Manganese dioxide (MnO2) nanoparticles (NPs) were discovered in previous work to be effective in improving tumor oxygenation (hypoxia) and reducing H2O2 and acidity in the tumor microenvironment (TME) via local injection. To develop MnO2 formulations useful for clinical application, hybrid NPs are designed with tailored hydrophobicity and structure suitable for intravenous injection, with good blood circulation, biocompatibility, high tumor accumulation, and programmable oxygen generation rate. Two different hybrid NPs are constructed by embedding polyelectrolyte‐MnO2 (PMD) in hydrophilic terpolymer/protein‐MnO2 (TMD) or hydrophobic polymer/lipid‐MnO2 (LMD) matrices. The in vitro reactivity of the MnO2 toward H2O2 is controlled by matrix material and NP structure and dependent on pH with up to two‐fold higher O2 generation rate at acidic (tumor) pH than at systemic pH. The hybrid NPs are found to be safe to cells in vitro and organs in vivo and effectively decrease tumor hypoxia and hypoxia‐inducible‐factor‐1alpha through local or systemic administration. Fast acting TMD reduces tumor hypoxia by 70% in 0.5 h by local injection. Slow acting LMD exhibits superior tumor accumulation and retention through the systemic administration and decreased hypoxia by 45%. These findings encourage a broader use of hybrid MD NPs to overcome TME factors for cancer treatment.

Isoniazid (INH)‐induced hepatotoxicity remains a significant clinical problem, and the current mechanistic hypothesis is incomplete; it is simply referred to as metabolic idiosyncrasy,1 which is believed to involve cytotoxicity caused by bioactivation of acetylhydrazine,2 a metabolite of INH. However, this hypothesis is based on animal studies, involving characteristics that are very different from those that pertain to hepatotoxicity in humans, such as delayed onset. This issue therefore deserves a fresh look. Clinical Pharmacology & Therapeutics (2011) 89 6, 911–914. doi:

Reactive oxygen and nitrogen species (RONS) are implicated in the pathogenesis of several autoimmune diseases. Also, increased lipid peroxidation and protein nitration are reported in systemic autoimmune diseases. Lipid peroxidation-derived aldehydes (LPDAs) such as malondialdehyde (MDA) and 4-hydroxynonenal (HNE) are highly reactive and bind proteins covalently, but their potential to elicit an autoimmune response and contribution to disease pathogenesis remain unclear. Similarly, nitration of protein could also contribute to disease pathogenesis. To assess the status of lipid peroxidation and/or RONS, autoimmune-prone female MRL +/+ mice (5-week old) were treated with trichloroethene (TCE), an environmental contaminant known to induce autoimmune response, for 48 weeks (0.5 mg/ml via drinking water), and formation of antibodies to LPDA-protein adducts was followed in the sera of control and TCE-treated mice. TCE treatment led to greater formation of both anti-MDA-and and-HNE-protein adduct antibodies and higher serum iNOS and nitrotyrosine levels. The increase in TCE-induced oxidative stress was associated with increases in anti-nuclear-, anti-ssDNA-and anti-dsDNA-antibodies. These findings suggest that TCE exposure not only leads to oxidative/nitrosative stress, but is also associated with induction/exacerbation of autoimmune response in MRL +/+ mice. Further interventional studies are needed to establish a causal role of RONS in TCE-mediated autoimmunity.

Two new diketopiperazine dimers, WIN 64821 (la) and WIN 64745 (2), were isolated from an Aspergillus culture originally isolated from soil and their structures established on the basis of chemical and spectroscopic evidence. The dimer la has Cl symmetry with each of two equivalent

Key Points• ADAMTS13 controls key steps of vascular remodeling during stroke recovery.• Recombinant ADAMTS13 enhances ischemic neovascularization and vascular repair.Angiogenic response is essential for ischemic brain repair. The von Willebrand factor (VWF)-cleaving protease disintegrin and metalloprotease with thrombospondin type I motif, member 13 (ADAMTS13) is required for endothelial tube formation in vitro, but there is currently no in vivo evidence supporting a function of ADAMTS13 in angiogenesis. Here we show that mice deficient in ADAMTS13 exhibited reduced neovascularization, brain capillary perfusion, pericyte and smooth muscle cell coverage on microvessels, expression of the tight junction and basement membrane proteins, and accelerated blood-brain barrier (BBB) breakdown and extravascular deposits of serum proteins in the peri-infarct cortex at 14 days after stroke. Deficiency of VWF or anti-VWF antibody treatment significantly increased microvessels, perfused capillary length, and reversed pericyte loss and BBB changes in Adamts13 2/2 mice. Furthermore, we observed that ADAMTS13 deficiency decreased angiopoietin-2 and galectin-3 levels in the isolated brain microvessels, whereas VWF deficiency had the opposite effect. Correlating with this, overexpression of angiopoietin-2 by adenoviruses treatment or administration of recombinant galectin-3 normalized microvascular reductions, pericyte loss, and BBB breakdown in Adamts13 2/2 mice. The vascular changes induced by angiopoietin-2 overexpression and recombinant galectin-3 treatment in Adamts13 2/2 mice were abolished by the vascular endothelial growth factor receptor-2 antagonist SU1498. Importantly, treating wild-type mice with recombinant ADAMTS13 at 7 days after stroke markedly increased neovascularization and vascular repair and improved functional recovery at 14 days. Our results suggest that ADAMTS13 controls key steps of ischemic vascular remodeling and that recombinant ADAMTS13 is a putative therapeutic avenue for promoting stroke recovery. (Blood. 2017;130(1):11-22)