Phylogenetic Theory Of General Pathology Research Articles

A view on coronovirus infection based on the Titov’s phylogenetic theory of general pathology

The article is devoted to the creation of the prevention of severe course of COVID-19 molecular model from the standpoint of the Titov’s phylogenetic theory of general pathology. The role of the renin-angiotensin and kallikrein-kinin systems in the severe course of COVID-19 is discussed. Using the example of activation of the renin-angiotensin system in non-communicable diseases, the importance of controlling traditional risk factors for the prevention of severe COVID-19 is shown.

Clinical biochemistry methods in objectiva evalution of overeating foood of carnivores (meat)by a phylogenetically herbivorous homo sapiens (a patient).

The abuse of food of carnivores (meat) by phylogeneticallyI herbivorous Homo sapiens (a patient) initiates atherosclerosis. Addressing biogenetic law of E. Haeckel that ontogeny recapitulates phylogeny (a universal anamnesis), we suggest a diagnostic technique that allows evaluation of the meat diet abuse by a herbivorous Homo sapiens. This technique is based on application of phylogenetic theory of general pathology to clinical practice. The degrees of objective evaluation of nonphysiological overeating of meat are: the first, an increase in the fast plasma content of oleic triglycerides palmitoyl-oleyl-palmitate (POP). The second, hyperglyceridemia + an increase in low density lipoprotein cholesterol (LDL-CL) content. The third, increased plasma content of apoС-III. The fourth, an increase in the concentration of apoВ-48. If electrophoregrams are analyzed and hyperlipoproteinemia (HLP) type is determined according to WHO classification, the first degree of meat overeating is not informative, the second, corresponds to type IV HLP; the third, to type IIb HLP, and the forth, to type V HLP, i.e, the patient diet consists practically of the food of carnivores. Hyperlipoproteinemia coincides with insulin resistance syndrome, hyperglycemia and hyperinsulinemia, which is based on blood increase of fatty acids in the form of polar unesterified fatty acids (UFA). According to phylogenetic theory of general pathology, in vivo cells do not internalize glucose if there is a possibility to internalize UFA. Preventive examination allows evaluation of disorders in the biological function of trophology (food consumption). Thus, the use of different methods in the analysis of this function offers evaluation of the effectiveness of diet therapy from the level of disorders when treatment was started.

Clinical biochemistry methods in objectiva evalution of overeating foood of carnivores (meat) by a phylogenetically herbivorous homo sapiens (a patient).

The abuse of food of carnivores (meat) by phylogeneticallyI herbivorous Homo sapiens (a patient) initiates atherosclerosis. Addressing biogenetic law of E. Haeckel that ontogeny recapitulates phylogeny (a universal anamnesis), we suggest a diagnostic technique that allows evaluation of the meat diet abuse by a herbivorous Homo sapiens. This technique is based on application of phylogenetic theory of general pathology to clinical practice. The degrees of objective evaluation of nonphysiological overeating of meat are: the first, an increase in the fast plasma content of oleic triglycerides palmitoyl-oleyl-palmitate (POP). The second, hyperglyceridemia + an increase in low density lipoprotein cholesterol (LDL-CL) content. The third, increased plasma content of apoС-III. The fourth, an increase in the concentration of apoВ-48. If electrophoregrams are analyzed and hyperlipoproteinemia (HLP) type is determined according to WHO classification, the first degree of meat overeating is not informative, the second, corresponds to type IV HLP; the third, to type IIb HLP, and the forth, to type V HLP, i.e, the patient diet consists practically of the food of carnivores. Hyperlipoproteinemia coincides with insulin resistance yndrome, hyperglycemia and hyperinsulinemia, which is based on blood increase of fatty acids in the form of polar unesterified fatty acids (UFA). According to phylogenetic theory of general pathology, in vivo cells do not internalize glucose if there is a possibility to internalize UFA. Preventive examination allows evaluation of disorders in the biological function of trophology (food consumption). Thus, the use of different methods in the analysis of this function offers evaluation of the effectiveness of diet therapy from the level of disorders when treatment was started.

Biologocally active peptides in metabolism regulation. Peptons, peptides, amino acids, fatty acids, lipoproteins, lipids, and the effect of nutriceuticals.

According to phylogenetic theory of general pathology, formation of multicellular organisms started when each cell (a unicellular organism) reached the first level of relative biological perfection. By that time the stimuli for perfection of the unicellular exhausted, and formation of the multicellular became a biological necessity. All cells, being associated, formed the second level of relative biological perfection within the principle of biological succession. The association included highly organized unicellular organisms with their specific autocrine biological functions and reactions. At the second level of relative biological perfection all humoral mediators in paracrine regulated cell communities (PC) and organs were predominantly hydrophilic and short living. They had a small molecular weight and were probably biologically active peptides (BAP). We believe that functional difference of PC and later of organs is based on differentiation of lysosomal function and production of various enzymes involved in proteolysis of dietary proteins. This allowed various PC and organs to form chemically and functionally different BAP pools from one protein upon proteolysis. Individual peptide pools in PC created the basis for morphologically and functionally different cells and organs. Cell that produces peptides can modify their concentration, chemical parameters and ratios by varying the selectivity of its proteases. In vivo regulation of metabolism by BAP has a common root in bacteria, plants and vertebrates, including Homo sapiens. The third level of relative biological perfection in the organism has formed in close association with cognitive biological function.

Biological role of insulin: transformation of carnivores leaving in the ocean into herbivores living on the dry land. Development of the biological function of locomotion and kinetic parameters of the body.

Phylogenetic theory of general pathology draws researchers' attention to the following aspects of the biological effects of insulin. 1. Phylogenetically, in vivo insulin is primarily involved in the metabolism of fatty acids (FA) and only in the second turn in glucose metabolism; regulation of FA metabolism in cells started millions of years earlier than that of glucose metabolism. Phylogenetically late insulin blocks lipolysis only in phylogenetically late insulin-dependent subcutaneous adipocytes but not in phylogenetically early visceral fat cells of the omentum. 2. Biological role of insulin consists in the formation of the biological function of locomotion, i.e., movement arising from contraction of striated myocytes provided with substrates (FA and glucose) for energy production as macroergic ATP. 3. Biological destiny of phylogenetically late insulin is transformation of carnivorous (fish-eating) animals living in the ocean into herbivores living on the dry land. 4. Insulin has formed in vivo highly efficient oleic variant of FA metabolism instead of phylogenetically early less efficient palmitic variant. 5. Biologically, insulin is destined for providing cells with energy and perfection of physical activity and kinetic parameters of the organism. According to phylogenetic theory of general pathology and basic principles of endocrinology, clinical cases should be regarded as: 1. rare structurally-related insulindeficient type I diabetes mellitus, 2. rare structurally-related (receptor pathology) hyperinsulinemic type II diabetes mellitus, and 3. a great number of patients with functional disorders in the hormone activity, insulin resistance syndrome, metabolic syndrome and obesity. We believe that the food of herbivores should contain palmitic acid in the amounts that hepatocytes can esterify into oleic very low density lipoproteins and cells can internalize as ligand oleic by apoЕ/В-100 endocytosis without formation of low density lipoproteins.

Phylogenetic theory of general pathology. Pericytes, function of the distal arterial bed, metabolic arterial hypertension and hypovolemic shock.

The in vivo roles of pericyte contractile sphincters, smooth muscle cells, endothelial monolayer, precapillary muscle arterioles, exchange and volume capillaries in the physiological balance between peripheral blood pool and the blood pool volume in the distal arterial bed are not fully understood. However, it is highly probable that: 1. There is no primary arterial hypertension. The compensatory biological reaction of arterial pressure (AP) is always secondary, thus indicating the presence of symptomatic or metabolic arterial hypertension (AH). 2. Elevation of AP in proximal arterial bed is a compensatory response to metabolic disorders and impaired microcirculation and metabolism↔microcirculation biological reaction. The response develops locally in the distal arterial bed (muscle arterioles, functional sphincters, pericytes). 3. Metabolic AH is a pathology of the phylogenetically early distal arterial bed , endothelial monolayer, smooth muscle cell and pericyte function. 4. We believe that formation of acute hypovolemic shock is the condition of sphincter (pericyte) atonia in precapillary muscle arterioles with formation of a nonphysiological blood volume in the distal arterial bed when physiological volume of peripheral blood is insufficient to fill the bed. 5. When local disorder in the biological reaction metabolism↔microcirculation is not compensated by endothelium-dependent vasodilation, an efferent innervation signal from the vasomotor center at the entire organism level is sent to the heart and systemic AP increases first in the proximal then in the distal arterial bed. 6. Systemic AP elevation impairs function of the target organs: kidneys, brain and lungs. Each of these organs regulates hydrodynamics in the local pool of extracellular medium, their dysfunction inducing a compensatory response. 7. Metabolic arterial hypertension results from discoordinated systemic compensation of local disorders in the following biological functions: homeostasis, endoecology, trophology and adaptation. This discoordination occurs at the level of paracrine regulated cell communities of functionally different cells which are structural units of each internal organ.

Atherosclerosis and atheromatosis are consequtive metabolic disordes. Pathology of the biological functions of trophology and endoecology is the basis for ischemic heart disease prevention.

Atherosclerosis and atheromatosis are different nonphysiological processes with different etiology and pathogenesis. They manifest alterations in different biological functions. According to our original phylogenetic theory of general pathology, atherosclerosis is associated with altered biological function of trophology, eating, biological reaction of exotrophy. Atherosclerosis is induced by eating of nonoptimal for phylogenetically herbivorous Homo sapiens meat diet with high content of palmitic saturated fatty acid (SFA), which leads to in vivo formation of phylogenetically early low-efficient palmitic pathway of FA metabolism instead of highly-efficient oleic pathway operating in herbivores. Accumulation of nonligand palmitic very low density lipoproteins (VLDL) and low density lipoproteins (LDL) in the bloodstream results from nonphysiological reaction of compensation upon transport of palmitic SFA to cells. An increase in blood content of palmitic triglycerides (TG) and nonligand palmitic VLDLЛ→LDL coincides with the development of hypercholesterolemia: type IV→ type IIb → type V. Atheromatosis compensates changes in lipoproteins by activation of the biological function of endoecology (purity of the extracellular medium) in vivo, thus fulfilling the biological reaction of inflammation. This is physiological denaturation of apoВ-100 in nonligand VLDL→LDL by neutrophils via peroxidation, opsonization by the complement components, transcytosis across the endothelial monolayer and removal to the intima of elastic arteries that serves as a collection and utilization pool for phogogens from local intravascular pool of the intercellular medium. Endogenous phlogogens are utilized by phylogenetically early polyfunctional resident macrophages which are small in number and do not proliferate. Blood-borne monocytes-macrophages are also involved in this process, however, they do not express acid hydrolase of polyenic cholesteryl esters. Atheromatous masses are partially catabolized polyenic FA esterified by the alcohol cholesterol which were not internalized by cells. Atheromatosis is a process of pathological compensation in the realization of the function of endoecology. Prevention of atherosclerosis and atheromatosis should be based on elimination of the effects produced by a nonphysiological meat diet.

The person in philogenesis is not (omnivores), but the herbivores with the carnivores past and the fuzzy future. Biological function of trophology (nutrition) in ontogenesis.

According to the phylogenetic theory of general pathology, seven biological functions have been formed over billions of years. 1. biological function of trophology, nutrition; 2. homeostasis function; 3. biological function of endoecology; 4. function of adaptation; 5. function of the continuation of the species; 6. function of locomotion and 7. cognitive biological function, including intelligence. Millions of years in life consistently in the waters of several oceans, all the ancestors of man were carnivorous (Carnivores), fish-eating mammals. When the ocean retreated and the carnivorous (fish-eating) were on land, each individual privatized a "piece" of the ocean. Animals transformed it ito a pool of intercellular medium in vivo. The biological role of the late in the phylogeny of insulin is the formation of new biological functions in vivo. The action of insulin has transformed the carnivorous (fish-eating) ocean into herbivorous (Herbivores) species on land. There was it by synthesis in vivo from exogenous glucose of fatty acids (FA). Regulatory action of insulin was the directed conversion of exogenous glucose into ω-6 C18: 1 cis-oleic FA. Insulin late in phylogeny expressed the synthesis of new, conjugated enzymes: it is palmitoyl-CoA-elongase and stearyl-CoAdesaturase. Two enzymes synthesized FAs along the way: synthesized in situ de novo, from exogenous glucose, C16: 0 palmitic acid → C18: 0 stearic acid → ω-6 C18: 1 cis-oleic acid without accumulation of stearic FA. Insulin is not converted into an oleic FA exogenous palmitic acid from carnivorous food. On land, the action of insulin transformed the species Homo sapiens, into a herbivore, but with carnivorous, fish-eating, past. The idea of a person as omnivorous (Omnivor) - nonsense; such forms of nature did not form. Violation of the function of nutrition, the biological reaction of exotrophy (external nutrition), is the etiological and pathogenetic basis of the seven metabolic pandemics, the diseases of civilization. 1. Atherosclerosis and atheromatosis; 2. metabolic arterial hypertension; 3. metabolic syndrome; 4. obesity; 5. syndrome of insulin resistance; 6. non-alcoholic fatty liver disease and 7. endogenous hyperuricemia. The primary prevention of metabolic pandemics in the biological function of nutrition, in the biological reactions of exo-and endotrophy, will allow us to understand the theoretical bases and implementation of preventive actions that will determine the characteristics of nutrition in the future.

Formation in the phylogenesis of three pulls of cells with expressed different absorption and metabolism of fatty acids. Insulin and medium chains fatty acids.

Somatic cells at the early stages of phylogenesis realized the metabolism of long-chain fatty acids (FA), primarily palmitic saturated FA. It dominated the construction of a bilayer cell membrane and as a substrate for oxidation in mitochondria during energy production. Later, polyene FAs became involved in the construction of the cell membrane, the membranes of intracellular organelles, and became the substrate for the synthesis of biologically active eicosanoids. At later stages of phylogenesis, the metabolism of medium-chain FAs is activated and the formation of ketone bodies as a substrate, which is available for oxidation by the mitochondria of the formed cells of the nervous tissue in the absence of first substrate glucose. In the later stages of phylogenesis, insulin initiated: a) the transformation of carnivorous ancestors of the species Homo sapiens in the ocean into a herbivorous species while living on land; b) the formation of the new biological function of locomotion and c) the dominance of the oleic variant of the metabolism of long-chain fatty acids with higher kinetic parameters of mitochondria oxidation. Metabolites of medium chain FA have become humoral mediators of metabolism and the formation of feedback mechanisms in the function of trophology and cognitive biological function. The formation of an oleic variant of the metabolism of fatty acids under the action of insulin led to the improvement of the energy supply of cells and the high kinetic parameters of many species of herbivorous mammals, including Homo sapiens. The species Homo sapiens was not omnivorous (Omnivores); the insulin's regulatory action during life on land has turned it into a herbivorous species (Herbivore), but with a carnivorous (Carnivore) (fish-eating) past. Seven metabolic pandemics (1. atherosclerosis and atheromatosis; 2. metabolic arterial hypertension; 3. metabolic syndrome; 4. insulin resistance syndrome; 5. obesity; 6. nonalcoholic fatty liver disease and 7. endogenous hyperuricemia) are only functional disorders and can be, in most cases, eliminated. From the standpoint of the phylogenetic theory of general pathology, atherosclerosis and atheromatosis of the arteries have no great future. As soon, as the majority of individuals of the Homo sapiens species realize that in phylogenesis they have formed as herbivores and stop eating excessive amounts of meat food, exogenous palmitic FA, the incidence in the population will begin to decrease. Patients are still obliged to justify the binary, biological name of the species - reasonable man. Prevention and other metabolic pandemics, diseases of civilization, can be discussed. It takes time, an understanding of what happens by the doctors, diligence and the desire of patients to be healthy.

The becoming of reactions of lipolysis in phylogenesis. The palmitic and oleic triglycerides as substrates. Insulin, condition of normolipemia and formation of hyper lipoproteinemia type IIb, IV and V

According to phylogenetic theory of general pathology, when living in ocean all were carnivorous (piscivorous) fatty acids transferring to cells in form of non-polar triglycerides nitially began apoB-48 chylomicrons, continued lipoproteins of very low and low density and fnalized its apoB-100 endocytosis. The fatty acids are transferred by chylomicrons + lipoproteins of very low density + lipoproteins of low density and non-polar triglycerides are hydrolyzed by hepatic glycerolhydrogenase and co-enzyme apoC-III; according WHO classifcation, hyperlipoproteinemia corresponds to type V. On land, in herbivorous who are not yet synthesized insulin, apoB-48 and chylomicrons left process of non-polar triglycerides transferring. In lipoproteins of very low density and lipoproteins of low density, the carnivorous transfer exogenous palmitic non-polar triglycerides. The herbivorous also transfer palmitic non-polar triglycerides though synthesized by hepatocytes from glucose endogenically. In herbivorous, transferring of palmitic non-polar triglycerides prior to synthesis of insulin is forming apoB-100 in composition of lipoproteins of very low density and lipoproteins of low density. The hydrolysis of palmitic non-polar triglycerides in lipoproteins of very low density is activated by hepatic glycerol hydrogenase and apoC-III; cells absorb lipoproteins of low density by means of apoB-100 endocytosis. The content on lipoproteins in blood plasma under electrophoresis of lipoproteins corresponds to hepatic glycerol hydrogenase type IIb. In frst and second types of fatty acids transferring in form of triglycerides to lipoproteins of very low density + lipoproteins of low density predominate palmitic fatty acid, triglycerides of the same name and palmitic metabolism of fatty acids in vivo. The insulin initiated the third type of transferring of oleic fatty acid by now to insulin-depended cells only in oleic lipoproteins of very low density; hydrolysis of oleic triglycerides is activated by late in phylogenesis post-heparin hepatic glycerol hydrogenase and apoC-II cofactor. The dynamic apoE is actively bound by apoB-100 forming apoE/B-100 ligand. At later stages of phylogenesis insulin formed fatty acids transferring in form of oleic triglycerides in lipoproteins of very low density of the same name without forming of oleic lipoproteins of low density; the electrophoregram of lipoproteins reflects absence of hepatic glycerol hydrogenase. In phylogenesis three types of fatty acids transferring to triglycerides in composition of lipoproteins formed sequentially: 1) chylomicrons + lipoproteins of very low and density + lipoproteins of low density; 2) lipoproteins of very low density + lipoproteins of low density; 3) only in lipoproteins of very low density. The frst one is specifc to piscivorous (carnivorous) while living in ocean. The second one is implemented by herbivorous while they didn't begin to synthesize insulin and hepatocytes not yet transform all endogenous palmitic fatty acid into oleic fatty acid. Insulin initiated: a) transferring of oleic fatty acids to lipoproteins of very low density without forming oleic lipoproteins of low density; b) highly effective oleic metabolism of fatty acids in vivo: c) becoming of biological function of locomotion. The aphysiological induction by substrate, surplus of palmitic fatty acids in food initiate negative alterations in composition of lipoproteins in opposite direction than in case of phylogenesis. When homo sapiens, herbivorous in phylogenesis, begins to misuse carnivorous (meat) food then instead of normolipoproteinemia in blood plasma under electrophoresis of lipoproteins one can initially detect transitory hyperlipoproteinemia type IV and then prolonged hyperlipoproteinemia type IIb. If patient factually passes on to carnivorous diet then hyperlipoproteinemia type V is developing. If content of exogenous palmitic fatty acid in food surpasses physiological capacities of its transferring in oleic triglycerides as palmitoyl-oleyl-palmitate glycerol, palmitic triglycerides as oleyl-palmitoyl-palmitate glycerol begin to form and epigenetically aphysiological non-ligand palmitic lipoproteins of very low density → lipoproteins of low density are formed. Their circulation in blood is a cause of hypertriglyceridemia, higher level of cholesterol-lipoproteins of low density, compensatory increasing of apoC-III. Then occurs induced by substrate formation of hyperlipoproteinemia initially of type IV, then of type IIb and fnally of type V. The pathogenesis of atherosclerosis and atheromotosis is activated when homo sapiens, herbivorous in phylogenesis, begin to misuse carnivorous food affecting biological functions of trophology, reaction of exotrophy (external nutrition), function of homeostasis, endoecology and function of adaptation. The formation of palmitic metabolism if fatty acids instead of oleic one is a cause of chronic defciency of energy and ATP synthesis in vivo. Insulin activates absorption of glucose by cells with purpose to use it for synthesis of oleic fatty acids. In the frst place, insulin regulates in vivo metabolism of fatty acids and only in second place metabolism of glucose.

The phylogenetic theory of general pathology. The development of seven biological functions, seven specific ones and etiological factors of metabolic epidemics, millions years' common pathogenesis and basics of prevention.

The clearer realization is coming that in general biology, medicine, historical science, in biologic phylogenetic anamnesis of Homo sapiens a task exists only one by its significance and unresolved still: to establish historical succession of becoming of specific etiologic factors of every metabolic epidemic and to understand becoming of millions years' common pathogenesis of all metabolic pandemics. The carnivorous feeding by ocean, herbivorous feeding of ancestors of rodents and Homo sapiens by dry land; misusing carnivorous food by phylogenetically herbivorous human during last centuries, disorder of biological function of trophology, biological reaction of exotrophy, pathology of biologic functions of adaptation and endoecology, features of cognitive biological function formed etiological factors of atherosclerosis and atheromatosis. The abnormalities of biological reaction metabolism↔micro-circulation; discrepancy of mechanisms of regulation of biological reaction at 2d and 3d levels of relative biological perfection in vivo, disorder of biological function of adaptation, biological reaction of compensation formed etiological factors of metabolic arterial hypertension. The synthesis of fatty acids in phylogenesis millions of years before of glucose, preference of cells to absorb fatty acids instead of glucose; previously in phylogenesis effect of hyperglycemia, glucagon and late function of insulin formed priority of metabolism of fatty acids in energetics of organisms and glucose only in the second instance. The formation in phylogenesis of methodological mode of biological subordination in functioning of humoral mediators, incapability of insulin late in phylogenesis of blocking adaptive action of humoral mediators earlier in phylogenesis, especially in visceral fatty tissue form etiological factors of resistance to insulin. The functional limitation of cognitive biological function, difficulties in maintaining unity of internal medium of organism and effects of aphysiologic factors of external medium produces necessity of completing cognitive biological function with activation of biological reaction of apoptosis and autophagy. This occurrence forms etiologic factors of metabolic syndrome - a local pathology of early, visceral, limited in numbers of cells of pool of insulin-independent visceral fatty tissue. The inconsistency of cognitive biological function, necessity of correcting it by more effective biological function of intellect, role of insulin in energy support of new biological function - locomotion, formation of unlimited in numbers of cells а pool late in phylogenesis of insulin-dependent subcutaneous adipocytes, formed etiological factors of obesity. The biological function of depositing of fatty acids in phylogenesis in vivo is characterized by etiological dependence: depositing of fatty acids occurs in the form of non-polar triglycerides and releasing into intercellular medium occurs only in form of polar unesterified fatty acids. The features of induction with substrate, formation of positioning isoforms of fatty acids, impossibility of hydrolyzing them at effecting of hormone-dependent lipase compel to eliminate aphysiologic triglycerides from liver together with hepatocytes implementing biological reactions of apoptosis and autophagy. They become etiological factors of non-alcoholic fatty disease of liver; these are aphysiologic positioning iusoforms of triglycerides as palmitoyl-palmitol-palmitate and stearyl-stearyl-stearate. The formation of endogenous hyperuricemia in phylogenesis was initiated by 2 mutations. The first one - a gene of ascorbic acid "minus" deprived Homo sapiens of synthesis of hydrophilic acceptor of active forms of oxygen. The second one - a gene of uricase "minus" blocked synthesis of allantoin but provided a possibility of re-absorbing uric acid from a pool of primary urine and use it in vivo as an acceptor of active forms of oxygen instead of ascorbic acid under realization of biological function of endoecology,biologic reaction of inflammation.

The integrated etiology and separate pathogenesis of atherosclerosis and atheromatosis. The differences of fatty acids transfer in lipoproteins of herbivorous and carnivorous animals.

According phylogenetic theory of general pathology, overconsumption of meat food by herbivorous animals always results in atherosclerosis and atheromatosis of intima of arteries. The etiological factors of atherosclerosis, atheromatosis in vivo: a) absorption by cells of polyene fatty acids in anoB-100 lipoproteins of low density; b) impossibility of converting exogenous palmitic saturated fatty acids into mono-unsaturated oleic fatty acid; c) monocytes-macrophages in intima inactively hydrolyze polyene fatty acids esterified by alcohol cholesterol. The disorder of biological function of trophology (nutrition), biological reaction of exotrophy (external nutrition) and aphysiologically high content of palmitic unsaturated fatty acids and alcohol cholesterol in food become a pathogenic factors. The key stage of pathogenesis is formation in blood of non-ligand palmitic lipoproteins of very low density. At that: a) how to utilize in vivo non-ligand palmitic lipoproteins of very low density; it is possible under activation of biological function of endoecology, biological reaction of inflammation, formation of atheromatosis of intima of arteries and b) how to prolong function to cells at impossibility of of absorbing from inter-cellular medium polyene fatty acids; this is a foundation of atherosclerosis, disorders of biological function of adaptation, biological reaction of compensation. The primary prevention of myocardium infarction requires elimination of consumption of surplus amount of animal food. At low content of palmitic saturated fatty acids in food insulin forms optimal oleic alternative of metabolism of fatty acids supporting high "kinetic parameters" of organism and effective synthesis of ATP. According single pathogenesis of atherosclerosis and atheromatosis it is necessary to prevent development of non-ligand palmitic lipoproteins of very low density in blood. Without them no development of both atherosclerosis and atheromatosis is possible.

The individual fatty acids of blood plasma: biological role of substrates, parameters of quantity and quality, diagnostic of atherosclerosis and atheromotosis.

The atherosclerosis and atheromotosis are supposed to be, according to phylogenetic theory of general pathology, two etiologically different aphysiological processes, unified by community of pathogenesis. The atherosclerosis is a derangement of biological function of trophology (feeding), biological reaction of exotrophy (external feeding) and biological function of adaptation, biological reaction of compensation in response to deficiency of ῳ-3 and ῳ-6 polyenoic fatty acids. In case of deficiency of polyenoic fatty acids in cells and during synthesis of eicosanoids of group I from unsaturated endogenous ῳ-6 С20: 3 digomo-γ-linoleic unsaturated fatty acid, atherosclerosis is developed, a complex metabolism disorder in vivo. The atheromotosis is a derangement of biological function of endoecology, biological reactions of inflammation and inherent immunity. This incomplete utilization in intima of arteries of non-ligand palmitic lipoproteins of very low → low density under effect not of polyfunctional resident macrophage but monocytes of hematogenic origin without expression of acid hydrolase of polyenoic ethers of cholesterol. In intima, in area of cumulation of endogenous phlogogens (initiator of inflammation) from the pool of intra-vascular medium, polyenoic unsaturated fatty acids are cumulated that were not absorbed by cells in structure of ligand low density palmitic lipoproteins using apoB-100- endocytosis. The pathogenic factor of atherosclerosis - derangement of biological function of trophology. biological function of exotrophy under alimentary deficiency of in vivo of ῳ-3 and ῳ-6 polyenoic fatty acids with physiological parameters of feeding. The pathogenic factor of atheromotosis - phylogenetically herbivorous (carnivorous) human misusing of animal (meat) food, palmitic unsaturated fatty acids, development by hepatocytes of a large number of palmitic triglycerides and lipoproteins of very low density of the same name. The late in phylogenesis insulin-dependent lipoproteins of very low density transfer palmitic lipoproteins of very low density to cells slowly. The cells absorb them also slowly. The cumulation of non-ligand palmitic lipoproteins of very low density → low density in blood competitively blocks physiological absorption of polyenoic unsaturated fatty acids by cells in structure of physiological palmitic lipoproteins of low density. The atherosclerosis occurs blood flow and atheromotosis in intima of arteries of elastic type.

The phylogenetic theory of general pathology. The becoming of function of at mitochondria at symbiosis of bacterial cells and archaea. Inconsistency of Randle cycle, regulation metabolism of fatty acids and glucose by insulin.

The implementation of Randle rule is not a cycle; fatty acids C4 - ketone bodies at interrelationships with glucose metabolite - pyruvate regulate production of mitochondria of acetyl-KoA by induction of substrate and its conversion in Krebs cycle, reactions of respiratory chain, oxidative phosphorylation and formation of ATP. In phylogenesis, the early substrate for formation of ATP by mitochondria is acetyl-KoA from C4 fatty acids 4; this is alternative A of induction by substrate adopted from archaea. The alternative B of induction in bacteria is based on synthesis of acetyl-KoA by mitohondria from pyruvate developed in cytosol from exogenous glucose. The insulin is late activator of absorption by glucose cells in phylogenesis; using induction by substrate, insulin inhibits absorption of fatty acids by cells and specifically activates absorption of glucose by them. The insulin activates absorption of glucose only by insulin-dependent cells by force of decreasing of "bioavailability" of fatty acids. These cells are preferred to be metabolize by mitochondria from times of archaea. The insulin, blocking lipolysis in insulin-dependent adipocytes "forces" mitochondria, instead of formation of acetyl-KoA from fatty acids, to produce it from pyruvate at activation of glycolysis and pyruvate-dehydrogenased complex. Under effect of insulin, mitochondria form acetyl-KoA and synthesize ATP from oleic mono-saturated fatty acids but not from palmitic saturated fatty acids. The kinetic parameters of second reaction and formation of ATP per unit of time (effectiveness) are much higher than in first reaction. The effectiveness of i9mplementation of alternative A in synthesis of ATP, kinetic parameters of production of acetyl-KoA in mitochondria in alternative A are more effective than in case of alternative B and metabolic conversion of glucose. The syndrome of resistance to insulin is, at the first place, pathology of metabolism of fatty acids and only in the second place metabolism of glucose. The incapacity of insulin to block lipolysis in the phylogenetically earlier visceral fatty cells is the basis of resistance.

INVERSION OF THE CONCEPT ABOUT BIOLOGICAL ROLE OF RENIN → ANGIOTENSIN-II → ALDOSTERONE SYSTEM AND FUNCTION OF ARTERIAL BLOOD PRESSURE AS A METABOLISM REGULATOR

The phylogenetic theory of general pathology postulates an inversion of the concept about the role of arterial blood pressure (AP) in physiology and pathology. Activation of the synthesis of the renin → angiotensin-II (AG-II) system components by nephron and increase in aldosterone secretion are not aimed at elevating AP., but at maintaining the volume of extracellular medium, part of the Third Word Ocean where all cells still live as millions of years ago. Phylogenetically early internal organs cannot regulate the effects of phylogenetically late AP., a physical factor of metabolism. AP is not increased by kidneys, but by the vasomotor center that attempts to reanimate nephronal function, the biological function of endoecology and biological reaction of excretion by increasing AP in proximal and, subsequently, hydrodynamic pressure in the distal region of arterial bed. In addition to the major role in the realization of the biological function of locomotion, AP is a physical factor involved in compensation of impaired functions of homeostasis, trophology, endoecology and adaptation. Levels of metabolism regulation have developed during phylogenesis. Biochemical reactions are specifically regulated at the autocrine level. In paracrine-regulated cell communities of distal arterial bed, metabolism is regulated by millions of local peristaltic pumps by compensating the biological reactions of endothelium-dependent vasodilation, microcirculation, effects of humoral messengers and hormones. In vivo metabolism is regulated nonspecifically from the vasomotor center level by a physical factor (AP) by sympathetic activation of the heart; AP in proximal and distal regions of arterial bed overcomes peripheral resistance and «squeezes through» the arterioles where microcirculation is impaired. AG-II acts as a vasoconstrictor only in the distal arterial bed. In essential (metabolic) arterial hypertension, paracrine cell communities of nephrons and kidneys are involved in realization of pathologic compensation in the second turn and often “suffer being innocent” , similar to other “target” organs”, such as brain, lungs and heart.

ENDOGENOUS INTOXICATION AND INFLAMMATION: REACTION SEQUENCE AND INFORMATIVITY OF THE MARKERS (review)

Abstract According to modern phylogenetic theory of general pathology (V.N. Titov, 2003, 2013) inflammation is a nonspecific biological reaction, providing the removal of excessive amount of high-molecular macromolecules and maintenance of metabolic homeostasis (endoecology). The increase of any metabolite concentration above the physiological range is a violation of the «purity» of inter-cellular medium. This triggers two nonspecific biological reactions, namely the excretion used to re-move «biological waste» of a molecular weight less than 70 kD and the inflammation in case the lar-ger molecules and their complexes should be removed via neutrophils, resident macrophages and en-dothelial cells. Blood concentration of leukocytes has been used for evaluation of inflammation and intoxication activity for many decades. However, at the molecular level there is a requirement in precise differentiation of metabolites, activating leukocytes, and metabolites, excessively forming as a result of activation, because the last disturb molecular homeostasis and may damage cells and tissues. Validity of leucocytal intoxication index (LII) of Ya.Ya. Kalf-Kalif, concentration ratio of low and medium molecular weight substances, average molecular peptides, total and effective albumin as markers of endogenous intoxication (M.Ya. Malakhova, 2005) are considered. It is shown that pri-mary agent, activating neutrophils and some factors of humoral immunity, is a lipopolysaccharide (endotoxin) of gram-negative microflora (M.Yu. Yakovlev, 2003; O.W. McIntyre, 2011). An excess of endotoxin inflow is possible under intestine and liver pathologies, and due to sympathoadrenal system activation, and also with feed and air. The overload of systems and organs of elimination of endotoxin causes secondary immunodeficiency, which becomes the cause of acute and chronic in-flammatory processes of various localizations. It is offered to consider lipopolysaccharide of gram-negative microflora as a primary agent of endogenous intoxication and all the metabolites, produces at increased concentrations as a result of polymorphonuclear leukocytes activation such as reactive oxygen species, oxidated proteins, products of lipid peroxidation and proteolysis, as a secondary one. Such an approach allows to single out various points of application for therapy of endogenous intoxi-cation: i) elimination of excessive concentration of lipopolysaccharide in blood by limiting its pro-duction and income from internal and external sources, as well as by a variety of methods of active binding and excretion of endotoxin (S.V. Smirnov et al., 2003; K. Battenschoen et al., 2010); ii) re-ducing the concentration of «secondary» metabolites in blood and tissues. Keywords: endogenous intoxication, segmentated neutrophils, lipopolysaсcharides, inflamma-tion, endotoxinemia, endoecology.

Adiponeсtin as humoral mediator of feedback in adipocytes of subcutaneous fatty tissue. Phylogenetic theory of general pathology; functional difference of leptin and adiponeсtin.

In spite of difference both in concentration of mono- and oligomers and in humoral regulation of visceral fatty cells and subcutaneous adipocytes, leptin and adiponeсtin are phylogenetically two different humoral mediators of biological function of trophology in paracrin regulated cenosises and at the level of organism. They separately regulate in visceral fatty cells and adipocytes realization by fatty cells such biological reactions as exotrophy, deposit of fatty acids and triglycerides and endotrophy (releasing of fatty acids in form of unesterified fatty acids). They are related both physiologically and under development of pathology. The surplus induction by physiological substrate (food), besides its amount, is aphysiological effect of environment - syndrome of overeating. The accumulation of surplus saturated and monoenic fatty acids in triglycerides in visceral fatty cells continues till: a) size of cells under their constant amount will exceed physiological size; b) there is no endoplasmic stress; c) loss of visceral fatty cells by type of apoptosis; d) development of biological reaction of inflammation in visceral fatty cells (autocrine) and paracrin cenosises; e) compensating increase of synthesis by visceral fatty cells' mediator of feedback of leptin under development of metabolic syndrome. The deposit of fatty acids in form of triglycerides is proceeded by adipocytes in case that surplus induction by substrate continues. The algorithm of compensating effect of adiponeсtin on autocrine level and cenosises of cells is the same as for leptin in visceral fatty cells. Hence, formation of alimentary obesity and compensative activation of synthesis by adipocytes of adiponeсtin with regulation of feedback. How the effect of leptin and adiponeсtin at the level of organism under expressed difference of their structure is still to be exposed.

PALMITIC AND OLEIC ACIDS AND THEIR ROLE IN PATHOGENESIS OF ATHEROSCLEROSIS

On the basis of phylogenetic theory of general pathology, the cause of a noninfectious disease whose occurrence in a population is more than 5–7% is an impaired biological function or reaction to the environment. From the general biology viewpoint, high mortality rate related to cardio-vascular diseases and atherosclerosis (intercellular deficiency of polyenic fatty acids (PFA)) is just extinction of the Homo sapiens population upon adaptation to new environmental factors. The biological function of throphology (feeding) and biological reaction of exotrophy (external feeding) are impaired in several aspects, the major of which is nonphysiologically high dietary content of saturated fatty acids, primarily, of palmitic fatty acid (FA). The lipoprotein system formed at early stages of phylogenesis cannot transport and provide physiological deposition of great amounts of palmitic FA, which leads to the development of an adaption (compensatory) and accumulation disease. This results in hypermipidemia, impaired bioavailability of PFA to cells, compesatory production of humoral mediators from ω-9 eicosatrienoic mead FA, disorders in physiological parameters of cell plasma membrane and integral proteins, nonphysiological conformation of apoВ-100 in lipoproteins, formation of ligandless lipoproteins (biological litter) and impairments in the biological function of endoecology, utilization of ligandless lipoproteins in arterial intima by phylogenetically early macrophages that do not hydrolyze polyenic cholesterol esters, increase in the intensity of the biological reaction of inflammation, and destructive and inflammatory lesions in arterial intima of an atheromatosis or atherothrombosis type. Atheromatous masses are catabolites of PFA which were not internalized by phylogenetically late cells via receptor-mediated pathway.

Russian

The phylogenetic theory of general pathology postulates that notions of the biological role of arterial pressure (AP) in physiology and pathology have been subjected to inversion. The nephron’s activation of the synthesis of the components renin → angiotensin-II (A-II) and the augmentation of aldosterone secretion are directed not at an increase in AP but at preserving the volume of the piece of the third world ocean, privatized by each species, - the pool of the intercellular milieu in which, just like millions of years before, there continue to live all cells. Phylogenetically earlier organs cannot regulate the action of a later one in AP phylogenesis – a physical factor in metabolism regulation. It is not the kidneys that increase AP but the vasomotor center, which, increasing AP in the proximal segment and further hydrodynamic pressure in the distal segment of the arterial bed, seeks to reanimate the function of nephrons, the biological function of endoecology and the biological reaction of excretion. In addition to playing a major role in the biological function of locomotion, AP is a physical factor in compensating for impairments in the biological functions of homeostasis, trophology, endoecology, and adaptation. There have formed sequentially three levels of metabolic regulation in phylogenesis. At an autocrine level, there occurs a specific regulation of biochemical reactions. Within paracrinally regulated communities of cells, in the distal segment of the arterial bed, metabolism is regulated by millions of local peristaltic pumps through compensating for the biological reaction of endothelium-dependent vasodilation, microcirculation, and the action of humoral mediators and hormonal principles. In vivo from the level of the vasomotor center metabolism is non-specifically, systemically regulated by the physical factor – AP – through sympathetic activation of the heart; in the proximal segment of the arterial bed and the distal one, AP, overcoming the resistance, virtually “collapses” arterioles with impaired microcirculation. A-II acts as a vasoconstrictor only in the distal segment of the arterial bed. In the pathogenesis of essential, metabolic AH, the paracrine communities of the nephron and the kidney are involved in the realization of pathological compensation secondarily and are often “wrongfully accused”, just like the other “target organs” – the brain, the lungs, and the heart.