Selective delivery of pentamidine toward cancer cells by self-assembled nanoparticles.

Pentamidine (PTM) is an aromatic diamidine approved for the treatment of parasitic infections that has been recently proposed for possible repositioning as an anticancer drug. To this aim, efforts have been made to improve its therapeutic efficacy and reduce associated adverse effects through both covalent derivatization and association with nanocarriers. To efficiently encapsulate PTM into biocompatible nanoparticles and to enhance its selectivity toward cancer cells, a squalene (SQ) derivative (1,1',2-tris-norsqualenoic acid, SQ-COOH) was selected to prepare PTM-loaded nanocarriers. Indeed, SQ and its derivatives self-assemble into nanoparticles in aqueous media. Furthermore, SQ-bioconjugates strongly interact with low-density lipoproteins (LDL), thus favoring preferential accumulation in cells overexpressing the LDL receptor (LDLR). We report here the preparation of nanocarriers by ion-pairing between the negatively charged SQ-COOH and the positively charged PTM free base (PTM-B), which allowed the covalent grafting of SQ to PTM to be avoided. The nanoparticles were characterized (mean size < 200 nm and zeta potential < -20 mV for SQ-COOH/PTM-B 3:1 molar ratio) and molecular modelling studies of the SQ-COOH/PTM-B interaction confirmed the nanocarrier stability. Finally, the ability to indirectly target LDLR-overexpressing cancer cells was evaluated by in vitro cell viability assays and confirmed by LDLR silencing, serum privation and simvastatin treatment.

The role of iron impurities in the toxic effects exerted by short multiwalled carbon nanotubes (MWCNT) in murine alveolar macrophages.

Lung toxicity mediated by multiwalled carbon nanotubes (MWCNT) has been widely demonstrated and recently associated with induction of carcinogenic asbestos-like effects, but the chemical features that drive this toxic effect have still not been well elucidated. The presence of metals as trace contaminants during MWCNT preparation, in particular iron (Fe) impurities, plays an important role in determining a different cellular response to MWCNT. Our goal was to clarify the mechanisms underlying MWCNT-induced toxicity with correlation to the presence of Fe impurities by exposing murine alveolar macrophages to two different MWCNT samples, which differed only in the presence or absence of Fe. Data showed that only Fe-rich MWCNT were significantly cytotoxic and genotoxic and induced a potent cellular oxidative stress, while Fe-free MWCNT did not exert any of these adverse effects. These results confirm that Fe content represents an important key constituent in promoting MWCNT-induced toxicity, and this needs to be taken into consideration when planning new, safer preparation routes.

Pleiotropic effects of cardioactive glycosides.

Cardioactive glycosides, like digoxin, ouabain and related compounds, are drugs that inhibit Na(+)/K(+)-ATPase and have a strong inotropic effect on heart: they cause the Na(+)/Ca(2+) exchanger to extrude Na+ in exchange with Ca(2+) and therefore increase the [Ca(2+)](i) concentration. For this reason, some of these drugs are currently used in the treatment of congestive heart failure and cardiac arrhythmias. Recently it has been discovered that cardiac glycosides exert pleiotropic effects on many aspects of cell metabolism. Na(+)/K(+)-ATPase is not the exclusive target, as they affect the cell response to hypoxia, modulate several signaling pathways involved in cell death and proliferation, regulate the transcription of different genes and modify the pharmacokinetics of other drugs, by altering the expression and activity of drug-metabolizing enzymes. Some of these effects are related to the steroid structure of glycosides, a property which also makes them fine modulators of the synthesis of cholesterol and steroid hormones. Moreover, new endogenously synthesized glycosides have been discovered in the last years: these molecules are involved in the balance of salt and in the control of blood pressure. This review will focus on the recent studies which have demonstrated that exogenous and endogenous glycosides, besides playing a role as inotropic agents, are also important in the pathogenesis and therapy of different human diseases, such as stroke, diabetes, neurological diseases and cancer.

Fluoride effects: the two faces of janus.

The behavior of fluoride ions in the human organism is a classic example of double-edged sword. On the one hand the daily supplementation with fluoride is undoubtedly an important preventing factor in protecting teeth from caries, and, as an important mitogenic stimulus for osteoblasts, it may enhance mineral deposition in bone, but on the other hand fluoride, above a threshold concentration, has been demonstrated to be toxic. We present here a brief review of fluoride metabolism and exposure, its use in caries prevention and its effects on bone, followed by an updating about the main hypotheses concerning its mechanism of action and toxicity. The effects of fluoride have been related mainly to its ability to evoke the activation of G proteins and the inhibition of phosphotyrosine phosphatases, leading to an intracellular increase of tyrosine phosphorylation and activation of the mitogen-activated protein kinase pathway, and its capacity to cause generation of reactive oxygen species. We present also a unifying hypothesis accounting for these apparently different effects, although the available experimental models and conditions are highly variable in the literature. A lot of experiments still need to be performed to clarify the positive and negative effects of fluoride. Finding the mechanisms accounting for fluoride toxicity is an important point: indeed, the use of fluoride has been proposed in the preparation of new biomaterials to be inserted in the bone, in order to improve their stable and safe integration.

Digoxin and ouabain increase the synthesis of cholesterol in human liver cells.

Digoxin and ouabain are steroid drugs that inhibit the Na(+)/K(+)-ATPase, and are widely used in the treatment of heart diseases. They may also have additional effects, such as on metabolism of steroid hormones, although until now no evidence has been provided about the effects of these cardioactive glycosides on the synthesis of cholesterol. Here we report that digoxin and ouabain increased the synthesis of cholesterol in human liver HepG2 cells, enhancing the activity and the expression of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the rate-limiting enzyme of the cholesterol synthesis. This effect was mediated by the binding of the sterol regulatory element binding protein-2 (SREBP-2) to the HMGCR promoter, and was lost in cells silenced for SREBP-2 or loaded with increasing amounts of cholesterol. Digoxin and ouabain competed with cholesterol for binding to the SREBP-cleavage-activating protein, and are critical regulators of cholesterol synthesis in human liver cells.

[Acute group A beta-hemolytic streptococcus membranous laryngotracheobronchitis in an adult]. / Laryngotrachéobronchite aiguë membraneuse à streptocoque bêta-hémolytique du groupe A de l'adulte.

OBJECTIVE: To describe the first case of a group A beta-hemolytic streptococcus laryngotracheobronchitis as well as the other possible etiologies in a case of acute dyspnea. METHODS: We report the case of a 46-year-old woman with a doubtful vaccination status who presented clinical features of croup (laryngotracheobronchitis). She developed respiratory distress and required endotracheal intubation. RESULTS: The endoscopy demonstrated a great deal of crust and pseudomembrane detachment. Bacterial culture grew group A beta-hemolytic streptococcus. Progression was good with antibiotics and corticosteroid treatment. CONCLUSION: Bacterial acute pseudomembranous croup (laryngotracheobronchitis) is rare. We must search for the most frequent diagnoses such as diphtheria and epiglottitis. This is the first case to be reported in the literature.

Asbestos induces doxorubicin resistance in MM98 mesothelioma cells via HIF-1alpha.

Human malignant mesothelioma (HMM), which is strongly related to asbestos exposure, exhibits high resistance to many anticancer drugs. Asbestos fibre deposition in the lung may cause hypoxia and iron chelation at the fibre surface. Hypoxia-inducible factor (HIF)-1alpha, which is upregulated by a decreased availability of oxygen and iron, controls the expression of membrane transporters, such as P-glycoprotein (Pgp), which actively extrude the anticancer drugs. The present study aimed to assess whether asbestos may play a role in the induction of doxorubicin resistance in HMM cells through the activation of HIF-1alpha and an increased expression of Pgp. After 24-h incubation with crocidolite asbestos or with the iron chelator dexrazoxane, or under hypoxia, HMM cells were tested for HIF-1alpha activation, Pgp expression, accumulation of doxorubicin and sensitivity to its toxic effect. Crocidolite, dexrazoxane and hypoxia caused HIF-1alpha activation, Pgp overexpression and increased resistance to doxorubicin accumulation and toxicity. These effects were prevented by the co-incubation with the cell-permeating iron salt ferric nitrilotriacetate, which caused an increase of intracellular iron bioavailability, measured as increased activity of the iron regulatory protein-1. Crocidolite, dexrazoxane and hypoxia induce doxorubicin resistance in human malignant mesothelioma cells by increasing hypoxia-inducible factor-1alpha activity, through an iron-sensitive mechanism.

[Frontal sinus pathology and epilepsy]. / Epilepsie et pathologie du sinus frontal.

OBJECTIVES: Because of its location and the fragility of its physiology, the frontal sinus is the first of the facial sinuses to cause complications. In this context, orbital sepsis, cranial vault osteitis, meningitis, cerebral abscess, longitudinal sinus thrombophlebitis can occur. A more uncommon consequence of frontal sinusitis is isolated epilepsy. METHODS: We report two cases of patients admitted in our department after a generalised epilepsy seizure with, on the CT-scan, an opacity of the frontal sinus with a posterior wall lysis. RESULTS: We operated on quickly both patients after the seizure via an eyebrow approach. The first one had a purulent collection of the frontal sinus, the second an infected cholesteatoma. Both had a stenosis of the nasofrontal canal and a lysis of the sinus posterior wall with a bare dura mater. The surgical treatment consisted in the cleaning of the sinus associated with an antibiotic treatment in one case and the cholesteatoma matrix removal in the other. The nasofrontal canal was calibrated for respectively four and two months. An antiepileptic treatment was administered for one year. Four years later the nasofrontal canal is pervious and the frontal sinus sound in both patients. CONCLUSION: An epilepsy seizure can follow a frontal sinusitis. It does not convey the existence of an endocranial complication but requires researching it. The posterior wall lysis of the sinus with a bare dura mater is sufficient to lead to a seizure in case of sinus infection.