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В руслі авторських концепцій функціонально-метаболічного континууму і нейроендокринно-імунного комплексу з використанням методів дискримінантного і канонічного кореляційного аналізів продемонстровано, що молекула сечової кислоти проявляє відчутну фізіологічну активність і може вважатися четвертою ендогенною сигнальною молекулою поряд з NO, CO і H2S. Для біохіміків, патофізіологів, ендокринологів, імунологів. The monograph highlights the results of priority experimental and clinical-physiological studies of the relationship between uricemia and uricosuria with the parameters of urea, creatinine and electrolyte metabolism and the neuro-endocrine-immune complex. In line with the author's concepts of the functional-metabolic continuum and the neuroendocrine-immune complex using the methods of discriminant and canonical correlation analyses, it was demonstrated that the uric acid molecule exhibits significant physiological activity and can be considered the fourth endogenous signal molecule along with NO, CO and H2S. For biochemists, pathophysiologists, endocrinologists, immunologists. Аннотація В експерименті на здорових щурах виявлено широкий діапазон параметрів обміну сечової кислоти і вперше показано, що з ними значуще корелюють 34 імунні параметри із 41 зареєстрованого. Урикозурія (більшою мірою) і урикемія (меншою мірою), взяті разом, детермінують стан імунітету на 71%. Сечова кислота стимулює фагоцитоз Staph. aureus нейтрофілами (але не моноцитами) крові, збільшує відносний вміст лімфоцитів загалом і В-лімфоцитів зокрема в крові, Т-лімфоцитів і макрофагів в тимусі та фібробластів в селезінці, а також нарощує ентропію імуноцитограми крові. З іншого боку, сечова кислота зменшує ентропію лейкоцитограми крові, загальний вміст в крові лейкоцитів і відносний вміст в лейкоцитограмі моноцитів і паличкоядерних нейтрофілів, натуральних кілерів в імуноцитограмі, а також ентропію тимоцитограми і вміст в ній епітеліоцитів і ретикулоцитів. Вперше показано, що з-поміж нейро-ендокринних факторів адаптації урикозурія і урікемія негативно корелюють з ВРС-маркерами симпатичного тонусу і циркулюючих катехоламінів, рівнем в плазмі кортикостерону і товщиною фасцикулярної зони кори наднирників, а також рівнем в плазмі трийодтироніну і Са-Р-маркером кальцитонінової активності, натомість позитивно корелюють з ВРС-маркером вагального тонусу і екскрецією з сечею 17-кетостероїдів. Міра детермінації сечовою кислотою нейро-ендокринних факторів адаптації становить 62%. Сукупний детермінуючий вплив параметрів обміну сечової кислоти (за значної переваги урикозурії над урикемією) на констеляцію метаболічних параметрів становить 56%. Максимальній позитивній детермінації з боку сечової кислоти підлеглі діурез і екскреція фосфатів та калію, меншою мірою детермінуються екскреція кальцію, креатиніну і сечовини, ще меншою – рівні креатиніну, сечовини і калію в плазмі, а мінімальній детермінації підлегла магнійурія. У людей обох статей, хворих на хронічний пієлонефрит в фазі ремісії, виявлено чотири варіанти обміну сечової кислоти. У 34% помірна гіпоурикозурія поєднується з нижньопограничною урикемією. У 24% помірно підвищена урикозурія асоціюється із нормальною урикемією. У 17% помірно підвищена урикозурія поєднується з вираженою гіпоурикемією. Нарешті, у 25% пацієнтів нижньопогранична урикемія супроводжується вираженою гіперурикозурією. З-поміж усіх зареєстрованих параметрів в якості розпізнавальних щодо чотирьох варіантів обміну сечової кислоти виявлено 28. У дискримінантну модель включено, окрім урикозурії і урикемії за визначенням, 6 нейроендокринних параметрів адаптації (кортизол, трийодтиронін, тестостерон, кальцитонін, вегетативний індекс Кердьо і Са/К-маркер симпато-вагального балансу), 8 параметрів імунітету (активність і завершеність фагоцитозу нейтрофілами грампозитивних і грамнегативних бактерій, рівень в крові загальних лімфоцитів, інтерлейкіну-1β, IgG та IgA в слині), два інформаційні параметри (індекс напруження лейкоцитограми Поповича і ентропія імуноцитограми), 7 параметрів метаболізму електролітів (магній, калій, фосфати) і неелектролітів (глюкоза, сечовина і креатинін), а також маркери хронічного пієлонефриту (бaктерійурія і лейкоцитурія) і мікробіоти (Bifidobacteria). Вперше показано, що динаміка урикозурії позитивно детермінує динаміку діурезу і екскреції сечовини, креатиніну, кальцію, фосфатів, магнію, хлориду і калію та калійемії, рівня Т-гелперів, ВРС-маркерів вагального тонусу і симпато-вагального балансу. Натомість негативній детермінації підлеглі зміни вегетативного індексу Кердьо та інтенсивності фагоцитозу Staph. aureus. Динаміка такої констеляції параметрів організму детермінується динамікою сечової кислоти на 97%. Динаміка урикемії детермінує динаміку вегетативного індексу Кердьо, кортизолу і кальцитоніну негативно, натомість електролітних маркерів паратироїдної активності і симпато-вагального балансу та тестостерону – позитивно. З-поміж імунних параметрів негативній сечокислій детермінації підлеглі зміни Т-гелперів і TNF-α, натомість позитивній – ЦІК, моноцитів і IgG. Стосовно параметрів метаболізму спостерігається лише позитивна сечокисла детермінації їх динаміки. Метаболічна констеляція включає кальційемію, хлоридемію, магнійемію, а також діурез та екскрецію хлориду, натрію, сечовини і креатиніну. В цілому сечокисла детермінація динаміки перелічених параметрів організму становить 80%. Одержані результати розвивають і доповнюють концепцію, що ендогенна сечова кислота володіє фізіологічною активністю, яка проявляється у модуляції параметрів нейроендокринно-імунного комплексу і метаболізму. 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. Odesa. Feniks; 2023: 266 p. Annotation In an experiment on healthy rats, a wide range of parameters of uric acid metabolism 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. For the first time, 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, are 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 metabolism (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 people of both sexes, patients with chronic pyelonephritis in the phase of remission, four variants of uric acid metabolism were found. 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 identified as identifying four variants of uric acid metabolism. In addition to uricosuria and uricemia by definition, the discriminant model included 6 neuroendocrine parameters of adaptation (cortisol, triiodothyronine, testosterone, calcitonin, Kerdoe’s autonomic index and Ca/K-marker of sympatho-vagal balance), 8 parameters of immunity (activity and completion of phagocytosis by neutrophils of gram-positive and gram-negative bacteria, the levels of total lymphocytes, interleukin-1β, IgG in the blood and IgA in saliva), two informational parameters (the Popovych’s leukocytogram strain index and the entropy of the immunocytogram), 7 parameters of electrolyte metabolism (magnesium , potassium, phosphates) and non-electrolytes (glucose, urea and creatinine), as well as markers of chronic pyelonephritis (bacteriuria and leukocyturia) and microbiota (Bifidobacteria). It was shown for the first time that the dynamics of uricosuria upregulates the dynamics of diuresis and excretion of urea, creatinine, calcium, phosphates, magnesium, chloride and potassium and plasma potassium, the level of T-helpers, HRV-markers of vagal tone and sympatho-vagal balance. Instead, changes in the Kerdoe’s vegetative index and the intensity of Staph. aureus phagocytosis are subject to downregulation. The dynamics of such a constellation of body parameters is determined by the dynamics of uric acid by 97%. The dynamics of uricemia determines the dynamics of the Kerdoe’s autonomic index, cortisol and calcitonin negatively, instead of the electrolyte markers of parathyroid activity and sympatho-vagal balance and testosterone - positively. Among the immune parameters, changes in T-helpers and TNF-α are subject to negative uric acid determination, while positive ones include CIC, monocytes, and IgG. Regarding metabolic parameters, only positive uric acid determination of their dynamics is observed. The metabolic constellation includes calciumemia, chlorideemia, magnesiumemia, as well as diuresis and excretion of chloride, sodium, urea, and creatinine. In general, uric acid determines the dynamics of the listed parameters of the body by 80%. 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.

Rat liver lysosomes, isolated from metrizamide gradients by the method of Wattiaux et al. (Wattiaux, R., Wattiaux-de Coninck, S., Ronveaux-Dupol, M.F., and Dubois, F. (1978) J. Cell Biol. 78, 349-368) took up from the medium and degraded several marker protein preparations, viz. 125I-asialofetuin, [35S]methionine-labeled hemoglobin, and [3H]leucine-labeled rat liver cytosol proteins. Rates were indistinguishable for all the markers, indicating that uptake was by a nonspecific process analogous to fluid pinocytosis. No effect of added MgATP or K+ was observed. Lysosomal degradation of all the markers was inhibited by 10(-4) M chloroquine. Swainsonine, on the other hand, at 10(-5) M, inhibited the breakdown only of the glycoprotein, 125I-asialofetuin. In the presence of the inhibitors, there was an accumulation of markers in the lysosomes in amount corresponding to the decreased breakdown, indicating that uptake was unaffected. Degradation and inhibition were measured at pH 7.0, 6.0, and 5.0 with both intact lysosomes and with lysosomes disrupted by the addition of 0.2% Triton X-100. Degradation with intact lysosomes was relatively independent of pH. On the other hand, activity with disrupted lysosomes was negligible at pH 7.0 and rose rapidly with decreasing pH. Inhibition by 10(-4) M chloroquine and 10(-5) M swainsonine with intact lysosomes decreased sharply with decreasing pH and did not occur with disrupted lysosomes.

Rat liver lysosomes, isolated from metrizamide gradients by the method of Wattiaux et al. (Wattiaux, R., Wattiaux-de Coninck, S., Ronveaux-Dupol, M.F., and Dubois, F. (1978) J. Cell Biol. 78, 349-368) took up from the medium and degraded several marker protein preparations, viz. 125I-asialofetuin, [35S]methionine-labeled hemoglobin, and [3H]leucine-labeled rat liver cytosol proteins. Rates were indistinguishable for all the markers, indicating that uptake was by a nonspecific process analogous to fluid pinocytosis. No effect of added MgATP or K+ was observed. Lysosomal degradation of all the markers was inhibited by 10(-4) M chloroquine. Swainsonine, on the other hand, at 10(-5) M, inhibited the breakdown only of the glycoprotein, 125I-asialofetuin. In the presence of the inhibitors, there was an accumulation of markers in the lysosomes in amount corresponding to the decreased breakdown, indicating that uptake was unaffected. Degradation and inhibition were measured at pH 7.0, 6.0, and 5.0 with both intact lysosomes and with lysosomes disrupted by the addition of 0.2% Triton X-100. Degradation with intact lysosomes was relatively independent of pH. On the other hand, activity with disrupted lysosomes was negligible at pH 7.0 and rose rapidly with decreasing pH. Inhibition by 10(-4) M chloroquine and 10(-5) M swainsonine with intact lysosomes decreased sharply with decreasing pH and did not occur with disrupted lysosomes.

In order to study the intracellular localization of the proteolytic processing steps in the maturation of alpha-glucosidase and cathepsin D in cultured human skin fibroblasts we have used incubation with glycyl-L-phenylalanine-beta-naphthylamide (Gly-Phe-NH-Nap) as described by Jadot et al. [Jadot, M., Colmant, C., Wattiaux-de Coninck, S. & Wattiaux, R. (1984) Biochem. J. 219,965-970] for the specific lysis of lysosomes. When a homogenate of fibroblasts was incubated for 20 min with 0.5 mM Gly-Phe-NH-Nap, a substrate for the lysosomal enzyme cathepsin C, the latency of the lysosomal enzymes alpha-glucosidase and beta-hexosaminidase decreased from 75% to 10% and their sedimentability from 75% to 20-30%. In contrast, treatment with Gly-Phe-NH-Nap had no significant effect on the latency of galactosyltransferase, a marker for the Golgi apparatus, and on the sedimentability of glutamate dehydrogenase and catalase, markers for mitochondria and peroxisomes, respectively. The maturation of alpha-glucosidase and cathepsin D in fibroblasts was studied by pulse-labelling with [35S]methionine, immunoprecipitation, polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulphate and fluorography. When homogenates of labelled fibroblasts were incubated with Gly-Phe-NH-Nap prior to immunoprecipitation, 70-80% of all proteolytically processed forms of metabolically labelled alpha-glucosidase and cathepsin D was recovered in the supernatant. The earliest proteolytic processing steps in the maturation of alpha-glucosidase and cathepsin D appeared to be coupled to their transport to the lysosomes. Although both enzymes are transported via the mannose-6-phosphate-specific transport system, the velocity with which they arrived in the lysosomes was consistently different. Whereas newly synthesized cathepsin D was found in the lysosomes 1 h after synthesis, alpha-glucosidase was detected only after 2-4 h. When a pulse-chase experiment was carried out in the presence of 10 mM NH4Cl there was a complete inhibition of the transport of cathepsin D and a partial inhibition of that of alpha-glucosidase to the lysosomes. Leupeptin, an inhibitor of lysosomal thiol proteinases, had no effect on the transport of labelled alpha-glucosidase to the lysosomes. However, the early processing steps in which the 110-kDa precursor is converted to the 95-kDa intermediate form of the enzyme were delayed, a transient 105-kDa form was observed and the conversion of the 95-kDa intermediate form to the 76-kDa mature form of the enzyme was completely inhibited.(ABSTRACT TRUNCATED AT 400 WORDS)

The intracellular localization of diamine oxidase (EC 1.4.3.6) in rabbit kidney cortex was studied. The distribution of diamine oxidase in the subcellular fractions, obtained by modifying the classical method of Wattiaux-De Coninck, S., Rutgeerts, M.T. and Wattiaux, R. (Biochim. Biophys. Acta (1965) 105, 446-459) demonstrated that this activity is concentrated (greater than 60%) in the microsomal fraction. Biochemical and morphological data indicate a 20-30% contamination of this fraction by plasma membrane and brush border fragments. Subfractionation of the microsomes, obtained by centrifuging in a continuous sucrose-Ficoll gradient (d 1.038-1.064) for 75 min, showed that diamine oxidase is concentrated in membrane deriving from the endoplasmic reticulum. In fact the bulk of diamine oxidase activity was recovered in a subfraction of the gradient which was shown both biochemically and morphologically to derive from the endoplasmic reticulum. The possible significance of this result is discussed.

The subcellular localization of the ω-hydroxylase of Saccharomycopsis lipolytica was assessed by the analytical fractionation technique, originally described by de Duve C., Pressman, B.C., Gianetto, R., Wattiaux, R. and Appelmans, F., and hitherto little, if at all, applied to yeast. Protoplasts were separated in six fractions by differential centrifugation. Some of these fractions were further fractioned by density gradient centrifugation. The distribution of ω-hydroxylase and 15 other constituents chosen as possible markers of its subcellular membranes has been established. ω-Hydroxylase resulted in being bound to a membrane that containes also cytochrome P-450 and NADPH-cytochrome c reductase. This membrane clearly differs from five other subcellular entities. (1) Mitochondria were characterized by particulate malate dehydrogenase, particulate Antimycin A-insensitive NADH-cytochrome c reductase, oligomycin-sensitive and K+-stimulated ATPase pH 9. (2) Most if not all of the catalase and urate oxidase is peroxisomal. (3) Free ribosomes account for most RNA. (4) Nucleoside diphosphatase is for the first time reported in a yeast and appears to belong to an homogeneous population of small membranes. (5) The soluble compartment contains magnesium pyrophosphatase, alkaline phosphatase, 5′-nucleotidase and part of the NADH-cytochrome c reductase. Latent arylesterase and ATPase pH7 have an unspecific distribution. Alkaline phosphodiesterase I has not been detected.