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Sterile inflammation is initiated by damage-associated molecular patterns (DAMPs) and a key contributor to acute liver injury (ALI). However, the current knowledge on those DAMPs that activate hepatic inflammation under ALI remains incomplete. We report here that circulating peroxiredoxin-1 (Prdx1) is a novel DAMP for ALI. Intraperitoneal injection of acetaminophen (APAP) elicited a progressive course of ALI in mice, which was developed from 12 to 24 h post injection along with liver inflammation evident by macrophage infiltration and upregulations of cytokines (IL-1β, IL-6 and TNF-α); these alterations were concurrently occurred with a robust and progressive production of serum Prdx1. Similar observations were also obtained in carbon tetrachloride (CCl 4)-induced ALI in mice. Removal of the source of serum Prdx1 protected mice deficient in Prdx1 from APAP and CCl 4 -induced liver injury, and decreased macrophage infiltration, IL-1β, IL-6 and TNF-α production. As a result, Prdx1 −/− mice were strongly protected from APAP-induced death that was likely progressed from ALI. Additionally, intravenous re-introduction of recombinant Prdx1 (rPrdx1) in Prdx1 −/− mice reversed or reduced all the above events, demonstrating an important contribution of circulating Prdx1 to ALI. rPrdx1 potently induced in primary macrophages the expression of pro-IL-1β, IL-6, TNF-α, and IL-1β through the NF-κB signaling as well as the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome signaling, evident by caspase-1 activation. Furthermore, a significant elevation of serum Prdx1 was demonstrated in patients (n = 15) with ALI; the elevation is associated with ALI severity. Collectively, we provide the first demonstration for serum Prdx1 contributing to ALI. Image 1 • Increases in serum Prdx1 in patients and mice with acute liver injury (ALI). • Prdx1 −/− mice are protected from drug-induced ALI and ALI-associated inflammation. • Intravenous injection of recombinant Prdx1 (rPrdx1) causes ALI in Prdx1 −/− mice. • rPrdx1 induces IL-1β, IL-6, and TNF-α expression in primary macrophages. • Circulating Prdx1 is a novel DAMP promoting ALI. [ABSTRACT FROM AUTHOR]

Abstract: In an on-going effort to discover metallotherapeutic alternatives to the chemotherapy drug cisplatin, neutral distorted square pyramidal gold(III) coordination complexes possessing 2,9-disubstituted-1,10-phenanthroline ligands {[(Rphen)AuCl3]; R=n-butyl, sec-butyl} have been previously synthesized and characterized. A structurally analogous gold(III) complex bearing a 6,6′-di-methylbipyridine ligand ([(methylbipy)AuCl3]) has been synthesized and fully characterized to probe the effect of differing aromatic character of the ligand on solution stability and tumor cell cytotoxicity. The two compounds [( sec-butylphen)AuCl3] and [(methylbipy)AuCl3]) were subsequently assessed for their stability against the biological reductant glutathione, and it was found that the [( sec-butylphen)AuCl3] complex exhibits slightly enhanced stability compared to the [(methylbipy)AuCl3] complex and significantly higher stability than previously reported square planar gold(III) complex ions. Furthermore, these complexes were tested for cytotoxic effects against existing lung and head and neck cancer cell lines in vitro. The [( sec-butylphen)AuCl3] complex was found to be more cytotoxic than cisplatin against five different tumor cell lines, whereas [(methylbipy)AuCl3] had more limited in vitro antitumor activity. Given that [( sec-butylphen)AuCl3] had significantly higher antitumor activity, it was tested against an in vivo tumor model. It was found that this complex did not significantly reduce the growth of xenograft tumors in mice and initial model binding studies with bovine serum albumin indicate that interactions with serum albumin proteins may be the cause for the limited in vivo activity of this potential metallotherapeutic. [Copyright &y& Elsevier]

Abstract: A gold(III) complex possessing 5,6-dimethyl-1,10-phenanthroline (5,6DMP) was synthesized and fully characterized using standard spectroscopic techniques, as well as X-ray crystallography and elemental analysis. The complex [(5,6DMP)AuCl2][BF4] (2) was found to possess a distorted square planar geometry about the gold(III) center, commonplace for d8 Au(III) cations possessing sterically un-hindered polypyridyl ligands. Compound 2 was evaluated for its potential use as an anticancer therapeutic. It was determined that the complex is stable in phosphate buffer over a 24-hour period, thought it does undergo rapid reduction in the presence of equimolar amounts of reduced glutathione (GSH) and ascorbic acid. The DNA binding and in vitro tumor cytotoxicity of the title compound 2 were also determined. It was found to undergo weak and reversible binding to calf thymus DNA, and was more cytotoxic towards a panel of human cancer cell lines than the commonly used chemotherapy agent cisplatin. Cytotoxicity experiments with the free 5,6DMP ligand indicate that the ligand has IC50 values that are slightly lower than those observed for the gold complex (2), and coupled with the fact that the ligand appears to be released from the gold(III) metal center in reducing environments, this suggests the ligand itself may play an important role in the antitumor activity of the parent gold complex. [Copyright &y& Elsevier]