Investigation of TNBC in vitro Antiproliferative Effects of Versatile Pirrolo[1,2-a]quinoxaline Compounds

he triple-negative breast cancer (TNBC) is characterized by a more aggressive nature and poorer prognosis, nowadays none pharmaceutical approach is still available. For this reason, the research of new active compounds and attractive targets represents an interesting field. In this context MDA- MB-231 cell line was selected to evaluate the antiproliferative effects of new [1,2-a]-pyrroloquinoxaline derivatives. The MTT assay revealed that the amine forms of synthesized molecules were more active compared to iminic ones at 72 h of incubation. The antiproliferative effect of the most promising compounds highlighted the formation of autophagic vacuoles

Spotted fever from Rickettsia typhi in an older woman: a case report from a geographic area where it would not be expected

Summary We describe the case of a 75-year-old woman presenting with spotted fever followed by acute renal failure and septic shock. The infection was caused by Rickettsia typhi , not reported in Calabria district (southern Italy) since World War II. The diagnosis of murine typhus was made 3 days after admission and was based solely on clinical criteria when her worsening condition required a prompt move to the intensive care unit. Therapy with tigecycline was then started immediately and the patient improved dramatically. The diagnosis of murine typhus was confirmed 10 days after admission by immunofluorescence assay. Our case is an example of how the diagnosis of murine typhus is challenging. However, in the case of a disease lacking specific symptoms, clinicians should never forget that, even in geographic areas considered free of flea-borne diseases, the components of the enzootic cycle are present and the diagnosis should never be underestimated

When nutraceuticals reinforce drugs side effects: A case report

INTRODUCTION: Nutraceutical is a term applied for a plethora of products ranging from isolated nutrients, herbal products to dietary supplements and recently, the interest for a nutraceutical approach to lipid and metabolic disorders is growing. Patients with metabolic conditions seem to appreciate a therapeutic management that does not involve drug treatment, particularly for the side effects due to statins, a class of drug used for lipid disorders. Statins directly induce skeletal muscle injury and in the elderly patients, under polytherapy treatments, this risk relies to an increase in adverse drug reactions due to drug interactions. CASE DESCRIPTION: Herein we report a 70-year-old woman under polytherapy who developed rhabdomyolysis after starting the administration of a dietary supplement containing monacolin K. Using the Drug Interaction Probability Scale, we postulated that rhabdomyolysis was possibly related to a drug interaction between sertraline, rosuvastatin and monacolin K. These treatments were discontinued leading to a remission of both clinical symptoms and biochemical parameters. CONCLUSION: This case report highlights how pharmacological treatment must be periodically reassessed, since elderly people could take drugs by themselves when they donot need

Theophylline action on primary human bronchial epithelial cells under proinflammatory stimuli and steroidal drugs: a therapeutic rationale approach

Theophylline is a natural compound present in tea. Because of its property to relax smooth muscle it is used in pharmacology for the treatment of airway diseases (ie, chronic obstructive pulmonary disease, asthma). However, this effect on smooth muscle is dose dependent and it is related to the development of side effects. Recently, an increasing body of evidence suggests that theophylline, at low concentrations, also has anti-inflammatory effects related to the activation of histone deacetylases. In this study, we evaluated the effects of theophylline alone and in combination with corticosteroids on human bronchial epithelial cells under inflammatory stimuli. Theophylline administrated alone was not able to reduce growth-stimulating signaling via extracellular signal-regulated kinases activation and matrix metalloproteases release, whereas it strongly counteracts this biochemical behavior when administered in the presence of corticosteroids. These data provide scientific evidence for supporting the rationale for the pharmacological use of theophylline and corticosteroid combined drug. © 2017 Gallelli et al.Theophylline is a natural compound present in tea. Because of its property to relax smooth muscle it is used in pharmacology for the treatment of airway diseases (ie, chronic obstructive pulmonary disease, asthma). However, this effect on smooth muscle is dose dependent and it is related to the development of side effects. Recently, an increasing body of evidence suggests that theophylline, at low concentrations, also has anti-inflammatory effects related to the activation of histone deacetylases. In this study, we evaluated the effects of theophylline alone and in combination with corticosteroids on human bronchial epithelial cells under inflammatory stimuli. Theophylline administrated alone was not able to reduce growth-stimulating signaling via extracellular signal-regulated kinases activation and matrix metalloproteases release, whereas it strongly counteracts this biochemical behavior when administered in the presence of corticosteroids. These data provide scientific evidence for supporting the rationale for the pharmacological use of theophylline and corticosteroid combined drug

Delayed diagnosis of coeliac disease increases cancer risk

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Dynamic effects of retinoic acid and its isomers on cancer and physiology

Dottorato di Ricerca in Cellular Biochemistry and drug activity in oncology, Ciclo XXIII, a.a. 2009-2010In the search for new cancer chemo-preventive compounds, hundreds of naturally occurring molecules have been evaluated. Among these, antioxidants appear to be very promising. In this contest, over the last decade retinoids, natural and synthetic substances structurally related to vitamin A, are often used as part of a combined therapy and have been object of intense investigation. However, clinical trials have shown that retinoids can also be deleterious and are associated with the activation of proto-oncogenes, leading to an increased incidence of neoplasias. In fact, retinoic acid (RA) partition is regulated by cognate intracellular lipid binding proteins (iLBPs): cellular retinoic acid binding protein II (CRABP-II) delivers RA to RARs, while fatty acid binding protein 5 (FABP5) shuttles the RA to PPARβ/δ. In cells with high CRABP-II/FABP5 ratio, RA functions through RAR acting as a pro-apoptotic agent, while signaling through PPARβ/δ promotes survival in those cells highly expressing FABP5. So that, in some tissues RA promotes cell survival and hyperplasia. The apparently conflicting data regarding the pro-oxidant/ anti-oxidant and proliferative/anti-proliferative potential of different retinoids molecules, stimulated us to investigate the effect of RA on cell proliferation and its mechanisms in two different tumor Leydig cell lines (MLTC-1 and R2C) using as normal phenotype counterpart the Leydig TM-3 cell line. Our previous data demonstrated how pharmacological doses of RA induce cell death via the apoptotic pathway in Leydic TM-3 cell line. Recently dose-response treatment of TM-3, MLTC-1 and R2C with RA at nutraceutic/physiological doses, promotes cell proliferation accompanied by stimulation of antioxidant enzymes activity (CAT, GST), decreases p21 levels and fosters cell cycle progression via activation of the IP3K/Akt pathway in the cancer cell line, while administration of pharmacological doses of RA still results in apoptosis. Interestingly treatment with 500 nM of RA resulted in cytosolic vacuolization, hallmark of the autophagic process. Autophagy is a major cellular pathway for the degradation of long-lived proteins and organelles in eukaryotic cells. A large number of intracellular/extracellular stimuli, including amino acid starvation, testosterone production and invasion of microorganisms are able to induce autophagic response. In addition, retinoic acid is also implicated in a post-translation modification called retinoylation that modify, in vitro, the activity of the mitochondrial carrier oxo-chetoglutarate (OCG). Moreover, retinoids are often used as part of a combined therapy, their action is prevalently mediated by two types of receptor RAR and RXR. This latter, is also called master coordinator due to its versatility to heterodimering with several nuclear receptor. Thus, we have elucidated the molecular mechanism by which combined treatment with rosiglitazone (BRL) and 9 cis retinoic acid (9cRA) at nanomolar doses triggers apoptotic events in breast cancer cells, suggesting potential therapeutic uses for these compounds, demonstrating an up-regulation of tumor suppressor gene p53 and its activity is due to the NFkB site, giving emphasis to the potential use of the combined therapy with low doses of both BRL and 9cRA as novel therapeutic tool particularly for breast cancer patients who develop resistance to anti-estrogen therapy. Recently, 9cRA was found as endogenous in pancreas highlighted its rule in both glucose stimulated insulin secretion (GSIS) mechanism and glucose homeostasis, establishing it as autocoid hormone with a unique physiological function among retinoids, and broaden insight into mechanisms of GSISUniversity of Calabri

Biochemical and chemical characterization of Cynara cardunculus L. extract and its potential use as co-adjuvant therapy of chronic myeloid leukemia

Ethnopharmacological relevance Ancient mediterranean diet was characterized by consuming the spontaneous forms of Cynara cardunculus L. (CCL), commonly called artichoke. Cultivated and/or spontaneous forms of CC studies have demonstrated that methanol extract of CCL flower and/or cynaropicrin showed remarkable anti-proliferative activity in vitro models of leukocyte cancer cell. Aim of the study Chronic myeloid leukemia (CML) is associated with a reciprocal translocation of the long arms of chromosomes 9 and 22 generating the BCR/ABL fusion gene, translated in the p210BCR/ABLoncoprotein kinase. This chimeric protein is the target of a kinase inhibitor, imatinib, but the development of mutations in the ABL kinase domain resulting in drug resistance and several approaches to overcoming resistance have been study. In this concern, we investigated the effect of CCL extract on human K562 CML and K562 imatinib resistant (IMAR) cell proliferation and on p210BCR/ABLexpression. Materials and methods Chemical characterization of the CCL extracts was performed by GC/MS analysis and semipreparative RP-HPLC chromatography. Structural characterization of compounds was assessed by1Hâ13C NMR and LC/MS analysis. The effects of CCL extracts on the proliferation of K562 CML human cell line and K562 IMAR were screened by MTT assay. The p210BCR/ABLmRNA and protein expressions were analyzed by qRT-PCR and Western blot techniques respectively. Results We demonstrate that CCL extract affect cell viability of both K562 CML human cell line and K562 IMAR. The biocomponents of CCL were chemical characterized and we identify cynaropicrin and its deacyl derivative having the capability to down-regulate the p210BCR/ABLoncoprotein. Conclusions Our study suggests that the use of those molecules could represent a novel and promising strategy to potentiate the ability of imatinib or of its analogues to induce cancer growth arrest in CML and to delay or overcome the resistance of CML to chemotherapy

Quercetin-3-Oleoyl Derivatives as New GPR40 Agonists: Molecular Docking Studies and Functional Evaluation

The G-protein-coupled receptor 40 (GPR40) is an attractive molecular target for the treatment of type 2 diabetes mellitus. Previously, based on the natural oleic acid substrate, an exogenous ligand for this receptor, named AV1, was synthesized. In this context, here we validated the activity of AV1 as a full agonist, while the corresponding catechol analogue, named AV2, was investigated for the first time. The ligand-protein interaction between this new molecule and the receptor was highlighted in the lower portion of the GPR40 groove that generally accommodates DC260126. The functional assays performed have demonstrated that AV2 is a suitable GPR40 partial agonist, showing a therapeutic potential and representing a useful tool in the management of type 2 diabetes

Dual Effect of Ziconotide in Primary Erythromelalgia

Erythromelalgia (EM) is a rare disabling clinical syndrome more commonly known to affect the lower extremities. There is no single effective treatment for this disease that often requires a multidisciplinary approach. Herein, we report the case of a 31-year-old woman affected by primary erythromelalgia who was successfully treated with intrathecal Ziconotide. We also observed an unexpected result following therapy with Ziconotide. The legs and feet of the patient that at the time of admission were swollen and tumefied dramatically improved after one week of the drug administration

Altered RBP1 Gene Expression Impacts Epithelial Cell Retinoic Acid, Proliferation, and Microenvironment

Vitamin A is an essential diet-derived nutrient that has biological activity affected through an active metabolite, all-trans retinoic acid (atRA). Retinol-binding protein type 1 (RBP1) is an intracellular chaperone that binds retinol and retinal with high affinity, protects retinoids from non-specific oxidation, and delivers retinoids to specific enzymes to facilitate biosynthesis of RA. RBP1 expression is reduced in many of the most prevalent cancers, including breast cancer. Here, we sought to understand the relationship between RBP1 expression and atRA biosynthesis in mammary epithelial cells, as well as RBP1 expression and atRA levels in human mammary tissue. We additionally aimed to investigate the impact of RBP1 expression and atRA on the microenvironment as well as the potential for therapeutic restoration of RBP1 expression and endogenous atRA production. Using human mammary ductal carcinoma samples and a series of mammary epithelial cell lines representing different stages of tumorigenesis, we investigated the relationship between RBP1 expression as determined by QPCR and atRA via direct liquid chromatography-multistage-tandem mass spectrometry-based quantification. The functional effect of RBP1 expression and atRA in epithelial cells was investigated via the expression of direct atRA targets using QPCR, proliferation using Ki-67 staining, and collagen deposition via picrosirius red staining. We also investigated the atRA content of stromal cells co-cultured with normal and tumorigenic epithelial cells. Results show that RBP1 and atRA are reduced in mammary tumor tissue and tumorigenic epithelial cell lines. Knock down of RBP1 expression using shRNA or overexpression of RBP1 supported a direct relationship between RBP1 expression with atRA. Increases in cellular atRA were able to activate atRA direct targets, inhibit proliferation and inhibit collagen deposition in epithelial cell lines. Conditions encountered in tumor microenvironments, including low glucose and hypoxia, were able to reduce RBP1 expression and atRA. Treatment with either RARα agonist AM580 or demethylating agent Decitabine were able to increase RBP1 expression and atRA. Cellular content of neighboring fibroblasts correlated with the RA producing capacity of epithelial cells in co-culture. This work establishes a direct relationship between RBP1 expression and atRA, which is maintained when RBP1 expression is restored therapeutically. The results demonstrate diseases with reduced RBP1 could potentially benefit from therapeutics that restore RBP1 expression and endogenous atRA