Search results for "Azoles"

Current treatment options for HER2-positive breast cancer patients with brain metastases

2020

Abstract Brain metastases (BMs) are frequently associated with HER2+ breast cancer (BC). Their management is based on a multi-modal strategy including both local treatment and systemic therapy. Despite therapeutic advance, BMs still have an adverse impact on survival and quality of life and the development of effective systemic therapy to prevent and treat BMs from HER2 + BC represents an unmet clinical need. Trastuzumab-based therapy has long been the mainstay of systemic therapy and over the last two decades other HER2-targeted agents including lapatinib, pertuzumab and trastuzumab emtansine, have been introduced in the clinical practice. More recently, novel agents such as neratinib, tuc…

PPAR Agonists, Atherogenic Dyslipidemia and Cardiovascular Risk.

2016

Peroxisome proliferator-activated receptors (PPAR) are implicated in the pathology of several metabolic diseases including obesity, diabetes, and atherosclerosis. PPAR agonists exert multiple lipid modifying actions which are beneficial to the prevention of atherosclerosis. Such benefits in lipid lowering actions include improvements in atherogenic dyslipidemia that seems to be particularly expressed in individuals at higher cardiovascular (CV) risk. In addition, the favorable effects of PPAR agonists on different cardio-metabolic parameters are established in several metabolic conditions, such as diabetes mellitus, insulin resistance, and heightened systemic inflammation. The goal of this …

PPARδ Modulation by GW501516: An Unsuccessful Exercise Mimetic.

2017

The dissociation of the Hsp60/pro-Caspase-3 complex by bis(pyridyl)oxadiazole copper complex (CubipyOXA) leads to cell death in NCI-H292 cancer cells

2017

Abstract Cell survival and proliferation are central to carcinogenesis, involving various mechanisms among which those that impede apoptosis are important. In this, the role of the molecular chaperone Hsp60 is unclear since it has been reported that it can be both, pro- or anti-apoptotic. A solution to this riddle is crucial to the development of anti-cancer therapies targeting Hsp60. We addressed this question using a tumor cell line, NCI-H292, and [Cu(3,5-bis(2′-pyridyl)-1,2,4-oxadiazole) 2 (H 2 O) 2 ](ClO 4 ) 2 , CubipyOXA , a copper-containing compound with cytotoxic properties. We treated cells with various doses of the compound and measured cell viability; apoptosis indicators; and le…

Metabolic and inflammatory reprogramming of macrophages by ONC201 translates in a pro-inflammatory environment even in presence of glioblastoma cells

2020

Tumor-associated macrophages facilitate tumor progression and resistance to therapy. Their capacity for metabolic and inflammatory reprogramming represents an attractive therapeutic target. ONC201/TIC10 is an anticancer molecule that antagonizes the dopamine receptor D2 and affects mitochondria integrity in tumor cells. We examined whether ONC201 induces a metabolic and pro-inflammatory switch in primary human monocyte-derived macrophages that reactivates their antitumor activities, thus enhancing the onco-toxicity of ONC201. Contrary to glioblastoma cells, macrophages exhibited a low ratio of dopamine receptors D2/D5 gene expression and were resistant to ONC201 cytotoxicity. Macrophages re…

Daclatasvir-based regimens in HCV cirrhosis: experience from the Italian early access program

2019

AbstractWe reported the efficacy and safety data for daclatasvir (DCV)-based all-oral antiviral therapy in patients treated in the Italian compassionate-use program. 275 patients were included (202 male-73.5%, mean age: 57.4 years, 62 HIV-coinfected, 94 with recurrence of hepatitis C post-OLT). Forty-nine patients (17.8%) had Child-Pugh B, Genotype(G) distribution was: G1a:72 patients (26.2%), G1b:137 (49.8%); G3:40 (14.5%) and G4:26 (9.5%). Patients received DCV with sofosbuvir(SOF) (n = 221, 129 with ribavirin(RBV) or with simeprevir (SMV) or asunaprevir (ASU) (n = 54, 19 with RBV) for up to 24 weeks. Logistic regression was used to identify baseline characteristics associated with sustai…

Synthesis and biofilm formation reduction of pyrazole-4-carboxamide derivatives in some Staphylococcus aureus strains

2016

The ability of several N-phenyl-1H-pyrazole-4-carboxamide derivatives and other pyrazoles opportunely modified at the positions 3, 4 and 5, to reduce the formation of the biofilm in some Staphylococcus aureus strains (ATCC 29213, ATCC 25923 and ATCC 6538) were investigated. All the tested compounds were able, although to a different extent, to reduce the biofilm formation of the three bacterial strains considered. Among these, the 1-(2,5-dichlorophenyl)-5-methyl-N-phenyl-1H-pyrazole-4-carboxamide 14 resulted as the best inhibitor of biofilm formation showing an IC50 ranging from 2.3 to 32 μM, against all the three strains of S. aureus. Compound 14 also shows a good protective effect in vivo…

Exploring Strategies for Labeling Viruses with Gold Nanoclusters through Non-equilibrium Molecular Dynamics Simulations.

2017

Biocompatible gold nanoclusters can be utilized as contrast agents in virus imaging. The labeling of viruses can be achieved noncovalently but site-specifically by linking the cluster to the hydrophobic pocket of a virus via a lipid-like pocket factor. We have estimated the binding affinities of three different pocket factors of echovirus 1 (EV1) in molecular dynamics simulations combined with non-equilibrium free-energy calculations. We have also studied the effects on binding affinities with a pocket factor linked to the Au102pMBA44 nanocluster in different protonation states. Although the absolute binding affinities are over-estimated for all the systems, the trend is in agreement with r…

Thiazole–amino acids: influence of thiazole ring on conformational properties of amino acid residues

2021

Abstract Post-translational modified thiazole–amino acid (Xaa–Tzl) residues have been found in macrocyclic peptides (e.g., thiopeptides and cyanobactins), which mostly inhibit protein synthesis in Gram + bacteria. Conformational study of the series of model compounds containing this structural motif with alanine, dehydroalanine, dehydrobutyrine and dehydrophenylalanine were performed using DFT method in various environments. The solid-state crystal structure conformations of thiazole–amino acid residues retrieved from the Cambridge Structural Database were also analysed. The studied structural units tend to adopt the unique semi-extended β2 conformation; which is stabilised mainly by N–H⋯N…

Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation

2015

Unwinding DNA and unleasing inflammation Fighting infections often comes with collateral damage, which sometimes can be deadly. For instance, in septic shock, the overwhelming release of inflammatory mediators drives multi-organ failure. Rialdi et al. now report a potential new therapeutic target for controlling excessive inflammation: the DNA unwinding enzyme topoisomerase I (Top1) (see the Perspective by Pope and Medzhitov). Upon infection, Top1 specifically localizes to the promoters of pathogen-induced genes and promotes their transcription by helping to recruit RNA polymerase II. Pharmacological inhibition of Top1 in a therapeutic setting increased survival in several mouse models of s…