Recent progress in the imaging of c-Met aberrant cancers with positron emission tomography

Tyrosine‐protein kinase Met—also known as c‐Met or HGFR—is a membrane receptor protein with associated tyrosine kinase activity physiologically stimulated by its natural ligand, the hepatocyte growth factor (HGF), and is involved in different ways in cancer progression and tumourigenesis. Targeting c‐Met with pharmaceuticals has been preclinically proved to have significant benefits for cancer treatment. Recently, evaluating the protein status during and before c‐Met targeted therapy has been shown of relevant importance by different studies, demonstrating that there is a correlation between the status (e.g., aberrant activation and overexpression) of the HGFR with therapy response and clinical prognosis. Currently, clinical imaging based on positron emission tomography (PET) appears as one of the most promising tools for the in vivo real‐time scanning of irregular alterations of the tyrosine‐protein kinase Met and for the diagnosis of c‐Met related cancers. In this study, we review the recent progress in the imaging of c‐Met aberrant cancers with PET. Particular attention is directed on the development of PET probes with a range of different sizes (HGF, antibodies, anticalines, peptides, and small molecules), and radiolabeled with different radionuclides. The goal of this review is to report all the preclinical imaging studies based on PET imaging reported until now for in vivo diagnosis of c‐Met in oncology to support the design of novel and more effective PET probes for in vivo evaluation of c‐Met

Evidence-based successful example of a structure-based approach for the prediction of designer fentanyl-like molecules

© 2024 The Author(s). Published by Elsevier Ltd on behalf of International Society for the Study of Emerging Drugs. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/In 2019, we published three innovative quantitative structure-activity relationship models (QSAR) for predicting the affinity of mu-opioid receptor (µOR) ligands. The three different models were then combined to produce a consensus model used to explore the chemical landscape of 3000 virtual fentanyl-like structures, also generated by us by a theoretical scaffold-hopping approach to explore potential novel active substances and predict their activity. Interestingly, five years have passed, and some of the virtual predicted compounds have been identified/reported to e.g. the EU Early Warning System or the United Nations Office on Drugs and Crime, thus confirming our warning hypothesis that new emerging drugs from our screen would find way to the market.Peer reviewe

A powerful mitochondria-targeted iron chelator affords high photoprotection against solar ultraviolet A radiation

Mitochondria are the principal destination for labile iron, making these organelles particularly susceptible to oxidative damage on exposure to ultraviolet A (UVA, 320–400 nm), the oxidizing component of sunlight. The labile iron-mediated oxidative damage caused by UVA to mitochondria leads to necrotic cell death via adenosine triphosphate depletion. Therefore, targeted removal of mitochondrial labile iron via highly specific tools from these organelles may be an effective approach to protect the skin cells against the harmful effects of UVA. In this work, we designed a mitochondria-targeted hexadentate (tricatechol-based) iron chelator linked to mitochondria-homing SS-like peptides. The photoprotective potential of this compound against UVA-induced oxidative damage and cell death was evaluated in cultured primary skin fibroblasts. Our results show that this compound provides unprecedented protection against UVA-induced mitochondrial damage, adenosine triphosphate depletion, and the ensuing necrotic cell death in skin fibroblasts, and this effect is fully related to its potent iron-chelating property in the organelle. This mitochondria-targeted iron chelator has therefore promising potential for skin photoprotection against the deleterious effects of the UVA component of sunlight

Levator alae nasi muscle V-Y island flap for nasal tip reconstruction

Nasal tip reconstruction can be very challenging. It requires close attention to skin texture, colour and thickness matching, with the respect of the nasal aesthetic units and symmetry. Flaps are usually preferred to skin grafts where possible. Based on different donor areas, various flaps have been described for reconstruction of this region. Here we present a new V-Y myocutaneous island flap based on the levator alae nasi muscle (LAN muscle) blood supply. This flap may represent an alternative to the nasalis myocutaneous sliding V-Y flap previously described by Rybka. As its pivot point it is located more cranially than the nasalis flap, and it can advance more medially than the Rybka flap, with the possibility of covering larger defects of the nasal tip area, up to 1.8 cm in diameter. Over the past 5 years, 24 patients received nasal tip reconstruction with this flap following the resection of basal cell carcinomas. Good tip projection was maintained, and the aesthetic outcome was satisfactory, with well healed scars. We recommend this technique as an alternative to other flaps for nasal tip defects, especially if paramedian

Dual selective iron chelating probes for the monitoring of mitochondrial labile iron pools

Mitochondria-targeted peptides incorporating dual fluorescent and selective iron chelators have been designed as novel biosensors for the mitochondrial labile iron pool.</p

Iron overload down-regulates the expression of the HIV-1 Rev cofactor eIF5A in infected T lymphocytes

Background Changes in iron metabolism frequently accompany HIV-1 infection. However, while many clinical and in vitro studies report iron overload exacerbates the development of infection, many others have found no correlation. Therefore, the multi-faceted role of iron in HIV-1 infection remains enigmatic. Methods RT-qPCR targeting the LTR region, gag, Tat and Rev were performed to measure the levels of viral RNAs in response to iron overload. Spike-in SILAC proteomics comparing i) iron-treated, ii) HIV-1-infected and iii) HIV-1-infected/iron treated T lymphocytes was performed to define modifications in the host cell proteome. Data from quantitative proteomics were integrated with the HIV-1 Human Interaction Database for assessing any viral cofactors modulated by iron overload in infected T lymphocytes. Results Here, we demonstrate that the iron overload down-regulates HIV-1 gene expression by decreasing the levels of viral RNAs. In addition, we found that iron overload modulates the expression of many viral cofactors. Among them, the downregulation of the REV cofactor eIF5A may correlate with the iron-induced inhibition of HIV-1 gene expression. Therefore, we demonstrated that eiF5A downregulation by shRNA resulted in a significant decrease of Nef levels, thus hampering HIV-1 replication. Conclusions Our study indicates that HIV-1 cofactors influenced by iron metabolism represent potential targets for antiretroviral therapy and suggests eIF5A as a selective target for drug development

Molecular dynamics of electrosprayed water nanodroplets containing sodium bis(2-ethylhexyl)sulfosuccinate

The behavior of aqueous solutions of sodium bis(2-ethylhexyl)sulfosuccinate (AOTNa) subject to electrospray ionization (ESI) has been investigated by molecular dynamics (MD) simulations at three temperatures (350, 500 and 800 K). We consider several types of water nanodroplets containing AOTNa molecules and composed of a fixed number of water molecules (1000), N0 AOT AOT anions (N0 AOT = 0, 5, 10) and N0 Na sodium ions (N0 Na = 0, 5, 10, 15, 20): in a short time scale (less than 1 ns), the AOTNa molecules, initially forming direct micelles in the interior of the water nanodroplets, are observed in all cases to diffuse nearby the nanodroplet surface, so that the hydrophilic heads and sodium ions become surrounded by water molecules, whereas the alkyl chains lay at the droplet surface. Meanwhile, evaporation of water molecules and of solvated sodium ions occurs, leading to a decrease of the droplet size and charge. At 350 K, no ejection of neutral or charged surfactant molecules is observed, whereas at 500 K, some fragmentation occurs, and at 800 K, this event becomes more frequent. The interplay of all these processes, which depend on the values of temperature, N0 AOT and N0 Na eventually leads to anhydrous charged surfactant aggregates with prevalence of monocharged ones, in agreement with experimental results of ESI mass spectrometry. The quantitative analysis of theMD trajectories allows to evidencemolecular details potentially useful in designing future ESI experimental conditions