On BH3 mimetics and Ca2+ signaling

BH3 mimetics are anticancer agents that reproduce the spatial arrangement of the BH3 domain of Bcl-2 family proteins. Just like the BH3-only proteins, these compounds bind to the hydrophobic cleft of the pro-survival Bcl-2 members such as Bcl-2 or Bcl-xL, and disrupt their heterodimerization with pro-apoptotic Bax or Bak, sensitizing cells to chemotherapy. In recent years, it has become clear that Bcl-2 family proteins are engaged in regulation of intracellular Ca2+ homeostasis, including Ca2+ release from the intracellular stores as well as Ca2+ fluxes across the plasma membrane. Given that BH3 mimetics shift the balance between the prosurvival and proapoptotic Bcl-2 members, they might indirectly exert effects on intracellular Ca2+ signals. Indeed, it has been reported that some BH3 mimetics release Ca2+ from the intracellular stores causing Ca2+ overload in the cytosol. Therefore, the effects of any new BH3 mimetics on cellular Ca2+ homeostasis should be tested before these compounds progres

CONTINUOUS AND DISCRETE SLIDING MODE CONTROL OF AN ACTIVE CAR SUSPENSION SYSTEM

In this paper, sliding mode control (SMC) algorithms are tested for their use in an active car suspension system. Using the quarter model of the car as an example, the comparison of the efficiency of the algorithms is made. A continuous and two discrete versions of the sliding mode control are taken into consideration. The study is limited to finding the relation between the control parameters and the comfort factor. This is done by analyzing the response of the model to the harmonic and impulse excitation

Biology of pancreatic stellate cells—more than just pancreatic cancer

Pancreatic stellate cells, normally quiescent, are capable of remarkable transition into their activated myofibroblast-like phenotype. It is now commonly accepted that these cells play a pivotal role in the desmoplastic reaction present in severe pancreatic disorders. In recent years, enormous scientific effort has been devoted to understanding their roles in pancreatic cancer, which continues to remain one of the most deadly diseases. Therefore, it is not surprising that considerably less attention has been given to studying physiological functions of pancreatic stellate cells. Here, we review recent advances not only in the field of pancreatic stellate cell pathophysiology but also emphasise their roles in physiological processes

Agnieszka Łoza, Paweł Beyga, Zaraza w Kościele, wyd. Leksem Studio, Żmigród 2021, ss. 169

In the opinion of Bogdan Ferdek, the new book of Agnieszka Łoza and Paweł Beyga is a special theological report on the state of the Church in Poland. During the pandemic time since 2021 the Catholic Church has had to search for solving problems in the Christian community. According to the authors of this new book, in the Polish Catholic Church two kinds of problems can be discovered. Firstly, there is a problem with morality among the clergy, the problems of sexual abuse and teaching the Catholic religion in Polish schools. Conversely, there is a problem related to the secularization of Polish people. Bogdan Ferdek in his review showed that the new book of two young Polish theologians is an answer to very important questions in the Polish Christendom in the time of the pandemic.In the opinion of Bogdan Ferdek, the new book of Agnieszka Łoza and Paweł Beyga is a special theological report on the state of the Church in Poland. During the pandemic time since 2021 the Catholic Church has had to search for solving problems in the Christian community. According to the authors of this new book, in the Polish Catholic Church two kinds of problems can be discovered. Firstly, there is a problem with morality among the clergy, the problems of sexual abuse and teaching the Catholic religion in Polish schools. Conversely, there is a problem related to the secularization of Polish people. Bogdan Ferdek in his review showed that the new book of two young Polish theologians is an answer to very important questions in the Polish Christendom in the time of the pandemic

Aurora Jakuba Böhme w świetle czterech zasad reformacji

Böhm’s mysticism aroused the opposition of orthodox Lutheranism. Evangelical parish priest of the Peter and Paul church in Görlitz Gregorius Richter suspect a heresy in Aurora and threate- ned Böhm with banishment. Numerous Aurora texts indicate that Böhme took into account the four principles of the Reformation. Böhm’s Aurora contains the reformational principle the grace itself and the anthropology implied by it, about the non-free will of human being. While in Luther thoughts were dominated by the functional Christology, in the Böhme’s – essential Christology. The essence of this Christology is to call Christ Aurora. From the essential Christology, Böhme, however, derived a functional conclusion, which is the postulate of the following Christ. In contrast to Luther, who focused on the des qua, Böhme focuses primarily on des quae. Although Auroracontains numerous references to the Bible, the very title of Böhme’s most famous work is the result of an experience with a tin vessel. Luther would blame Böhme of illumination, that is, the possibili- ty of an internal, omitting the biblical Word, communicating the Spirit of God with human. Böhme was a theosophist, means either theologian and philosopher, in one person. As a theologian, he drew the knowledge from God’s revelation, and as a philosopher he perceived the traces of God in the world. He had a premonition that reason and faith can not contradict themselves, because ultimately they have a common source in God.Böhm’s mysticism aroused the opposition of orthodox Lutheranism. Evangelical parish priest of the Peter and Paul church in Görlitz Gregorius Richter suspect a heresy in Aurora and threate- ned Böhm with banishment. Numerous Aurora texts indicate that Böhme took into account the four principles of the Reformation. Böhm’s Aurora contains the reformational principle the grace itself and the anthropology implied by it, about the non-free will of human being. While in Luther thoughts were dominated by the functional Christology, in the Böhme’s – essential Christology. The essence of this Christology is to call Christ Aurora. From the essential Christology, Böhme, however, derived a functional conclusion, which is the postulate of the following Christ. In contrast to Luther, who focused on the des qua, Böhme focuses primarily on des quae. Although Auroracontains numerous references to the Bible, the very title of Böhme’s most famous work is the result of an experience with a tin vessel. Luther would blame Böhme of illumination, that is, the possibili- ty of an internal, omitting the biblical Word, communicating the Spirit of God with human. Böhme was a theosophist, means either theologian and philosopher, in one person. As a theologian, he drew the knowledge from God’s revelation, and as a philosopher he perceived the traces of God in the world. He had a premonition that reason and faith can not contradict themselves, because ultimately they have a common source in God

The role of Bcl-2 family proteins and calmodulin in calcium signalling in pancreatic acinar cells

Bcl-2 proteins are very well known regulators of the programmed cell death. Accumulating evidence suggests that they are also involved in regulation of calcium signalling events. Bcl-2 has been reported to affect calcium release from the intracellular calcium stores through regulation of inositol trisphosphate receptors and endoplasmic reticulum calcium pumps. Physiological and pathological processes in pancreatic acinar cells are controlled by calcium. Intracellular Ca2+ signals regulate not only gene expression and trigger enzyme secretion but also might contribute to premature trypsinogen activation and development of pancreatitis, which is characterised by extensive necrosis of the pancreatic tissue. Detailed investigation of Bcl-2 family-dependent mechanisms of intracellular Ca2+ regulation and its association with cell death induction is required for understanding of the basic physiological signalling pathways as well as pathophysiological processes leading to development of severe diseases of pancreas. This study investigates the effects of Bcl-2 family proteins on intracellular calcium homeostasis, with particular focus on their involvement in Ca2+ fluxes and CICR phenomenon. Also, the Ca2+-related actions of different doses of ethanol in pancreatic acinar cells and their contribution to pancreatitis are presented and assessed. The results indicate that pharmacological inhibition of anti-apoptotic Bcl-2 and Bcl-xL proteins with BH3 mimetics BH3I’-2' or HA14-1 sensitizes pancreatic acinar cells to CICR; and overexpression of Bcl-2 has the opposite effect significantly decreasing rising phase of CICR-types of responses in pancreatic cell line AR42J. Responses to BH3 mimetics are at least partially dependent on both IP3Rs and RyRs, 5 since inhibition of either of them results in a substantial decrease in Ca2+ release from the intracellular stores. However, simultaneous blockade of IP3Rs and RyRs did not completely abolish BH3 mimetic-elicited Ca2+ release, which indicates engagement of other factors in the development of the response. Importantly, the effects of BH3 mimetics on intracellular Ca2+ were effectively inhibited by loss of Bax protein, suggesting Bax involvement in the regulation of Ca2+ release from the ER. Further, the results presented here demonstrate that moderate concentrations of ethanol (10 - 100 mM), although having only a minor effect on intact cells, induce substantial Ca2+ release from both the ER and the acidic store in permeabilized cells, and trigger intracellular trypsinogen activation - the hallmark of acute pancreatitis. The data suggest that calmodulin, which is present in intact cells but is lost in permeabilized cells, constitutes a part of natural defence mechanism responsible for the differences in the severity of the responses to ethanol. What is more, the evidence indicates that specific pre-activation of calmodulin by Ca2+-like peptides boosts this defence and reduces the pathological calcium responses to ethanol as well as to BH3 mimetics in pancreatic acinar cells decreasing necrosis. Finally, the effects of Bcl-2 protein on calcium fluxes in pancreatic acinar cells were investigated. Cells lacking functional Bcl-2 showed substantially more rapid clearance of thapsigargin / high Ca2+-induced cytosolic calcium plateau as compared to wild type cells. This effect has been explained by increased activity of the PMCA that results in a marked increase of apoptosis / necrosis ratio in oxidative stress induced cell death. Overexpression of Bcl-2 in AR42J cells reduces ER calcium content, while silencing of Bcl-2 expression by siRNA results in substantially increased releasable calcium 6 pool in the ER. The data indicate that at least a fraction of Bcl-2 in both AR42J cells and pancreatic acinar cells locates in the ER and is present in close proximity to the plasma membrane, making possible the direct regulation of the PMCA. In conclusion, this study provides new insights into roles of Bcl-2 family proteins and calmodulin in intracellular calcium homeostasis. This thesis presents evidence for involvement of anti-apoptotic Bcl-2 members in Ca2+-induced Ca2+ release; demonstrates previously unknown regulation of the PMCA by Bcl-2; and suggests involvement of Bax protein in regulation of Ca2+ release from the intracellular stores. The study also proposes that Ca2+-like peptides can boost natural protective mechanisms and suggests their potential applications as therapeutic agents

Comparison of different control strategy in semi-active vehicle suspension system

This paper examined the quarter model of the vehicle suspension with dampers, represented by the hystereses models of Spencer type. The effectiveness of vibration reduction through the use of semi-active and passive systems with asymmetric damping force characteristics was compared. In case of semi-active dampers several different control algorithms of on-off type were considered. The impact of these algorithms on parameters associated with comfort and safety of the drive was analyzed. The results of the numerical simulations were presented in the form of graphs showing the values of performance indicators in the frequency domain

Bile acids induce necrosis in pancreatic stellate cells dependent on calcium entry and sodium-driven bile uptake

Acute biliary pancreatitis, caused by bile reflux into the pancreas, is a serious condition characterised by premature activation of digestive enzymes within acinar cells, followed by necrosis and inflammation. Bile acids are known to induce pathological Ca2+ signals and necrosis in acinar cells. However, bile acid-elicited signalling events in stellate cells remain unexplored. This is the first study to demonstrate the pathophysiological effects of bile acids on stellate cells in two experimental models: ex vivo (mouse pancreatic lobules) and in vitro (human cells). Sodium cholate and taurocholate induced cytosolic Ca2+ elevations in stellate cells, larger than those elicited simultaneously in the neighbouring acinar cells. In contrast, taurolithocholic acid 3-sulfate (TLC-S), known to induce Ca2+ oscillations in acinar cells, had only minor effects on stellate cells in lobules. The dependence of the Ca2+ signals on extracellular Na+ and the presence of sodium-taurocholate cotransporting polypeptide (NTCP) indicate a Na+-dependent bile acid uptake mechanism in stellate cells. Bile acid treatment caused necrosis predominantly in stellate cells, which was abolished by removal of extracellular Ca2+ and significantly reduced in the absence of Na+, showing that bile-dependent cell death was a downstream event of Ca2+ signals. Finally, combined application of TLC-S and the inflammatory mediator bradykinin caused more extensive necrosis in both stellate and acinar cells than TLC-S alone. Our findings shed new light on the mechanism by which bile acids promote pancreatic pathology. This involves not only signalling in acinar cells but also in stellate cells