ObjectiveTo evaluate the effects of L-lysine (Lys)/L-arginine (Arg) on lipid and protein oxidation of emulsion sausage during storage and its possible mechanism.MethodsFour samples were prepared based on the presence or absence of additional sodium isoascorbate, Lys, or Arg: sample A (control), sample B (0.05 g of sodium isoascorbate), sample C (0.4 g of Lys), and sample D (0.4 g of Arg). Peroxide value (POV), thiobarbituric reactive substances (TBARS), protein carbonyls and thiols were measured. 2,2-Diphenyl-1-picrylhydrazyl (DPPH) and hydroxyl radical-scavenging, ferrous ion-chelating ability were also measured.ResultsCompared with the control, the sample treated with sodium isoascorbate, Lys or Arg had significantly lower POV during the initial 20 days, TBARS during the initial 15 days. Protein carbonyls were significantly lower compared Sample B, C, and D with A during the later storage (10 to 25 days); basically, protein thiols became lower during storage when the samples were treated with sodium isoascorbate, Lys, or Arg. Both Lys and Arg had weak reducing power but strong ferrous ion-chelating activity and DPPH radical- and hydroxyl radical-scavenging activity.ConclusionBoth Lys and Arg effectively inhibited the oxidation of lipids and proteins in emulsion sausage by scavenging free radicals and chelating ferrous ions. The results obtained may be favorable for the prevention of lipid and protein oxidation during processing and storage of meat products.
Some estrogen receptor‐α (ERα)‐targeted breast cancer therapies such as tamoxifen have tissue‐selective or cell‐specific activities, while others have similar activities in different cell types. To identify biophysical determinants of cell‐specific signaling and breast cancer cell proliferation, we synthesized 241 ERα ligands based on 19 chemical scaffolds, and compared ligand response using quantitative bioassays for canonical ERα activities and X‐ray crystallography. Ligands that regulate the dynamics and stability of the coactivator‐binding site in the C‐terminal ligand‐binding domain, called activation function‐2 (AF‐2), showed similar activity profiles in different cell types. Such ligands induced breast cancer cell proliferation in a manner that was predicted by the canonical recruitment of the coactivators NCOA1/2/3 and induction of the GREB1 proliferative gene. For some ligand series, a single inter‐atomic distance in the ligand‐binding domain predicted their proliferative effects. In contrast, the N‐terminal coactivator‐binding site, activation function‐1 (AF‐1), determined cell‐specific signaling induced by ligands that used alternate mechanisms to control cell proliferation. Thus, incorporating systems structural analyses with quantitative chemical biology reveals how ligands can achieve distinct allosteric signaling outcomes through ERα.
Earlier, we found estrogen receptor (ER) ligands having a novel three-dimensional oxabicyclo[2.2.1]heptene core scaffold and good ER binding affinity acted as partial agonists via small alkyl ester substitutions on the bicyclic core that indirectly modulate the critical switch helix in the ER ligand-binding domain, helix 12, by interactions with helix 11. This contrasts with the mechanism of action of tamoxifen, which directly pushes helix 12 out of the conformation required for gene activation. We now report that a much larger substitution can be tolerated at this position of the bicyclic core scaffold, namely a phenyl sulfonate group, which defines a novel binding epitope for the estrogen receptor. We prepared an array of 14 of these oxabicycloheptene sulfonates (OBHS), varying the phenyl sulfonate group. As with OBHS itself, these compounds showed preferential affinity for ERα, and the disposition and size of the phenyl substituents were important determinants of the binding affinity and selectivity of these compounds, with those having ortho substituents giving the highest, and para substituents the lowest affinities for ERα. A few analogs have ERα binding affinity that is comparable to or, in the case of the ortho chloro analog, higher than that of OBHS itself. In cell-based studies, we found several compounds with activity profiles comparable to tamoxifen, but acting entirely as indirect antagonists, allosterically interfering with recruitment of coactivator proteins to the receptor. Thus, the OBHS binding epitope represents a novel approach to the development of estrogen receptor antagonists via an indirect mechanism of antagonism.
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