway regulating the progress of fibrosis and facilitating the therapeutic role of T3. [ABSTRACT FROM AUTHOR]

Simple Summary: This research aims to explore how specific imaging features on computed tomography (CT) scans, related to lipid metabolism, can be linked to a protein called adipose differentiation-related protein (ADFP) in clear cell renal cell carcinoma. This study suggests that tumors with higher lipid content, which can be seen as lower values on a CT scan, are associated with lower-grade, less aggressive cancers that express ADFP. This finding is significant because it could lead to non-invasive methods for evaluating tumor characteristics, potentially helping better understand the nature of the cancer and tailor treatment plans without needing invasive procedures. This study aimed to investigate the association between metabolic lipid computed tomography (CT) features and adipose differentiation-related protein (ADFP) expression in clear cell renal cell carcinoma (ccRCC), providing insights into non-invasive methods for assessing ADFP expression and tumor characteristics. This study utilized data from The Cancer Genome Atlas and the Cancer Imaging Archive to analyze genetic alterations and imaging characteristics in ccRCC patients. Tumoral Hounsfield units (HU) analysis and quantification of abdominal adipose tissue compartments were performed using CT images. Statistical analyses were conducted to compare tumoral HU values according to ADFP gene expression and World Health Organization/International Society of Urological Pathology (WHO/ISUP) tumor grade, as well as to explore correlations between tumoral HU values and adipose tissue quantification. Among the 174 identified patients, those with ADFP gene expression showed significantly lower minimum tumoral HU values in low-grade cancers compared to high-grade cancers. Similarly, patients with low-grade cancers expressing ADFP exhibited lower minimum tumoral HU values compared to those without ADFP expression. Negative correlations were observed between minimum tumoral HU values and visceral adipose tissue, subcutaneous adipose tissue, and total adipose tissue in both ccRCC patients with and without ADFP expression. This study reveals a significant association between metabolic lipid CT features and ADFP expression in ccRCC patients. Lower minimum tumoral HU values, suggestive of higher intracellular lipid accumulation, were observed in tumors with low WHO/ISUP grade and ADFP expression. [ABSTRACT FROM AUTHOR]

Background: Chronic alcohol users often exhibit an increased minimum alveolar concentration (MAC) of sevoflurane, yet the specific mechanism remains unclear. It has been reported that ethanol exposure can upregulate the protein expression and enzyme activity of cytochrome P450 2E1 (CYP2E1). CYP2E1 is a key enzyme that converts 2–5% of sevoflurane into equimolar amounts of hexafluoroisopropanol (HFIP) and F−. This study aims to explore whether ethanol exposure could alter sevoflurane metabolism through CYP2E1 modulation, potentially explaining the increased MAC observed in alcohol users. Methods: Eighty adult male Sprague-Dawley (SD) rats were randomly divided into two groups and received either 50% ethanol (dose: 3 g/kg) or 0.9% saline twice daily by gavage. After 1, 2, 3, and 4 weeks of gavage, ten rats were randomly selected from each group to undergo 1-hour anesthesia with 2.3% sevoflurane. Blood samples were collected after anesthesia to measure the concentration of free HFIP using gas chromatography. Additionally, the left lobe tissue of the liver was collected for the analysis of CYP2E1 protein expression by Western blot and CYP2E1 enzyme activity by colorimetric assay. Correlations between these parameters were analyzed using Pearson's correlation. Results: In the ethanol group, CYP2E1 expression, activity, and the concentration of free HFIP were significantly higher at all time points compared to the control group (P < 0.05), except for protein expression in the first week (P > 0.05). Within-group comparisons indicated no significant changes in any of the parameters for the control group (P > 0.05). In the ethanol group, there was no difference in free HFIP concentration between the first and second weeks (P > 0.05), but a significant increase was observed in the third and fourth weeks (P < 0.01); protein expression and enzyme activity significantly varied over time, especially showing a notable increase from the first to the third and fourth weeks (P < 0.05). Correlation analysis revealed strong positive correlations between free HFIP concentration and CYP2E1 activity (r = 0.7898), free HFIP concentration and CYP2E1 expression (r = 0.8418), and CYP2E1 activity and expression (r = 0.8740), all with P < 0.001. Conclusions: Ethanol exposure increased both the expression and enzymatic activity of CYP2E1, consequently enhancing the metabolism of sevoflurane. [ABSTRACT FROM AUTHOR]

Background: Tyrosine-rich amelogenin peptide (TRAP) is the main amelogenin digestion product in the developmental enamel matrix. It has been shown to promote remineralization of demineralized enamel in our previous study. However, direct evidence of the effect of TRAP on the morphology and nanostructure of crystal growth on an enamel surface has not been reported. This study aimed to examine the effect of TRAP on the morphology of calcium phosphate crystals grown on early enamel erosion using a pH-cycling model. Methods: Eroded lesions were produced in human premolars by 30-second immersion in 37% phosphoric acid. Forty-five samples of eroded human premolar enamel blocks were selected and randomly divided into 3 groups: deionized water (DDW, negative control); 100 µg/mL TRAP, and 2 ppm sodium fluoride (NaF, positive control group). For 14 days, the specimens were exposed to a pH-cycling model. Using scanning electron microscopy (SEM) and atomic force microscopy (AFM) methods, the surface morphology, calcium-phosphorus ratio, and enamel surface roughness were examined. X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FT-IR) were used to assess crystal characteristics. Results: After pH-cycling, compared to the two control groups, the surface of the eroded enamel of the peptide TRAP group shows a large number of new, densely arranged rod-like crystals, parallel to each other, regularly arranged, forming an ordered structure, with crystal morphology similar to that of natural enamel. The crystals are mostly hydroxyapatite (HA). Conclusion: This study demonstrates that the peptide TRAP modulates the formation of hydroxyapatite in eroded enamel and that the newly formed crystals resemble natural enamel crystals and promote the remineralization of enamel, providing a promising biomaterial for remineralization treatment of enamel lesions. [ABSTRACT FROM AUTHOR]

Background: Increased hemoglobin concentrations may increase the risk of varicose veins. However, the underlying relationship between them was not yet understood. Methods: Mendelian randomization (MR) analysis was performed to investigate causal effect between mean corpuscular hemoglobin concentration (MCHC, exposure factor) and varicose veins (outcome). Afterward, sensitivity analysis was used to ensure the reliability of MR analysis results. Then Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of SNPs were performed. A search tool for recurring instances of neighbouring genes (STRING) database was used to construct a protein-protein interaction (PPI) network. Results: Therefore, the inverse-variance weighted (IVW) results showed there existed a causal relationship between MCHC and varicose veins (p = 0.0026), with MCHC serving as a significant risk factor. (odd ratio [OR] = 1.2321). In addition, the validity of the results of the forward MR analysis was verified by sensitivity analysis. Further, a PPI network of 92 single-nucleotide polymorphisms (SNPs) which used for forward MR analysis related genes was constructed. And they were found to be closely associated with the peroxisome proliferator-activated receptor (PPAR) signalling pathway and cellular response to external stimulus by enrichment analysis. In addition, we clarified that the effect of varicose veins on MCHC was minimal by reverse MR analysis, suggesting that the results of forward MR analysis were not disturbed by reverse results. Conclusion: This study found a causal relationship between varicose veins and MCHC, which provided strong evidence for the effect of hemoglobin on varicose veins, and a new thought for the diagnosis and prevention of varicose veins in the future. [ABSTRACT FROM AUTHOR]

Introduction The emergence of colistin resistance threatens the treatment of Pseudomonas aeruginosa infections. Methods In this study, in vitro development of colistin resistance was investigated using comparative phenotypic and proteomic analysis of P. aeruginosa ATCC 9027, its 14-day colistin sub-MIC exposed strain (Col-E1), and 10-day antibiotic-free cultured Col-E1 strain (Col-E2). Antibiotic susceptibility, morphology, virulence factors, and proteomic changes were assessed using disc-diffusion, agar-based, spectrophotometry, SEM, and iTRAQ-LC-MS/MS methods. Results Colistin-exposed strains decreased susceptibility to colistin while remaining susceptible to other antibiotics. Col-E1 reduced the cell lengths by 17.67% and the colony size by 36.16% compared to the initial strain. The reduction remained in Col-E2. The pyocyanin production was reduced in Col-E1 (p=0.025, Tukey HSD) and increased again in Col-E2 (p=0.005, Tukey HSD). In contrast, no significant changes in elastase, protease, rhamnolipid, pyoverdine, and biofilm production were observed (p>0.05, Tukey HSD). In Col-E1, the proteome analysis showed 135 differentially expressed proteins (DEPs) of which 94 DEPs (69.23%) maintained their expression change in Col-E2. Among DEPs, 82 were involved in metabolism and protein synthesis. Some DEPs (6/135) played a role in stress response such as GrpE (fold change: 14.93) and Hmp (fold change: 12.08). In particular, membrane proteins like OprD, DdlB, and OprI showed significant colistin response with fold change of -8.47, 6.43 and 6.19, respectively. Conclusions In summary, colistin response in P. aeruginosa seemed to affect morphology, production of pyocyanin, and proteins of metabolism, protein synthesis, stress response and membrane. [ABSTRACT FROM AUTHOR]

BACKGROUND: A broad suite of bisphenol S (BPS) derivatives as alternatives for BPS have been identified in various human biological samples, including 4-hydroxyphenyl 4-isopropoxyphenylsulfone (BPSIP) detected in human umbilical cord plasma and breast milk. However, very little is known about the health outcomes of prenatal BPS derivative exposure to offspring. OBJECTIVES: Our study aimed to investigate the response of hepatic cholesterol metabolism by sex in offspring of dams exposed to BPSIP. METHODS: Pregnant ICR mice were exposed to 5μg/kg body weight (BW)/day of BPSIP, BPS, or E2 through drinking water from gestational day one until the pups were weaned. The concentration of BPSIP, BPS, or E2 in the plasma and liver of pups was determined by liquid chromatography-tandem mass spectrometry. Metabolic phenotypes were recorded, and histopathology was examined for liver impairment. Transcriptome analysis was employed to characterize the distribution and expression patterns of differentially expressed genes across sexes. The metabolic regulation was validated by quantitative real-time PCR, immunohistochemistry, and immunoblotting. The role of estrogen receptors (ERs) in mediating sex-dependent effects was investigated using animal models and liver organoids. RESULTS: Pups of dams exposed to BPSIP showed a higher serum cholesterol level, and liver cholesterol levels were higher in females and lower in males than in the controls. BPSIP concentration in the male liver was 1.22±0.25 ng/g and 0.69±0.27 ng/g in the female liver. Histopathology analysis showed steatosis and lipid deposition in both male and female offspring. Transcriptome and gene expression analyses identified sex-specific differences in cholesterol biosynthesis, absorption, disposal, and efflux between pups of dams exposed to BPSIP and those in controls. In vivo, chromatin immunoprecipitation analysis revealed that the binding of ERα protein to key genes such as Hmgcr, Pcsk9, and Abcg5 was attenuated in BPSIP-exposed females compared to controls, while it was enhanced in males. In vitro, the liver organoid experiments demonstrated that restoration of differential expression induced by BPSIP in key genes, such as Hmgcr, Ldlr, and Cyp7a1, to levels comparable to the controls was only achieved when treated with a combination of ERα agonist and ERβ; agonist. DISCUSSION: Findings from this study suggest that perinatal exposure to BPSIP disrupted cholesterol metabolism in a sex-specific manner in a mouse model, in which ERa played a crucial role both in vivo and in vitro. Therefore, it is crucial to systematically evaluate BPS derivatives to protect maternal health during pregnancy and prevent the transmission of metabolic disorders across generations [ABSTRACT FROM AUTHOR]

Amyloid precursor protein (APP), secretase enzymes, and amyloid beta (Aβ) have been extensively studied in the context of Alzheimer's disease (AD). Despite this, the function of these proteins and their metabolism is not understood. APP, secretase enzymes, and APP processing products (Aβ and C‐terminal fragments) localize to endosomes, mitochondria, endoplasmic reticulum (ER), and mitochondrial/ER contact sites. Studies implicate significant relationships between APP, secretase enzyme function, APP metabolism, and mitochondrial function. Mitochondrial dysfunction is a key pathological hallmark of AD and is intricately linked to proteostasis. Here, we review studies examining potential functions of APP, secretase enzymes, and APP metabolites in the context of mitochondrial function and bioenergetics. We discuss implications and limitations of studies and highlight knowledge gaps that remain in the field. [ABSTRACT FROM AUTHOR]

Background: Renal ischaemia‒reperfusion injury (IRI) is the primary cause of acute kidney injury (AKI). To date, effective therapies for delaying renal IRI and postponing patient survival remain absent. Ankyrin repeat domain 1 (ANKRD1) has been implicated in some pathophysiologic processes, but its role in renal IRI has not been explored. Methods: The mouse model of IRI‐AKI and in vitro model were utilised to investigate the role of ANKRD1. Immunoprecipitation‐mass spectrometry was performed to identify potential ANKRD1‐interacting proteins. Protein‒protein interactions and protein ubiquitination were examined using immunoprecipitation and proximity ligation assay and immunoblotting, respectively. Cell viability, damage and lipid peroxidation were evaluated using biochemical and cellular techniques. Results: First, we unveiled that ANKRD1 were significantly elevated in renal IRI models. Global knockdown of ANKRD1 in all cell types of mouse kidney by recombinant adeno‐associated virus (rAAV9)‐mitigated ischaemia/reperfusion‐induced renal damage and failure. Silencing ANKRD1 enhanced cell viability and alleviated cell damage in human renal proximal tubule cells exposed to hypoxia reoxygenation or hydrogen peroxide, while ANKRD1 overexpression had the opposite effect. Second, we discovered that ANKRD1's detrimental function during renal IRI involves promoting lipid peroxidation and ferroptosis by directly binding to and decreasing levels of acyl‐coenzyme A synthetase long‐chain family member 3 (ACSL3), a key protein in lipid metabolism. Furthermore, attenuating ACSL3 in vivo through pharmaceutical approach and in vitro via RNA interference mitigated the anti‐ferroptotic effect of ANKRD1 knockdown. Finally, we showed ANKRD1 facilitated post‐translational degradation of ACSL3 by modulating E3 ligase tripartite motif containing 25 (TRIM25) to catalyse K63‐linked ubiquitination of ACSL3, thereby amplifying lipid peroxidation and ferroptosis, exacerbating renal injury. Conclusions: Our study revealed a previously unknown function of ANKRD1 in renal IRI. By driving ACSL3 ubiquitination and degradation, ANKRD1 aggravates ferroptosis and ultimately exacerbates IRI‐AKI, underlining ANKRD1's potential as a therapeutic target for kidney IRI. Key Points/Highlights: Ankyrin repeat domain 1 (ANKRD1) is rapidly activated in renal ischaemia‒reperfusion injury (IRI) models in vivo and in vitro.ANKRD1 knockdown mitigates kidney damage and preserves renal function.Ferroptosis contributes to the deteriorating function of ANKRD1 in renal IRI.ANKRD1 promotes acyl‐coenzyme A synthetase long‐chain family member 3 (ACSL3) degradation via the ubiquitin‒proteasome pathway.The E3 ligase tripartite motif containing 25 (TRIM25) is responsible for ANKRD1‐mediated ubiquitination of ACSL3. [ABSTRACT FROM AUTHOR]