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The Hippo pathway plays essential roles in organ size control and cancer prevention via restricting its downstream effector, Yes-associated protein (YAP). Previous studies have revealed an oncogenic function of YAP in reprogramming glucose metabolism, while the underlying mechanism remains to be fully clarified. Accumulating evidence suggests long noncoding RNAs (lncRNAs) as attractive therapeutic targets, given their roles in modulating various cancer-related signaling pathways. In this study, we report that lncRNA breast cancer anti-estrogen resistance 4 (BCAR4) is required for YAP-dependent glycolysis. Mechanistically, YAP promotes the expression of BCAR4, which subsequently coordinates the Hedgehog signaling to enhance the transcription of glycolysis activators HK2 and PFKFB3. Therapeutic delivery of locked nucleic acids (LNAs) targeting BCAR4 attenuated YAP-dependent glycolysis and tumor growth. The expression levels of BCAR4 and YAP are positively correlated in tissue samples from breast cancer patients, where high expression of both BCAR4 and YAP is associated with poor patient survival outcome. Taken together, our study not only reveals the mechanism by which YAP reprograms glucose metabolism, but also highlights the therapeutic potential of targeting YAP-BCAR4-glycolysis axis for breast cancer treatment.

The bacteria contained in air aerosols from poultry houses are closely connected to animal health and production. This study aimed to investigate the seasonal factors on microbial aerosol concentration, particle size and bacterial spectrum composition inside a closed-cage broiler house. Then, 16S rDNA sequencing technology was applied to analyze the characteristics of bacterial abundance and diversity. The results indicated that the concentration of bacterial aerosol in the broiler house varied significantly in different seasons, with a concentration range of 5.87–15.77 × 103 CFU/m3, and the highest and lowest concentrations in the summer and winter, respectively. Microbiological analysis showed that the proportion of Gram-negative bacteria in autumn was significantly higher than that in summer (P < 0.05). In addition, the floral structure of potential pathogenic bacterial genera also differed by season. Escherichia-Shigella, Streptococcus, Acinetobacter, Pseudomonas were identified in the bacterial aerosols. Importantly, the relative abundance of Firmicutes in spring and autumn was much higher. In contrast, the relative abundance of Proteobacteria in spring and autumn was lower than that in summer and winter. Altogether, results revealed the effects of seasonal factors on the diversity and abundance of bacteria and the distribution characteristics of major opportunistic pathogens in the air of closed-cage broiler houses. These results will provide important information for exploring the potential risk of aerosols from poultry houses all four seasons.

Abstract Tamoxifen resistance (TamR) prevents ER-positive breast cancer patients from benefitting from endocrine therapy, and miR-221 or miR-222 plays vital roles in inducing TamR. In this study, we designed synthetic sponges to reverse TamR by targeting these two miRs. First, we established a tamoxifen resistant breast cancer cell line (MCF-7TamR), we verified the high expressing level of these two miRs in TamR cells. miR-221 or miR-222 inhibitors rendered MCF-7TamR cells responsive to tamoxifen. Next, we designed a miR-221/222 sponge, which contains total 8 multi-antisense binding sites (MBSs) for these two onco-miRs, and inserted it into CMV promoter- or hTERT promoter-driven expressing vectors. After transfected miR-221/222 sponge expressing vectors into MCF-7TamR cells, we identified a strong interaction between miR-221/222 sponge and endogenous miR-221 or miR-222 by RNA pulldown assay. We also found that miR-221/222 sponge restored the expression of ERα and PTEN, arrested cells in G1 phase, and finally resulted in reduced cell growth and cell migration. Notably, miR-221/222 sponge expressing cells abrogates tamoxifen resistance through restoring the expression of ERα, suggesting that miR-221/222 sponge gene therapy especially driven by tumor specific promoter could provide an effective therapeutic approach against TamR in breast cancer.

Antrocin is a novel compound isolated from Antrodia cinnamomea, and is classified as a sesquiterpene lactone. The therapeutic efficacy of antrocin has been studied, and it has shown an antiproliferative effect on various cancers. The aim of this study was to evaluate the anti-oxidant activity, potential genotoxicity, and oral toxicity of antrocin. Ames tests with five different strains of Salmonella typhimurium, chromosomal aberration tests in CHO-K1 cells, and micronucleus tests in ICR mice were conducted. The results of anti-oxidant capacity assays showed that antrocin has great anti-oxidant activity and is a moderately strong antimutagenic agent. In the results of the genotoxicity assays, antrocin did not show any mutagenic potential. In the 28-day oral toxicity test, Sprague Dawley rats were gavaged with 7.5 or 37.5 mg/kg of antrocin for 28 consecutive days. In addition, 7.5 mg/kg sorafenib, an anti-cancer drug, was used as a positive control for toxicity comparison. At the end of the study, antrocin did not produce any toxic effects according to hematology, serum chemistry, urine analysis, or histopathological examinations. According to the results of the genotoxicity and 28-day oral toxicity study, antrocin, at a dose of 37.5 mg/kg, did not cause adverse effects and can be a reference dose for therapeutic agents in humans.

Mycoplasma synoviae (MS) infection is a serious threat to poultry industry in China. Tilmicosin is a semisynthetic macrolide antibiotic used only in animals and has shown potential efficacy against MS, but there were no reported articles concerning the pharmacokinetics/pharmacodynamics (PK/PD) interactions of tilmicosin against MS in vitro and vivo. This study aimed to assess the antibacterial activity of tilmicosin against MS in vitro and in vivo using PK/PD model to provide maximal efficacy. The minimum inhibitory concentration (MIC) and killing rates of different drug concentrations were measured using the microdilution method in vitro. Then, tilmicosin was administered orally to the MS‐infected chickens at doses of 7.5 and 60 mg/kg, and the PK parameters of tilmicosin in joint dialysates were determined using high‐pressure liquid chromatography/tandem mass spectrometry (HPLC‐MS/MS) combined with the microdialysis technique. The antibacterial effect (△E) was calculated when the infected chickens were administered a single oral dose of tilmicosin at 4, 7.5, 15, 30, and 60 mg/kg b.w. The PK and PD data were fitted using the Sigmoid Emax model to evaluate the PK/PD interactions of tilmicosin against MS. The bactericidal activity of tilmicosin against MS was concentration dependent. Furthermore, the PK/PD index of AUC0–72h/MIC exhibited the most optimal fitting results (R2 =.98). The MS load decreased by 1, 2, and 3 Log10 CFU/mL, then AUC/MIC was determined as 13.99, 20.53, and 28.23 h, respectively, and the bactericidal effect can be achieved when the dose of MS‐infected chickens is at 31.64 mg/kg b.w. The findings of this study hold significant implications for optimizing the treatment regimen for MS infection. [ABSTRACT FROM AUTHOR]

Iron (Fe) deficiency is one of the most common micronutrient imbalances limiting plant growth globally, especially in arid and saline alkali regions due to the decreased availability of Fe in alkaline soils. Malus halliana grows well in arid regions and is tolerant of Fe deficiency. Here, a physiological and metabolomic approach was used to analyze the short-term molecular response of M. halliana roots to Fe deficiency. On the one hand, physiological data show that the root activity first increased and then decreased with the prolongation of the stress time, but the change trend of root pH was just the opposite. The total Fe content decreased gradually, while the effective Fe decreased at 12 h and increased at 3 d. The activity of iron reductase (FCR) increased with the prolongation of stress. On the other hand, a total of 61, 73, and 45 metabolites were identified by GC–MS in three pairs: R12h (Fe deficiency 12 h) vs. R0h (Fe deficiency 0 h), R3d (Fe deficiency 3 d) vs. R0h, and R3d vs. R12h, respectively. Sucrose, as a source of energy, produces monosaccharides such as glucose by hydrolysis, while glucose accumulates significantly at the first (R12h vs. R0h) and third time points (R3d vs. R0h). Carbohydrates (digalacturonate, L-xylitol, ribitol, D-xylulose, glucose, and glycerol) are degraded into pyruvate through glycolysis and pentose phosphate, which participate in the TCA. Glutathione metabolism and the TCA cycle coordinate with each other, actively respond to Fe deficiency stress, and synthesize secondary metabolites at the same time. This study thoroughly examines the metabolite response to plant iron deficiency, highlighting the crucial roles of sugar metabolism, tricarboxylic acid cycle regulation, and glutathione metabolism in the short-term iron deficiency response of apples. It also lays the groundwork for future research on analyzing iron deficiency tolerance. [ABSTRACT FROM AUTHOR]

Abstract. Background:. Pre-existing liver disease is a risk factor for the worse prognosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We aimed to evaluate whether chronic hepatitis B (CHB) and hepatocellular carcinoma (HCC) affect the expression of viral receptor angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) in the liver. Methods:. Twelve pairs of matched liver tissues of HCC and para-carcinoma were collected from the First Affiliated Hospital of Zhejiang University School of Medicine. And 20 liver biopsies from CHB patients were collected from Peking University People's Hospital. The expression of ACE2 and TMRPSS2 were detected using immunofluorescence staining, western blot, and RT-qPCR. The effects of hepatitis B virus (HBV) replication or interferon on ACE2 and TMPRSS2 expression were tested in hepatic cell lines. Results:. The mRNA expression of TMPRSS2 in HCC tissues was six-fold higher than that of para-carcinoma tissues (P = 0.002), whereas that of ACE2 was not statistically different between HCC and para-carcinoma tissues. Hepatocellular ACE2 expression was detected in 35% (7/20) of CHB patients and mostly distributed in the inflammatory areas. However, there was no difference in TMPRSS2 expression between areas with or without inflammation. IFN-α2b slightly induced ACE2 expression (2.4-fold, P = 0.033) in HepG2 cells but not in Huh-7, QSG-7701, and L-02 cells. IFN-α2b did not affect TMPRSS2 expression in these cell lines. In addition, HBV replication did not alter ACE2 expression in HepAD38 cells. Conclusions:. Although HBV replication does not directly affect the expression of ACE2 and TMPRSS2, intrahepatic inflammation and carcinogenesis may increase their expression in some patients, which, in turn, may facilitate SARS-CoV-2 infection in hepatocytes.

Summary: We previously showed stabilization of NIK−induced activation of NF-κB non-canonical signaling suppresses MLL-AF9−induced AML. In the current study, we demonstrate that deletion of NF-κB non-canonical RelB prevents the inhibitory effect of NIK stabilization in MLL-AF9 AML. Mechanistically, RelB suppresses its direct target, TIFAB, which is upregulated in human AML and correlates negatively with the survival of AML patients. Forced expression of TIFAB reverses NIK−induced impaired AML development through downregulation of RelB and upregulation of HOXA9. Consistent with upregulation of HOXA9, gene set enrichment analysis shows that forced expression of TIFAB blocks myeloid cell development, upregulates leukemia stem cell signature and induces similar gene expression patterns to those of HOXA9-MEIS1 and HOXA9-NUP98, and upregulates oxidative phosphorylation. Accordingly, forced expression of HOXA9 also largely releases the inhibitory impact of NIK stabilization via downregulation of RelB and upregulation of RelA. Our data suggest that NIK/RelB suppresses MLL-AF9−induced AML mainly through downregulation of TIFAB/HOXA9.