Explore the vast range of titles available.

Background/Objectives: Low fasting blood lysosomal acid lipase (LAL) activity is associated with the pathogenesis of metabolic hepatic steatosis. We measured LAL activity in blood and plasma before and after an oral fat tolerance test (OFTT) in patients with metabolic-dysfunction-associated steatotic liver disease (MASLD). Methods: Twenty-six controls and seventeen patients with MASLD but without diabetes were genotyped for the patatin-like phospholipase 3 (PNPLA3) rs738409 variant by RT-PCR and subjected to an OFTT, measuring LAL activity in blood and plasma with a fluorimetric method. Results: LAL activity in blood both under fasting and 4 h after OFTT (0.846 ± 0.309 nmol/spot/h vs. 1.180 ± 0.503 nmol/spot/h p < 0.01) was lower in patients with MASLD compared to controls. These differences were present only in carriers of the PNPLA3 variant. In controls not carrying the PNPLA3 variant, the postprandial increase in blood LAL activity was negatively correlated with that of serum triglycerides (p < 0.05). Extracellular LAL activity in plasma was lower in patients with MASLD (n = 9) compared to controls (n = 8) in the fasting state (p < 0.01) and 4 h post-meal (p < 0.05). The area under the curve up to 6 h of plasma LAL activity was lower in patients with MASLD than in controls (p < 0.05) and correlated negatively with that of triglycerides only in controls (r = −0.841; p < 0.01). Conclusions: Patients with MASLD have reduced LAL activity in blood and plasma both before and 4 h after a meal. In patients with MASLD, the physiological negative correlation between circulating LAL levels and postprandial hypertriglyceridemia is lost.

Background Lysophosphatidic acid (LPA) is a bioactive phospholipid with a potentially causative role in neurotrauma. Blocking LPA signaling with the LPA-directed monoclonal antibody B3/Lpathomab is neuroprotective in the mouse spinal cord following injury. Findings Here we investigated the use of this agent in treatment of secondary brain damage consequent to traumatic brain injury (TBI). LPA was elevated in cerebrospinal fluid (CSF) of patients with TBI compared to controls. LPA levels were also elevated in a mouse controlled cortical impact (CCI) model of TBI and B3 significantly reduced lesion volume by both histological and MRI assessments. Diminished tissue damage coincided with lower brain IL-6 levels and improvement in functional outcomes. Conclusions This study presents a novel therapeutic approach for the treatment of TBI by blocking extracellular LPA signaling to minimize secondary brain damage and neurological dysfunction.

Botrytis cinerea, the causative agent of the gray mold disease, causes crop failures of many economically important crops worldwide and its control is usually difficult. This study aims to evaluate the effectiveness of RNA interference (RNAi)-based control strategy to suppress the growth of B. cinerea, through exogenous application of double-strand RNA (dsRNA) targeting single and multiple genes encoding crucial enzymes for the fungal cell wall development. The dsRNA molecules were designed to target three single chitin synthase (BcCHSI, BcCHSIIIa, BcCHSVI) and two glucan synthase (alpha-1, 3-glucan synthase (Bcags), β-1, 3-glucan synthase (Bcbgs)), genes. Furthermore, two dsRNA chimeras targeting multiple Chitin synthase (BcCHSI/IIIa/VI) and Glucan synthase genes (Bcags/bgs) have been produced to inhibit Botrytis infection. Here we show that the dsRNAs treatments strongly affect the virulence of the fungus and result in the downregulation of BcCHSI, BcCHSIIIa, BcCHSVI, Bcags, and Bcbgs genes. Overall, our data indicate that exogenous application of dsRNAs can compromise the virulence of B. cinerea and that RNAi-based strategy targeting genes important for B. cinerea cell wall synthesis may provide an effective means to halt the growth of B. cinerea and consequently limit the infection.

Cystic fibrosis (CF) is caused by different mutations related to the cystic fibrosis transmembrane regulator protein (CFTR), with F508del being the most common. Pioneering the development of CFTR modulators, thanks to the development of effective correctors or potentiators, more recent studies deeply encouraged the administration of triple combination therapeutics. However, combinations of molecules interacting with other proteins involved in functionality of the CFTR channel recently arose as a promising approach to address a large rescue of F508del-CFTR. In this context, the design of compounds properly targeting the molecular chaperone Hsp70, such as the allosteric inhibitor MKT-077, proved to be effective for the development of indirect CFTR modulators, endowed with ability to amplify the accumulation of the rescued protein. Herein we performed structure-based studies of a number of allosteric HSP70 inhibitors, considering the recent X-ray crystallographic structure of the human enzyme. This allowed us to point out the main interaction supporting the binding mode of MKT-077, as well as of the related analogues. In particular, cation-π and π–π stacking with the conserve residue Tyr175 deeply stabilized inhibitor binding at the HSP70 cavity. Molecular docking studies had been followed by QSAR analysis and then by virtual screening of aminoaryl thiazoles (I–IIIa) as putative HSP70 inhibitors. Their effectiveness as CFTR modulators has been verified by biological assays, in combination with VX-809, whose positive results confirmed the reliability of the whole applied computational method. Along with this, the “in-silico” prediction of absorption, distribution, metabolism, and excretion (ADME) properties highlighted, once more, that AATs may represent a chemical class to be further investigated for the rational design of novel combination of compounds for CF treatment.