CRB Journal

Introduction

Human health, life and its quality are determined by the state of the regulatory systems of cells, organs and the body as a whole. The words of Rudolf Virchow (1821-1902) are still relevant: «It is not life in abnormal conditions, not a violation as such that causes the disease. On the contrary, the disease begins with a failure of the regulatory apparatus». Analysis of the literature data and the results of our morphological and biochemical studies made it possible to identify the main mechanisms leading to the transition from normal physiological processes to the development of general pathological changes. Previously, we proposed a generalizing concept of the development of pathological processes, according to which a typical pathological process is based on nonspecific violations of cyclic regulatory processes, when the content of reactive nitrogen and oxygen forms simultaneously increases and ^•NO₂ and peroxynitrites, capable of oxidizing unsaturated fatty acids that are part of cell membranes and subcellular structures; oxidize and damage DNA/RNA guanine bases; oxidize SH-groups of amino acids and proteins, and also participate in the nitrosylation of tyrosine residues of proteins [13,29,55-70]. We will begin the analysis of the problem of gaseous signaling molecules in living organisms [14-21,23- 29,31-42] from the emergence of the primary and secondary atmosphere of the Earth and the properties of those atoms that became the main components of cells and became part of NO, ^•O₂^-, H₂S/SO₂ and CO.

Primary and Secondary Atmosphere of Earth and Atoms Becoming the Main Components of Cells

According to modern concepts, most of the primary atmosphere of the Earth consisted of hydrogen (¹H₂) and helium (⁴He). This atmosphere was formed from a protoplanetary cloud during the formation of the solar system as a result of the capture of the above substances / elements by the Earth’s gravitational field [1]. Events that took place in the solar system 5 billion years ago can be observed using modern astrophysical methods in the Andromeda galaxy [2]. The secondary atmosphere of the Earth, which arose after volcanic eruptions, mainly contained hydrogen (H₂), methane (CH₄), ammonia (NH₃), and interconnected hydrogen and oxygen atoms (H₂O) [3-6]. Atoms that were part of the primary and secondary atmosphere of the Earth have become the main components of the cells of microorganisms, plants and animals [7]. Figuratively speaking, nature created life from what was. It is now known that all living organisms are 96% composed of hydrogen, carbon, nitrogen and oxygen atoms, which were part of the primary and secondary atmosphere of the Earth in a free (H₂) state or in a state bound to other atoms (CH₄, NH₃, H₂O) [8]. The rest of the atoms, according to modern concepts, including metals and trace elements that can be found in living organisms, make up no more than 4%. They appeared, as some researchers suggest, from the bowels of the planet as a result of volcanic eruptions [1-8]. The question of how inorganic compounds and organic substances entered the composition of living organisms, realizing numerous regulatory mechanisms and systems at various structural and functional levels, is the subject of research for the entire set of biomedical disciplines [9-12]. Why this became possible, and why nature is the same at all structural and functional levels, remains one of the mysteries that physicists, chemists and biologists have been trying to solve over the past centuries [8,14]. However, these questions, formulated in a different form, have worried almost all natural scientists in the world, at least for 2500 years. In this article, analyzing the problem of gas transmitters in mammals, we will try to give one of the possible answers to the questions posed.

Gas Transmitters in Intercellular and Intracellular Signaling Systems

Compounds were formed with the participation of hydrogen, carbon, nitrogen, and oxygen atoms, which began to perform an energetic function under the conditions of the existence of unicellular organisms [9-12]. The same atoms laid the foundation for nitric oxide (NO), superoxide radical anion (^•O₂^-), carbon monoxide (CO), as well as hydrogen sulfide (H₂S), sulfur dioxide (SO₂) and polysulfides (H₂S_n), which began to function as intracellular mediators [13-37].

After the emergence of multicellular organisms, compounds ^•O₂^-/O₂, NO₃^-/NO₂^-, SO₄^-/SO₃^-, CO₂/CO, which were previously formed during respiration, were used as electron acceptors, or in intracellular signaling systems, were adapted for intercellular signaling. However, these processes and phenomena were unknown in science in the second half of the XX century. Before the discovery of these compounds in living organisms, the discovery of their endogenous production, these molecules were known as toxic substances. Therefore, we can say with good reason that the problem of gaseous intermediaries (gas transmitters) has become a new problem in the 21^st century. It is in recent decades that scientists have come to realize the specific role of gas transmitters that perform a signaling function in cells [15-20]. These substances have been assigned to a new class of biologically active substances.

Chemical Nature of Gas Mediators / Transmitters

Gas transmitters are small molecules that easily cross biological membranes and do not act through special receptors [41- 47]. These compounds are synthesized in the body using special enzymes and are labile (their half-life is measured in seconds). They do not accumulate in cells and subcellular structures, since they cannot be enclosed in vesicles, like neurotransmitters [43-51]. Sometimes they can be bound by metals of proteins and enzymes, as well as SH-groups that are part of amino acids, bio phenols, for example, tyrosine and its derivatives, free or part of proteins, etc. Gas transmitters have endocrine, paracrine, autocrine, and intracrine effects [52-54].

Cyclic Organization of Gas Transmitters: Cycles of Nitric Oxide (NO), Superoxide Anion-Radical (^•O₂^-) and Hydrogen Sulfur/Sulfur Dioxide (H₂S/SO₂) In Mammals

Over the past decades, we have suggested that the cyclical organization ^•NO and ^•O₂^- in cells and in the whole organism may be a consequence of the existence of such a principle, the universality (or globality) of which is comparable to the principle of the atomic structure of matter [7,8,55]. This principle extends its influence to almost all structural and functional levels in animate and inanimate nature, subordinates the behavior of living subjects and inanimate objects, and, sets the rules for the functioning of all regulatory systems that contain elements of negative and positive feedback. Moreover, this principle explains the nature of positive and negative feedbacks in living organisms and nonliving systems. It also answers the question of why development is carried out in a spiral, and why spirals are one of the main structural elements in DNA, proteins, in nerve fibers (myelin sheaths), glial cells (glial wraps in the central nervous system), etc. This principle also explains the nature of the cyclical / periodic pattern in the functioning of regulatory systems at almost all structural and functional levels in living organisms [7,8,55-69]. In addition, this principle and the consequences arising from it are in good agreement with other concepts and theories of Russian and foreign scientists. Suffice it to recall L.A. Orbeli, who, analyzing physiological processes, noted: we have little regard for the fact that all processes are carried out cyclically, and each process has its own cyclicity. The position of R. Virchow is well known: “It is not life in abnormal conditions, not a violation as such that causes the disease. On the contrary, the disease begins with a failure of the regulatory apparatus.”

Thus, studying very specific substances (nitrates / nitrites and nitrogen oxides) [13], we came to the cyclic organization of their functioning [56-70], then found the same cyclic organization in the systems of other gas transmitters, analyzed the functioning of these compounds in health and development pathological processes [22,72]. These concepts, developed both for gas transmitters and for other processes and phenomena of animate and inanimate nature, are fundamentally new. They do not repeat other developments of foreign and Russian scientists. At the same time, they are in good agreement with practically all other known experimental data and theoretical constructions. Let’s give one more example. French mathematician, physicist and philosopher Henri Poincaré (1854-1912) created a new branch of mathematics - the qualitative theory of differential equations (1881–1882). He showed the existence of a huge class of phenomena that obey periodic laws. He also answered the question of how, without solving equations, one can obtain important information about the behavior of a family of solutions. “Any generalization,” according to Poincaré, “to a certain extent presupposes belief in the unity and simplicity of nature. As far as unity is concerned, scientists usually do not encounter any difficulties. The question is, how is nature one? “How is nature united?” (A. Poincaré).

From our point of view, the atomic principle of the structure of matter, as well as the principle of cyclicity and the holographic principle proposed and substantiated as a global principle, answer the question of A. Poincaré: how is nature united? Let us recall that the holographic principle got its name from the Greek word holos – all, complete and grapho - I write, I draw. The result is: the optical equivalent of the object, the ideas of which were formulated by the Hungarian physicist Denis (Denesh) Gabor (1900-1979) in 1948 with the improvement of the electron microscope [56-60]. A. Poincaré realized that behind the numerous periodic processes that he described and analyzed using a system of differential equations, there are global laws. However, he could not know about the existence of the principles of cyclicity and the principle of holography. There, after posing the question and formulating the problem, A. Poincaré left its solution to future generations of researchers. The principle of cyclicity in combination with the holographic principle means that cyclic properties (or properties of a spiral in space, and periodicity in time) should be repeated at all structural and functional levels. In the same way, like the atomic principle of the structure of matter, it should also manifest itself at all structural and functional levels, because these principles are universal or global. Thus, the above three principles: the atomic principle of the structure of matter, the principle of cyclicity and the holographic principle, structure and combine the phenomena of animate and inanimate nature. It is these three principles, from our point of view, that make nature one, including inorganic compounds and organic substances into a single system. The cyclic organization of gas transmitters in mammals is one of the manifestations of this unity. To say that this is philosophy and not biochemistry, biophysics or physiology, from our point of view, is inappropriate. Good, deep and concrete science always has a direct connection with the philosophy of natural science. In the same way, like the philosophy of natural science, finds its embodiment and manifestation in specific sciences. Scientists from different countries have always strived to achieve the unity of the philosophy of natural science and specific sciences. Deep concrete science always has a direct connection with the philosophy of natural science.

Cycles of Nitrogen Oxide (NO), Superoxide Anion-Radical (^•O₂^-) and Hydrogen Sulfur / Sulfur Dioxide (H₂S/SO₂)

The concept of the nitric oxide cycle (Figure 1a) was substantiated more than 25 years ago [57-69]. Its substantiation became possible due to the detection of nitrite reductase activity of heme-containing proteins in mammals [70]. After 20 years, the nitrite reductase activity of hemoglobin in the deoxy-form was confirmed in the works of researchers from the United States [71]. Subsequently, this concept has repeatedly found its development and application for various normal and pathological processes [29,37-52,72]. The essence of this concept is that NO₂^-, ions formed from L-arginine can again, with the participation of nitrite reductase systems, including Hb, Mb, cyt a + a₃ and cyt P-450, close the chain: in to L-arginine → NO → NO₂^-/NO₃^- into cycle. Oxygen, binding with heme, inhibits the nitrite reductase activity of these proteins [70]. Thus, at various functional states associated with insufficient oxygen supply to the body, the nitrite reductase component of the nitric oxide cycle will be activated (Figure 1a) [56-61]. However, such activation can be observed until the depletion of L-arginine occurs [66], which is included in the Krebs cycle at the level α-ketoglutarate complex and serves as one of the sources of formation of succinate (or succinic acid). During relatively prolonged hypoxia / ischemia, as is known, succinate is actively used as an oxidation substrate for the formation of ATP and membrane potential in mitochondria. Therefore, researchers can sometimes observe a decrease in NO formation during prolonged experimental hypoxia / ischemia.

Cycle of Superoxide Anion-Radical

Analysis of the literature data and the results of our own research allowed us to put forward a hypothesis that, in addition to the nitric oxide cycle, there should also be a cycle of superoxide anion radical (Figure 1b) [59]. Oscillations in the concentrations of reactive oxygen species in biological systems, obtained by a number of authors, testified in favor of the existence of such a cycle. Since all cyclic processes always involve periodic oscillations, one could expect that the previously considered reaction products associated with the neutral O₂ molecule and its active forms - superoxide, peroxide, as well as enzymes for activating molecular oxygen (Fe²⁺ and Сu²⁺ -containing proteins), superoxide dismutase and catalase can be closed in a cycle. The analysis of numerous literature data allowed us to propose a scheme for the cyclic organization of reactive oxygen species, which we called the superoxide anion radical cycle (Figure 1b) [59].

Hydrogen Sulfur / Sulfur Dioxide Cycle (H₂S / SO₂)

The initial substrate for the synthesis of all three mediators (H₂S/H₂S_n/SO₂) (Fig.2) is sulfur-containing amino acids, primarily L-cysteine. Polysulfides are formed from hydrogen sulfide (H₂S), and sulfur dioxide (SO₂) is sulfite anhydride (sulfurous acid), which is formed during the oxidation of Н₂S. The end product of the oxidation (degradation) of Н₂S, like the oxidation of sulfur dioxide, is sulfate, which is excreted in the urine. It is known that the intestinal microflora synthesizes hydrogen sulfide from sulfate, reducing it. It is characteristic that an enzyme that oxidizes Н₂S in mitochondria in animals, sulfide quinone oxidoreductase, SQR, was also found in plants and bacteria [73]. The reduction of sulfate (SO₄) to Н₂S is possible in mammals with the participation of intestinal microflora. Thus, the cycle of hydrogen sulfide in the whole body of mammals exists (Figure 2). Our assumption about the reduction of SO₄ to Н₂S in mammalian cells is hypothetical. If such a reaction occurs, then we can say that the hydrogen sulfide cycle exists not only in the whole organism of mammals, but also in their cells. The cycles presented above are, from our point of view, a manifestation of the global principle of cyclicity [56,58,60]. At the same time, the geochemical cycles of nitrogen, carbon, sulfur and water are known as the natural cycles. Together with the cycles we are analyzing, they are a manifestation of the principle of holography, when the cyclic properties of the general are manifested in the cyclic properties and regularities of the particular, which lies at other structural and functional levels of animate and inanimate nature. Thus, through these three principles, the philosophy of natural science manifests itself in specific sciences.

Is There A Cycle of Carbon Oxide (CO)?

This question remains open. However, based on the fact that along with other cycles in nature - nitrogen, sulfur, etc. (circulation of substances in nature), and the presence of the principle of holography in addition to the principle of cyclicity [56,60], it can be expected that in the future the carbon monoxide (CO) cycle will take its rightful place among other fundamental cyclic processes.

Conclusion

For several centuries, scientists and doctors have tried to identify specific changes in cells, subcellular structures and membranes in each pathological process and disease. However, it turned out that in many pathological processes, first of all, universal nonspecific changes in cells, plasma membranes and membranes of subcellular structures are observed. This made it possible to speak about the existence of typical nonspecific disorders of various cellular and subcellular structures. The concept we are developing about the cyclical organization of gas transmitters (NO, ^•O₂^-, H₂S/SO₂) in the norm and its violation during the development of pathological processes makes it possible to understand the mechanisms of development of a typical pathological process, which is the common denominator of almost all pathological processes. For at least half a century, almost all scientists, including physicists, chemists and biologists working in the field of free radical processes in biology and medicine, have been trying to solve the riddle: how living systems provide regulation and stabilization of reactive oxygen, nitrogen, and also other free radicals. Our proposed concept for the cyclic organization of gas transmitters (NO, ^•O₂^- and H₂S/SO₂) may be one of the answers to the question posed more than half a century ago. In addition, the principles of cyclicity, the holographic principle, together with the principle of the atomic structure of matter, can give an answer to the question of A. Poincaré: “how is nature united?”

Acknowledgement

This work was supported by the Russian Academy of Sciences and partially by grants from the Russian Science Foundation 17-15-01487 and RFBR 17-00-00106.

References

1. Ceccarelli C, Favre C, López-Sepulcre A, Fontani F (2019) Hydrogen molecular ions and the violent birth of the Solar System. Philos. Trans A Math. Phys. Eng. Sci. 377: 20180403.
2. Darnley MJ, Hounsell R, O'Brien TJ, Henze M, Rodriguez-Gil P (2019) A Recurrent Nova Super-Remnant in the Andromeda Galaxy. Nature 565: 460-463.
3. Francl M (2016) A brief history of water. Nat Chem 8: 897-898.
4. Taverne YJ, Merkus D, Bogers AJ, Halliwell B, Duncker DJ (2018) Reactive Oxygen Species: Radical Factors in the Evolution of Animal Life: A molecular timescale from Earth's earliest history to the rise of complex life. 40 (3).
5. Lyons TW, Reinhard CT, Planavsky NJ (2014) The rise of oxygen in Earth's early ocean and atmosphere. Nature 506: 307-315.
6. Stanley SM (2016) Estimates of the magnitudes of major marine mass extinctions in earth history. Proc Natl Acad Sci 113: E6325-E6334.
7. Reutov VP (1999) Biochemical predetermination of the NO-synthase and nitrite reductase components of the nitric oxide cycle. Biochemistry 64: 634-651.
8. Reutov VP, Shekhter AN (2010) How in the 20^th century physicists, chemists and biologists answered the question: what is life? Physics–Uspekhi. 53:4., 377-396.
9. Broda E Evolution of bioenergetic processes. M Peace 303 .
10. Margelis L (1983) The role of symbiosis in cell evolution. M Mir 351 .
11. Fox R (1992) Energy and evolution of life on Earth. M Mir 216 .
12. Thomazo C, Couradeau E, Garcia-Pichel F (2018) Possible nitrogen fertilization of the early Earth Ocean by microbial continental ecosystems. Nat Commun 9: 2530.
13. Reutov VP, Sorokina EG, Pinelis VG (1994) Are nitrite ions involved in the regulation of intra- and intercellular signaling systems?. Vopr med chemistry 40: 27-30.
14. Lundberg JO, Gladwin MT, Ahluwalia A, et al. Nitrate and nitrite in biology, nutrition and therapeutics. Nat Chem Biol 5: 865-869.
15. Verma A, Hirsch DJ, Glatt CE, et al. (1993) Carbon monoxide: a putative neural messenger. Science 259: 381-384.
16. Kimura H (2014) Hydrogen sulfide and polysulfides as biological mediators. Molecules 19: 16146-16157.
17. Kimura H (2015) Hydrogen sulfide and polysulfides as signaling molecules. Proc Jpn Acad Ser B Phys Biol Sci 91: 131-159.
18. Kimura H, Mikami Y, Osumi K, Tsugane M, Oka JI, et al. (2013) Polysulfides are possible H₂S-derived signaling molecules in rat brain. FASEB J 27: 2451-2457.
19. Strutinskaya NA, Dorofeeva NO, Vavilova GL, Sagach VF (2013) Hydrogen sulfide inhibits calcium-induced mitochondrial pore opening in the heart of rats with spontaneous hypertension. Fiziol zhurn (Kiev) 59: 3-10.
20. Sukmansky OI, Sukmansky IO (2014) Gas transmitters – a new type of bioregulators. Zhurn NAMS of Ukraine 20: 153-159.
21. Abe K, Kimura H (1996) The possible role of hydrogen sulfide as an endogenous neuromodulator. J Neurosci 16: 1066-1071.
22. Azhipa Ya I, Reutov VP, Kayushin LP (1993) Ecological and medico-biological aspects of environmental pollution by nitrates and nitrites. Human Fiziology 16: 220.
23. Deng J, Lei C, Chen Y, Fang Z, Yang Q, et al. (2014) Neuroprotective gases – fantasy or reality for clinical use?. Prog Neurobiol 115: 210-245.
24. Du SX, Jin HF, Bu DF, Zhao X, Geng B, et al. (2008) Endogenously generated sulfur dioxide and its vasorelaxant effect in rats. Acta Pharmacol Sin 29: 923-930.
25. Gainullina DK, Kiryukhina OO, Tarasova OS (2013) Nitric oxide in vascular endothelium: regulation of production and mechanisms of action. Advances in physiological sciences 44: 88-102.
26. Gerasimova EV, Sitdikova GF, Zefirov AL (2008) Hydrogen sulfide as an endogenous modulator of mediator release in the neuromuscular synapse of the frog. Neurochemistry 25: 138-145.
27. Gurin AV (1997) The functional role of nitric oxide in the central nervous system. Advances in physiological sciences 28: 53-60.
28. Gusakova SV, Kovalev IV, Smagliy LV, Birulina YG Nosarevi AV, et al. (2015) Gas signaling in mammalian cells. Advances in physiological sciences. 46: 53-73.
29. Zenkov NK, Menshchikova EB, Reutov VP (2000) NO-synthases in health and disease of various genesis. Bull of the Russ Acad of Med Sci 4: 30-34.
30. Zinchuk VV, Glutkina NV (2013) Oxygen-binding properties of hemoglobin and nitric oxide. Sechenov IM Ross Fiziol Zhurn 99: 537-554.
31. Kolesnikov SI, Vlasov B Ya, Kolesnikova LI (2015) Hydrogen sulfide as the third essential gas molecule of living tissues. Vestn of the Russ Acad of Med Sci 2: 237-241.
32. Kondakova IV, Zagrebelnaya GV, Reutov VP (2003) Influence of peroxide radicals and nitric oxide on the proliferating activity of tumor cells. Bull of the National Acad of Sci of Belarus Life Sciences Series : 78-82.
33. Kositsyn NS, Reutov VP, Svinov MM, et al. (1998) The mechanism of morpho-functional changes in mammalian tissue cells during hypoxia. Mol biol 32: 369-370.
34. Koshelev VB, Krushinsky AL, Kuzenkov VS, Reutov VP (2004) Decrease of the protective effect from pressure chamber adaptation to hypoxia in K–M rats under the influence of NO-synthase inhibitor. Novosti Mediko-Biol Sci 1: 41-43.
35. Sitdikova GF, Zefirov AL (2010) Hydrogen sulfide: from the sewers of Paris to the signaling molecule. Priroda : 29-37.
36. Sukmansky OI, Reutov VP (2016) Gas transmitters: physiological role and participation in the pathogenesis of diseases. Advances in physiological sciences 47: 30-58.
37. Gusakova SV, Smagliy LV, Birulina Yu G, Kovalev IV, Nosarev V, et al. (2017) Molecular mechanisms of action of NO, CO and H₂S gas transmitters in smooth muscle cells and the effect of NO-generating compounds (nitrates and nitrites) on average life expectancy. Uspekhi Fiziologicheskikh Nauk 48: 24-52.
38. Fadyukova OE, Kuzenkov VS, Reutov VP, Krushinskiĭ AL, Buravkov SV, et al. (2005) Antistress and angioprotective effects of nitric oxide on Krushinsky-Molodkina rats genetically predisposed to audiogenic epilepsy. Sechenov IM Russian Journal of Physiology 90: 89-96.
39. D'yakonova T, Reutov V (2009) Sodium nitrite causes hyperactivation of identified snail neurons. Nitric Oxide 20: S32-S33.
40. Diyakonova TL, Reutov VP (1998) Effect of nitrite on the excitability of brain neurons in helix. Sechenov IM Russian Journal of Physiology 84: 1264-1272.
41. Dyakonova TL, Reutov VP (1994) Nitrites block Ca²⁺-dependent addiction of neurons at the level of the electroexcitable membrane: a possible role of nitric oxide. Vopr. of Med. Chem. 40: 20-25.
42. D'yakonova T, Reutov V (2000) The effects of nitrite on the excitability of brain neurons in the common snail. Neuroscience and Behavioral Physiology 30: 179-186.
43. Larionova NP, Reutov VP, Samosudova NV, Chailakhyan LM (2003) Comparative analysis of the plasticity of neuro-neuronal and neuro-glial encapsulating interactions of the molecular layer of the isolated frog cerebellum under conditions of excess L-glutamate and NO-generating compound. Dokl Rus Akad Nauk 393: 698-702.
44. Samosudova NV, Reutov VP, Larionova NP (2010) The role of glycogen in the processes of glial cells of the cerebellum under conditions of its damage by sodium nitrite. Byull Expim Biol and Medicine 150: 212-215.
45. Larionova NP, Reutov VP, Samosudova NV, Chailakhyan LM (2010) Neuroglial chemical synapse in the cerebellum of an adult frog. Doklady Biological Sciences of the Russian Academy of Sciences 432: 276-280.
46. Larionova NP, Reutov VP, Samosudova NV, Chailakhyan LM (2003) Comparative analysis of plasticity of neuron-neuronal and neuron-glial encapsulating interactions of molecular layer of isolated frog cerebellum exposed to excess L-glutamate and NO-generating compound. Doklady Biological Sciences of the Russian Academjy of Sciences. 393: 515-519.
47. Larionova NP, Reutov VP, Samosudova NV, Chailakhyan LM (2010) Neuroglial chemical synapses in the cerebellum of adult frog. Doklady Biological Sciences of the Russian Academjy of Sciences. 432: 171-175.
48. Zefirov AL, Petrov AM (2010) Synaptic vesicle and neurotransmitter release mechanism. Kazan: Art Cafe : 323.
49. Samosudova NV, Reutov VP, Larionova NP (2008) Changes in the ultrastructure of synaptic vesicles of glutamatergic synapses under the influence of the NO-generating compound NaNO₂. Bul Experim Biol and Med 1461: 13-17.
50. Samosudova NV, Reutov VP (2016) Plastic Rearrangements of Synapse Ultrastructure in the Cerebellum in Toxicity due to glutamate and NO-Generating Compounds. Neuroscience and Behavioral Physiology 46: 843-848.
51. Samosudova NV, Reutov VP (2018) Ultrastructural changes in the frog brain in the presence of high concentrations of glutamate and NO-generating compounds. Biophysics 63: 528-543.
52. Streeter E, Ng HH, Hart JL (2013) Hydrogen sulfide as a vasculoprotective factor. Med Gas Res 3: 9.
53. Okhotin VE, Kalinichenko SG, Dudina Yu V (2002) NO-ergic transmission and NO as a volumetric neurotransmitter. Influence of NO on the mechanisms of synaptic plasticity and epileptogenesis. Uspekhi Fiziologicheskikh Nauk 33: 41-55.
54. Pinelis VG, Sorokina EG, Reutov VP, et.al. (1997) The influence of the toxic effects of glutamate and nitrite on the content of cyclic GMP in neurons and their survival. Doklady Biological Sciences of the Russian Academjy of Sciences 352: 259-261.
55. Menshchikova EB, Zenkov NK, Reutov VP (2000) Nitric oxide and NO synthase in mammals under various functional states. Biochemistry 65: 485-503.
56. Reutov VP, Sorokina EG, Kositsyn NS, Okhotin VE (2003) The problem of nitric oxide in biology and medicine and the principle of cyclicity. MURSS 94 .
57. Reutov VP (1995) The nitric oxide cycle in mammals. Uspekhi Biol Chem 35: 189-228.
58. Reutov VP (1999) Biochemical predetermination of the NO-synthase and nitrite reductase components of the nitric oxide cycle. Biochemistry 64: 634-651.
59. Reutov VP (2000) Biomedical aspects of the cycles of nitric oxide and superoxide anion radical. Vestn RAMS 35-41.
60. Reutov VP (2002) The nitric oxide cycle in mammals and the principle of cyclicity. Biochemistry 67: 353-376.
61. Reutov VP, Kayushin LP, Sorokina EG (1994) Physiological role of the nitric oxide cycle in humans and animals. Human Physiology 20: 165-174.
62. Reutov VP, Kayushin LP, Sorokina EG (1994) The nitric oxide cycle as an adaptation mechanism in the body's hypoxia. Uspekhi Fiziologicheskikh Nauk 25: 36.
63. Reutov VP, Kositsyn NS, Svinov MM, et al. (1998) Activation of the nitric oxide cycle during hypoxia induces the redistribution of proteins in mammalian tissue cells from a soluble to a membrane-bound state. Mol biol 32: 378-379.
64. Reutov VP, Sorokina EG (1998) NO-synthase and nitrite reductase components of the nitric oxide cycle. Biochemistry 63: 1029-1040.
65. Reutov VP, Sorokina EG (1998) The nitric oxide cycle is a new metabolic cycle involved in the regulation of intracellular signaling. Mol biol 32: 377-378.
66. Reutov VP, Sorokina EG, Okhotin VE, Kositsyn NS (1978) Cyclic transformations of nitric oxide in mammals. M Science 156.
67. Reutov VP, Sorokina EG, Gozhenko AI, et al. (2008) The nitric oxide cycle as a mechanism for stabilizing the content of NO and its conversion products in mammals. Actual problems of transport medicine 11: 22-28.
68. Reutov VP, Sorokina EG, Kayushin LP (1994) Nitric oxide cycle in mammals and nitrite reductase activity of heme-containing proteins. Vopr Med Chem 40: 31-35.
69. Reutov VP, Sorokina EG, Kositsyn NS (2005) Problems of nitric oxide and cyclicity in biology and medicine. Uspekhi Sovrem Biol 125: 41-65.
70. Reutov VP, Azhipa Ya I, Kayushin LP (1983) Oxygen as an inhibitor of hemoglobin nitrite reductase activity. Izv Acad of Sci of the USSR Ser biol 3: 408-418.
71. Cosby K, Partovi KS, Crawford JH, Patil RP, Reiter CD, et al. (2003) Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med 9: 1498-1505.
72. Reutov VP, Samosudova NV, Sorokina EG (2019) Model of glutamate neurotoxicity and mechanisms of development of a typical pathological process. Biophysics 64: 316-336.
73. Kabil O, Banerjee R (2014) Enzymology of H₂S biogenesis, decay and signaling. Antioxid Redox Signal 20: 770-782.