Nanoparticles of various shapes, sizes, and materials carrying different surface modifications have numerous technological and biomedical applications. Yet, the mechanisms by which nanoparticles interact with biological structures as well as their biological impact and hazards remain poorly investigated. Due to their large surface to volume ratio, nanoparticles usually exhibit properties that differ from those of bulk materials. Particularly, the surface chemistry of the nanoparticles is crucial for their durability and solubility in biological media as well as for their biocompatibility and biodistribution. Polystyrene does not degrade in the cellular environment and exhibits no short-term cytotoxicity. Because polystyrene nanoparticles can be easily synthesized in a wide range of sizes with distinct surface functionalizations, they are perfectly suited as model particles to study the effects of the particle surface characteristics on various biological parameters. Therefore, we have exploited polystyrene nanoparticles as a convenient platform to study bio–nano interactions. This review summarizes studies on positively and negatively charged polystyrene nanoparticles and compares them with clinically used superparamagnetic iron oxide nanoparticles.

Review of the available evidence for physiological and pathophysiological roles of the serine protease plasmin in inflammatory processes. The serine protease plasmin generated from its zymogen plasminogen is best known for its function as a key enzyme of the fibrinolytic cascade. However, beyond fibrinolysis, plasmin has a number of crucial functions in a variety of processes, including inflammation. Various cells can bind plasminogen and plasmin via plasminogen-binding sites exposing a C-terminal lysine. Plasmin, generated as a result of plasminogen activation at the cell surface, is protected from its physiological inhibitors. Apart from its ability to facilitate cell migration in tissues, plasmin is capable of triggering signaling, which depends on cellular binding via its lysine-binding sites and its proteolytic activity. Plasmin-induced signaling affects various functions of monocytes, macrophages, DCs, and others, with the list of affected cells still growing. In vitro and in vivo studies have demonstrated the ability of plasmin to stimulate the production of cytokines, ROS, and other mediators, thereby contributing to inflammation. Plasmin-induced chemotaxis of monocytes and DCs indicates that it is also a potent chemoattractant for immune cells. Therefore, excessive activation of plasmin in chronic inflammatory or autoimmune diseases might exacerbate the activation of inflammatory cells and the pathogenesis of the disease. This review focuses on the available evidence for physiological and pathophysiological roles the serine protease plasmin in inflammatory processes.

Objective— Fibrinolytic activity is upregulated in atherosclerotic lesions, yet little is known about the role of plasmin in macrophage function. We postulated a direct effect of plasmin on human monocyte-derived macrophages. Methods and Results— Plasmin activates macrophages via the annexin A2 heterotetramer composed of annexin A2 and S100A10 with subsequent stimulation of Janus kinase JAK1/TYK2 signaling. JAK1/TYK2 leads to STAT3 activation, Akt-dependent NF-κB activation, and phosphorylation of extracellular signal-regulated kinase 1/2 and mitogen-activated kinase p38. These signaling pathways trigger nuclear translocation of STAT3 and p65 transcription factors and the induction of the proinflammatory cytokines tumor necrosis factor-α and IL-6. Inhibitors of JAK, p38, and NF-κB revealed that these signaling pathways are indispensable for the plasmin-mediated tumor necrosis factor-α and IL-6 induction. By contrast, the extracellular signal-regulated kinase 1/2 activation is essential only for the IL-6 expression. The activation clearly depends on the proteolytic activity of plasmin, which cleaves the A2 subunit of the annexin A2 heterotetramer. Downregulation of each of the receptor subunits by antisense oligodeoxynucleotides abolished the plasmin-induced expression of proinflammatory cytokines stressing the crucial role the annexin A2 heterotetramer. Conclusions— Plasmin generated at sites of inflammation such as atherosclerotic lesions will trigger cytokine expression in human macrophages.

Artemisia annua L. has gained increasing attention for its anticancer activity. However, beside artemisinin, less is known about the possible bioactive ingredients of Artemisia annua and respective herbal preparations. We hypothesized that, in addition to artemisinin, Artemisia annua preparations might contain multiple ingredients with potential anticancer activity. MDA-MB-231 triple negative human breast cancer (TNBC) cells along with other treatment resistant, metastatic cancer cell lines were used to investigate in vitro and in vivo the anticancer efficacy of an Artemisia annua extract marketed as a herbal preparation, which contained no detectable artemisinin (limit of detection = 0.2 ng/mg). The extract was characterized by HPLC-DAD and the most abundant compounds were identified by 1H- and 13C NMR spectroscopy and quantified by UHPLC-MS/MS. Cell viability and various apoptotic parameters were quantified by flow cytometry. In vitro data were validated in two in vivo cancer models, the chick chorioallantoic membrane (CAM) assay and in orthotopic breast cancer xenografts in nude mice. The Artemisia annua extract, the activity of which could be enhanced by acetonitrile maceration, inhibited the viability of breast (MDA-MB-231 and MCF-7), pancreas (MIA PaCa-2), prostate (PC-3), non-small cell lung cancer (A459) cells, whereas normal mammary epithelial cells, lymphocytes, and PBMC were relatively resistant to extract treatment. Likewise, the extract's most abundant ingredients, chrysosplenol D, arteannuin B, and casticin, but not arteannuic acid or 6,7-dimethoxycoumarin, inhibited the viability of MDA-MB-231 breast cancer cells. The extract induced accumulation of multinucleated cancer cells within 24 h of treatment, increased the number of cells in the S and G2/M phases of the cell cycle, followed by loss of mitochondrial membrane potential, caspase 3 activation, and formation of an apoptotic hypodiploid cell population. Further, the extract inhibited cancer cell proliferation, decreased tumor growth, and induced apoptosis in vivo in TNBC MDA-MB-231 xenografts grown on CAM as well as in nude mice. An extract of an artemisinin-deficient Artemisia annua herbal preparation exhibits potent anticancer activity against triple negative human breast cancer. New active ingredients of Artemisia annua extract with potential anticancer activity have been identified.