Endogenous multiple modified LDL (mLDL) and the renin-angiotensin system play a significant role in the development of atherosclerosis. It has been found that by behavioral and hemodynamic parameters the physiological activity of angiotensin II (Ang II) in combination with mLDL is considerably modified due to weakening of its diuretic effect and the inversion of hypertensive and tachyarrhythmic effects. Atherosclerosis is a long-term pathological process, so a single administration of artificially synthesized Ang I-mLDL complexes can be considered a model of the first contact of the body with pathogenic factors. We believe that angiotensin complexes with mLDL participate in adaptive and compensatory mechanisms at the initial stages of atherosclerosis and later contribute to its progression.

Citation: Kuzmina IV, Tolpygo SM, Kotov AV, Shoibonov BB and Zamolodchikova TS (2024) Basal pancreatic secretion in a comparative aspect in poultry and rodents. Front. Physiol. 15:1340130. doi: 10.3389/fphys.2024.1340130

OPINION article Front. Endocrinol., 23 January 2024Sec. Diabetes: Molecular Mechanisms Volume 15 - 2024 | https://doi.org/10.3389/fendo.2024.1293221

Irina V. Kuzmina*Svetlana M. TolpygoAlexander V. KotovBatogab B. ShoibonovTatyana S. ZamolodchikovaNatalya V. Ovchinnikova

The research task has been testing of the method of modified low density lipoproteins (mLDLP) determina- tion as the chronic inflammatory process marker in poultry and laboratory mammals (rats and mice) serum. Experiments have been carried out with 3 days chicks and 180 days layers and also with laboratory rat males from Wistar population and laboratory mice males from C57BI/6 line. Serum investigation results have shown that poultry had increased mLDLP content in 3 and 180 days age. It means that mLDLP determination in poultry at different ontogenesis stages will give the possibility to identify metabolic process disruption timely and to carry out necessary treatment and preventive measures and to correct poultry feeding and management at different raising periods. Determination of mLDLP levels in laboratory mammals will give the possibility to form personalized animal groups for researches with normal and increased mLDLP lev- els for the results reliability increasing.

Serine proteases, including trypsin, thrombin, plasminogen activators, plasmin and several others, are synthesized in nervous tissue, mainly in the brain, including the cortex, limbic system and cerebellum. This review examines the involvement of serine proteases in neuroplasticity and behavioral regulation. Endogenous serine proteases play an important role in the formation, development and maintenance of the nervous system. Through limited proteolysis, these proteases activate PARs (protease-activated receptors), modify other receptors or their ligands, process neurotrophic factors, degrade intercellular matrix and cell adhesion proteins and initiate complex signal transduction cascades necessary for structural modification of synapses. The involvement of serine proteases in morphological and functional synaptic plasticity may underlie cognitive processes, including learning and memory in animals and humans.

The modern period of medicinal and pharmacologic development is characterized by significant achievements in the area of peptide-based drugs. The concept of peptide regulation of organism biological functions detected feasibility for the development of new highly efficient regulatory peptide-based drugs that has resulted in heavy growth of pharmacologic studies in the area of peptide drugs, including the agonists of receptors associated with G proteins (GPCR) (Wacker et al., 2017; Grieco and GomezMonterrey, 2019). The use of peptides as drugs is limited due to their short half-life, rapid degradation, and high clearance, but in some cases, for example, for Giapreza, containing angiotensin II (AngII), a short plasma half-life may be clinically beneficial (Khalique and Ferguson, 2019). In order to improve pharmacologic properties of the peptide drugs, a special strategy of peptide conjugation with high molecular weight compounds, including proteins, is developed (Bumbaca et al., 2019; Davenport et al., 2020). A similar approach is used to create conjugate peptide vaccines for stabilization, delivery to the immune competent cells, and stimulation of the immune reaction; the target peptide antigen is conjugated with any protein, such as keyhole limpet hemocyanin or bovine serum albumin (BSA). An analogous method for vaccine creation is proposed for the prospective method of hypertension immune treatment: peptide–protein antihypertensive vaccines contain different factors of the renin–angiotensin system (RAS), including protein-conjugated angiotensins (Downham et al., 2003; GarayGutiérrez et al., 2021). In pursuit of the goal of correcting pathologic conditions using synthetic peptide–protein preparations, it should be borne in mind that the incorporation of a peptide into an artificial macromolecular construct is inevitably accompanied with changes in its structural conformation characteristics due to new peptide–protein interactions. For this reason, the peptide hormone integrated into the peptide–protein complex is an altered ligand with globally modified signaling properties. There are cases when the use of GPCRtargeted peptide drugs leads to unexpected reactions and dangerous side effects (Allen and Roth, 2011). Based on literature and own data, we show by the example of angiotensins–multifunctional factors of the RAS that the hormones included into the synthetic peptide–protein complexes could globally change their properties till reverse agonism and cause unpredictable physiological effects. Edited by: Salvatore Salomone, University of Catania, Italy

OPINION article Front. Immunol., 03 March 2020Sec. Nutritional Immunology Volume 11 - 2020 | https://doi.org/10.3389/fimmu.2020.00411

In order to establish the supposed role of the complement system in the regulation of homeostasis and defense reactions in the intestinal epithelium, an immunofluorescent analysis was conducted of localizing the C1q complement component in the inflamed mucosa of the human duodenum (DM) (duodenitis II-III degree) using C1q-specific antibodies. The findings suggest a pronounced presence of the C1q complement component in various DM areas during inflammation, both in the epithelial layer and in the lamina propria, where C1q is localized in the region of the basolateral membrane of enterocytes and some free cells, presumably neutrophils, macrophages and mast cells. A C1q-specific reaction in the epithelial cells and secretory ducts of the duodenal glands indicates a possible secretion of C1q. Co-localization of C1q, cathepsin G and cell adhesion proteins in the DM epithelium implies their interaction in the regulation of tissue metabolism, modification and maintenance of the barrier properties of the intestinal epithelium in normal and with inflammation.

In order to establish the supposed role of the complement system in the regulation of homeostasis and defense reactions in the intestinal epithelium, an immunofluorescent analysis was conducted of localizing the C1q complement component in the inflamed mucosa of the human duodenum (DM) (duodenitis II-III degree) using C1q-specific antibodies. The findings suggest a pronounced presence of the C1q complement component in various DM areas during inflammation, both in the epithelial layer and in the lamina propria, where C1q is localized in the region of the basolateral membrane of enterocytes and some free cells, presumably neutrophils, macrophages and mast cells. A C1q-specific reaction in the epithelial cells and secretory ducts of the duodenal glands indicates a possible secretion of C1q. Co-localization of C1q, cathepsin G and cell adhesion proteins in the DM epithelium implies their interaction in the regulation of tissue metabolism, modification and maintenance of the barrier properties of the intestinal epithelium in normal and with inflammation.

The application of sensitive logic in the modeling of intelligent aerospace complexes is considered. The morphological properties of sensitive logic are set by the metrological paradigm "the more precisely, the better", which ensures the effectiveness (reliability) of sensible logic in the prefix control of the formation of output reactions.

Aim of the study. Determination of the potential opportunity of immune protease cathepsin G (Cat G) to participate in the regulation of homeostasis and protective reactions in the intestinal epithelium by interacting with cell adhesion proteins (cadherins). Materials and methods. Biopsies of the human duodenal mucosa were examined by confocal immunofluorescence microscopy using specific antibodies to desmogleins 1-3 (DSGs 1-3), E-cadherin and Cat G of human. Results. The presence of DSG 2 in the contact area of the basolateral membrane of epitheliocytes of intestinal villi and intestinal glands (crypts) with the basal membrane was demonstrated. DSGs 1 and 3 were not detected in the test samples. E-cadherin is located in the zone of the basolateral membrane of enterocytes, goblet cells and Paneth cells. E-cadherin-specific fluorescence is also found between the secretory granules of Paneth cells, which indicates the synthesis of this protein by Paneth cells and/or E-cadherin role in intracellular signaling. In inflammation (duodenitis II-III degree) Cat G-containing granules are localized near the basal membrane of villi and intestinal glands. Conclusions. The catalytic properties of Cat G and its close proximity to the cell adhesion proteins (DSG 2 and E-cadherin) indicate the possibility of interaction of these proteins and their role in the regulation of tissue metabolism, modification and maintenance of the barrier properties of the epithelium during the development of protective and / or pathological processes.

Proteases play a key role in the physiological processes of the small intestine, supporting its normal physiological functions as a part of the digestive system, in which hydrolysis and assimilation of nutrients are implemented. A high concentration of antigens in the intestinal lumen activates immunity and stimulates a chronic weakly expressed inflammatory response in a normal gastrointestinal tract (GIT). Cathepsin G , a serine protease controlling the functional state of immune cells, directly participates in the complicated system for the regulation of balance between physiological and pathological inflammations. To determine the role of cathepsin G in the small intestine, an immunofluorescent investigation of biopsies from the human duodenal mucosa were investigated using the confocal immunofluorescence microscopy method and human antibodies to cathepsin G . It has been shown for the first time that cathepsin G , which was regarded conventionally as one of the effectors of the inflammatory process, is a constitutive enzyme of the human duodenum and is constantly present in its normal mucosa. The new cell sources for the cathepsin G biosynthesis identified: intraepithelial lymphocytes (IELs), lamina propria lymphocytes, CD 14-positive intestinal macrophages, and Paneth cells, which are specialized epitheliocytes of intestinal glands. Our data on the cathepsin G expression by immunocytes and Paneth cells in the duodenum allow us to attribute cathepsin G to the main proteases of intestinal immunity, which indicates the important role of this enzyme in the regulation of human GIT functions.

The renin-angiotensin system (RAS) is the universal multiple-factor regulator of many vital processes at the organismal, tissue and cellular levels. Classical (circulating) RAS provides maintenance of arterial pressure, a water and salt balance, lipid and glucose homeostasis. Local tissue RAS are functioning independently and participating in metabolic processes and protective reactions. Local RAS of a small intestine mucosa is presented practically by a complete rangeof the components (renin, angiotensinogen, angiotensin-converting enzymes, angiotensin receptors) localized, mainly, in an intestinal epithehum, lamina propria and muscularis mucosa. Local RAS participates in regulation of the most levels of activity ofa small intestine, influencing on an intestinal motility, secretory-transport processes, adaptation and protective reactions. The experimental data presented in this review are very promising for the detection of possible complications when using drugs that alter the activity of the RAS-related unexplored effects of the interaction of these drugs with their potential targets, localized not only in the blood vessels, but also directly to the niucosa of the gastrointestinal tract. This is especially important in connection with the extensive use of drugs that modulate the activity of the RAS in the practice of the treatment of cardiovascular diseases such as hypertension, atherosclerosis, endothelial dysfunction, and others.

We proposed a new indicator for evaluation of functional activity of Ca 2+ in human blood serum based on lysis of sheep erythrocytes with 10% human blood serum in the presence of 0.55 mM ethylene glycol tetraacetic acid at 37оC for 10 min. After incubation, the degree of sheep erythrocytes lysis inhibition is estimated: inhibition of complement hemolytic activity <30% is considered as high functional Са 2+ activity, inhibition by 31-70% corresponds to normal activity, and >71% indicates low activity. The comparative studies of complement activating function of heterophilic antibodies, complement system reactivity in the presence of 0.29 M NaCl, and functional activity of ionized Ca 2+ make possible estimation of the individual’s immune status.

A method for determining atherogenicity of the immune complexes containing multiple modified low-density lipoprotein (mmLDL) in complement fixation test has been found. In the proposed method, the precipitate immune complexes containing mmLDL (IC mmLDL) was prepared from human serum by treating it with buffer (8.3% of th PEG 3350 and 3.3% PVP 12600 th in the ratio 1: 1.2) for 10 min at 23 °C. IC mmLDL aggregates were separated by centrifugation at 3100g for 10 min at 23 °C. The precipitate IC mmLDL was dissolved in buffer without PEG and PVP, cholesterol content and the degree of binding of guinea pig complement were measured. Atherogenicity of the IC mmLDL was registered as the ratio of the degree of complement binding to cholesterol in the the immune complexes.

The gastrointestinal tract is subject to a huge antigenic load, which is especially significant in the intestinal lumen. Being the connecting link between the organism and the external environment, the small intestine fulfils not only digestive and transport functions, but also protective ones and acts as a selective barrier for the flow of nutrients. This review considers proteases of the protective system of small intestine cells, their biochemical properties and activation mechanisms, and involvement in biochemical processes responsible for normal functioning and defense reactions of the intestine. Serine proteases of intestinal immunity are multifunctional enzymes making proteolytic attack aimed to immediately exterminate aggressive elements of the intestinal contents (allergens, toxins), to activate (inactivate) zymogens, receptors, and peptide hormones, and to hydrolyze protein precursors and other biologically active factors. Proteases of intestinal immunity control the inflammatory response, proliferation of B-lymphocytes, apoptosis, and secretory and contractive activity of the intestine; they release neurogenic factors, inactivate biologically active substances, and are involved in degradation of the intercellular matrix and in tissue remodeling.

A duodenase, a protease structurally related to human cathepsin G, was found earlier in bovine duodenal mucosa. It was demonstrated that under the influence of duodenase an enteropeptidase zymogen is activated in vitro showing the possible participation of duodenase in the cascade of activation of digestive enzymes. To identify a duodenase functional analog in human duodenum, an immunofluorescence study of duodenal mucosa was conducted by confocal microscopy using antibodies to human cathepsin G and to bovine duodenase. The previously unknown place of synthesis and secretion of cathepsin G — Paneth cells located at the bottom of Lieberkuhn crypts — was revealed. Binding of cathepsin G-specific antibodies in a rough endoplasmic reticulum zone and in the cryptal duct was observed. Duodenase-specific immunofluorescence but not that of cathepsin G was found in the epitheliocytes and secretory ducts of Brunner’s glands, which are characteristic sites of duodenase biosynthesis in cattle. Binding of CD14-specific antibodies in the Brunner’s glands, where the antibodies co-localized with the antibodies to duodenase, was also demonstrated. These data indicate the presence of a protein immunologically similar to duodenase in the human duodenal mucosa. Our study demonstrated the absence of its colocalization with cathepsin G in Brunner’s glands.

In this review we present data about small intestine serine proteases, which are a considerable part of the proteolytic apparatus in this major part of the gastrointestinal tract. Serine proteases of intestinal epitheliocytes, their structural-functional features, cellular localization, physiological substrates, and mechanisms of activity regulation are examined. Information about biochemical and functional properties of serine proteases is presented in a common context with morphological and physiological data, this being the basis for understanding the functional processes taking place in upper part of the intestine. Serine proteases play a key role in the physiology of the small intestine and provide the normal functioning of this organ as part of the digestive system in which hydrolysis and suction of food substances occur. They participate in renewal and remodeling of tissues, retractive activity of smooth musculature, hormonal regulation, and defense mechanisms of the intestine.