Histone acetylation is required for many aspects of gene regulation, genome maintenance and metabolism and dysfunctional acetylation is implicated in numerous diseases, including cancer. Acetylation is regulated by histone acetyltransferases (HATs) and histone deacetylases and currently, few general HAT inhibitors have been described. We identified the HAT Tip60 as an excellent candidate for targeted drug development, as Tip60 is a key mediator of the DNA damage response and transcriptional co-activator. Our modeling of Tip60 indicated that the active binding pocket possesses opposite charges at each end, with the positive charges attributed to two specific side chains. We used structure based drug design to develop a novel Tip60 inhibitor, TH1834, to fit this specific pocket. We demonstrate that TH1834 significantly inhibits Tip60 activity in vitro and treating cells with TH1834 results in apoptosis and increased unrepaired DNA damage (following ionizing radiation treatment) in breast cancer but not control cell lines. Furthermore, TH1834 did not affect the activity of related HAT MOF, as indicated by H4K16Ac, demonstrating specificity. The modeling and validation of the small molecule inhibitor TH1834 represents a first step towards developing additional specific, targeted inhibitors of Tip60 that may lead to further improvements in the treatment of breast cancer.

Isoorientin (ISO) is a natural flavonoid, which is a 6- C-glucoside of luteolin, and has been demonstrated to possess multiple biological properties. In this study, the effects of ISO on the growth performance and gut microbiota of BALB/c mice were investigated. The results showed that ISO could promote food intake and body weight gain, increase the digestibility of crude proteins and utilization of the gross energy, and strengthen antioxidant capacity of mice. We also demonstrated it has no side effects on hepatic and renal functions. Moreover, ISO inhibited the growth of most bacteria in gut microbiota, especially the pathogenic genera of Alistipes, Helicobacter, and Oscillibacter, which could lead to inflammation. Metabolisms of epithelial cell signaling in Helicobacter pylori infection, lipopolysaccharide (LPS) biosynthesis, and LPS biosynthesis proteins in gut microbiota of the control group were more abundant than those in the ISO group, while lipid metabolism and vitamin B metabolism were enriched in the ISO group. We found the changes in enrichments of metabolic pathways of the gut microbiota along with the ISO application were positively correlated with the antioxidation, anti-inflammation, and antibiosis. This work provided a fundamental basis for the future development of ISO-functional foods used for resistance to oxidation, inflammation, and pathogens.

As a common polycyclic aromatic hydrocarbon compound, benzo[a]pyrene (BaP) is readily produced in processing of oil and fatty foods. It is not only a strong carcinogen but also a substance with strong immunotoxicity and reproduction toxicity. Autophagy and pyroptosis are two types of programmed cell death. Whether or not BaP damages body tissues via autophagy or pyroptosis remains unknown. The present study investigated the effects of BaP on autophagy and pyroptosis in HL-7702 cells. The results showed that BaP induced cell death in HL-7702 cells enhanced the intracellular levels of ROS and arrested the cell cycle at the S phase. Additionally, BaP resulted in cell death through autophagy and pyroptosis. Compared with the BaP group, the autophagy inhibitor 3-MA significantly (p < 0.01) inhibited the release of LDH by 70.53% ± 0.46 and NO by 50.36% ± 0.80, the increase of electrical conductivity by 12.08% ± 0.55, and the expressions of pyroptotic marker proteins (Caspase-1, Cox-2, IL-1β, IL-18). The pyroptosis inhibitor Ac-YVAD-CM also notably (p < 0.01) blocked BaP-induced autophagic cell death characterized by the increase of autophagic vacuoles and overexpression of Beclin-1 and LC3-II. In conclusion, BaP led to injury by inducing autophagy and pyroptosis simultaneously, the two of which coexisted and promoted each other in HL-7702 cells.

Peroxiredoxins are H2O2 scavenging enzymes that also carry H2O2 signaling and chaperone functions. In yeast, the major cytosolic peroxiredoxin, Tsa1 is required for both promoting resistance to H2O2 and extending lifespan upon caloric restriction. We show here that Tsa1 effects both these functions not by scavenging H2O2, but by repressing the nutrient signaling Ras-cAMP-PKA pathway at the level of the protein kinase A (PKA) enzyme. Tsa1 stimulates sulfenylation of cysteines in the PKA catalytic subunit by H2O2 and a significant proportion of the catalytic subunits are glutathionylated on two cysteine residues. Redox modification of the conserved Cys243 inhibits the phosphorylation of a conserved Thr241 in the kinase activation loop and enzyme activity, and preventing Thr241 phosphorylation can overcome the H2O2 sensitivity of Tsa1-deficient cells. Results support a model of aging where nutrient signaling pathways constitute hubs integrating information from multiple aging-related conduits, including a peroxiredoxin-dependent response to H2O2.

Appropriate germination can improve the nutritional value and bioactivity of soybeans; however, few studies have assessed the effect of germination on soybean proteins. This study examined the physicochemical property, antioxidation, and cytoprotective effect of the germinated soybean proteins (Gsp). Gsp was extracted from soybeans which germinated for 0–3 days using the method of alkali‐solution and acid‐isolation extraction. The results showed that germination could digest soybean proteins into the smaller molecules; enhance the degree of hydrolysis, emulsifiability, and foaming capacity; increase the removal rate of ABTS, DPPH, O2−˙, and ˙OH radical; and decrease the reducing power and lipid peroxidation of Gsp. Additionally, Gsp was able to protect HL‐7702 human hepatocyte cells against benzo(a)pyrene (BaP)‐induced cytotoxicity through mediating the cell cycle arrest, suppressing apoptosis, and increasing reactive oxygen species (ROS) levels. This work demonstrated that germination could enhance the physicochemical property and antioxidant activity of Gsp, which also displayed the remarkable cytoprotective effect. This study provided a fundamental basis for substantiating dietary of Gsp used for resistance to oxidation and hepatic injury.

A set of azoheteroarenes have been synthesized with Buchwald-Hartwig coupling and microwave-assisted O oxidation as the key steps. Several compounds exhibit good to excellent photoswitching properties (high switching efficiency, good fatigue resistance, and thermal stability of Z-isomer) relevant for photocontrolled applications, which pave the way for use in photopharmacology.

Methicillin resistant Staphylococcus aureus (MRSA) has become a major health concern which has brought about an urgent need for new therapeutic agents. As the S. aureus Sortase A (SrtA) enzyme contributes to the adherence of the bacteria to the host cells, inhibition thereof by small molecules could be employed as potential antivirulence agents, also towards resistant strains. Albeit several virtual docking SrtA campaigns have been reported, no strongly inhibitatory non-covalent binders have as yet emerged therefrom. In order to better understand the binding modes of small molecules, and the effect of different receptor structures employed in the screening, we herein report on an exploratory study employing 10 known binders and 500 decoys on 100 SrtA structures generated from regular or steered molecular dynamics simulations on four different SrtA crystal/NMR structures. The results suggest a correlation between the protein structural flexibility and the virtual screening performance, and confirm the noted immobilization of the β6/β7 loop upon substrate binding. The NMR structures reported appear to perform slightly better than the Xray-crystal structures, but the binding modes fluctuate tremendously, and it might be suspected that the catalytic site is not necessarily the preferred site of binding for some of the reported active compounds.

Oxidation of a highly conserved cysteine (Cys) residue located in the kinase activation loop of mitogen-activated protein kinase kinases (MAPKK) inactivates mammalian MKK6. This residue is conserved in the fission yeast Schizosaccharomyces pombe MAPKK Wis1, which belongs to the H2O2-responsive MAPK Sty1 pathway. Here, we show that H2O2 reversibly inactivates Wis1 through this residue (C458) in vitro. We found that C458 is oxidized in vivo and that serine replacement of this residue significantly enhances Wis1 activation upon addition of H2O2. The allosteric MAPKK inhibitor INR119, which binds in a pocket next to the activation loop and C458, prevented the inhibition of Wis1 by H2O2 in vitro and significantly increased Wis1 activation by low levels of H2O2 in vivo. We propose that oxidation of C458 inhibits Wis1 and that INR119 cancels out this inhibitory effect by binding close to this residue. Kinase inhibition through the oxidation of a conserved Cys residue in MKK6 (C196) is thus conserved in the S. pombe MAPKK Wis1.