A role of peptidoglycan recognition proteins in regulating innate immune response

By now, a whole number of pathogenic antibiotic-resistant or tolerant microorganisms has been progressively increased. Hence, efficient fight against them requires to change the class of antibiotics, increase their dose, or develop new antimicrobial drugs. On the contrary, another option could rely on augmenting innate immunity. During coevolution, eukaryotes have developed several ways for their protection against microorganisms. Innate immunity conserved in all multicellular organisms. The essential principles of innate immunity include recognition of a foreign structures and their subsequent destruction. A set of specific receptors recognize conserved pathogen-derived structures. Elimination occurs due to phagocytosis and cleavage, e.g. via oxidative burst in phagocytic cells, compliment system or antimicrobial peptides. Recognition system in innate immunity is based on the pattern recognition receptors. Due to the pathogen diversity, multiple conserved structures typical to pathogens (e.g. lipopolysaccharide, peptidoglycan, flagellin etc.) are sensed by numerous receptors. The family of peptidoglycan recognition proteins is among such receptors, which were first isolated in 1996 from the silkworm Bombyx mori and mice. Later, it was demonstrated that this family is conserved and its members are found in insects, fish and mammals. Here, functions of insect peptidoglycan recognition proteins in Drosophila melanogaster as well as mammals are discussed. Such proteins are expressed mainly in liver cells (insects — in adipose tissue cells as analogue of mammalian liver), intestinal cells, and epidermis. Numerous studies demonstrate that peptidoglycan-recognition proteins moderate immune response, and may act as antimicrobial proteins, or to regulate microbiota as well as prevent enterocyte activation and restrict inflammatory response. Due to evolutionary conservatism observed for such proteins and inability for bacteria to evade their protective effects, it seems promising to use peptidoglycan recognition proteins in a combination therapeutic approach against antibiotic-resistant and antibiotic-tolerant forms of microorganisms

MODELING OF EJECTOR PUMPS OPERATION WITH USING ANSYS

To optimize designs of the ejector pumps being developed, modeling was performed using the ANSYS CFX package. A comparison is made with the experimental data of pressure measurements in chambers of the experimental model

Системы для контролируемого высвобождения и адресной доставки факторов роста в лечении хронических ран

Growth factors (GFs) are endogenous signaling proteins, that regulate cell migration, proliferation and differentiation in tissue regeneration. GFs’ concentrations in chronic wounds are pathologically reduced. This leads to a disruption of the healing process and makes chronic wounds treatment more complicated. There are drugs currently used in clinical practice, that contain GFs in a free form. However, their efficiency for chronic wounds treatment is limited, as GFs are quickly degraded in a proteolytic environment of chronic wounds. In order to overcome this limitation biocompatible molecular systems for targeted delivery and controlled release are proposed, such as: micro- and nanoparticles, hydrogels, scaffolds. GFs roles in the healing process, chronic wounds pathophysiology and molecular systems for GFs targeted delivery and controlled release are reviewed.Факторы роста (ФР) – это эндогенные сигнальные белки, которые регулируют миграцию, пролиферацию и дифференцировку клеток в процессах репарации тканей. Концентрация этих белков в хронических ранах патологически снижена, что приводит к нарушению нормального течения раневого процесса и существенно затрудняет их лечение. В клинической практике используются препараты, содержащие рекомбинантные ФР в свободной форме. Однако их эффективность для лечения хронических ран ограничена, так как в протеолитической среде таких ран ФР подвергаются быстрой деградации. Для преодоления этого недостатка предложены системы для адресной доставки и контролируемого высвобождения на основе биосовместимых материалов: микро- и наночастицы, гидрогели, биопластические материалы. В настоящем обзоре рассмотрены роли ФР в раневом процессе, особенности патофизиологии хронических ран и системы для контролируемого высвобождения и адресной доставки ФР

Identification of Nedd4 E3 Ubiquitin Ligase as a Binding Partner and Regulator of MAK-V Protein Kinase

MAK-V/Hunk is a scantily characterized AMPK-like protein kinase. Recent findings identified MAK-V as a pro-survival and anti-apoptotic protein and revealed its role in embryonic development as well as in tumorigenesis and metastasis. However molecular mechanisms of MAK-V action and regulation of its activity remain largely unknown. We identified Nedd4 as an interaction partner for MAK-V protein kinase. However, this HECT-type E3 ubiquitin ligase is not involved in the control of MAK-V degradation by the ubiquitin-proteasome system that regulates MAK-V abundance in cells. However, Nedd4 in an ubiquitin ligase-independent manner rescued developmental defects in Xenopus embryos induced by MAK-V overexpression, suggesting physiological relevance of interaction between MAK-V and Nedd4. This identifies Nedd4 as the first known regulator of MAK-V function

INHIBITION OF THE NKG2D ACTIVATING RECEPTOR EXPRESSION ON CYTOTOXIC LYMPHOCYTES BY RECOMBINANT MICA PROTEIN

Genome instability of transformed cells, being the most common factor of malignancy, may result into production of abnormal proteins in these cells. Normally, the newly formed proteins are recognized by immune system, thus causing elimination of the transformed cells. Nevertheless, the phenotypic instability promotes formation of specific transformed cells which suppress effector immune reactions and/or are unrecognizable by cytotoxic lymphocytes. NKG2D is one of the most important activating receptors expressed by NK cells. It serves as a major recognition receptor for detection and elimination of tumor and infected cells. The ligands for NKG2D include surface or circulating non-canonical MICA/B molecules from class I major histocompatibility complex (MHC class I chain–related proteins A and B). MICA and MICB are expressed scarcely, if at all, by the most normal cells, being, however, upregulated in cancer cells and virus-infected cells.NKG2D receptor-ligand interaction is important for regulation of anti-tumor immune reactions. The soluble form of MICA accumulated in blood due to proteolytic shedding from tumor cell membranes is able to inhibit the NKG2D mediated anti-tumor cytotoxicyty and, therefore, promote the immune escape. The aim of our study was to estimate blocking effects of soluble recombinant human MICA protein (rhsMICA) upon NKG2D receptor of NK cells.Mononuclear cells were isolated from peripheral blood, followed by incubation with of rhsMICA at different concentrations (0, 1, 5, or 10 µg/ml), staining with anti-CD314 (NKG2D) mAbs on the CD3- CD56+NK cells, and flow cytometry analysis. A similar treatment protocol was applied for IL2- and IL15-activated mononuclear cells isolated from the melanoma patients.It has been shown that brief incubation of lymphocytes with rhsMICA caused a significantly reduced expression of NKG2D receptor on the surface of cytotoxic lymphocytes, both from healthy donors and melanoma patients. These changes depended on the MICA dose. Meanwhile, the cytokine-activated lymphocytes seem to become more resistant to inhibiting effects of rhsMICA, and, thus, do not cause any significant reduction of NKG2D expression on the activated NK cells. This fact may be a pre-requisite for usage of activated NK-cells for adoptive immunotherapy of cancer patients with MICA-positive malignancies

INHIBITION OF THE NKG2D ACTIVATING RECEPTOR EXPRESSION ON CYTOTOXIC LYMPHOCYTES BY RECOMBINANT MICA PROTEIN

Genome instability of transformed cells, being the most common factor of malignancy, may result into production of abnormal proteins in these cells. Normally, the newly formed proteins are recognized by immune system, thus causing elimination of the transformed cells. Nevertheless, the phenotypic instability promotes formation of specific transformed cells which suppress effector immune reactions and/or are unrecognizable by cytotoxic lymphocytes. NKG2D is one of the most important activating receptors expressed by NK cells. It serves as a major recognition receptor for detection and elimination of tumor and infected cells. The ligands for NKG2D include surface or circulating non-canonical MICA/B molecules from class I major histocompatibility complex (MHC class I chain–related proteins A and B). MICA and MICB are expressed scarcely, if at all, by the most normal cells, being, however, upregulated in cancer cells and virus-infected cells.NKG2D receptor-ligand interaction is important for regulation of anti-tumor immune reactions. The soluble form of MICA accumulated in blood due to proteolytic shedding from tumor cell membranes is able to inhibit the NKG2D mediated anti-tumor cytotoxicyty and, therefore, promote the immune escape. The aim of our study was to estimate blocking effects of soluble recombinant human MICA protein (rhsMICA) upon NKG2D receptor of NK cells.Mononuclear cells were isolated from peripheral blood, followed by incubation with of rhsMICA at different concentrations (0, 1, 5, or 10 µg/ml), staining with anti-CD314 (NKG2D) mAbs on the CD3- CD56+NK cells, and flow cytometry analysis. A similar treatment protocol was applied for IL2- and IL15-activated mononuclear cells isolated from the melanoma patients.It has been shown that brief incubation of lymphocytes with rhsMICA caused a significantly reduced expression of NKG2D receptor on the surface of cytotoxic lymphocytes, both from healthy donors and melanoma patients. These changes depended on the MICA dose. Meanwhile, the cytokine-activated lymphocytes seem to become more resistant to inhibiting effects of rhsMICA, and, thus, do not cause any significant reduction of NKG2D expression on the activated NK cells. This fact may be a pre-requisite for usage of activated NK-cells for adoptive immunotherapy of cancer patients with MICA-positive malignancies