Determinants of prognosis and management of patients with pulmonary hypertension due to left heart disease: a systematic review

Patients with pulmonary hypertension (PH) associated with left heart disease usually have a complex comorbidity status and a postcapillary component of PH. The presence and identification of a combined post-/precapillary PH in a cohort of patients with left heart disease is reflected in the more pronounced structural and functional right ventricular changes due to higher pulmonary vascular resistance. Patients with combined post-/ precapillary PH have reduced exercise tolerance and PH phenotype similar to pulmonary arterial hypertension. Detection of combined PH is critical as it may influence the prognosis and management of patients. This review presents modern prognosis markers for patients with PH due to left heart disease, which can be used in clinical practice. The results of randomized clinical trials and pilot studies on the expansion of treatment options in group 2 patients, including the use of PAH-specific agents, were analyzed. The prospects for the treatment of this cohort of patients are discussed

Фенотип пациентов с легочной гипертензией вследствие патологии левых отделов сердца: особенности патофизиологии и дифференциальной диагностики

The cohort of patients with postcapillary pulmonary hypertension (PH), associated with the left heart diseases, is the most numerous, but is still not fully understood. This review presents the pathophysiological aspects of the PH group 2 development as well as the influence of comorbid pathology on the course of the PH. The features of the differential diagnosis of post-capillary PH and combined post-/ precapillary PH, as well as methods of the differential diagnosis of these forms of PH with pulmonary arterial hypertension using modern non-invasive and invasive approaches are discussed.Наиболее многочисленной, при этом не до конца изученной остается когорта пациентов с посткапиллярной легочной гипертензией (ЛГ), ассоциированной с заболеваниями левых отделов сердца. В данном обзоре детально представлены патофизиологические аспекты развития ЛГ на фоне патологии левых отделов сердца на примере сердечной недостаточности с низкой/сохранной фракцией выброса, а также описано влияние коморбидной патологии на характер течения ЛГ. Обсуждены особенности дифференциального диагноза посткапиллярной и комбинированной (пост- и прекапиллярной) форм ЛГ, а также подходы к дифференциальному диагнозу данных форм ЛГ с легочной артериальной гипертензией с использованием современных неинвазивных и инвазивных подходов.

A Novel Inhibitor of Human La Protein with Anti-HBV Activity Discovered by Structure-Based Virtual Screening and In Vitro Evaluation

Background: Over 350 million people worldwide are infected with hepatitis B virus (HBV), a major cause of liver failure and hepatocellular carcinoma. Current therapeutic agents are highly effective, but are also associated with development of viral resistance. Therefore, strategies for identifying other anti-HBV agents with specific, but distinctive mechanisms of action are needed. The human La (hLa) protein, which forms a stabilizing complex with HBV RNA ribonucleoprotein to promote HBV replication, is a promising target of molecular therapy. Aims: This study aimed to discover novel inhibitors of hLa that could inhibit HBV replication and expression. Methods: A multistage molecular docking approach was used to screen a Specs database and an in-house library against hLa binding sites. Sequential in vitro evaluations were performed to detect potential compounds with high scores in HepG2.2.15 cells. Results: Of the 26 potential compounds with high scores chosen for experimental verification, 12 had HBV DNA inhibition ratios of less than 50 % with P,0.05. Six had significant inhibition of HBV e antigen (HBeAg) levels, and 13 had significant inhibition of HBV surface antigen (HBsAg) levels by in vitro assays. Compounds HBSC-11, HBSC-15 and HBSC-34 (HBSC is system prefix for active compounds screened by the library) were selected for evaluation. HBSC-11 was found to have an obvious inhibitory effect on hLa transcription and expression

Популяционный и субпопуляционный состав лимфоцитов и функциональная активность нейтрофил в у больных бронхиальной астмой разного возраста

This work is devoted to population spectrum of lymphocytes and oxlgen-dependent metabolism of neutrophils in 140 moderate persisting asthma patients of young, middle and old ages. Markers of persisting inflammation such as increased levels of immunoglobulin E and circulating immune complexes, considerable activation of spontaneous and induced NST-test, increased in elderly, various shifts In lymphocyte populations and subpopulations were revealed in all the groups. These features require additional attention of a doctor and special therapeutic measures.Настоящая работа посвящена изучению популяционного спектра лимфоцитов, кислородзависимого метаболизма нейтрофилов у 140 больных с умеренно персистирующей бронхиальной астмой в трех группах: молодого, среднего, пожилого возраста. Во всех группах выявлены маркеры персистирую щ его воспаления: повышение уровней иммуноглобулина Е и циркулирую щ их иммунных комплексов, значительная активация спонтанного и индуцированного ЫЗТ-теста, усиливающаяся у пожилых больных, разнонаправленные изменения в популяционном и субпопуляционном составе лимфоцитов, что требует дополнительного внимания врача и проведения лечебных мероприятий

Prevention of Wear Particle-Induced Osteolysis by a Novel V-ATPase Inhibitor Saliphenylhalamide through Inhibition of Osteoclast Bone Resorption

Wear particle-induced peri-implant loosening (Aseptic prosthetic loosening) is one of the most common causes of total joint arthroplasty. It is well established that extensive bone destruction (osteolysis) by osteoclasts is responsible for wear particle-induced peri-implant loosening. Thus, inhibition of osteoclastic bone resorption should prevent wear particle induced osteolysis and may serve as a potential therapeutic avenue for prosthetic loosening. Here, we demonstrate for the first time that saliphenylhalamide, a new V-ATPase inhibitor attenuates wear particle-induced osteolysis in a mouse calvarial model. In vitro biochemical and morphological assays revealed that the inhibition of osteolysis is partially attributed to a disruption in osteoclast acidification and polarization, both a prerequisite for osteoclast bone resorption. Interestingly, the V-ATPase inhibitor also impaired osteoclast differentiation via the inhibition of RANKL-induced NF-κB and ERK signaling pathways. In conclusion, we showed that saliphenylhalamide affected multiple physiological processes including osteoclast differentiation, acidification and polarization, leading to inhibition of osteoclast bone resorption in vitro and wear particle-induced osteolysis in vivo. The results of the study provide proof that the new generation V-ATPase inhibitors, such as saliphenylhalamide, are potential anti-resorptive agents for treatment of peri-implant osteolysis

Stress granules, RNA-binding proteins and polyglutamine diseases: too much aggregation?

Stress granules (SGs) are membraneless cell compartments formed in response to different stress stimuli, wherein translation factors, mRNAs, RNA-binding proteins (RBPs) and other proteins coalesce together. SGs assembly is crucial for cell survival, since SGs are implicated in the regulation of translation, mRNA storage and stabilization and cell signalling, during stress. One defining feature of SGs is their dynamism, as they are quickly assembled upon stress and then rapidly dispersed after the stress source is no longer present. Recently, SGs dynamics, their components and their functions have begun to be studied in the context of human diseases. Interestingly, the regulated protein self-assembly that mediates SG formation contrasts with the pathological protein aggregation that is a feature of several neurodegenerative diseases. In particular, aberrant protein coalescence is a key feature of polyglutamine (PolyQ) diseases, a group of nine disorders that are caused by an abnormal expansion of PolyQ tract-bearing proteins, which increases the propensity of those proteins to aggregate. Available data concerning the abnormal properties of the mutant PolyQ disease-causing proteins and their involvement in stress response dysregulation strongly suggests an important role for SGs in the pathogenesis of PolyQ disorders. This review aims at discussing the evidence supporting the existence of a link between SGs functionality and PolyQ disorders, by focusing on the biology of SGs and on the way it can be altered in a PolyQ disease context.ALG-01-0145-FEDER-29480, SFRH/BD/133192/2017, SFRH/BD/133192/2017, SFRH/BD/148533/2019info:eu-repo/semantics/publishedVersio

Bafilomycin A1 activates respiration of neuronal cells via uncoupling associated with flickering depolarization of mitochondria

Bafilomycin A1 (Baf) induces an elevation of cytosolic Ca2+ and acidification in neuronal cells via inhibition of the V-ATPase. Also, Baf uncouples mitochondria in differentiated PC12 (dPC12), dSH-SY5Y cells and cerebellar granule neurons, and markedly elevates their respiration. This respiratory response in dPC12 is accompanied by morphological changes in the mitochondria and decreases the mitochondrial pH, Ca2+ and ΔΨm. The response to Baf is regulated by cytosolic Ca2+ fluxes from the endoplasmic reticulum. Inhibition of permeability transition pore opening increases the depolarizing effect of Baf on the ΔΨm. Baf induces stochastic flickering of the ΔΨm with a period of 20 ± 10 s. Under conditions of suppressed ATP production by glycolysis, oxidative phosphorylation impaired by Baf does not provide cells with sufficient ATP levels. Cells treated with Baf become more susceptible to excitation with KCl. Such mitochondrial uncoupling may play a role in a number of (patho)physiological conditions induced by Baf

Modelling of the effect of ELMs on fuel retention at the bulk W divertor of JET

Effect of ELMs on fuel retention at the bulk W target of JET ITER-Like Wall was studied with multi-scale calculations. Plasma input parameters were taken from ELMy H-mode plasma experiment. The energetic intra-ELM fuel particles get implanted and create near-surface defects up to depths of few tens of nm, which act as the main fuel trapping sites during ELMs. Clustering of implantation-induced vacancies were found to take place. The incoming flux of inter-ELM plasma particles increases the different filling levels of trapped fuel in defects. The temperature increase of the W target during the pulse increases the fuel detrapping rate. The inter-ELM fuel particle flux refills the partially emptied trapping sites and fills new sites. This leads to a competing effect on the retention and release rates of the implanted particles. At high temperatures the main retention appeared in larger vacancy clusters due to increased clustering rate