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Recommended for publication by the Academic Council State Institution
"Horbachevskyi National Medical University"
(Protocol No. 3 of March 27, 2024)
DEDICATED TO IVAN YAKOVYCH HORBACHEVSKYI
IVAN YAKOVYCH HORBACHEVSKY - A PIONEER IN THE SYNTHESIS OF URIC ACID IN VITRO
Academician Ivan Gorbachevsky left behind a considerable legacy in the world of science, consisting of numerous scientific works that have retained their value, continue to inspire, and awe biochemists. His passion for knowledge and the pursuit of truth were evident even during his school years when he attended Ternopil Gymnasium. His involvement in the secret student group "Hromada" (Community) played a role in this. Members of the group read the works of Taras Shevchenko, Panteleimon Kulish, and Ivan Kotliarevsky, with the goal of awakening national consciousness and exploring the historical past of their people. However, he embarked on his scientific path for the first time while already a student and working as a demonstrator in the Department of Medical Chemistry under Professor Ludwig.
As a 22-year-old student in 1875, he conducted his first independent scientific work, dedicated to the vestibular nerve, and published it in the proceedings of the Vienna Academy of Sciences. This achievement earned him recognition from the university administration and admission to the German scientific society.
Three years later, in the same proceedings of the Vienna Academy of Sciences, his new scientific work appeared, titled "On the Decomposition Products Formed Under the Action of Hydrochloric Acid on Albuminoids." Then, in 1882, another publication followed titled "On the Digestion of Elastin," which he conducted under the influence of the enzyme pepsin. Having obtained amino acids as the final products from albuminoids and elastin, the young assistant Ivan Gorbachevsky came to the entirely logical conclusion that these were the building blocks from which proteins were constructed. Thus, Ivan Gorbachevsky's early scientific works were dedicated to the physiology of digestion. This research direction was quite common among scientists at that time, and it was passed on to the young assistant by Professor Ludwig.
However, by then, Ivan Gorbachevsky was already captivated by the idea of synthesizing organic compounds, especially those found in the human body, the functions of which were unknown. Such substances were considered to be exclusively characteristic of living organisms, and it was believed that they could not be synthesized outside the body.
Gorbachevsky's attention was drawn to a substance discovered in urine in 1776 by the Swedish researcher K. Scheele, which he named uric acid. A bit later, this acid was also found in urinary stones associated with gout attacks.
Many renowned scientists sought to artificially synthesize uric acid. Eminent biochemists like Liebig, Wöhler, Fischer, A. Rosen, and Nensky dedicated themselves to this goal but without success. Nensky even claimed to have synthesized uric acid first. However, fate had a different plan. Gorbachevsky was familiar with the work of the German scientist D. Stecker, who had established that upon heating uric acid with hydrogen iodide, it decomposed into carbon dioxide, ammonia, and the amino acid glycine.
Logical reasoning led him to assume that the ammonia and carbon dioxide obtained by Stecker from the heating of uric acid were the end products of uric acid decomposition, which, obviously, had formed from uric acid itself. This is why the young scientist, Ivan Gorbachevsky, at the Institute of Medical Chemistry at the University of Vienna, used the products of uric acid breakdown, glycine, and urea, for the synthesis of uric acid. Taking a mixture of these two substances in a 1:10 ratio, he heated it to a temperature of 230°C, cooled the melt, and then dissolved it in diluted potassium lye. Subsequently, using a magnesium mixture and a solution of [Ag(NH3)2]OH, silver urate was precipitated. Uric acid was obtained from the alkaline solution upon acidification with hydrochloric acid. Thus, for the first time in the history of world science, in 1882, uric (ureatic) acid was synthesized. This discovery brought great fame and honor to Austrian science, especially the University of Vienna.
The significant attention devoted to the synthesis of uric acid by scientists can be explained not only by the fact that it was first synthesized by a young, relatively unknown worker at the University of Vienna, but also by the fact that many famous scientists around the world had worked unsuccessfully on this issue. Furthermore, during this period, there was a dominant vitalistic approach in biology and medicine, according to which substances characteristic of living organisms could not be artificially obtained outside of them.
Ivan Gorbachevsky's work on the synthesis of uric acid contributed to the advancement of science and our understanding of the biological role and origin of uric acid in the body. This laid the foundation for his future theory on uric acid formation in the human body and other mammals.
After 1882, the entire scientific community began to take notice of Ivan Gorbachevsky. Some were enthusiastic and joyful about his discovery, while others were surprised and skeptical. Skeptics couldn't believe that a young 28-year-old Slavic scientist had achieved what many renowned German and French chemists had failed to do. Not only did this young scientist manage to synthesize a substance that others couldn't using his original method, but he also defended his priority in scientific discussions with opponents. Based on scientific facts and the results of his own research, Ivan Gorbachevsky convincingly proved the correctness of his findings, and most of his opponents agreed with him and became his friends.
Ivan Gorbachevsky's discovery of uric acid synthesis led to his appointment as an associate professor of medical chemistry at Charles University in Prague in 1983, and within a few months, he became a full professor. Here, he developed the foundations and organized the field of medical chemistry, which the university had lacked before his arrival. At the beginning of his professorial career in Prague, he taught not only chemistry but also pharmacology, physiology, and lectured on dietetics and toxicology.
However, the main focus of his scientific work at that time was the study of nitrogen compound metabolism and the synthesis of organic compounds in general.
In 1885, Ivan Gorbachevsky achieved the synthesis of methyluric acid by heating uric acid with methylglyoxal or isopropyl ether of allophanic acid. Then, in 1887, he proposed another method, which involved melting uric acid with chloroacetic acid or trichloroacetic acid or the amide of the latter. All these synthesis methods, pioneered by our compatriot, became classic and engraved Ivan Gorbachevsky's name in golden letters in the annals of world science.
In 1885, Ivan Gorbachevsky also successfully synthesized another crucial nitrogen-containing compound for the body - creatine. He proposed a volumetric method for determining nitrogen in various body fluids, which found application both in experiments and in clinical practice.
In the following years, Professor Gorbachevsky directed his research towards understanding the mechanisms of uric acid formation in mammals' bodies. In 1889, while studying this question, he discovered the enzyme xanthine oxidase, which plays a role in the oxidation of the purine compound xanthine into uric acid. By 1890, Gorbachevsky published a paper in a German chemistry journal on the origin of uric acid in mammals' bodies.
The following year, he became the first among biochemists to establish a connection between the transformation of xanthine bases, produced during nucleic acid breakdown, and the biosynthesis of uric acid. Through experiments with mammalian leukocytes, our scientist demonstrated that uric acid is formed from nuclear components of cells. His systematic studies on uric acid synthesis, the establishment of its chemical structure, and experiments on mammals' transformations of purine bases allowed him to propose the world's first theory of uric acid formation in the body. This groundbreaking theory was presented in 1891 in Wiesbaden when Ivan Gorbachevsky delivered his report on "The Theory of Uric Acid Formation." This theory, based on all his previous research, logically reflected the concept of nucleic acid transformations.
The theory of uric acid formation in the body has not lost its significance to this day. Contemporary views on uric acid biosynthesis have only been slightly supplemented with new data regarding the influence of various exogenous and endogenous factors on uric acid biosynthesis and its content in body tissues. The direction initiated by Gorbachevsky continues to flourish in many scientific schools worldwide, especially in the study of nucleic acid metabolism disorders.
It can be confidently stated, echoing the French scientist Coste (1953), that the works of Academician Ivan Horbachevsky on the artificial synthesis of uric acid and the investigation of its biosynthesis in the organism remain unrivaled and significant to this day.
Between 1891 and 1893, Ivan Horbachevsky published works that demonstrated that the formation of uric acid and its content in the organism significantly depend on a person's clinical condition, nutritional factors, the type of food products consumed, and more.
It's worth noting that while developing the theory of uric acid formation, Professor Horbachevsky simultaneously developed a methodology for isolating nucleic acids from organ tissues. His work on this topic was published in 1898 in a paper titled "A General Method for Extracting Nucleic Acid from Organs" ("Lіkarskiy zbіrnyk NTSh," 1898, Vol. 1, pp. 1-4). Modern methods for extracting nucleic acids are essentially slight modifications of the approach proposed by our compatriot.
Ivan Horbachevsky, who consistently worked in the field of natural sciences, also took an interest in the life of his fellow countrymen, particularly the economic condition of peasants. He collected materials on topics related to the physiology, hygiene, and nutrition of the population. This represented a new scientific direction in the field of medical and biological research. The results of his research in this area were published in an article titled "Contributions to the Knowledge of the Rural Population of Galician Podillya," which was published in "Lіkarskiy zbіrnik NTSh" in 1899, Vol. 2, Issue 2, page 1.
Professor Ivan Horbachevsky's recognized authority in the scientific world is evident from his election as Vice President of the International Medical Congress, held in Paris from August 2 to 9, 1900, where he also served as the President of the Chemical Section. During the congress, Ivan Horbachevsky led the Ukrainian delegation.
In the same year, he presided over the Biological Section at the 3rd Congress of Czech Naturalists and Physicians in Prague. At this event, he presented a paper titled "On the Formation of Fat in the Animal Organism." Additionally, another one of his methodologies for detecting blood pigment for forensic medical purposes was published in the congress proceedings.
Much of Ivan Horbachevsky's time was occupied by his work on the Regional Sanitary Council, aimed at improving the environment and reducing the negative health impact of industrial waste on people's health. As the outbreak of World War I approached, his scientific work did not slow down despite his extensive commitments to teaching and public affairs.
During this period, he conducted interesting and original research on the issue of pellagra. In 1911, he published a series of works on this topic, including "Experimental Approaches to the Etiology of Pellagra." Based on observations of the diets of pellagra patients, he concluded that the cause of this disease was the inadequacy of nutrition, primarily from plant-based foods, particularly corn products, which seemed to lack certain vitamins, similar to the known vitamins A, B, C, and D. Horbachevsky's hypothesis was later confirmed with the discovery of vitamin "PP" as the anti-pellagra factor.
The following year marked the publication of another work in the journal of Czech physicians titled "On Poisoning with Alcohol - Denatured Methyl Alcohol," in which he described the effects of alcohol on the organism. He also published a paper in the same journal in 1916 titled "On Lead Poisoning When Using Galvanized Iron Water Pipes," addressing toxicological issues.
Ivan Horbachevsky's research had a significant impact on the population of Prague. His work on sanitary standards for drinking water led to the construction of a water supply system from the clean Izera River instead of the polluted Vltava River. This led to a significant reduction in typhoid fever cases. However, later investigations revealed that the use of galvanized water pipes did not pose such a significant risk of poisoning, and Horbachevsky conducted further research and recommendations to minimize or eliminate the illness.
Professor Ivan Horbachevsky's research and contributions reflected his keen awareness of the social needs of the population, particularly issues related to malnutrition and food quality. His research papers, such as "Experimental Studies on the Nutritional Value of Lichens" (1917), exemplify this commitment. Unfortunately, this research direction did not receive further development due to his appointment as Minister of Health, which demanded a great deal of his daily work. Nevertheless, his scientific approach to finding new methods and sources of nutritious human food, initiated by Prof. Horbachevsky, continues to be relevant today, as a significant portion of the global population still lacks adequate nutrition, especially in terms of protein-rich food. Ivan Horbachevsky's genius was directed towards addressing this problem as early as 1917.
With the dissolution of the Austro-Hungarian Empire, Horbachevsky became an active participant in the formation of the Western Ukrainian People's Republic (ZUNR). He developed a healthcare program for the ZUNR, organized the opening of the Ukrainian Free University in Vienna and Prague, and served as its rector in 1923-1924 and 1931-1935. In 1924, he published the first Ukrainian university textbook on "Organic Chemistry" in Prague and worked extensively on Ukrainian scientific chemical terminology.
As a renowned scientist, Ivan Horbachevsky was elected as an academician of the All-Ukrainian Academy of Sciences (VUAN) in 1925. In Prague, he founded and chaired the administration of the "Museum of the Liberation Struggle of Ukraine" society. He prepared numerous medical professionals and scientists for service in Ukraine. He also organized and chaired the First and Second Ukrainian Congresses in Prague in 1926 and 1932.
With the declaration of independence of the Carpatho-Ukrainian State in 1939, Horbachevsky organized a committee for the defense of Carpathian Ukraine in Czechoslovakia.
For many years, Horbachevsky was a professor of organic chemistry at the Ukrainian Free University in Prague and served as its rector for several years. His scientific legacy comprises more than 50 publications in German, Czech, and Ukrainian languages.
Professor Ivan Horbachevsky made a significant contribution to the development of Ukrainian scientific chemical terminology, which was of great importance for Ukrainian science and culture. He dedicated much time and effort to establishing and popularizing Ukrainian terminology in the field of chemistry.
In the first Ukrainian textbook on organic chemistry published in 1924, Ivan Horbachevsky expanded and explained his approach to introducing Ukrainian chemical terminology. He aimed to make it accessible and understandable for students and scientists by combining Ukrainian and international terms.
Notably, in 1927-1928, Ivan Horbachevsky chaired the Chemical Commission for Nomenclature at the Ukrainian Economic Academy in Poděbrady. This commission developed the principles of Ukrainian chemical terminology, which were published in the "Protocol" dated January 4, 1928. Prominent chemistry professors were among its members.
His final work on the subject, "The Current State of Ukrainian Nomenclature of Inorganic Chemistry," like his previous efforts, was used and implemented by scientists in Ukraine. In preparing textbooks in the Ukrainian language, he extensively studied folk chemical terminology and compared it with international and other Slavic chemical nomenclatures.
In 1903, Professor Ivan Horbachevsky published an article titled „Remarks on Chemical Terminology” in the collection of the Shevchenko Scientific Society (NTSh). This article marked the beginning of Ukrainian chemical nomenclature, which was essential for him in writing chemistry textbooks.
According to Professor Ivan Horbachevsky, the nomenclature he proposed for the main types of chemical compounds, based on a combination of Ukrainian folk terminology and international systems, is exceptionally straightforward, logical, and poses no difficulties in its understanding and adoption. He was deeply convinced that over time, in line with the progress of science and language, chemical nomenclature would continue to evolve and adapt.
Professor Ivan Horbachevsky's proposed nomenclature for organic (1924-1926) and inorganic (1939-1941) compounds formed the basis for the classification and nomenclature of chemical substances, which were developed and implemented in Ukraine before the Second World War.
Throughout his long life, Ivan Horbachevsky initiated and advanced numerous new scientific disciplines. His genius spanned fields such as inorganic, organic, and biological chemistry, hygiene, forensic medicine, and toxicology. In the field of biochemistry, he made significant contributions by researching protein structure and digestion, vitamins, purine metabolism, the structure and isolation of nucleic acids, dietary hygiene, and the search for new nutritious food products.
Equally important for the advancement of science was his establishment of a scientific school that continued his work. Among his most prominent students in Czechoslovakia were academician, professor, and medical doctor Emanuel Formanek (1869-1922), who essentially succeeded Ivan Horbachevsky as the head of the chemistry department at Charles University in 1918. Other notable students included Professor Karel Cherni (1871-1921), Professor Doctor Antonin Gamzik, Professor Doctor Richter, Professor Doctor Karel Kacel, Professor Doctor Jan Shula, Doctor Kukula, Professor Doctor Mlodajowski, Professor Nadislav Gashkoveci, Professor Doctor Sillaba, Professor Doctor Emil Schwagr, and others.
The name of Ivan Horbachevsky is indeed well-known in the scientific world and is engraved with golden letters in the annals of global science. The portrait of Rector Ivan Horbachevsky, along with portraits of other rectors, adorns the walls of the central hall of the main building of Charles University, where solemn meetings of the university's academic council take place. A bust of Academician, Professor, and Doctor Ivan Horbachevsky, created by the renowned Ukrainian sculptor M. Brynsky, stands among the busts of academicians in the Czech Academy of Sciences building in Prague. Ivan Horbachevsky's name has been resurrected from Soviet oblivion and is held in great esteem in his homeland. Ivan Horbachevsky continues to work for Ukraine and its independence to this day. |
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Annotation
In an experiment on healthy rats, a wide range of parameters of uric acid exchange was revealed, and it was shown for the first time that 34 immune parameters out of 41 registered were significantly correlated with them. Uricosuria (to a greater extent) and uricemia (to a lesser extent), taken together, determine the state of immunity by 71%. Uric acid stimulates the phagocytosis of Staph. aureus by neutrophils (but not monocytes) of the blood, increases the relative content of lymphocytes in general and B-lymphocytes in particular in the blood, T-lymphocytes and macrophages in the thymus and fibroblasts in the spleen, and also increases the entropy of the blood immunocytogram. On the other hand, uric acid reduces the entropy of the blood leukocytogram, the total content of leukocytes in the blood and the relative content of monocytes and rod-shaped neutrophils in the leukocytogram, natural killers in the immunocytogram, as well as the entropy of the thymocytogram and the content of epitheliocytes and reticulocytes in it.
It was shown that among the neuro-endocrine factors of adaptation, uricosuria and uricemia are negatively correlated with HRV-markers of sympathetic tone and circulating catecholamines, the plasma level of corticosterone and the thickness of the fascicular zone of the adrenal cortex, as well as the plasma level of triiodothyronine and the Ca-P marker calcitonin activity, on the other hand, and positively correlated with HRV-marker of vagal tone and urinary excretion of 17-ketosteroids. The rate of determination of neuro-endocrine adaptation factors by uric acid is 62%. The cumulative determining influence of parameters of uric acid exchange (due to the significant advantage of uricosuria over uricemia) on the constellation of metabolic parameters is 56%. Diuresis and excretion of phosphates and potassium are subject to the maximum positive determination by uric acid, excretion of calcium, creatinine and urea are determined to a lesser extent, levels of creatinine, urea and potassium in plasma are even less determined, and magnesiumuria is subject to the minimum determination.
In human of both sexes, patients with chronic pyelonephritis in the phase of remission, four variants of uric acid exchange were found too. In 34%, moderate hypouricosuria is combined with lower borderline uricemia. In 24%, moderately increased uricosuria is associated with normal uricemia. In 17%, moderately increased uricosuria is combined with pronounced hypouricemia. Finally, in 25% of patients, subliminal uricemia is accompanied by marked hyperuricosuria.
Among all the registered parameters, 28 were selected as identifying four variants of uric acid metabolism. In addition to uricosuria and uricemia by definition, the discriminant model included 10 neuroendocrine parameters (6 EEG, vagal tone, indices of sympatho-vagal balance of Kerdö and Baevsky, calcitonin), 5 parameters of immunity (activity and completion of phagocytosis by neutrophils of gram-positive bacteria, the level of total lymphocytes and IgG in the blood and IgA in saliva), two informational parameters (Popovych’s strain index of the leukocytogram and the Entropy of the immunocytogram), 6 parameters of metabolism (serum magnesium, potassium, phosphates and creatinine, creatinineuria, body mass index), as well as markers of chronic pyelonephritis (bacteriuria) and microbiota (Bifidobacteria).
According to the results of the canonical correlation analysis, it was established that balneotherapy-induced changes in uricemia downregulate changes in PSD of beta-rhythm in 5 loci and alpha-rhythm in the T5 locus, as well as calcitonin and T-helpers. On the other hand, changes in PSD of delta-rhythm in the T5 locus, the alpha-rhythm in the P4 and P3 loci, serum levels of calcium, magnesium, chloride and sodium, as well as monocytes and CIC are subject to upregulation. The changes in uricosuria downregulate changes in PSD of the alpha-rhythm index and serum levels of testosterone and catecholamines, but upregulate changes in HRV-markers of vagal tone, serum PTH and blood T-helper lymphocytes levels as well as diuresis and excretion of urea, magnesium, phosphates, calcium and potassium. In general, the rate of uric acid determination of the dynamics of the listed parameters of the body is 96%.
Sexual dimorphism in relationships between serum uric acid and some psycho-neuro-endocrine parameters was found in another cohort of subjects.
The obtained results develop and complement the concept that endogenous uric acid has physiological activity, which is manifested in the modulation of the parameters of the neuroendocrine-immune complex and metabolism.
The materials from the monograph have been reflected in the following publications:
1.Popovych IL, Gozhenko AI, Bombushkar IS, Korda MM, Zukow W. Sexual dimorphism in relationships between of uricemia and some psycho-neuro-endocrine parameters. Journal of Education, Health and Sport. 2015; 5(5): 556-581.
2.Gozhenko AI, Smagliy VS, Korda IV, Zukow W, Popovych IL. Cluster analysis of uric acid exchange parameters in female rats. Journal of Education, Health and Sport. 2019; 9(11): 277-286.
3.Gozhenko AI, Smagliy VS, Korda IV, Badiuk NS, Zukow W, Popovych IL. Features of immune status in different states of uric acid metabolism in female rats. Journal of Education, Health and Sport. 2019; 9(12): 167-180.
4.Gozhenko AI, Smagliy VS, Korda IV, Badiuk NS, Zukow W, Popovych IL. Functional relationships between parameters of uric acid exchange and immunity in female rats. Actual problems of transport medicine. 2019; 4(58): 123–131.
5.Smagliy VS, Gozhenko AI, Korda IV, Badiuk NS, Zukow W, Kovbasnyuk MM, Popovych IL. Variants of uric acid metabolism and their immune and microbiota accompaniments in patients with neuroendocrine-immune complex dysfunction. Actual problems of transport medicine. 2020; 1(59): 114–125.
6.Gozhenko AI, Smagliy VS, Korda IV, Badiuk NS, Zukow W, Kovbasnyuk MM, Popovych IL. Relationships between parameters of uric acid exchange and immunity as well as microbiota in patients with neuroendocrine-immune complex dysfunction. Journal of Education, Health and Sport. 2020; 10(1): 165-175.
7.Gozhenko AI, Smagliy VS, Korda IV, Badiuk NS, Zukow W, Kovbasnyuk MM, Popovych IL. Relationships between changes in uric acid parameters metabolism and parameters of immunity and microbiota in patients with neuroendocrine-immune complex dysfunction. Journal of Education, Health and Sport. 2020; 10(2): 212-222.
8.Popovych IL, Bombushkar IS, Badiuk NS, Korda IV, Zukow W, Gozhenko AI. Features of the state of neuro-endocrine factors of adaptation under different options of uric acid metabolism in healthy female rats. Journal of Education, Health and Sport. 2020; 10(3): 352-362.
9.Bombushkar IS, Gozhenko AI, Korda IV, Badiuk NS, Zukow W, Popovych IL. Features of the exchange of electrolytes and nitrogenous metabolites under different options of uric acid exchange in healthy female rats. Journal of Education, Health and Sport. 2020; 10(4): 405-415.
10.Bombushkar IS. Features of the state of the neuroendocrine-immune complex and electrolyte-nitrogenous exchange under different variations of uric acid metabolism in female rats. Journal of Education, Health and Sport. 2020; 10(5): 410-421.
11.Kozyavkina NV, Popovych IL, Popovych DV, Zukow W, Bombushkar IS. Sexual dimorphism in some psycho-neuro-endocrine parameters at human. Journal of Education, Health and Sport. 2021; 11(5): 370-391.
12.Bombushkar IS, Gozhenko AI, Badiuk NS, Smagliy VS, Korda MM, Popovych IL, Blavatska OM. Relationships between uric acid exchange parameters and neuroendocrine adaptation factors [in Ukrainian]. Bulletin of Maritime Medicine. 2022; 2(95): 59-74.
13.Bombushkar IS, Korda MM, Żukow X, Popovych IL. Sexual dimorphism in relationships between of plasma uric acid and some psycho-neuro-endocrine parameters. Journal of Education, Health and Sport. 2022; 12(12): 357-372.
14.Bombushkar IS. Metabolic accompaniments of variants of uric acid exchange. Journal of Education, Health and Sport. 2022; 12(12): 372-390.
15.Gozhenko AI, Korda MM, Smagliy VS, Badiuk NS, Zukow W, Klishch MI, Korda IV, Bombushkar IS, Popovych IL. Uric Acid, Metabolism, Neuro-Endocrine-Immine Complex [in Ukrainian]. Odesa. Feniks; 2023: 229.
16.Bombushkar IS, Popovych IL, Zukow W. Relationships between the parameters of uric acid exchange and electroencephalograms in humans. Journal of Education, Health and Sport. 2023; 13(3): 458-485.
17.Popovych IL, Bombushkar IS, Żukow X, Kovalchuk HY. Uric acid, neuroendocrine-immune complex and metabolism: relationships. Journal of Education, Health and Sport. 2023; 36(1): 135-159. |
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