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Text from PDF Page: 002Cancers 2021, 13, 893 2 of 10 This review describes the role of H2 and H+ in relation to OS and outlines the potential anticancer activity of this endogenous ion and different types of H2 donors. 2. Background: The Different Forms of Oxygen and Hydrogen The structure and dynamics of the different forms of hydrogen and oxygen are the subjects of numerous studies. When oxygen combines with another element, referred to as oxidation, more energy is released than when any other elements are combined. In the cell, the energy released is slow. The atomic number of oxygen is 8 on the Periodic Table of Elements, implying that an oxygen atom holds eight electrons. Its electrons are filled in the following order: two electrons in the first orbital, and six electrons in the second orbital. Therefore, there are 16 electrons in the oxygen molecule. Oxygen has two unpaired electrons in separate orbitals in its outer shell. This electronic structure makes oxygen especially susceptible to radical formation. A free radical is defined as any chemical species that contains unpaired electrons in its outer orbital. Atomic hydrogen (H) is number 1 on the Periodic Table of Elements. It consists of one proton and one unpaired electron, and it is consequently a free radical. When the hydrogen atom loses an electron, all that remains is a proton. It becomes the positively charged hydrogen ion known as H+. H2 is a gas that forms when two hydrogen atoms bond together and become a hydrogen molecule consisting of two protons and two electrons. Hydroxide (OH−), also known as the hydroxyl ion, is not a free radical. Sequential reduction of molecular oxygen leads to formation of a group of ROS, such as the superoxide anion and hydroxyl radical. Hydroxyl radical •OH is the neutral form of the hydroxide ion (OH−) and is a highly reactive free radical. Superoxide anion (O2−•) is of major importance in cellular biology because it leads to the formation of ROS. O2−• can be dismutated to molecular oxygen (O2) and hydrogen peroxide (H2O2), either spontaneously or in a reaction catalyzed by superoxide dismutases (SODs). H2O2 is converted to •OH via several routes, catalyzed by Haber-Weiss reactions and metal-catalyzed by Fenton reactions (Figure 1). Concerning ROS in biology, a process of chemical chain reaction has been described involving three stages: initiation, propagation, and termination . Protons (H+) and hydroxide (OH−) ions in the cell are critical for a wide variety of biological processes. Proton transport across the plasma membrane is central for the maintenance of pH. Cells maintain intracellular pH (pHi) within a narrow range (7.1–7.2) by controlling membrane proton pumps and transporters . The normal physiological pH of mammalian arterial blood is maintained at 7.40 ± 0.05, depending in part on several pH buffering systems such as albumin. Body fluid acidosis is involved in the pathogenesis of metabolic diseases. For instance, chronic ketoacidosis is found in diabetes mellitus patients due to increased levels of ketone bodies in the blood [4,5]. In humans, the maintenance of pH in the diverse cell compartments (intracellular and extracellular) is achieved through various regulatory systems. Ions utilize several paths to enter the cytosolic environment. In this area, the bicarbonate ion (HCO3−) has a fundamental role, and acid–base homeostasis with HCO3− is critically regulated in various systems through various transporters, which have been extensively reviewed [6,7]. The acid–base balance is a critical factor in the heart, and, consequently, acid–base imbalance contributes to organ disease . Additionally, it is suggested that pHi plays an essential role in cancer metabolism, where a reverse pH gradient is a hallmark that is evidenced by extracellular acidosis and intracellular alkalization .
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