Targeting Relevant HDACs to Support the Survival of Cone Photoreceptors in Inherited Retinal Diseases: Identification of a Potent Pharmacological Tool with In Vitro and In Vivo Efficacy.

Inherited retinal diseases, which include retinitis pigmentosa, are a family of genetic disorders characterized by gradual rod-cone degeneration and vision loss, without effective pharmacological treatments. Experimental approaches aim to delay disease progression, supporting cones' survival, crucial for human vision. Histone deacetylases (HDACs) mediate the activation of epigenetic and nonepigenetic pathways that modulate cone degeneration in RP mouse models.

Development of Potent and Selective Monoacylglycerol Lipase Inhibitors. SARs, Structural Analysis, and Biological Characterization.

New potent, selective monoacylglycerol lipase (MAGL) inhibitors based on the azetidin-2-one scaffold ((±)--, (±)--, and (±)--) were developed as irreversible ligands, as demonstrated by enzymatic and crystallographic studies for (±)-, (±)-, and (±)-. X-ray analyses combined with extensive computational studies allowed us to clarify the binding mode of the compounds. was identified as selective for MAGL when compared with other serine hydrolases.

Pioneering first-in-class FAAH-HDAC inhibitors as potential multitarget neuroprotective agents.

Aiming to simultaneously modulate the endocannabinoid system (ECS) functions and the epigenetic machinery, we selected the fatty acid amide hydrolase (FAAH) and histone deacetylase (HDAC) enzymes as desired targets to develop potential neuroprotective multitarget-directed ligands (MTDLs), expecting to achieve an additive or synergistic therapeutic effect in oxidative stress-related conditions. We herein report the design, synthesis, and biological evaluation of the first-in-class FAAH-HDAC multitarget inhibitors. A pharmacophore merging strategy was applied, yielding 1-phenylpyrrole-based compounds 4a-j.

An Exploratory Study of Hydrochar as a Matrix for Biotechnological Applications.

This paper explores the potentialities of hydrochar in protein separation and enzyme immobilization for non-energy biorefinery applications of hydrothermal carbonization. An innovative experimental procedure monitors soluble protein-hydrochar interactions and enzymatic reactions in a continuously stirred tank reactor. The hydrochar comes from hydrothermal carbonization of silver fir (200 °C, 30 min, 1/7 solid/water ratio) and standard activation (KOH, oven, 600 °C).

Development of potent and selective FAAH inhibitors with improved drug-like properties as potential tools to treat neuroinflammatory conditions.

The neuroprotective performance against neuroinflammation of the endocannabinoid system (ECS) can be remarkably improved by indirect stimulation mediated by the pharmacological inhibition of the key ECS catabolic enzyme fatty acid amide hydrolase (FAAH). Based on our previous works and aiming to discover new selective FAAH inhibitors , we herein reported a new series of carbamate-based FAAH inhibitors (4a-t) which showed improved drug disposition properties compared to the previously reported analogues 2a-b. The introduction of ionizable functions allowed us to obtain new FAAH inhibitors of nanomolar potency characterized by good water solubility and chemical stability at physiological pH.

Synthesis of Unsymmetrical Squaramides as Allosteric GSK-3β Inhibitors Promoting β-Catenin-Mediated Transcription of TCF/LEF in Retinal Pigment Epithelial Cells.

The glycogen synthase kinase 3β (GSK-3β) is a ubiquitous enzyme that is a validated target for the development of potential therapeutics useful in several diseases including retinal degeneration. Aiming at developing an innovative class of allosteric inhibitors of GSK-3β potentially useful for retinal degeneration, we explored the class of squaramides. The developed compounds (6 a-l) were obtained through a nontoxic one-pot synthetic protocol, which employs low-cost goods and avoids any purification step.

Azetidin-2-one-based small molecules as dual hHDAC6/HDAC8 inhibitors: Investigation of their mechanism of action and impact of dual inhibition profile on cell viability.

The search of new therapeutic tools for the treatment of cancer is being a challenge for medicinal chemists. Due to their role in different pathological conditions, histone deacetylase (HDAC) enzymes are considered valuable therapeutic targets. HDAC6 is a well-investigated HDAC-class IIb enzyme mainly characterized by a cytoplasmic localization; HDAC8 is an epigenetic eraser, unique HDAC-class I member that displays some aminoacidic similarity to HDAC6.

Design and Synthesis of Oligopeptidic Parvulin Inhibitors.

Pin1 catalyzes the cis-trans isomerization of pThr-Pro or pSer-Pro amide bonds of various proteins involved in several physio/pathological processes. In this framework, recent research activity is directed toward the identification of new selective Pin1 inhibitors. Here, we developed a set of peptide-based Pin1 inhibitors.

Polypharmacological Approaches for CNS Diseases: Focus on Endocannabinoid Degradation Inhibition.

Polypharmacology breaks up the classical paradigm of "one-drug, one target, one disease" electing multitarget compounds as potential therapeutic tools suitable for the treatment of complex diseases, such as metabolic syndrome, psychiatric or degenerative central nervous system (CNS) disorders, and cancer. These diseases often require a combination therapy which may result in positive but also negative synergistic effects. The endocannabinoid system (ECS) is emerging as a particularly attractive therapeutic target in CNS disorders and neurodegenerative diseases including Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), stroke, traumatic brain injury (TBI), pain, and epilepsy.

Selective Fatty Acid Amide Hydrolase Inhibitors as Potential Novel Antiepileptic Agents.

Temporal lobe epilepsy is the most common form of epilepsy, and current antiepileptic drugs are ineffective in many patients. The endocannabinoid system has been associated with an on-demand protective response to seizures. Blocking endocannabinoid catabolism would elicit antiepileptic effects, devoid of psychotropic effects.

Modulation of the Innate Immune Response by Targeting Toll-like Receptors: A Perspective on Their Agonists and Antagonists.

Toll-like receptors (TLRs) are a class of proteins that recognize pathogen-associated molecular patterns (PAMPs) and damaged-associated molecular patterns (DAMPs), and they are involved in the regulation of innate immune system. These transmembrane receptors, localized at the cellular or endosomal membrane, trigger inflammatory processes through either myeloid differentiation primary response 88 (MyD88) or TIR-domain-containing adapter-inducing interferon-β (TRIF) signaling pathways. In the last decades, extensive research has been performed on TLR modulators and their therapeutic implication under several pathological conditions, spanning from infections to cancer, from metabolic disorders to neurodegeneration and autoimmune diseases.

Hydrothermal carbonization of waste biomass: An experimental comparison between process layouts.

This paper contributes to the knowledge on waste biomass conversion processes occurring in the presence of hot compressed water. The experimental procedure detailed herein assesses different process schemes based on the low-temperature reaction known as hydrothermal carbonization. The performances of two lab-scale reactor configurations, with and without a downstream flash expansion step, were evaluated and compared.

Hydrothermal conversions of waste biomass: Assessment of kinetic models using liquid-phase electrical conductivity measurements.

This experimental study proposes the systematic monitoring of liquid phase electrical conductivity as a new technique for evaluating kinetic models for hydrothermal conversion of biomass. The application to the hydrothermal carbonization of three different wooden materials is validated by batch experiments at 200 °C, up to 120 min of reaction time, and at a 7:1 water to solid ratio. Whatever the biomass, the time course of electrical conductivity follows a unique law, unquestionably corresponding to the evolution of solid-phase carbon content.

Hydrothermal carbonization of Biomass: New experimental procedures for improving the industrial Processes.

This study aims to introduce new experimental methods, not yet described in the literature, to be adopted in hydrothermal carbonization processes. Silver fir was selected as model biomass in batch experiments in the range 200-300°C, up to 120min of reaction time, and at a 7:1 water to solid ratio. Simple equations were proposed for modeling the evolution of the process variables during the reaction, particularly the electrical conductivity of the liquid phase, correctly described by a simple two-step first order mechanism, regardless of the reaction temperature.

Berezinskii-Kosterlitz-Thouless phase transitions in two-dimensional non-Abelian spin models.

It is argued that two-dimensional U(N) spin models for any N undergo a Berezinskii-Kosterlitz-Thouless (BKT)-like phase transition, similarly to the famous XY model. This conclusion follows from the Berezinskii-like calculation of the two-point correlation function in U(N) models, approximate renormalization group analysis, and numerical investigations of the U(2) model. It is shown, via Monte Carlo simulations, that the universality class of the U(2) model coincides with that of the XY model.

Clinical Trial Accrual Targeting Genomic Alterations After Next-Generation Sequencing at a Non-National Cancer Institute-Designated Cancer Program.

Purpose: Successful clinical trial accrual targeting uncommon genomic alterations will require broad national participation from both National Cancer Institute (NCI)-designated comprehensive cancer centers and community cancer programs. This report describes the initial experience with clinical trial accrual after next-generation sequencing (NGS) from three affiliated non-NCI-designated cancer programs.

Materials And Methods: Clinical trial participation was reviewed after enrollment of the first 200 patients undergoing comprehensive genomic profiling by NGS as part of an institutional intuitional review board-approved protocol at three affiliated hospitals in Rhode Island and was compared with published experience from NCI-designated cancer centers.