Study of Antioxidant and Membrane Resistant Peculiarities of a New Cyan Containing Lactone in Membranes of Hepatocytes with Sarcoma-45

The antioxidant and membrane resistant peculiarities of a new derivative (2-cyan-3,4,4-trymethil-2-buten-4-olyd - CTBO) of cyan containing unsaturated lactones have been studied in membranes of hepatocytes with Sarcoma-45 1. The results of our previous research 1, 2, 3 showed significant changes of phospholipid (PL) exchange in hepatocytes of microsomal membranes at experimental animals vaccinated with Sarcoma-45 tumor strain. It is manifested in significant changes of quantitative and qualitative contents of membrane phospholipids separate fractions, increase of cytotoxic lysophospholipids (LPCs), phosphatidylinositol (PI) and phosphatidic acid (PA) levels, significant decrease of phosphatitylcholines (PC) and sphingomyeline (SP) contents, statistically significant changes of PL/PL ratio, peroxidation ratio intensity, dramatic increase of phospholipase A2 (PLA2)activity, quantitative and qualitative changes of adenyl nucleotides, as well as disorders of adenosine triphosphatase (ATPase) system activity 3, 4, 5, 6, 7.

Endogenous Bufadienolides, Fibrosis and Preeclampsia

Frequency of preeclampsia has no tendency to decrease, and it still takes the leading position in the structure of maternal mortality and morbidity worldwide. In this review, we present the “fibrotic concept” of the etiology and pathogenesis of preeclampsia which involves system consisting of Na/K-ATPase and its endogenous ligands including marinobufagenin. New therapy of preeclampsia includes modulation of the Na/K-ATPase system by immunoneutralization of the marinobufagenin and use of mineralocorticoid antagonists which are capable to impair marinobufagenin-Na/K-ATPase interactions.

Revisiting the protomotive vectorial motion of F0-ATPase

The elucidation of the detailed mechanism used by F0 to convert proton gradient to torque and rotational motion presents a major puzzle despite significant biophysical and structural progress. Although the conceptual model has advanced our understanding of the working principles of such systems, it is crucial to explore the actual mechanism using structure-based models that actually reproduce a unidirectional proton-driven rotation. Our previous work used a coarse-grained (CG) model to simulate the action of F0. However, the simulations were based on a very tentative structural model of the interaction between subunit a and subunit c. Here, we again use a CG model but with a recent cryo-EM structure of cF1F0 and also explore the proton path using our water flooding and protein dipole Langevin dipole semimacroscopic formalism with its linear response approximation version (PDLD/S-LRA) approaches. The simulations are done in the combined space defined by the rotational coordinate and the proton transport coordinate. The study reproduced the effect of the protomotive force on the rotation of the F0 while establishing the electrostatic origin of this effect. Our landscape reproduces the correct unidirectionality of the synthetic direction of the F0 rotation and shows that it reflects the combined electrostatic coupling between the proton transport path and the c-ring conformational change. This work provides guidance for further studies in other proton-driven mechanochemical systems and should lead (when combined with studies of F1) to a complete energy transduction picture of the F0F1-ATPase system.

Tissue-specific regulation of the Na, K-ATPase by the cytosolic NaAF: some thoughts on brain function

The dual topology P-2 ATPase, which consists of a α²β² tetramer, explains numerous functions of the cation transporting ATPase system. The ubiquitous cytosolic protein regulator (NaAF) of 170 k Da mass regulates P-2 ATPase function in a low Ca (µM) neighborhood where Ca acts as the terminal regulator in the intracellular signaling cascade. The Na, K- ATPase also seems to function as an H, K-ATPase or a Ca-ATPase in altered states based on the local environment (low pH or high Ca) in a tissue specific manner. These altered effects are analogous to that of the 80 k Da cytosolic HAF in regulating the gastric H, K-ATPase system of the parietal cells. However there are some important differences. The HAF stimulates the Na, K-ATPase but the NaAF cannot stimulate H, K-ATPase. Also, HAF is as effective as NaAF in stimulating the kidney Na, K-ATPase but about 60% as effective in stimulating brain Na, K-ATPase. These observations reveal that the Na, K- ATPase systems from kidney and brain, consisting of different kinds of αβ–isoforms, interact differently with the HAF molecule; thus substantiating that P-2 ATPase system plays different roles in different tissues in response to an universal NaAF. Another rare feature of the HAF is that it has histone kinase activity, suggesting that the HAF and NaAF may be capable of sending a direct signal to the nucleus for gene expression.In this paper, the central role of the NaAF-regulated Na, K-ATPase system in the activity and function of brain tissue is discussed. It is noted that the altered function of the nerve terminus located Na, K-ATPase system works as a Ca-pump (after depolarization) and as a Na-pump (in repolarization) in alternate sequence. The possible role of Ca-sensing receptor (CaR) in the voltage gated channeling of Ca has been raised and the possibility of a dual channel Na/H antiporter (NhaA) in pH homeostasis is discussed.

Brain cell volume regulation in hyponatremia: role of sex, age, vasopressin, and hypoxia

Hyponatremia is the most common electrolyte abnormality in hospitalized patients. When symptomatic (hyponatremic encephalopathy), the overall morbidity is 34%. Individuals most susceptible to death or permanent brain damage are prepubescent children and menstruant women. Failure of the brain to adapt to the hyponatremia leads to brain damage. Major factors that can impair brain adaptation include hypoxia and peptide hormones. In children, physical factors—discrepancy between skull size and brain size—are important in the genesis of brain damage. In adults, certain hormones—estrogen and vasopressin (usually elevated in cases of hyponatremia)—have been shown to impair brain adaptation, decreasing both cerebral blood flow and oxygen utilization. Initially, hyponatremia leads to an influx of water into the brain, primarily through glial cells and largely via the water channel aquaporin (AQP)4. Water is thus shunted into astrocytes, which swell, largely preserving neuronal cell volume. The initial brain response to swelling is adaptation, utilizing the Na+-K+-ATPase system to extrude cellular Na+. In menstruant women, estrogen + vasopressin inhibits the Na+-K+-ATPase system and decreases cerebral oxygen utilization, impairing brain adaptation. Cerebral edema compresses the respiratory centers and also forces blood out of the brain, both lowering arterial Po2 and decreasing oxygen utilization. The hypoxemia further impairs brain adaptation. Hyponatremic encephalopathy leads to brain damage when brain adaptation is impaired and is a consequence of both cerebral hypoxia and peptide hormones.