Evidences have suggested that impairment of CK activity cont

Evidences have suggested that impairment of CK activity contributes to inhibition of Na+, K+-ATPase and H+-ATPase activities during infectious diseases, since these ATPases are dependent of ATP, as observed by Baldissera et al. [31] in fish experimentally infected by Aeromonas caviae. We observed that serum Na+, K+-ATPase and H+-ATPase activities are inhibited in animals fed with a diet co-contaminated by aflatoxins and fumonisins, indicating that a possible ATP depletion caused by impairment of CK/PCr system compromises the proper functioning of these ATPases. The inhibition on ATPases activities was already reported in mouse and rat hepatic tissue exposed to aflatoxins B1, B2, G1 and G2 in a concentration-dependent manner (6 × 10−5 to 6 × 10−9 M) [32], which is in accordance to that observed in our study. Moreover, study conducted by Gutiérrez-Nájera [33] demonstrated that fumonisin B1 at concentration of 40 μM was able to inhibits plasma H+-ATPase activity in vitro, considering this inhibition an important target of fumonisin B1-induced toxicity, in agree to observed in this present study. The inhibition of Na+, K+-ATPase activity may lead to a disturbance in ionic homeostasis of Na+ and K+ ions, as observed in our study and in accordance to observed by Groopman et al. [34] in an exposure to aflatoxin B1. It is important emphasize that Na+, K+-ATPase and H+-ATPase are high sensitive to oxidation by free radicals, and its activities are inhibited during oxidative stress condition [35]. In this sense, recent evidence has demonstrated the augmentation on free radicals, as reactive oxygen species (ROS), and occurrence of oxidative stress in piglets fed with a diet containing mycotoxins, including aflatoxin and fumonisin [36], which may explain the inhibition of Na+, K+-ATPase and H+-ATPase activities. Low serum Na+ levels, a clinical condition known as hyponatremia, is associated with significant morbidity and mortality of affected individuals, with several consequences to the central nervous system [37], which is also directly affected by aflatoxins and fumonisins [38]. Moreover, the inhibition on serum K+ levels, a clinical condition known as hypokalemia, is associated with some clinical signs observed in humans or animals intoxicated with aflatoxins, such as malaise and weakness. An imbalance of K+ levels also significant affects the nerve impulse transmission, skeletal and Cyclo(RGDyK) contraction and the acid-base balance [39]. Finally, we observed a significantly increase in serum Ca+ levels on day 15 of experiment (control group), that may be consequence of ATP depletion, which result in the leakage of extracellular Ca+ ions into the intracellular space due to inhibition of Na+, K+-ATPase activity, which may be associated to increase of protein degradation, oxidative stress, inflammatory process and impairment of immune response [40]. In summary, the inhibition of serum Na+, K+-ATPase and H+-ATPase activities leads to an impairment on ionic metabolism. Based on these evidences, a diet co-contaminated by mycotoxins caused weight loss and inhibit serum CK activity, impairing the energetic homeostasis, which may contribute to impairment of body weight. Moreover, this inhibition alters the activities of ATPases (Na+, K+-ATPase and H+-ATPase), contributing to an imbalance of Na+, K+ and Ca+ ionic levels. In summary, the cascade of alterations contributes directly to disease pathogenesis of piglets intoxicated by mycotoxins.
Col statement
Conflicts of interest
()-Blebbistatin ()- is a micromolar ATPase inhibitor selective for myosin II and with extensive applications in research despite a number of physicochemical shortcomings ()., We and others have previously established that modification of ring D,, , , , and to a lesser extent ring A, leads to analogs with superior research tool properties, such as ()-4′-nitroblebbistatin ()-, ()-4′-aminoblebbistatin ()-, ()-3′-hydroxyblebbistatin ()- and ()-3′-aminoblebbistatin ()-. Myosin II has multiple physiological roles, such as in migration, neuronal functioning, biochemical signaling and gene transcription. The protein is considered a potential therapeutic target in a diverse range of diseases and disorders, e.g. cancer metastasis, methamphetamine use relapse, viral infections, glaucoma, liver fibrosis and thrombosis. Potent and drugable inhibitors of particular isoforms of this protein could thus be valuable pharmacological tools. However, obtaining significant potency enhancement modification of the aforementioned rings D and A of ()-blebbistatin ()- seems unattainable., , The goal of the present study was to examine the influence of small chemical modifications of ring C on ATPase inhibitory potency. No reports on the exploration of the structure-activity relationship (SAR) landscape of this part of the molecule have been published to date.