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The high incidence of breast cancer is the greastest threat to women’ health all over the world. Among them, HER-2 positive breast cancer has the characteristics of high malignancy, easy recurrence and metastasis, and poor prognosis. Traditional Chinese medicine (TCM) has a rich theoretical basis and clinical application for breast cancer. TCM believes that blood stasis syndrome is one of the important pathogenesis of breast formation and development. Taohong Siwu Decoction (TSHWD) is based on the “First Prescription of Gynecology” Siwu Decoction. It is widely used in various blood stasis and blood deficiency syndromes, mainly in gynecological blood stasis. Clinical studies have found that THSWD can treat breast cancer by reducing blood vessel and lymphangiogenesis with auxiliary chemotherapy. In this study, we aim to explore the material basis and mechanism of THSWD in the treatment of HER-2 positive breast cancer through literature review and network pharmacology studies. Through a literature review of the traditional application, chemical composition of Chinese herbal medicine of THSWD, as well as its clinical reports and pharmacological research on breast cancer treatment. Meanwhile, we conducted “component-pathway-target” network through network pharmacology reveals the main material basis, possible targets and pathways of THSWD in inhibiting HER-2 positive breast cancer. Literature review and network pharmacology research results had predicted that, baicalein, kaempferol, caffeic acid, amygdalin, quercetin, ferulic acid, gallic acid, catalpol, hydroxysafflor yellow A, paeoniflorin in THSWD are the main effective chemical composition. THSWD regulates 386 protein targets and 166 pathways related to breast cancer. The molecular mechanism is mainly to improve the microenvironment of tumor cells, regulate the process of tumor cell EMT, and inhibit tumor cell proliferation and metastasis. This study revealed the mechanism of action of THSWD in the treatment of HER-2 positive breast cancer through literature review and network pharmacology studies, providing a scientific basis for clinical application.

Fluoride and Pb are both toxic to organisms; however, their combination effects and the corresponding toxic mechanisms remain unclear. In this study, male and female zebrafish (1:1) were evaluated to understand the effects of F and Pb alone and combined on growth, tissue microstructure, oxidative stress, and immune system functions of the liver. Four different groups and two exposure periods were compared: control group (C group), 80 mg/L fluoride group (F group), 60 mg/L lead group (Pb group), and 80 mg/L fluoride + 60 mg/L lead group (F + Pb group) for 45 and 90 days. The results indicated that F and Pb reduced growth performances; F + Pb treatment inhibited the growth performance traits of male zebrafish more than those of female zebrafish. Histopathological examination revealed large areas with focal necrosis, hepatocytes with karyolysis, and pycnotic nuclei in zebrafish exposed to F and Pb. The oxidative balance indices in the liver in the F and Pb groups were disturbed. F + Pb co-exposure aggravated oxidative stress in a time-dependent manner. The most serious oxidative stress was observed in the male zebrafish of the F + Pb group. Moreover, F and Pb exposure of male zebrafish increased pro-inflammatory and anti-inflammatory cytokines expression, which was decreased after 90 days of exposure. These results demonstrated that both F and Pb could damage the liver via downstream alterations in the activities of immune-related enzymes and in the levels of immune-related genes. F and Pb showed synergistic or additive effects. Male zebrafish were found to be more sensitive to F and Pb than female zebrafish.

In this study, rumen content was used to obtain three enrichments of anaerobic fungi and methanogens (F + M enrichment), bacteria and methanogens (B + M enrichment), and whole rumen content (WRC enrichment), to evaluate their respective ability to degrade lignocellulose and produce methane. Among the treatments, F + M enrichment elicited the strongest lignocellulose degradation and methane production ability with both rice straw and wheat straw as substrates. Quantitative real-time PCR analysis and diversity analyses of methanogens in the three enrichment treatments demonstrated that F + M had larger number of 16S rRNA gene copies of methanogens and higher relative abundance of Methanobrevibacter, the predominant methanogen found in all enrichments. Caecomyces was the main anaerobic fungal genus for co-culturing to provide substrates for methanogens in this enrichment. Importantly, the F + M enrichment was stable and could be maintained with transfers supplied every 3 days, confirming its potential utility in anaerobic digestion for lignocellulose degradation and methane production.

Background The utilization of transcriptome technology in the identification of pivotal regulatory genes associated with immunity is of paramount importance. Previous studies have shown that undomesticated gayal ( Bos frontalis ) may have higher humoral responses which is comparable to yaks. However, research on immune function of gayal is limited, and comparisons with different breeds are rarely reported. The objective of this study was to inspect the immune status and compare splenic differential expression genes (DEGs) through comparative transcriptome analysis of gayal and domesticated local cattle (Yunan yellow cattle). Results Serum immunological status investigation showed the better humoral immune status and lower levels of pro-inflammatory cytokines of gayal when compared to the local cattle. Spleen RNA-seq showed that 708 DEGs (365 up- and 343 down-regulated genes) were obtained between the gayal and local cattle. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analysis showed that immune system pathways, immune disease pathways, and chemotaxis-related molecular function of gayal were significantly enriched, whereas T cell-related cellular component and biological process were downregulated in the gayal . Correlation analysis shown that CD1 , CD36 , CD38 , CD179a , CD179b , CXCL8 , IGCGAMMA , IGH , IGHG1 , IGLL1 , IL1R2 , SERPINB , and SERPINB4 had positive correlations with splenic IgA, IgD, IgE, IgG, and IgM, respectively (R > 0.5, P  < 0.05). ANPEP , BVD1.23 , CD1E , CD3D , CD3E , CD3G , CD5 , CD8 A , HBB , IDO1 , LCK , MGC126945 , MHC1 , TRAV , TRBV , and ZAP70 had negative correlations with splenic IgA, IgD, IgE, IgG, and IgM, respectively (R < -0.5, P  < 0.05). Conclusions Our results reveal the immunological mode of gayal with high-level humoral immunity and enhanced splenic immunoglobulin gene expression and B cell differentiation, which may enable gayal to adapt to the harsh environments.

Chemo-photodynamic combination therapy has demonstrated significant potential in the treatment of cancer. Triptolide (TPL), a naturally derived anticancer agent, when combined with the photosensitizer Chlorin e6 (Ce6), has shown to provide enhanced anti-tumor benefits. However, the development of stimuli-responsive nanovehicles for the co-delivery of TPL and Ce6 could further enhance the efficacy of this combination therapy. In this study, we synthesized a pH/ROS dual-responsive mPEG- -PBAE copolymer, which contains a pH-sensitive PBAE moiety and a ROS-sensitive thioketal (TK) linkage. Through a self-assembly process, TPL and Ce6 were successfully co-loaded into mPEG- -PBAE nanoparticles, hereafter referred to as TPL/Ce6 NPs. We evaluated the pH- and ROS-sensitive drug release and particle size changes. Furthermore, we investigated both the in vitro suppression of cellular proliferation and induction of apoptosis in HepG2 cells, as well as the in vivo anti-tumor efficacy of TPL/Ce6 NPs in H22 xenograft nude mice. The mPEG- -PBAE copolymer was synthesized through a one-pot Michael-addition reaction and successfully co-encapsulated both TPL and Ce6 by self-assembly. Upon exposure to acid pH values and high ROS levels, the payloads in TPL/Ce6 NPs were rapidly released. Notably, the abundant ROS generated by the released Ce6 under laser irradiation further accelerated the degradation of the nanosystem, thereby amplifying the tumor microenvironment-responsive drug release and enhancing anticancer efficacy. Consequently, TPL/Ce6 NPs significantly increased PDT-induced oxidative stress and augmented TPL-induced apoptosis in HepG2 cells, leading to synergistic anticancer effects in vitro. Moreover, administering TPL/Ce6 NPs (containing 0.3 mg/kg of TPL and 4 mg/kg of Ce6) seven times, accompanied by 650 nm laser irradiation, efficiently inhibited tumor growth in H22 tumor-bearing mice, while exhibiting lower systemic toxicity. Overall, we have developed a tumor microenvironment-responsive nanosystem for the co-delivery of TPL and Ce6, demonstrating amplified synergistic effects of chemo-photodynamic therapy (chemo-PDT) for hepatocellular carcinoma (HCC) treatment.

Background The nutrient availability of roughages could affect the dietary utilization efficiency of ruminants even in isocaloric and isonitrogenous diets. Here, we analyzed the bacterial composition and their metabolic pathways in the gastrointestinal tracts (GITs) of Hu sheep fed with wheat straw (WS) instead of alfalfa (AL) in isocaloric and isonitrogenous diets, trying to explore the reasons from the perspective of GITs bacterial network structure changes. Results We employed 16S rRNA gene sequencing in combination with the Kruskal–Wallis test, Spearman correlation analysis, and other statistical methods to describe the microbiota composition in the GITs of Hu sheep. The results showed after the roughage was replaced from AL to WS, the most positive response occurred in the rumen microbiota, resulting in a more obvious microbiological and functional redundancy phenomenon. Whereas extended biogeographic studies of the GITs bacterial community found opposite results for the hindgut microbiota and metabolism networks compared to the forestomach. The abundance of fiber-degrading bacteria such as Prevotella , Oscillospiraceae NK4A214 group , and Treponema was significantly increased in GITs, but low-efficiency crude fiber degradation inhibited energy use efficiency, the pentose phosphate pathway, gluconeogenesis, and volatile acid synthesis. In addition, dietary shifting from AL to WS decreased the abundance of beneficial bacteria such as the Lachnospiraceae NK3A20 group and Alistipes , thereby enhancing the underlying inflammatory response. Conclusions These findings suggest that feeding untreated WS affected the structure and function of the bacterial network in the GITs due to limited total digestible nutrients, and in particular increases the complexity of the rumen bacterial network, and limit the abundance of bacteria involved in the crude fiber degradation in the hindgut.

Background Lignocellulose biomass is the most abundant and renewable material in nature. The objectives of this study were to characterize two endoglucanases TrepCel3 and TrepCel4, and determine the effect of the combination of them (1.2 mg TrepCel3, 0.8 mg TrepCel4) on in vitro rumen fermentation characteristics. In this study, three nature lignocellulosic substrates (rice straw, RS; wheat straw, WS; leymus chinensis, LC) were evaluated for their in vitro digestibility, gas, NH 3 -N and volatile fatty acid (VFA) production, and microbial protein (MCP) synthesis by adding enzymatic combination. Methods Two endoglucanases’ genes were successfully expressed in Escherichia coli ( E. coli ) BL21 (DE3), and enzymatic characteristics were further characterized. The combination of TrepCel3 and TrepCel4 was incubated with lignocellulosic substrates to evaluate its hydrolysis ability. Results The maximum enzymatic activity of TrepCel3 was determined at pH 5.0 and 40 °C, while TrepCel4 was at pH 6.0 and 50 °C. They were stable over the temperature range of 30 to 60 °C, and active within the pH range of 4.0 to 9.0. The TrepCel3 and TrepCel4 had the highest activity in lichenan 436.9 ± 8.30 and 377.6 ± 6.80 U/mg, respectively. The combination of TrepCel3 and TrepCel4 exhibited the highest efficiency at the ratio of 60:40. Compared to maximum hydrolysis of TrepCel3 or TrepCel4 separately, this combination was shown to have a superior ability to maximize the saccharification yield from lignocellulosic substrates up to 188.4% for RS, 236.7% for wheat straw WS, 222.4% for LC and 131.1% for sugar beet pulp (SBP). Supplemental this combination enhanced the dry matter digestion (DMD), gas, NH 3 -N and VFA production, and MCP synthesis during in vitro rumen fermentation. Conclusions The TrepCel3 and TrepCel4 exhibited the synergistic relationship (60:40) and significantly increased the saccharification yield of lignocellulosic substrates. The combination of them stimulated in vitro rumen fermentation of lignocellulosic substrates. This combination has the potential to be a feed additive to improve agricultural residues utilization in ruminants. If possible, in the future, experiments in vivo should be carried out to fully evaluate its effect.

Objective: Previous research reported that dietary addition with phytosterols improved the energy utilisation of the rumen microbiome, suggesting its potential to alleviate the negative energy balance of perinatal cows. This experiment aimed to explore the effects of feeding phytosterols on the metabolic status of perinatal cows through plasma metabolomics and faecal bacteria metabolism.Methods: Ten perinatal Holstein cows (multiparous, 2 parities) with a similar calving date were selected four weeks before calving. After 7 days for adaptation, cows were allocated to two groups (n = 5), which respectively received the basal rations supplementing commercial phytosterols at 0 and 200 mg/d during a 42-day experiment. The milk yield of each cow was recorded daily after calving. On days 1 and 42, blood and faeces samples were all collected from perinatal cows before morning feeding for analysing plasma biochemicals and metabolome, and faecal bacteria metabolism.Results: Dietary addition with phytosterols at 200 mg/d had no effects on plasma cholesterol and numerically increased milk yield by 1.82 kg/d (p>0.10) but attenuated their negative energy balance in perinatal cows as observed from the significantly decreased plasma level of β-hydroxybutyric acid (p = 0.002). Dietary addition with phytosterols significantly altered 12 and 15 metabolites (p<0.05) within the plasma and faeces of perinatal cows, respectively. Of these metabolites, 5 upregulated plasma fatty acids indicated an improved energy status (i.e., C18:1T, C14:0, C17:0, C18:0, and C16:0). Milk yield negatively correlated with plasma concentrations of ketone bodies (p = 0.035) and 5-methoxytryptamine (p = 0.039). Furthermore, dietary addition with phytosterols at 200 mg/d had no effects on fermentation characteristics and bacterial diversity of cow faeces (p>0.10) but improved potentially beneficial bacteria such as Christensenellaceae family (p<0.05) that positively correlated with feed efficiency.Conclusion: Dietary addition with phytosterols at 200 mg/d could effectively improve the energy status in perinatal cows by attenuating their negative energy balance.

ObjectiveThe purpose of this study was to reveal the metabolic shift in the fungus co-cultured with the methanogen (Methanobrevibacter thaueri).MethodsGas chromatography-mass spectrometry was used to investigate the metabolites in anaerobic fungal (Pecoramyces sp. F1) cells and the supernatant.ResultsA total of 104 and 102 metabolites were detected in the fungal cells and the supernatant, respectively. The partial least squares-discriminant analysis showed that the metabolite profiles in both the fungal cell and the supernatant were distinctly shifted when co-cultured with methanogen. Statistically, 16 and 30 metabolites were significantly (p<0.05) affected in the fungal cell and the supernatant, respectively by the co-cultured methanogen. Metabolic pathway analysis showed that co-culturing with methanogen reduced the production of lactate from pyruvate in the cytosol and increased metabolism in the hydrogenosomes of the anaerobic fungus. Citrate was accumulated in the cytosol of the fungus co-cultured with the methanogen.ConclusionThe co-culture of the anaerobic fungus and the methanogen is a good model for studying the microbial interaction between H2-producing and H2-utilizing microorganisms. However, metabolism in hydrogenosome needs to be further studied to gain better insight in the hydrogen transfer among microorganisms.

Background Providing high-quality roughage is crucial for improvement of ruminant production because it is an essential component of their feed. Our previous study showed that feeding bio-fermented rice straw (BF) improved the feed intake and weight gain of sheep. However, it remains unclear why feeding BF to sheep increased their feed intake and weight gain. Therefore, the purposes of this research were to investigate how the rumen microbiota and serum metabolome are dynamically changing after feeding BF, as well as how their changes influence the feed intake, digestibility, nutrient transport, meat quality and growth performances of sheep. Twelve growing Hu sheep were allocated into 3 groups: alfalfa hay fed group (AH: positive control), rice straw fed group (RS: negative control) and BF fed group (BF: treatment). Samples of rumen content, blood, rumen epithelium, muscle, feed offered and refusals were collected for the subsequent analysis. Results Feeding BF changed the microbial community and rumen fermentation, particularly increasing ( P < 0.05) relative abundance of Prevotella and propionate production, and decreasing ( P < 0.05) enteric methane yield. The histomorphology (height, width, area and thickness) of rumen papillae and gene expression for carbohydrate transport ( MCT1 ), tight junction (claudin-1, claudin-4), and cell proliferation ( CDK4 , Cyclin A2 , Cyclin E1 ) were improved ( P < 0.05) in sheep fed BF. Additionally, serum metabolome was also dynamically changed, which led to up-regulating ( P < 0.05) the primary bile acid biosynthesis and biosynthesis of unsaturated fatty acid in sheep fed BF. As a result, the higher ( P < 0.05) feed intake, digestibility, growth rate, feed efficiency, meat quality and mono-unsaturated fatty acid concentration in muscle, and the lower ( P < 0.05) feed cost per kg of live weight were achieved by feeding BF. Conclusions Feeding BF improved the growth performances and meat quality of sheep and reduced their feed cost. Therefore, bio-fermentation of rice straw could be an innovative way for improving ruminant production with minimizing production costs. Graphical Abstract