Search results for "small molecules"

Extracellular vesicles from parasitic helminths contain specific excretory/secretory proteins and are internalized in intestinal host cells.

2012

The study of host-parasite interactions has increased considerably in the last decades, with many studies focusing on the identification of parasite molecules (i.e. surface or excretory/secretory proteins (ESP)) as potential targets for new specific treatments and/or diagnostic tools. In parallel, in the last few years there have been significant advances in the field of extracellular vesicles research. Among these vesicles, exosomes of endocytic origin, with a characteristic size ranging from 30-100 nm, carry several atypical secreted proteins in different organisms, including parasitic protozoa. Here, we present experimental evidence for the existence of exosome-like vesicles in parasitic…

Small Molecules Targeting and Modulating Toxic Tau Oligomeric Strains

Alzheimer’s disease (AD) is one of over 18 different disorders known as tauopathies, characterized by the pathological aggregation and accumulation of tau, a microtubule-associated protein. Tau aggregates are heterogeneous and can be divided into two major groups: large metastable neurofibrillary tangles (NFTs) and oligomers. Recently, it has been shown that tau oligomers are highly toxic in vitro and efficient seeds for the propagation of pathology as compared to NFTs. While the toxicity of recombinant tau oligomers has been studied extensively, within the same aggregation state, tau exhibits conformational differences, termed tau oligomeric strains. Due to the dynamic nature of these stra…

Reaction between Indazole and Pd-Bound Isocyanides-A Theoretical Mechanistic Study

2018

The mechanism of the addition of indazole (Ind)&mdash

Multi or Single-Kinase Inhibitors to Counteract Drug Resistance in Cancer: What is New?

2023

The concept of protein kinase inhibition starts from the groundbreaking research on the role of these proteins in the regulation of fundamental processes, including proliferation, cell cycle, apoptosis, metabolism, and inflammation. Kinase genetic mutations, as well as overexpression and dysregulation, can contribute to the development of several diseases, including neoplasms, leading to relapses and resistance to standard drug chemotherapy [1-3].

Tumor Microenvironment And Epithelial Mesenchymal Transition As Targets To Overcome Tumor Multidrug Resistance

2020

It is well established that multifactorial drug resistance hinders successful cancer treatment. Tumor cell interactions with the tumor microenvironment (TME) are crucial in epithelial-mesenchymal transition (EMT) and multidrug resistance (MDR). TME-induced factors secreted by cancer cells and cancer-associated fibroblasts (CAFs) create an inflammatory microenvironment by recruiting immune cells. CD11b+/Gr-1+ myeloid-derived suppressor cells (MDSCs) and inflammatory tumor associated macrophages (TAMs) are main immune cell types which further enhance chronic inflammation. Chronic inflammation nurtures tumor-initiating/cancer stem-like cells (CSCs), induces both EMT and MDR leading to tumor re…

CNS-Targeting Therapies for Lysosomal Storage Diseases: Current Advances and Challenges.

2020

During the past decades, several therapeutic approaches have been developed and made rapidly available for many patients afflicted with lysosomal storage disorders (LSDs), inborn organelle disorders with broad clinical manifestations secondary to the progressive accumulation of undegraded macromolecules within lysosomes. These conditions are individually rare, but, collectively, their incidence ranges from 1 in 2,315 to 7,700 live-births. Most LSDs are manifested by neurological symptoms or signs, including developmental delay, seizures, acroparesthesia, motor weakness, and extrapyramidal signs. The chronic and later-onset clinical forms are at one end of the continuum spectrum and are char…

Aspartoacylase-lacZ knockin mice: an engineered model of Canavan disease.

2011

Canavan Disease (CD) is a recessive leukodystrophy caused by loss of function mutations in the gene encoding aspartoacylase (ASPA), an oligodendrocyte-enriched enzyme that hydrolyses N-acetylaspartate (NAA) to acetate and aspartate. The neurological phenotypes of different rodent models of CD vary considerably. Here we report on a novel targeted aspa mouse mutant expressing the bacterial β-Galactosidase (lacZ) gene under the control of the aspa regulatory elements. X-Gal staining in known ASPA expression domains confirms the integrity of the modified locus in heterozygous aspa lacZ-knockin (aspa(lacZ/+)) mice. In addition, abundant ASPA expression was detected in Schwann cells. Homozygous (…

Bioconjugation of Small Molecules to RNA Impedes Its Recognition by Toll-Like Receptor 7

2017

A fundamental mechanism of the innate immune system is the recognition, via extra- and intracellular pattern recognition receptors, of pathogen-associated molecular patterns. A prominent example is represented by foreign nucleic acids, triggering the activation of several signaling pathways. Among these, the endosomal toll-like receptor 7 (TLR7) is known to be activated by single stranded RNA (ssRNA), which can be specifically influenced through elements of sequence structure and posttranscriptional modifications. Furthermore, small molecules TLR7 agonists (smTLRa) are applied as boosting adjuvants in vaccination processes. In this context, covalent conjugations between adjuvant and vaccine…

Differences between Human Plasma and Serum Metabolite Profiles

2011

BackgroundHuman plasma and serum are widely used matrices in clinical and biological studies. However, different collecting procedures and the coagulation cascade influence concentrations of both proteins and metabolites in these matrices. The effects on metabolite concentration profiles have not been fully characterized.Methodology/principal findingsWe analyzed the concentrations of 163 metabolites in plasma and serum samples collected simultaneously from 377 fasting individuals. To ensure data quality, 41 metabolites with low measurement stability were excluded from further analysis. In addition, plasma and corresponding serum samples from 83 individuals were re-measured in the same plate…

Determinants for Tight and Selective Binding of a Medicinal Dicarbene Gold(I) Complex to a Telomeric DNA G-Quadruplex: a Joint ESI MS and XRD Investi…

2016

International audience; The dicarbene gold(I) complex [Au(9-methylcaffein-8-ylidene)(2)]BF4 is an exceptional organometallic compound of profound interest as a prospective anticancer agent. This gold(I) complex was previously reported to be highly cytotoxic toward various cancer cell lines invitro and behaves as a selective G-quadruplex stabilizer. Interactions of the gold complex with various telomeric DNA models have been analyzed by a combined ESI MS and X-ray diffraction (XRD) approach. ESI MS measurements confirmed formation of stable adducts between the intact gold(I) complex and Tel 23 DNA sequence. The crystal structure of the adduct formed between [Au(9-methylcaffein-8-ylidene)(2)]…