ATF4 couples MYC-dependent translational activity to bioenergetic demands during tumour progression.

The c-Myc oncogene drives malignant progression and induces robust anabolic and proliferative programmes leading to intrinsic stress. The mechanisms enabling adaptation to MYC-induced stress are not fully understood. Here we reveal an essential role for activating transcription factor 4 (ATF4) in survival following MYC activation. MYC upregulates ATF4 by activating general control nonderepressible 2 (GCN2) kinase through uncharged transfer RNAs. Subsequently, ATF4 co-occupies promoter regions of over 30 MYC-target genes, primarily those regulating amino acid and protein synthesis, including eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), a negative regulator of translation. 4E-BP1 relieves MYC-induced proteotoxic stress and is essential to balance protein synthesis. 4E-BP1 activity is negatively regulated by mammalian target of rapamycin complex 1 (mTORC1)-dependent phosphorylation and inhibition of mTORC1 signalling rescues ATF4-deficient cells from MYC-induced endoplasmic reticulum stress. Acute deletion of ATF4 significantly delays MYC-driven tumour progression and increases survival in mouse models. Our results establish ATF4 as a cellular rheostat of MYC activity, which ensures that enhanced translation rates are compatible with survival and tumour progression

Effect of fructo-oligosaccharides on growth performance and meat quality in broilers

This study investigated the fructo-oligosaccharides (FOS) on growth performance and meat quality in broilers. Total 160 Xianghuang broilers aged 2 months were randomly assigned into 2 groups, CON (control), FOS (supplemented 0.5% fructo-oligosaccharides in diet). After 38 days, the breast, thigh muscle and liver samples were collected for further analysis. Results showed that no significant effect of 0.5% FOS on growth performance such as average daily gain (ADG), average daily feed intake (ADFI) or feed-to-gain ratio (F:G) were observed (P > 0.05). Broilers in FOS group had a yellower breast than that in CON group (P < 0.05). Breast pH45min and thigh pH24h value of FOS group were greater than that in CON group (P < 0.05). Max shear force and work of shear of cooked breast (pectoralis major) muscle was lower in FOS group compared with CON group (P < 0.05). Hardness (P = 0.065), fracturability (P = 0.063), gumminess (P = 0.079), chewiness (P = 0.080) of cooked thigh meat tended to be higher in FOS group compared to the CON group. Addition of 0.5% FOS resulted in lower thigh total superoxide dismutase (T-SOD) activity compared to CON group (P < 0.05). The malonaldehyde (MDA) concentration (P = 0.066) of breast muscle tended to be lower in FOS group compared with CON group. There was an increasing trend for total antioxidant capacity (T-AOC) activity of thigh muscle in FOS group compared to CON group (P = 0.053). Relative mRNA expression of breast catalase (CAT), superoxide dismutase 1 (SOD1), thioredoxin reductase 1 (TXNRD) were up-regulated by FOS supplementation compared with CON group (P < 0.05). In conclusion, FOS can be utilized at 0.5 % to improve meat quality such as elevating pH value, yellowness and decreasing max shear force of muscle through enhancing the antioxidant activity in broilers

Olmutinib (BI1482694/HM61713), a Novel Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, Reverses ABCG2-Mediated Multidrug Resistance in Cancer Cells

The main characteristic of tumor cell resistance is multidrug resistance (MDR). MDR is the principle cause of the decline in clinical efficacy of chemotherapeutic drugs. There are several mechanisms that could cause MDR. Among these, one of the most important mechanisms underlying MDR is the overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) super-family of transporters, which effectively pump out cytotoxic agents and targeted anticancer drugs across the cell membrane. In recent years, studies found that ABC transporters and tyrosine kinase inhibitors (TKIs) interact with each other. TKIs may behave as substrates or inhibitors depending on the expression of specific pumps, drug concentration, their affinity for the transporters and types of co-administered agents. Therefore, we performed in vitro experiments to observe whether olmutinib could reverse MDR in cancer cells overexpressing ABCB1, ABCG2, or ABCC1 transporters. The results showed that olmutinib at 3 μM significantly reversed drug resistance mediated by ABCG2, but not by ABCB1 and ABCC1, by antagonizing the drug efflux function in ABCG2-overexpressing cells. In addition, olmutinib at reversal concentration affected neither the protein expression level nor the localization of ABCG2. The results observed from the accumulation/efflux study of olmutinib showed that olmutinib reversed ABCG2-mediated MDR with an increasing intracellular drug accumulation due to inhibited drug efflux. We also had consistent results with the ATPase assay that olmutinib stimulated ATPase activity of ABCG2 up to 3.5-fold. Additionally, the molecular interaction between olmutinib and ABCG2 was identified by docking simulation. Olmutinib not only interacts directly with ABCG2 but also works as a competitive inhibitor of the transport protein. In conclusion, olmutinib could reverse ABCG2-mediated MDR. The reversal effect of olmutinib on ABCG2-mediated MDR cells is not due to ABCG2 expression or intracellular localization, but rather related to its interaction with ABCG2 protein resulting in drug efflux inhibition and ATPase stimulation

The correlation between cancer stem cells and epithelial-mesenchymal transition: molecular mechanisms and significance in cancer theragnosis

The connections between cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) is critical in cancer initiation, progression, metastasis, and therapy resistance, making it a focal point in cancer theragnosis. This review provides a panorama of associations and regulation pathways between CSCs and EMT, highlighting their significance in cancer. The molecular mechanisms underlined EMT are thoroughly explored, including the involvement of key transcription factors and signaling pathways. In addition, the roles of CSCs and EMT in tumor biology and therapy resistance, is further examined in this review. The clinical implications of CSCs-EMT interplay are explored, including identifying mesenchymal-state CSC subpopulations using advanced research methods and developing targeted therapies such as inhibitors and combination treatments. Overall, understanding the reciprocal relationship between EMT and CSCs holds excellent potential for informing the development of personalized therapies and ultimately improving patient outcomes

Breakthrough of Carbon–Ash Recalcitrance in Hydrochar via Molten Carbonate: Engineering Mineral-Rich Biowaste Toward Sustainable Platform Carbon Materials

The function-led design of porous hydrochar from mineral-rich biowaste for environmental applications inevitably suffers from carbon–ash recalcitrance. However, a method to alter the original carbon skeleton with ash remains elusive and hinders the availability of hydrochar. Herein, we propose a facile strategy for breaking the rigid structure of carbon–ash coupled hydrochar using phase-tunable molten carbonates. A case system was designed in which livestock manure and NaHCO3 were used to prepare the activated hydrochar, and NH3 served as the target contaminant. Due to the redox effect, we found that organic fractions significantly advanced the melting temperature of Na2CO3 below 800 °C. The Na species steadily broke the carbon–ash interaction as the thermal intensity increased and transformed inorganic constituents to facilitate ash dissolution, rebuilding the hydrochar skeleton with abundant hierarchical channels and active defect edges. The surface polarity and mesopore distribution collectively governed the five cycles NH3 adsorption attenuation process. Manure hydrochar delivered favorable potential for application with a maximum overall adsorption capacity of 100.49 mg·g−1. Integrated spectroscopic characterization and theoretical computations revealed that incorporating NH3 on the carbon surface could transfer electrons to chemisorbed oxygen, which promoted the oxidation of pyridine-N during adsorption. This work offers deep insight into the structure function correlation of hydrochar and inspires a more rational design of engineered hydrochar from high-ash biowaste

Effects of Enterotoxigenic <i>Escherichia coli</i> Challenge on Jejunal Morphology and Microbial Community Profiles in Weaned Crossbred Piglets

Pathogenic enterotoxigenic Escherichia coli (ETEC) is a major cause of bacterial diarrhea in weaning piglets, which are vulnerable to changes in environment and feed. This study aimed to determine the effects of the ETEC challenge on piglet growth performance, diarrhea rate, jejunal microbial profile, jejunal morphology and goblet cell distribution. A total of 13 piglets from one litter were selected on postnatal day 21 and assigned to treatments with or without ETEC challenge at 1 × 108 CFUs, as ETEC group or control group, respectively. On postnatal day 28, samples were collected, followed by the detection of serum biochemical indexes and inflammatory indicators, HE staining, PAS staining and 16S rDNA gene amplicon sequencing. Results showed that the growth performance decreased, while the diarrhea rate increased for the ETEC group. The jejunum is the main segment of the injured intestine during the ETEC challenge. Compared with the control, the ETEC group displayed fewer goblet cells in the jejunum, where goblet cells are more distributed at the crypt and less distributed at the villus. In addition, ETEC piglets possessed higher abundances of the genus Desulfovibrio, genus Oxalobacter and genus Peptococus and lower abundances of the genus Prevotella 2, genus Flavonifractor and genus Blautra. In terms of alpha diversity, Chao 1 and observed features indexes were both increased for the ETEC group. Our study provides insights into jejunal histopathological impairment and microbial variation in response to ETEC infection for weaned piglets and is a valuable reference for researchers engaged in animal health research to select stress models