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Bisphenol A (BPA), nonylphenol (NP), and octylphenol (OP) are common environmental phenolic endocrine disruptors and widely used industrial chemicals that have garnered significant attention due to their potential to disrupt endocrine functions. These compounds are known to interfere with hormonal activities, particularly those related to estrogen, and are linked to the onset and progression of breast cancer. This study aims to systematically investigate the potential relationship between BPA, NP, and OP and breast cancer risk, along with their underlying molecular mechanisms, by synthesizing data from multiple databases. We initially acquired the chemical structures and SMILES representations of BPA, NP, and OP from the PubChem database. Subsequently, we utilized multiple databases, including the Comparative Toxicogenomics Database (CTD), SEA, and Swiss Target Prediction, t0 estimate their probable biological targets. The predicted targets were standardized and consolidated to form a comprehensive target database. Breast cancer-related targets were subsequently identified from the GeneCards and DisGeNET databases, and their overlap with the targets of BPA, NP, and OP was analyzed to pinpoint potential breast cancer risk targets. To elucidate the functional pathways involved, we conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses using the DAVID database. This analysis offered insights into the molecular pathways influenced by BPA, NP, and OP in the context of breast cancer. Additionally, we utilized machine learning algorithms, specifically Least Absolute Shrinkage and Selection Operator (LASSO) regression and Support Vector Machine (SVM), to identify nuclear targets linked to BPA, NP, and OP-induced breast cancer. These nuclear targets were further validated through differential expression analysis and Receiver Operating Characteristic (ROC) curve analysis using the GEO dataset GSE42568. We also performed a Single Gene Gene Set Enrichment Analysis (GSEA) to investigate the potential regulatory mechanisms of these nuclear genes in breast cancer. The infiltration of immune cells in breast cancer tissues was analyzed using single-sample gene set enrichment analysis (ssGSEA), and the correlation between nuclear targets and immune cell infiltration was examined. Finally, molecular docking and molecular dynamics simulations were conducted to assess the binding affinity and stability of BPA, NP, and OP with their nuclear targets. In this study, we integrated network toxicology, machine learning and multi-omics validation, and identified for the first time that BPA, NP and OP may induce breast cancer through 156 common targets; among them, MAOA, MGLL, ADRA2A, RPN2, GF1R and CTSD were identified as the key causative genes, with a diagnostic efficacy of 0.80–0.94 AUC. Mechanistically, these genes are concentrated in the GPCR/MAPK/JNK, sphingolipid, and prolactin signaling pathways, which regulate the Wnt/TGF-β/chemokine network and dramatically modify the immunological infiltration of nine classes of M0-M2 macrophages and CD4⁺ T cells. Molecular docking and kinetic simulations suggested the strong affinity of BPA for MGLL, and the complex was stabilized with ≥ 3 hydrogen bonds. In conclusion, phenolic endocrine disruptors may cause breast cancer through the “multi-target-immune microenvironment-metabolic reprogramming” axis, and MAOA, MGLL, ADRA2A, and RPN2 may serve as new targets for early detection and management.

Resveratrol (Res), a natural plant antitoxin polyphenol, is widely used in animal husbandry due to its antioxidant and anti-inflammatory properties, and current research has focused on humans, sows, and female mice. This study aimed to analyze the effects of dietary Res supplementation in ewes on antioxidant activity, immune responses, hormone levels, rumen microbiota and metabolites across various reproductive stages (estrus, pregnancy, and lactation). Twenty-four healthy ewe lambs (Hu sheep, 2 months old) with a similar body weight (BW) (mean: 21.79 ± 2.09 kg) were selected and randomly divided into two groups: the control group (Con) and the Res group (Res). The Res group received 10 mg/kg Res (based on BW) in addition to their basal diet. Res increased the levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2) in ewes at sexual maturity (p < 0.05). Additionally, Res supplementation induced significant increases in serum glutathione peroxidase (GSH-Px), IgG, FSH, and LH levels during estrus (p < 0.05); serum IgA, IgG and IgM during pregnancy and lactation (p < 0.05); and serum LH, glucose, GSH-Px, and catalase (CAT) levels during lactation (p < 0.05). Meanwhile, serum interleukin 1β (IL-1β) (p =0.005) and cholesterol levels (p = 0.041) during the lactation stage decreased following Res supplementation. Notably, colostrum IgA, IgG, and fat concentrations were significantly higher in the Res group than in the Con group (p < 0.05). Moreover, Res altered the rumen microbiota in ewes. Specifically, the relative abundance of Prevotella (p < 0.05) during pregnancy and Rikenellaceae_RC9_gut_group (p < 0.001) during lactation were significantly increased in ewes under Res treatment. The abundance of Rikenellaceae_RC9_gut_group was positively correlated with the levels of Ig A, Ig M, E2, FSH, LH, GSH-PX, and CAT. Additionally, Res altered the activity of metabolic pathways such as progesterone-mediated oocyte maturation, the estrogen signaling pathway, ovarian steroidogenesis, and the AMPK signaling pathway, and the levels of AICAR and 2-hydroxyestradiol metabolites, both during pregnancy and lactation. There findings show that Res can improve health, antioxidant status, and immune activity throughout the reproductive cycle in ewes by regulating rumen microorganisms and metabolites.

The objective of this experiment was to evaluate the effect of different EOC (0.1425% cobalt lactate + 1.13% oregano essential oil + 98.7275% carrier) levels on in vitro rumen fermentation and microbial changes. Six EOC levels (treatments: 0 mg·L−1, CON; 50 mg·L−1, EOC1; 100 mg·L−1, EOC2; 400 mg·L−1, EOC3; 800 mg·L−1, EOC4 and 1500 mg·L−1, EOC5) were selected to be used to in vitro incubation. The in vitro dry matter digestibility (IVDMD), in vitro neutral detergent fiber digestibility (IVNDFD), in vitro acid detergent fiber digestibility (IVNDFD), pH, ammonia-nitrogen (NH3-N) concentration, total volatile fatty acid (TVFA) concentration and microbial protein (MCP) concentration were measured after 48 h incubation, after which the groups with significant nutrient digestibility and fermentation parameters were subjected to 16S rRNA sequencing. The results showed that the total gas production (GP) of the EOC5 group was higher than that of the other groups after 12 h of in vitro incubation. TVFA, NH3-N and MCP concentrations were also shown to be higher in group EOC5 than those in other groups (p < 0.05), while NH3-N and MCP concentrations in the EOC2 group were lower than those in other groups significantly (p < 0.05). The molar ratio of acetic acid decreased while the molar ratio of propionic acid increased after the addition of EOC. 16S rRNA sequencing revealed that the rumen microbiota was altered in response to adding EOC, especially for the EOC5 treatment, with firmicutes shown to be the most abundant (43.1%). The relative abundance of Rikenellaceae_RC9_gut_group was significantly lower, while the relative abundance of uncultured_bacterium_f_Muribaculaceae and Succiniclasticum was significantly higher in the EOC5 group than those in other groups (p < 0.05). Comprehensive analysis showed that EOC (1500 mg·L−1) could significantly increase gas production, alter sheep rumen fermentation parameters and microbiota composition.

The effects of incorporating yeast culture (YC) into pelleted feeds on sheep production and the potential impact on rumen microbial populations, microbial metabolism, and fermentation have not been extensively studied. This study aimed to evaluate the effect of YC on growth performance, rumen tissue development, rumen fermentation, and rumen microflora in sheep and to explore the potential microbial mechanisms involved. Fifty healthy 3-month-old male lambs of small-tailed Han sheep, with an average weight of 28.44 ± 0.63 kg, were randomly divided into five groups: control (0% YC), 3% YC, 6% YC, 9% YC, and 12% YC. The pre-feeding period lasted for 15 days, followed by an official feeding period of 60 days. On the last day of the formal feeding period, six lambs that exhibited the best growth performance were randomly selected from the control group and the 9% YC group. These sheep were slaughtered, then the rumen epithelial tissue and rumen contents were collected for the measurement of rumen fermentation, microbial populations, and metabolites. Compared to the control group, the YC-treated groups showed higher daily and final body weight gains, as well as increased levels of propionic acid, butyric acid, and total volatile fatty acids (p < 0.05). YC supplementation also enhanced rumen papilla length and width (p < 0.05). Additionally, YC increased the relative abundance of certain microbial species (p < 0.05). These results suggest that supplementing 9% YC in pelleted diets for small-tailed Han sheep may enhance growth performance and improve the rumen environment.

The sensory quality and flavor of lamb meat, critical to market competitiveness, are influenced by rumen microbial fermentation and dietary management strategies. Coated betaine (CBet), a rumen-protected methyl donor, exerts systemic nutritional regulation in ruminants. This study explored the effects of CBet supplementation on lamb meat quality using 18 Dorset ♂ × Hu sheep ♀ F1 crossbred lambs, randomly assigned to either a control group (basal diet) or a 0.20% CBet-supplemented diet for 60 days (n = 9 per group). The results demonstrated that CBet significantly increased ruminal concentrations of total volatile fatty acids (TVFAs), acetic acid, propionic acid, and butyric acid (p < 0.05). Additionally, CBet supplementation enhanced muscle redness (a*), crude fat, crude ash, heptadecanoic acid (C17:0), and tricosanoic acid (C23:0) (p < 0.05) while decreasing shear force and the concentration of cis-13,16-docosadienoic acid (C22:2) (p < 0.05). Furthermore, CBet elevated characteristic flavor compounds (e.g., nonanal) and their relative odor activity values (ROAVs), and decreased undesirable odors (e.g., dodecanal) (p < 0.05). As illustrated in the graphical abstract, these improvements were mediated through regulatory effects of CBet on rumen microbiota composition, muscle fatty acids, amino acids, and volatile flavor compounds. Specifically, CBet significantly increased the relative abundances of Firmicutes, Proteobacteria, Prevotella, and Bifidobacterium in the rumen (p < 0.05) and altered the Firmicutes/Bacteroidota ratio. In conclusion, dietary supplementation with 0.20% CBet effectively enhances lamb meat quality and flavor, effects closely associated with changes in the abundance of key ruminal microbial taxa.

Background The microbiota and metabolites in the gastrointestinal tracts of female animals at different reproductive periods are very important to the growth, development, and health of themselves and their offspring. However, the changes in the gastrointestinal microbiota and metabolites throughout reproductive period of different sheep breeds and their effects on the growth and development of offspring lambs are still unclear. Hence, this study presents an assessment of the reproductive hormone levels, immune levels, rumen microbiota, and metabolites in Hu sheep and Suffolk ewes at different reproductive periods and their effects on the growth and development of offspring lambs. Results Hu sheep and Suffolk during non-pregnancy, pregnancy, and lactation were used as the research objects to determine reproductive and immune indexes of ewes at different periods, analyze rumen microbiome and metabolome, and track the growth performance and development of offspring lambs. The results showed that the reproductive hormone and immune levels of Hu sheep and Suffolk underwent adaptive changes across different reproductive periods. Compared with non-pregnancy, the microbial energy metabolism and lipid metabolism function decreased during Hu sheep pregnancy, and energy metabolism function decreased during lactation. In Suffolk, energy metabolism, glycan biosynthesis, and metabolism function were enhanced during pregnancy, and the metabolism of cofactors and vitamins was enhanced during lactation. Prevotella increased in Suffolk during pregnancy and lactation ( P < 0.05) and was positively correlated with the birth weight and body size of the lambs ( P < 0.05). Moreover, the abundances of Butyrivibrio and Rikenellaceae_RC9_gut_group during pregnancy were positively correlated with the intestinal immunity of the offspring lambs ( P < 0.05), thereby regulating the intestinal immunity level of the lambs. Metabolomic analysis revealed that the protein digestion, absorption, and amino acid metabolism of Hu sheep were enhanced during pregnancy, which provided amino acids for the growth and development of pregnant ewes and fetuses and was significantly correlated with the birth weight, body size, and intestinal immunity of lambs ( P < 0.05). Simultaneously, there was an increase in acetate and propionate during the pregnancy and lactation period of both Hu sheep and Suffolk, providing energy for ewes during reproductive period. Moreover, the microbiota during the lactation period was significantly correlated with the milk quality and lambs daily gain ( P < 0.05). Conclusions This study revealed the characteristic succession changes in the rumen microbiota and its metabolites at different reproductive periods in sheep breeds and their regulation of reproductive hormone and immune levels and identified their potential effects on the growth and development of offspring lambs. The findings provide valuable insights into the health and feeding management of different sheep breeds during the reproductive stage. Cnu7uEJBESQuA-vs1kGzfa Video Abstract

Objective To address the question of axillary lymph node staging in ductal carcinoma in situ with microinvasion (DCIS‐MI), we retrospectively evaluated axillary lymph nodes metastasis (ALNM) rate in a cohort of postsurgical DCIS‐MI patients. By analyzing these data, we aimed to generate clinically relevant insights to inform treatment decision‐making for this patient population. Methods A systematic search was conducted on PubMed, Web of Science, Embase, The Cochrane Library, CNKI, Wanfang Database, Wipe, and China Biomedical Literature Database to identify relevant publications in any language. All the analyses were performed using Stata 16.0 software. Results Among the 28 studies involving 8279 patients, the pooled analysis revealed an ALNM rate of 8% (95% CI, 7% to 10%) in patients with DCIS‐MI. Furthermore, the rates of axillary lymph node macrometastasis, micrometastasis, and ITC in patients with DCIS‐MI were 2% (95% CI, 2% to 3%), 3% (95% CI, 2% to 4%), and 2% (95% CI, 1% to 3%), respectively. Moreover, 13 studies investigated the non‐sentinel lymph node (Non‐SLN) metastasis rate, encompassing a total of 1236 DCIS‐MI cases. The pooled analysis identified a Non‐SLN metastasis rate of 33% (95% CI, 14% to 55%) in patients with DCIS‐MI. Conclusion The SLNB for patients with DCIS‐MI is justifiable and could provide a novel therapeutic basis for systemic treatment decisions.

The incidence of developing cancer should increase with the body mass, yet is not the case, a conundrum referred to as Peto’s paradox. Elephants have a lower incidence of cancer suggesting that these animals have probably evolved different ways to protect themselves against the disease. The paradox is worth revisiting with the realization that most mammals encode an endogenous APOBEC3 cytidine deaminase capable of mutating single stranded DNA. Indeed, the mutagenic activity of some APOBEC3 enzymes has been shown to introduce somatic mutations into genomic DNA. These enzymes are now recognized as causal agent responsible for the accumulation of CG- > TA transitions and DNA breaks leading to chromosomal rearrangements in human cancer genomes. Here, we identified an elephant A3Z1 gene, related to human APOBEC3A and showed that it could efficiently deaminate cytidine, 5-methylcytidine and produce DNA breaks leading to massive apoptosis, similar to other mammalian APOBEC3A enzymes where body mass varies by up to four orders of magnitude. Consequently, it could be considered that eAZ1 might contribute to cancer in elephants in a manner similar to their proposed role in humans. If so, eAZ1 might be particularly well regulated to counter Peto’s paradox.

This study used oregano essential oil (EO), cobalt (Co) and synergistic of both of them additives instead of antibiotics to explore the effects of different additives on the corn silage fibre structure degradation, nutrient degradation rate and rumen fermentation characteristics of sheep. The additives used in the study as a product were provided by Ralco, Inc., USA. The Latin square experimental design was adopted with 5 treatments. The following treatments were fed through the rumen fistula: carrier (Car), carrier + EO, carrier + Co, carrier + EO + cobalt (EOC) and no additives as the control (CON). These treatments were fed to five sheep for five rounds at a dose of 80 mg/kg. At 48 h of degradation, the area of degraded corn leaf and husk reached 100%, SEM results showed that except for Car and CON treatment, there were obvious destroyed fibre structure differences under EO, Co and EOC treatment, showing total disappearance of leaf epidermal cells, palisade tissue and spongy tissue, especially under EOC. Under EOC treatment, DMD 48 h , CPD 48 h , NDFD 48 h and ADFD 48 h increased by 3.33%, 3.89%, 7.64% and 5.67%, respectively, compared with CON, while NDFD 48 h and ADFD 48 h increased by 4.70% and 6.05% under Co (p > 0.05). The NH 3 -N concentration in rumen fluid decreased by 19.36%, 27.20% and 19.48%, while the microbial protein (MCP) content increased by 6.32%, 4.29% and 5.97% (p > 0.05) under EO, Co and EOC treatments compared with CON at 48 h (p < 0.05). The total VFA concentration under EO, Co and EOC treatment was lower than CON at 6 and 48 h (p = 0.016, p = 0.022) and the propionate and acetate concentrations were higher under EOC treatment than CON at 48 h (p > 0.05). Feeding EOC increased the fibre structure degradation and nutrient degradation rate of corn silage and improved rumen fermentation in sheep, resulting in better effects than feeding EO or Co alone. HIGHLIGHTS This article revealed the significance of oregano essential oil synergistic with cobalt (EOC) on rumen fermentation characteristics and nutrient degradation rate of sheep. In this study, the degradation of leaves in the rumen was observed by scanning electron microscopy, and the degradation area was calculated by electron microscopy for the first time. The results of this study will provide the theoretical basis for EOC as a substitute for antibiotics.

The effects of isochlorogenic acid (ICGA) on ewes rumen environment, microbial diversity, and immunity at different physiological stages (estrus, pregnancy and lactation) were studied in this experiment. Twenty healthy female Hu lambs of 1.5 months with similar body weight (17.82 ± 0.98 kg) and body condition were selected and randomly divided into two groups: the control group (CON) and the ICGA group (ICGA). The lambs of CON were fed a basal diet, while the lambs of ICGA were supplemented with 0.1% ICGA based on the basal diet. Lambs rumen fermentation characteristics, microbial diversity and immunity at estrus, pregnancy, and lactation stages were determined and analyzed, respectively. The results showed that the rumen pH in CON increased first and then decreased as lambs grew (p < 0.05). However, it showed the opposite change in ICGA. The content of ammonia nitrogen (NH3-N) showed the highest at estrus stage in both groups, but it was significantly higher in ICGA than that in CON (p < 0.05). The Acetic acid/propionic acid (A/P) ratio at estrus stage and the volatile fatty acids (VFAs) at pregnancy stage in ICGA were significantly higher than those of the CON (p < 0.05). The 16S rDNA sequencing analysis showed that the Shannon, Chao 1 and ACE indexes of the ICGA were significantly higher than those of the CON both at estrus and lactation stages (p < 0.05), while they showed higher at the pregnancy stage in CON (p > 0.05). Principal component analysis (PCA) showed that there were significant differences in rumen microorganism structure between CON and ICGA at all physiological stages (p < 0.01). At the phylum level, compared with the CON, Firmicutes relative abundance of three physiological stages decreased (p > 0.05) while Bacteroidota increased (p > 0.05). The relative abundance of Synergistota at estrus stage and Patescibacteria at the lactation stage increased significantly too (p < 0.05). At the genus level, compared with the CON, the relative abundance of Prevotella at three stages showed the highest (p > 0.05), while the relative abundance of Succiniclasticum, unclassified_Selenomonadaceae and Rikenellaceae_RC9_gut_group showed different abundances at different physiological stages in ICGA. Compared with the CON, the lambs of the ICGA showed higher blood IgG, IgM, and TNF- α contents at three physiological stages and higher IL-6 contents at pregnancy stage (p < 0.05). Conclusion: Adding ICGA could regulate ewes rumen fermentation mode at different physiological stages by increasing rumen NH3-N at estrus, VFAs at pregnancy, and the ratio of A/P at lactation. It optimizes rumen microbial flora of different physiological stages by increasing Bacteroidota relative abundance while reducing Firmicutes relative abundance, maintaining rumen microbial homeostasis at pregnant stage, increasing the number of beneficial bacteria in later lactating and ewes blood immunoglobulins content at three physiological stages.