Cisplatin liposome and 6-amino nicotinamide combination to overcome drug resistance in ovarian cancer cells

Ovarian cancer is an aggressive and lethal cancer usually treated by cytoreductive surgery followed by chemotherapy. Unfortunately, after an initial response, many patients relapse owing mainly to the development of resistance against the standard chemotherapy regime, carboplatin/paclitaxel, which is also affected by heavy side effects. In view to addressing such issues here, an association of liposomal cisplatin with 6-amino nicotinamide is investigated. It is known that resistant cells increase their demand for glucose, which is partially redirected toward the pentose phosphate pathway (PPP). Interestingly, we have found that also a cisplatin-resistant subclone of the ovarian cancer cells IGROV1 switch their metabolism toward the glycolytic pathway and rely on PPP to elude cisplatin cytotoxicity. The drug 6-amino nicotinamide, an inhibitor of the enzyme glucose-6-phosphate dehydrogenase (the rate-limiting step of the PPP) can restore the sensitivity of resistant cells to cisplatin. Then, to reduce the toxicity of cisplatin and prolong its action, a lyophilized stealth liposomal formulation of cisplatin was developed. The combination treatment of liposomal cisplatin and 6-amino nicotinamide showed promising cytotoxic activities in drug-resistant cells and a prolonged pharmacokinetics in rats, thus opening the way for a new therapeutic option against ovarian cancer

Intramuscular Nodular Fasciitis of the Pectoralis Major.

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Plumbagin Induces Cell Cycle Arrest and Apoptosis in A431 Cisplatin-Resistant Cancer Cells

The onset of drug resistance represents the leading cause of chemotherapy failure in clinics. In the last decades, natural compounds have emerged as possible anticancer strategies used either alone or in combination with chemotherapeutic drugs, in order to overcome drug resistance. In fact, plant-derived therapies present biological activity and minimal side effects showing promising roles in the resensitization of resistant cancer cells. This work was aimed at investigating the anticancer potential of the natural naphthoquinone plumbagin in a cisplatin-resistant cancer cell line. The results indicated cytotoxic and pro-oxidant activity of plumbagin in both sensitive (A431wt) and cisplatin-resistant (A431/Pt) human cervix squamous carcinoma cell lines. Moreover, plumbagin treatment induced cell cycle arrest and apoptosis in A431/Pt cells and the inhibition of retinoblastoma complex, suggesting a stronger activity on the cisplatin-resistant cell line. Taken together, the data indicate appreciable in vitro anticancer activity of plumbagin, suggesting that this natural compound could become a tool to overcome cisplatin resistance. Although further studies are necessary, this work underlines a promising role of plumbagin in the resensitization of cisplatin-resistant cancer cells

Boswellia serrata Preserves Intestinal Epithelial Barrier from Oxidative and Inflammatory Damage

Aminosalicylates, corticosteroids and immunosuppressants are currently the therapeutic choices in inflammatory bowel diseases (IBD), however, with limited remission and often serious side effects. Meanwhile complementary and alternative medicine (CAM) use is increasing, particularly herbal medicine. Boswellia serrata is a traditional Ayurvedic remedy with anti-inflammatory properties, of interest for its usefulness in IBDs. The mechanism of this pharmacological potential of Boswellia serrata was investigated in colonic epithelial cell monolayers exposed to H2O2 or INF-\u3b3+TNF-\u3b1, chosen as in vitro experimental model of intestinal inflammation. The barrier function was evaluated by the transepithelial electrical resistance (TEER) and paracellular permeability assay, and by the tight junction proteins (zonula occludens-1, ZO-1 and occludin) immunofluorescence. The expression of phosphorylated NF-\u3baB and reactive oxygen species (ROS) generation were determined by immunoblot and cytofluorimetric assay, respectively. Boswellia serrata oleo-gum extract (BSE) and its pure derivative acetyl-11-keto-\u3b2-boswellic acid (AKBA), were tested at 0.1-10 \u3bcg/ml and 0.027\u3bcg/ml, respectively. BSE and AKBA safety was demonstrated by no alteration of intestinal cell viability and barrier function and integrity biomarkers. H2O2 or INF-\u3b3+TNF-\u3b1 treatment of Caco-2 cell monolayers significantly reduced TEER, increased paracellular permeability and caused the disassembly of tight junction proteins occludin and ZO-1. BSE and AKBA pretreatment significantly prevented functional and morphological alterations and also the NF-\u3baB phosphorylation induced by the inflammatory stimuli. At the same concentrations BSE and AKBA counteracted the increase of ROS caused by H2O2 exposure. Data showed the positive correlation of the antioxidant activity with the mechanism involved in the physiologic maintenance of the integrity and function of the intestinal epithelium. This study elucidates the pharmacological mechanisms mediated by BSE, in protecting intestinal epithelial barrier from inflammatory damage and supports its use as safe adjuvant in patients affected by IBD

Protective effects of \u3c8 taraxasterol 3-O-myristate and arnidiol 3-O-myristate isolated from Calendula officinalis on epithelial intestinal barrier

The triterpene esters psi taraxasterol-3-O-myristate (1) and amidio1-3-O-myristate (2) were tested for their ability to protect epithelial intestinal barrier in an in vitro model. Their effects on ROS production and on trans-epithelial resistance were investigated on CaCo-2 cell monolayers both in basal and stress -induced conditions. Both compounds were able to modulate the stress damage induced by H2O2 and INF gamma + TNF alpha, showing a potential use as model compounds for the study of new therapeutic agents for intestinal inflammations

Renal vein obstruction and orthostatic proteinuria: a review

Objectives. The cause of orthostatic proteinuria is not clear but may often relate to obstruction of the left renal vein in the fork between the aorta and the superior mesenteric artery (= renal nutcracker). However, reports dealing with proteinuria only marginally refer to this possible cause of orthostatic proteinuria. We analysed the corresponding literature. Results. Five reports addressed the frequency of renal nutcracker in 229 subjects with orthostatic proteinuria. Their age ranged between 5.2 and 17years (female-to-male ratio: 0.96:1.00). Imaging studies demonstrated renal nutcracker in 156 (68%) subjects. Renal nutcracker was also demonstrated in 9 anecdotal reports for a total of 53 subjects with postural proteinuria. Very recently, 13 Italian subjects with orthostatic proteinuria associated with renal nutcracker were reassessed 6years after the initial diagnosis: in nine subjects, both orthostatic proteinuria and renal nutcracker had disappeared; in three, both orthostatic proteinuria and renal nutcracker had persisted; and in one, orthostatic proteinuria had persisted unassociated with renal nutcracker. Conclusions. These data provide substantial support for renal nutcracker as a common cause of orthostatic proteinuri

Inhibition of glucose-6-phosphate dehydrogenase sensitizes cisplatin-resistant cells to death.

The mechanisms of cisplatin resistance, one of the major limitations of current chemotherapy, has only partially been described. We previously demonstrated that cisplatin-resistant ovarian cancer cells (C13), are characterized by reduced mitochondrial activity and higher glucose-dependency when compared to the cisplatin-sensitive counterpart (2008). In this work we further characterized the role of metabolic transformation in cisplatin resistance. By using transmitochondrial hybrids we show that metabolic reprogramming of cisplatin-resistant cell is not caused by inherent mtDNA mutations. We also found that C13 cells not only present an increased glucose-uptake and consumption, but also exhibit increased expression and enzymatic activity of the Pentose Phosphate pathway (PPP) enzyme Glucose-6-Phosphate Dehydrogenase (G6PDH). Moreover, we show that cisplatin-resistant cells are more sensitive to G6PDH inhibition. Even if the metabolomic fingerprint of ovarian cancer cells remains to be further elucidated, these findings indicate that PPP offers innovative potential targets to overcome cisplatin resistance.This work was financially supported by PRAT (University of Padova), grant no. CPDA124517/12 and MIUR grant no 60A04–0443. DC fellowship was supported by grant no. CPDR134012. AR was supported by the AIRC grant no. IG 15863 and by the University of Padova grant no. CPDA 123598.This is the final version of the article. It first appeared from Impact Journals via http://dx.doi.org/10.18632/oncotarget.494

Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio