Synthesis and Biological Evaluation of Novel 2-Aroyl Benzofuran-Based Hydroxamic Acids as Antimicrotubule Agents.

Because of synergism between tubulin and HDAC inhibitors, we used the pharmacophore fusion strategy to generate potential tubulin-HDAC dual inhibitors. Drug design was based on the introduction of a -hydroxyacrylamide or a -hydroxypropiolamide at the 5-position of the 2-aroylbenzo[]furan skeleton, to produce compounds - and -, respectively. Among the synthesized compounds, derivatives , , , , and showed excellent antiproliferative activity, with IC values at single- or double-digit nanomolar levels, against the A549, HT-29, and MCF-7 cells resistant towards the control compound combretastatin A-4 (CA-4).

A gibberellin-assisted study of the transcriptional and hormonal changes occurring at floral transition in peach buds (Prunus persica L. Batsch).

Background: Flower load in peach is an important determinant of final fruit quality and is subjected to cost-effective agronomical practices, such as the thinning, to finely balance the sink-source relationships within the tree and drive the optimal amount of assimilates to the fruits. Floral transition in peach buds occurs as a result of the integration of specific environmental signals, such as light and temperature, into the endogenous pathways that induce the meristem to pass from vegetative to reproductive growth. The cross talk and integration of the different players, such as the genes and the hormones, are still partially unknown.

A Novel MAO-B/SSAO Inhibitor Improves Multiple Aspects of Dystrophic Phenotype in Mice.

Duchenne muscular dystrophy (DMD) is one of the most frequent and severe childhood muscle diseases. Its pathophysiology is multifaceted and still incompletely understood, but we and others have previously shown that oxidative stress plays an important role. In particular, we have demonstrated that inhibition of mitochondrial monoamine oxidases could improve some functional and biohumoral markers of the pathology.

Molecular and functional profiling of chemotolerant cells unveils nucleoside metabolism-dependent vulnerabilities in medulloblastoma.

Chemotherapy resistance is considered one of the main causes of tumor relapse, still challenging researchers for the identification of the molecular mechanisms sustaining its emergence. Here, we setup and characterized chemotherapy-resistant models of Medulloblastoma (MB), one of the most lethal pediatric brain tumors, to uncover targetable vulnerabilities associated to their resistant phenotype. Integration of proteomic, transcriptomic and kinomic data revealed a significant deregulation of several pathways in resistant MB cells, converging to cell metabolism, RNA/protein homeostasis, and immune response, eventually impacting on patient outcome.

Design, synthesis and biological evaluation of novel 2,4-thiazolidinedione derivatives able to target the human BAG3 protein.

The Bcl-2-associated athanogene 3 (BAG3) protein plays multiple roles in controlling cellular homeostasis, and it has been reported to be deregulated in many cancers, leading tumor cell apoptosis escape. BAG3 protein is then an emerging target for its oncogenic activities in both leukemia and solid cancers, such as medulloblastoma. In this work a series of forty-four compounds were designed and successfully synthesized by the modification and optimization of a previously reported 2,4-thiazolidinedione derivative 28.

Oxidative Stress by the Mitochondrial Monoamine Oxidase B Mediates Calcium Pyrophosphate Crystal-Induced Arthritis.

Objective: Calcium pyrophosphate (CPP) crystal deposition in the joints is associated with a heterogeneous set of debilitating syndromes characterized by inflammation and pain, for which no effective therapies are currently available. Because we found that the mitochondrial enzyme monoamine oxidase B (MAO-B) plays a fundamental role in promoting inflammatory pathways, this study aims at assessing the efficacy of two clinical-grade inhibitors (iMAO-Bs) in preclinical models of this disease to pave the way for a novel treatment.

Methods: We tested our hypothesis in two murine models of CPP-induced arthritis, by measuring cytokine and chemokine levels, along with immune cell recruitment.

Blood phenylalanine fluctuation in phenylketonuric children treated by BH4 or low-phenylalanine diet from birth.

The prognosis of phenylketonuria (PKU) is related to the quality of metabolic control all life-long. PKU treatment is based on a low-Phe diet, 6R-tetrahydrobiopterin (BH4) treatment for the BH4-responsive PKU patients or enzyme replacement therapy. Fluctuations in blood phenylalanine (Phe) concentrations may be an important determinant of intellectual outcome in patients with early and continuously treated phenylketonuria (PKU).

The Clinical Impact of Recent Methamphetamine Exposure in Aneurysmal Subarachnoid Patients.

Background: Methamphetamines (MA) are a frequently used drug class with potent sympathomimetic properties that can affect cerebral vasculature. Conflicting reports in literature exist about the effect of exposure to MA on vasospasm risk and clinical outcomes in aneurysmal subarachnoid hemorrhage (aSAH). This study aimed to characterize the impact of recent MA use on the timing, severity and features of vasospasm in aneurysmal subarachnoid as well as neurological outcomes.

Grape Berry Responses to Sequential Flooding and Heatwave Events: A Physiological, Transcriptional, and Metabolic Overview.

Grapevine cultivation, such as the whole horticulture, is currently challenged by several factors, among which the extreme weather events occurring under the climate change scenario are the most relevant. Within this context, the present study aims at characterizing at the berry level the physiological response of cv. Sauvignon Blanc to sequential stresses simulated under a semi-controlled environment: flooding at bud-break followed by multiple summer stress (drought plus heatwave) occurring at pre-vèraison.

OPA1 drives macrophage metabolism and functional commitment via p65 signaling.

Macrophages are essential players for the host response against pathogens, regulation of inflammation and tissue regeneration. The wide range of macrophage functions rely on their heterogeneity and plasticity that enable a dynamic adaptation of their responses according to the surrounding environmental cues. Recent studies suggest that metabolism provides synergistic support for macrophage activation and elicitation of desirable immune responses; however, the metabolic pathways orchestrating macrophage activation are still under scrutiny.

Hysteroscopic removal of intrauterine device in early pregnancy.

Background: Intrauterine devices (IUDs) are commonly used as contraceptives worldwide. However, pregnancies in patients carrying this kind of device may occur. IUD removal when the woman wishes to continue their pregnancy may be very challenging.

3D in vitro Models of Pathological Skeletal Muscle: Which Cells and Scaffolds to Elect?

Skeletal muscle is a fundamental tissue of the human body with great plasticity and adaptation to diseases and injuries. Recreating this tissue helps not only to deepen its functionality, but also to simulate pathophysiological processes. In this review we discuss the generation of human skeletal muscle three-dimensional (3D) models obtained through tissue engineering approaches.

Evidence of chromatin and transcriptional dynamics for cold development in peach flower bud.

In temperate zones, fruit trees regulate their annual growth cycle to seasonal environmental changes. During the cold season, growth is limited by both environmental and genetic factors. After the exposure to low temperature and fulfillment of chilling requirements, mild temperatures promote the growth and flowering.

An efficient chromatin immunoprecipitation (ChIP) protocol for studying histone modifications in peach reproductive tissues.

Background: Perennial fruit trees display a growth behaviour characterized by annual cycling between growth and dormancy, with complex physiological features. Rosaceae fruit trees represent excellent models for studying not only the fruit growth/patterning but also the progression of the reproductive cycle depending upon the impact of climate conditions. Additionally, current developments in high-throughput technologies have impacted Rosaceae tree research while investigating genome structure and function as well as (epi)genetic mechanisms involved in important developmental and environmental response processes during fruit tree growth.

Vaccinated Patients Admitted in ICU with Severe Pneumonia Due to SARS-CoV-2: A Multicenter Pilot Study.

The aim of this study was to analyze the percentage of patients admitted to the ICU having received the vaccine against COVID-19, to describe the clinical profile of vaccinated patients admitted to the ICU, and to assess the humoral immune response to vaccination. In this multicenter prospective descriptive cohort study, consecutive critically ill patients with confirmed SARS-CoV-2 pneumonia who received at least one dose of the SARS-CoV-2 vaccine were included. The time of study was from 1 July to 10 August of 2021.

The J2-Immortalized Murine Macrophage Cell Line Displays Phenotypical and Metabolic Features of Primary BMDMs in Their M1 and M2 Polarization State.

Macrophages are immune cells that are important for the development of the defensive front line of the innate immune system. Following signal recognition, macrophages undergo activation toward specific functional states, consisting not only in the acquisition of specific features but also of peculiar metabolic programs associated with each function. For these reasons, macrophages are often isolated from mice to perform cellular assays to study the mechanisms mediating immune cell activation.

Reactive Oxygen Species in Macrophages: Sources and Targets.

Reactive oxygen species (ROS) are fundamental for macrophages to eliminate invasive microorganisms. However, as observed in nonphagocytic cells, ROS play essential roles in processes that are different from pathogen killing, as signal transduction, differentiation, and gene expression. The different outcomes of these events are likely to depend on the specific subcellular site of ROS formation, as well as the duration and extent of ROS production.

Efficient artificial microRNA vectors for gene silencing in citrus.

Three new artificial microRNA vectors were constructed and evaluated, and results showed that these vectors are highly efficient in the silencing of the citrus PHYTOENE DESATURASE gene.

Second-Generation Light-Fueled Supramolecular Pump.

We describe the modular design of a pseudorotaxane-based supramolecular pump and its photochemically driven autonomous nonequilibrium operation in a dissipative regime. These properties derive from careful engineering of the energy maxima and minima along the threading coordinate and their light-triggered modulation. Unlike its precursor, this second-generation system is amenable to functionalization for integration into more complex devices.

N-acetylaspartate release by glutaminolytic ovarian cancer cells sustains protumoral macrophages.

Glutaminolysis is known to correlate with ovarian cancer aggressiveness and invasion. However, how this affects the tumor microenvironment is elusive. Here, we show that ovarian cancer cells become addicted to extracellular glutamine when silenced for glutamine synthetase (GS), similar to naturally occurring GS-low, glutaminolysis-high ovarian cancer cells.

Treatment of ARS deficiencies with specific amino acids.

Purpose: Recessive cytosolic aminoacyl-tRNA synthetase (ARS) deficiencies are severe multiorgan diseases, with limited treatment options. By loading transfer RNAs (tRNAs) with their cognate amino acids, ARS are essential for protein translation. However, it remains unknown why ARS deficiencies lead to specific symptoms, especially early life and during infections.

Meta-analysis of RNA-Seq studies reveals genes with dominant functions during flower bud endo- to eco-dormancy transition in Prunus species.

In deciduous fruit trees, entrance into dormancy occurs in later summer/fall, concomitantly with the shortening of day length and decrease in temperature. Dormancy can be divided into endodormancy, ecodormancy and paradormancy. In Prunus species flower buds, entrance into the dormant stage occurs when the apical meristem is partially differentiated; during dormancy, flower verticils continue their growth and differentiation.

Regulation of Fruit Growth in a Peach Slow Ripening Phenotype.

Consumers' choices are mainly based on fruit external characteristics such as the final size, weight, and shape. The majority of edible fruit are by tree fruit species, among which peach is the genomic and genetic reference for Prunus. In this research, we used a peach with a slow ripening (SR) phenotype, identified in the Fantasia (FAN) nectarine, associated with misregulation of genes involved in mesocarp identity and showing a reduction of final fruit size.

SARS-CoV-2 Infection and Inflammatory Response in a Twin Pregnancy.

There is growing literature about the SARS-CoV-2 pathogenetic effects exerted during pregnancy and whether vertical transmission or premature birth is possible. It is not well known whether changes in the immune system of pregnant women may lead to a marked susceptibility to infectious processes and the risk of adverse maternal and neonatal complications such as preterm birth, spontaneous abortion, hospitalization in an intensive care unit, transmission to the fetus or newborns, and fetal mortality are poorly understood. Along with this ongoing debate, it is not well defined whether, during pregnancy, the role of host susceptibility in producing a specific inflammatory response to SARS-CoV-2 may represent distinctive markers of risk of vertical transmission.