Unlocking the Power of Human Ferritin: Enhanced Drug Delivery of Aurothiomalate in A2780 Ovarian Cancer Cells.

Aurothiomalate (AuTM) is an FDA-approved antiarthritic gold drug with unique anticancer properties. To enhance its anticancer activity, we prepared a bioconjugate with human apoferritin (HuHf) by attaching some AuTM moieties to surface protein residues. The reaction of apoferritin with excess AuTM yielded a single adduct, that was characterized by ESI MS and ICP-OES analysis, using three mutant ferritins and trypsinization experiments.

A Comparison of Bonded and Nonbonded Zinc(II) Force Fields with NMR Data.

Classical molecular dynamics (MD) simulations are widely used to inspect the behavior of zinc(II)-proteins at the atomic level, hence the need to properly model the zinc(II) ion and the interaction with its ligands. Different approaches have been developed to represent zinc(II) sites, with the bonded and nonbonded models being the most used. In the present work, we tested the well-known zinc AMBER force field (ZAFF) and a recently developed nonbonded force field (NBFF) to assess how accurately they reproduce the dynamic behavior of zinc(II)-proteins.

Early propranolol treatment of infantile hemangiomas improves outcome.

Background: Infantile hemangiomas (IH) are the most common soft tissue tumors of childhood. Although most of these tumors are not worrisome, some IH may be life or function-threatening, can lead to permanent disfigurement, or have associated structural congenital anomalies, requiring early recognition and referral to specialists for treatment consideration. Since 2008, oral propranolol has been widely considered to be the first-line treatment for IH.

Molecular Structure of Cu(II)-Bound Amyloid-β Monomer Implicated in Inhibition of Peptide Self-Assembly in Alzheimer's Disease.

Metal ions, such as copper and zinc ions, have been shown to strongly modulate the self-assembly of the amyloid-β (Aβ) peptide into insoluble fibrils, and elevated concentrations of metal ions have been found in amyloid plaques of Alzheimer's patients. Among the physiological transition metal ions, Cu(II) ions play an outstanding role since they can trigger production of neurotoxic reactive oxygen species. In contrast, structural insights into Cu(II) coordination of Aβ have been challenging due to the paramagnetic nature of Cu(II).

Atopic dermatitis in children and adolescents seen at a general hospital in the City of Buenos Aires.

Atopic dermatitis (AD) is an inflammatory skin disease highly prevalent in pediatrics as per international studies. There is scarce information on the epidemiological characteristics of AD in the Argentine pediatric population. The objective of this study was to describe the prevalence and clinical characteristics of AD in a population of Argentine children seen at the Department of Pediatrics of a general hospital.

Automated Determination of Nuclear Magnetic Resonance Chemical Shift Perturbations in Ligand Screening Experiments: The PICASSO Web Server.

Nuclear magnetic resonance (NMR) is an effective, commonly used experimental approach to screen small organic molecules against a protein target. A very popular method consists of monitoring the changes of the NMR chemical shifts of the protein nuclei upon addition of the small molecule to the free protein. Multidimensional NMR experiments allow the interacting residues to be mapped along the protein sequence.

Structural Biology in the Clouds: The WeNMR-EOSC Ecosystem.

Structural biology aims at characterizing the structural and dynamic properties of biological macromolecules at atomic details. Gaining insight into three dimensional structures of biomolecules and their interactions is critical for understanding the vast majority of cellular processes, with direct applications in health and food sciences. Since 2010, the WeNMR project (www.

Insights into the Dynamics of the Human Zinc Transporter ZnT8 by MD Simulations.

ZnT8 is a human zinc(II) transporter expressed at the membrane of secretory granules where it contributes to insulin storage importing zinc ions from the cytosol. In the human population, the two most common ZnT8 variants carry an arginine (R325) or a tryptophan (W325) in position 325. The former variant has the most efficient kinetics in zinc transport and has been correlated to a higher risk of developing insulin resistance.

Method Validation of Seven Synthetic Cathinones by LC-MS/MS Analysis and the Prevalence of N-Ethylpentylone in Postmortem Casework.

N-ethylpentylone (NEP, ephylone, bk-EBDP) was the most prevalent synthetic cathinone detected by the Miami-Dade Medical Examiner Toxicology Laboratory from 2016-2018. There is limited information regarding the toxicity of NEP, however the few published reports suggest that NEP can cause serious toxic effects and sudden death. The purpose of this publication is to describe a validated LC-MS/MS method for seven synthetic cathinones (methylone, ethylone, butylone, dibutylone, α-PVP, pentylone, and NEP) and to present a detailed summary regarding the presence of NEP in postmortem casework at the Miami-Dade Medical Examiner Department.

Transient paraplegia due to subarachnoid haemorrhage following spinal anaesthesia.

Spinal subarachnoid haemorrhage is a rare complication of spinal anaesthesia, especially following atraumatic lumbar puncture and in the absence of coagulopathies. The initial presentation of spinal subarachnoid haemorrhage is variable and paraplegia with full recovery within a few hours is rare. Bleeding can extend into the intracranial subarachnoid space, but there are only a few reports of symptomatic intracranial and spinal subarachnoid haemorrhage after spinal anaesthesia.

A protocol to automatically calculate homo-oligomeric protein structures through the integration of evolutionary constraints and NMR ambiguous contacts.

Protein assemblies are involved in many important biological processes. Solid-state NMR (SSNMR) spectroscopy is a technique suitable for the structural characterization of samples with high molecular weight and thus can be applied to such assemblies. A significant bottleneck in terms of both effort and time required is the manual identification of unambiguous intermolecular contacts.

ALDH3A1 Overexpression in Melanoma and Lung Tumors Drives Cancer Stem Cell Expansion, Impairing Immune Surveillance through Enhanced PD-L1 Output.

Melanoma and non-small-cell lung carcinoma (NSCLC) cell lines are characterized by an intrinsic population of cancer stem-like cells (CSC), and high expression of detoxifying isozymes, the aldehyde dehydrogenases (ALDHs), regulating the redox state. In this study, using melanoma and NSCLC cells, we demonstrate that ALDH3A1 isozyme overexpression and activity is closely associated with a highly aggressive mesenchymal and immunosuppressive profile. The contribution of ALDH3A1 to the stemness and immunogenic status of melanoma and NSCLC cells was evaluated by their ability to grow in 3D forming tumorspheres, and by the expression of markers for stemness, epithelial to mesenchymal transition (EMT), and inflammation.

Conformational characterization of full-length X-chromosome-linked inhibitor of apoptosis protein (XIAP) through an integrated approach.

The X-chromosome-linked inhibitor of apoptosis protein (XIAP) is a multidomain protein whose main function is to block apoptosis by caspase inhibition. XIAP is also involved in other signalling pathways, including NF-κB activation and copper homeostasis. XIAP is overexpressed in tumours, potentiating cell survival and resistance to chemotherapeutics, and has therefore become an important target for the treatment of malignancy.

An atomistic view of the YiiP structural changes upon zinc(II) binding.

Background: YiiP is a bacterial zinc-for-proton antiporter belonging to the cation diffusion facilitator family. The zinc(II) ions are transported across the cell membrane, from the cytosol to the extracellular space.

Methods: We performed atomistic molecular dynamics simulations of the YiiP dimer with zinc(II) ions in solution to elucidate how the metal ions interact with the protein while moving from the cytosol to the transport site.

West-Life: A Virtual Research Environment for structural biology.

The West-Life project (https://about.west-life.eu/) is a Horizon 2020 project funded by the European Commission to provide data processing and data management services for the international community of structural biologists, and in particular to support integrative experimental approaches within the field of structural biology.

Targeting endothelial-to-mesenchymal transition: the protective role of hydroxytyrosol sulfate metabolite.

Purpose: Endothelial-to-mesenchymal transition (EndMT) plays an important role in pathogenesis of a number of inflammatory diseases. Hydroxytyrosol (HT) and, particularly, its major plasma metabolite HT-3O sulfate (HT-3Os) are known olive oil antioxidant and anti-inflammatory polyphenols which exert benefits against vascular diseases by improving endothelial function. However, to date the HT-3Os role in EndMT is not well known.

Stemness marker ALDH1A1 promotes tumor angiogenesis via retinoic acid/HIF-1α/VEGF signalling in MCF-7 breast cancer cells.

Background: Aldehyde dehydrogenase 1A1 (ALDH1A1), a member of aldehyde dehydrogenase family, is a marker of stemness in breast cancer. During tumor progression cancer stem cells (CSCs) have been reported to secrete angiogenic factors to orchestrate the formation of pathological angiogenesis. This vasculature can represent the source of self-renewal of CSCs and the route for further tumor spreading.

ALDH2 Activity Reduces Mitochondrial Oxygen Reserve Capacity in Endothelial Cells and Induces Senescence Properties.

Endothelial cells (ECs) are dynamic cells that turn from growth into senescence, the latter being associated with cellular dysfunction, altered metabolism, and age-related cardiovascular diseases. Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme metabolizing acetaldehyde and other toxic aldehydes, such as 4-hydroxynonenal (4-HNE). In conditions in which lipid peroxidation products and reactive oxygen species (ROS) are accumulated, ECs become dysfunctional and significantly contribute to the progression of vascular-dependent diseases.

Bradykinin B2 Receptor Contributes to Inflammatory Responses in Human Endothelial Cells by the Transactivation of the Fibroblast Growth Factor Receptor FGFR-1.

Elevated levels of bradykinin (BK) and fibroblast growth factor-2 (FGF-2) have been implicated in the pathogenesis of inflammatory and angiogenic disorders. In angiogenesis, both stimuli induce a pro-inflammatory signature in endothelial cells, activating an autocrine/paracrine amplification loop that sustains the neovascularization process. Here we investigated the contribution of the FGF-2 pathway in the BK-mediated human endothelial cell permeability and migration, and the role of the B2 receptor (B2R) of BK in this cross-talk.

PGE2 mediates EGFR internalization and nuclear translocation caveolin endocytosis promoting its transcriptional activity and proliferation in human NSCLC cells.

Prostaglandin E (PGE) contributes to tumor progression by promoting cancer cell growth, invasion and by creating a favorable pro-tumor microenvironment. PGE has been reported to transactivate and internalize into the nucleus receptor tyrosine kinases such as Epidermal growth factor receptor (EGFR), thereby supporting tumor progression. Here we demonstrate that in non-small cell lung carcinoma (NSCLC) cells, PGE induces EGFR nuclear translocation via different dynamin-dependent endocytic pathways, promotes the formation of an EGFR-STAT3 complex, affects nuclear EGFR target gene expression and mediates tumor cell proliferation.