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Calcium Electroporation – A Novel Treatment to Overcome Cancer-Mediated Immune Suppression
Published in Marko S. Markov, James T. Ryaby, Erik I. Waldorff, Pulsed Electromagnetic Fields for Clinical Applications, 2020
In light of this knowledge, calcium channels have been targeted in the development of new cancer treatments. Inhibition of SERCA has been investigated in various cancer models. Thapsigargin, an inhibitor of SERCA, is known to deplete intracellular calcium stores by preventing reuptake of cytosolic calcium (Sehgal et al., 2017), leading to induction of apoptosis. Results from several studies have shown that SERCA inhibition using thapsigargin either sensitizes or directly kills LNCaP and PC3 prostate cancer (Huang, Wang, & Wang, 2018; Sehgal et al., 2017), EC109 and TE12 esophageal cancer (Ma et al., 2016), MCF-7 breast cancer (Sehgal et al., 2017), and A549 lung adenocarcinoma (Wang et al., 2014) cells.
Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
The three new drugs—depicted in the scheme opposite—for treating worsening chronic cardiac failure with reduced ejection are Cinaciguat (BAY 58–2667), Vericiguat and Omecamtiv mecarbil (CK-1827452). Cinaciguat (e.g., Lapp et al., 2009, Erdmann et al., 2013) is associated with the second messenger cyclic guanosine 3′,5′-momo-phosphate (cGMP), that is of importance in the regulation of a variety of processes among them ion channel conductance, glycogenolysis, cellular apoptosis or myocardial contractility. Patients suffering from heart failure show a pathologically reduced cGMP concentration. cGMP is produced from guanosine-5′ triphosphate by the action of soluble guanylate cyclase (sGC); Cinaciguat activates NO-nonresponsive sGC independent of oxidative stress and enhances cGMP concentration, thereby inducing vasodilation preferentially in diseased vessels. Vericiguat (Pieske et al., 2017) is also a sGC stimulator; stimulation is independent of NO, too, however sGC is sensibilized for NO so that Vericiguat acts synergistic with NO. Omecamtiv mecarbil (Cytokinetics) is a cardiac selective myosin activator (myosin is the molecular motor that drives muscle contraction), acting positively inotrope and augmenting the left ventricular systolic function (prolonging the duration of left ventricular systole) without the undesirable secondary effects of altered calcium homeostasis (Liu et al., 2016). Omecamtiv mecarbil activates the myocardial ATPase at the site where the myosin head domain binds to actin via phosphate hydrolysis as a prerequisite for a conformation change required for mechanical contraction. Omecamtiv mecarbil binds in a way that allows an allosterical modulation of both the enzymatic and mechanical properties of the cardiac myosin motor; in the absence of actin, this drug inhibits ATP hydrolysis, suggesting that the actin-bound conformation of myosin is stabilized by Omecamtiv mecarbil (Malik et al., 2011). Morgan et al. (2010) reported the design, synthesis, and optimization of omecamtiv mecarbil, starting from a nitro-aromatic hit compound. Alternatively, heart failure may be treated by gene therapy. SERCA, or sarco/endoplasmic reticulum Ca2+-ATPase transfers Ca2+ ions from the cytosol of the cell to the lumen of the SR at the expense of ATP hydrolysis during muscle relaxation. It has been demonstrated by experiments with human cells and animal studies that the gene for the SERCA isoform 2a, the expression rate of which is strongly reduced in case of heart failure, can be delivered virus-mediated (e.g., by lentiviral vector, adeno-associated virus type 1) into the cardiac myocardium to treat the failing myocardium (Periasamy and Kalyanasundaram, 2008; Penny and Hammond, 2017).
Computational modeling of inhibitory signal transduction in urinary bladder PDGFRα+ cells
Published in Computer Methods in Biomechanics and Biomedical Engineering, 2023
Amritanshu Gupta, Rohit Manchanda
We see from Figure 2a that the fraction of activated G-protein increases with an increase in the intensity of the ATP stimulus. This results in an enhancement in the production of IP3 in the cytosol (Figure 2b). Elevated IP3 releases Ca2+ from the ER via the IP3R receptors, followed by the uptake of Ca2+ from the cytosol back into the ER by the sarcoendoplasmic reticulum calcium ATPase (SERCA) pump. Due to the difference in the temporal response of the IP3R and the SERCA pump, Ca2+ transients of varying amplitude are set up in the cytosol, as seen in Figure 2c. The Ca2+ transients, in turn, activate the SK3 channels, resulting in outward hyperpolarizing potassium currents (ISK3). As seen in Figure 2d, the outward-flowing K+ currents match in amplitude with the peak values of the SK3 currents simulated by Yeoh et al. (2016), represented by black circles.
Plyometric exercise enhances twitch contractile properties but fails to improve voluntary rate of torque development in highly trained sprint athletes
Published in European Journal of Sport Science, 2022
Haiko Bruno Zimmermann, Filipe Estácio Costa, Raphael Sakugawa, Brian MacIntosh, Fernando Diefenthaeler, Juliano Dal Pupo
Among the twitch parameters evaluated, no effect was observed for contraction time and ½ relaxation time. For an individual to generate rapid movements in activities where consecutive agonist and antagonist muscle contractions are required, it is assumed that quick force relaxation and quick force generation could be a limiting factor (Mathern, Anhorn, & Uygur, 2019). The rate of muscle relaxation is mainly controlled by sarcoendoplasmic reticulum calcium transport ATPase (SERCA) and occurs when the available calcium is pumped back into the sarcoplasmic reticulum (Rossi & Dirksen, 2006). These results indirectly suggest that highly trained sprint athletes, who probably contain a high proportion of fast-twitch fibres in the leg muscles, do not modify the activity of this ion pump in an acute manner after a plyometric CA. So, it can be speculated that SERCA found in fast-twitch fibres was not affected by plyometric CA, consequently not affecting the voluntary performance. This also shows that, although phosphorylation of RLC is the main mechanism for an increase in PT and twitch RTD, a plyometric CA seems to not affect contraction time and ½ relaxation time. More studies using endurance athletes and other athletic populations need to be performed to test if different results may be found.
Effects of exposure to sediment-associated fipronil on cardiac function of Neotropical armored catfish Hypostomus regani
Published in Journal of Environmental Science and Health, Part A, 2023
Lucas Abreu Ferro, Suzana Luisa Alves Fernandes, Ana Lúcia Kalinin, Diana Amaral Monteiro
The amplified role of NCX in cardiomyocytes of Fp-exposed fish was confirmed after the addition of 0.01 and 0.1 µM of ouabain, which significantly increased force development (49% and 37%, respectively) (Fig. 5A). This ouabain-induced inotropic stimulation was not detected in the ventricular strips from the Ct group, which maintained a similar force development at low doses of ouabain. In both experimental groups, a subsequent development of toxicity with decrease in contractile force were observed at concentrations of 1.0 µM and higher. Previous studies have demonstrated that high concentrations of ouabain induced toxicity in heart muscle.[77,78] The inhibition of the NCX activity with ouabain increases the thermodynamic drive for Ca2+ influx by exchanger NCX (in reverse-mode) due to the intracellular Na+ rise and shifts the burden of Ca2+ removal to sarco/endoplasmic reticulum Ca2+-ATPase (SERCA).[79–81] Consequently, a higher SR Ca2+ loads induce increases in Ca2+ transient and contractile force.[81,82] The effects of glycosides depend on the degree of NCX activity and expression since ouabain changes Ca2+ cycling via this exchanger protein,[83] which may explain the positive inotropic effects of ouabain only in Fp-exposed fish. Moreover, in isolated ventricular myocytes, the reversal of the Na+/Ca2+-exchanger causes transient increase in cellular energy expenditure, oxygen consumption, and [Ca2+]i.[84] In cardiomyocytes, cytoplasmic [Ca2+], thermodynamically controlled by the NCX, is a major regulator of the respiratory rate.[85] These fipronil-induced changes can greatly affect fish energy budget, which may cause negative impacts at population and community levels.