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The effect of polysaccharides isolated from the aboveground parts of Saussurea salicifolia (L.) DC on Th2 type immune response reactions was studied. Administration of water-soluble polysaccharides presented by arabino-galacturonans (weight average molecular weight 158.49 kDa) to mice against the background of experimental Th2 immunity reduced the severity of anaphylactic and local immediate type hypersensitivity reactions. It also suppressed the production of ovalbumin-specific IgE and IgG1 and increased the stability of mast cell membranes. The studied polysaccharide complex increased IFNγ secretion and inhibited IL-4 synthesis. These findings suggest that these polysaccharides may be considered as potential anti-allergic agents that suppress the development of allergy in its early stages., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)

Substances of silver nanoparticles dialyzed through a 13 kDa membrane, synthesized in a medium of humic ligands modified with hydroquinone and 2-hydroxynaphthoquinone from PowHumus brown coal, specifically enhance the M2 properties of peritoneal macrophages due to inhibition of NO synthase and significant activation of arginase, thus enhancing anti-inflammatory properties of cells. In small, but effective concentrations, they do not have cytotoxic properties and do not contain pyrogenic impurities. The studied humates are able to influence the mechanisms of immune response formation and are an effective means for correcting inflammation and regeneration., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)

The genus Saussurea has been used in the preparation of therapies for a number of medical problems, yet not much is known about the therapeutic high-molecular-weight compounds present in extracts from these plants. Since polysaccharides are important in immune modulation, we investigated the chemical composition and immunomodulatory activity of Saussurea salicifolia L. and Saussurea frolovii Ledeb polysaccharides. Water-soluble polysaccharides from the aerial parts of these plants were extracted using water at pHs of 2 and 6 and subsequently precipitated in ethanol to obtain fractions SSP2 and SSP6 from S. salicifolia and fractions SSF2 and SSF6 from S. frolovii . The molecular weights of fractions SSP2, SSP6, SFP2, and SFP6 were estimated to be 143.7, 113.2, 75.3, and 64.3 kDa, respectively. The polysaccharides from S. frolovii contained xylose (67.1-71.7%) and glucose (28.3-32.9%), whereas the polysaccharides from S. frolovii contained xylose (63.1-76.7%), glucose (11.8-19.2%), galactose (4.7-8.3%), and rhamnose (6.8-9.4%). Fractions SSP2, SSP6, and SFP2 stimulated nitric oxide (NO) production by murine macrophages, and NO production induced by SSP2, SSP6, and SFP2 was not inhibited by polymyxin B treatment of the fractions, whereaspolymyxin B treatment diminished the effects of SFP6, suggesting that SFP6 could contain lipopolysaccharide (LPS). The LPS-free fractions SSP2, SSP6, and SFP2 had potent immunomodulatory activity, induced NO production, and activated transcription factors NF-κB/AP-1 in human monocytic THP-1 cells and cytokine production by human MonoMac-6 monocytic cells, including interleukin (IL)-1α, IL-1β, IL-6, granulocyte macrophage colony-stimulating factor (GM-CSF), interferon-γ, monocyte chemotactic protein 1 (MCP-1), and tumor necrosis factor (TNF). These data suggest that at least part of the beneficial therapeutic effects reported for water extracts of the Saussurea species are due to the modulation of leukocyte functions by polysaccharides.

Humic acids isolated by sodium pyrophosphate extraction from various types of peat activate macrophages in the classical proinflammatory pathway and stimulate nitric oxide production by these cells. This effect is mediated by activation of intracellular signaling pathways involving MAPK p38, PI3K, MEK 1/2 kinase, cAMP, and NF-κB via TLR-2 and TLR-4 receptors., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature.)

The course administration of humic acids isolated with sodium pyrophosphate from raised bog sphagnum peat reduces the parameters of a Th1-type immune response in C57BL/6 mice, the severity of an anaphylactic shock in outbred CD1 mice, and degranulation of mast cells after their immunization with ovalbumin. The addition of humic acids increases the stimulated production of IL-4, IL-10 and reduces the production of IL-2, IFNγ by peripheral blood mononuclear cells of healthy donors., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature.)

We studied the pharmacokinetics of a pegylated IFN-λ1 (PEG IFN-λ1) after its oral administration to rats in different therapeutic doses. The hypothesis on linear pharmacokinetics of PEG IFN-λ1 within the dose range of 2.6-7.8 μg/kg was confirmed, high for protein molecules bioavailability from 17.5 to 21%, the absence of intravascular deposition, and effective elimination with feces and urine (85 and 15% of the administered dose, respectively) were demonstrated. At the same time, the mean retention time for PEG IFN-λ1 in the circulation is 6.46-6.65 h and half-life is 3 h. These findings give ground for continuing experimental studies of PEG IFN-λ1 pharmacokinetics, in particular, tissue distribution of the drug., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)

The course administration of humic acids isolated by the sodium pyrophosphate method from pine-sphagnum-cotton sedge peat reduced the general anaphylaxis reaction in mice and guinea pigs immunized with ovalbumin and decreased serum content of IgG1 and IgE in mice. The serum from mice treated with humic acids and sensitized with ovalbumin did not increase the rate of degranulation of mast cells isolated from intact Wistar rats in the presence of ovalbumin in comparison with the serum of control animals., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)

The in vitro addition of water-soluble polysaccharides isolated from the leaves of Crataegus sanguinea Pall. to culture of mouse peritoneal macrophages induced classical activation of antigen-presenting cells by increasing NO synthase activity and reducing arginase expression., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Under conditions of steady-state hemopoiesis, nuclear factor NF-κB, in contrast to MAP kinase p38, plays an important role in the maintenance of the initial level of secretory activity of monocytes. The increase in the production of G-CSF under stress conditions (10-h immobilization) is mainly regulated by the alternative p38MARK signaling pathway via activation of p38 synthesis. It was shown that under conditions of cytostatic-induced myelosuppression, the production of protein kinase p38 in cells decreases, and it, like NF-κB, is not the main one in the production of hemopoietin by mononuclear phagocytes., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Humic acids extracted with sodium pyrophosphate from Oligotrophic Sphagnum magellanicum peat reduce mitogen-stimulated production of anti-inflammatory cytokine IL-10 by mouse peritoneal macrophages and do not affect the secretion of IL-4 by lymphocytes. The studied humic acid sample stimulates the production of proinflammatory cytokines IL-12, TNFα, IL-1β, and IFNγ by immunocompetent mouse cells and human mononuclear cells. Course administration of humic acids to mice enhances the humoral immunity, increasing the number of antibody-forming cells in the spleen and the titer of antibodies in the blood serum after immunization with sheep red blood cells.

A synthetic method for the promising new drug oseltamivir ethoxysuccinate is described in detail. Various conditions for obtaining the target substance are considered. Its complete physicochemical characteristics are given. The obtained agent is shown to be effective against influenza virus A (H1N1)pdm09., (© Springer Science+Business Media, LLC, part of Springer Nature 2021.)

Addition of water-soluble polysaccharides isolated from Conium maculatum L. to the mouse peritoneal macrophage culture induces classical activation of antigen-presenting cells due to an increase in NO synthase activity and a decrease in arginase expression.

A novel specific inhibitor of c-Jun N-terminal kinase, 11 H -indeno[1,2- b ]quinoxalin-11-one oxime sodium salt (IQ-1S), has a high affinity to JNK3 compared to JNK1/JNK2. The aim of this work was to study the mechanisms of neuroprotective activity of IQ-1S in the models of reversible focal cerebral ischemia (FCI) in Wistar rats. The animals were administered with an intraperitoneal injection of IQ-1S (5 and 25 mg/kg) or citicoline (500 mg/kg). Administration of IQ-1S exerted a pronounced dose-dependent neuroprotective effect, not inferior to the effects of citicoline. Administration of IQ-1S at doses of 5 and 25 mg/kg reduced the infarct size by 20% and 50%, respectively, 48 h after FCI, whereas administration of citicoline reduced the infarct size by 34%. The administration of IQ-1S was associated with a faster amelioration of neurological status. Control rats showed a 2.0-fold increase in phospho-c-Jun levels in the hippocampus compared to the corresponding values in sham-operated rats 4 h after FCI. Administration of IQ-1S at a dose of 25 mg/kg reduced JNK-dependent phosphorylation of c-Jun by 20%. Our findings suggest that IQ-1S inhibits JNK enzymatic activity in the hippocampus and protects against stroke injury when administered in the therapeutic and prophylactic regimen in the rat model of FCI.

Suppression of the production of granulocytic CSF under the effect of 5-fluorouracyl is related to disorders in the NF-κB-, cAMP-dependent signaling pathways and MAPK cascade. These secondary messengers are involved in the regulation of functional activity of nonadherent myelokaryocytes starting from day 10 of the experiment (initial period of the hemopoietic granulocytic stem regeneration after antimetabolite challenge). Granulocytic CSF does not play essential role in the formation of colony-stimulating activity of cells of the adherent and nonadherent fractions of the bone marrow. Only cAMP-dependent pathway is involved in the regulation of the realization of the granulocytic precursor growth potential in response to the challenge.

A course of treatment with humic acids extracted with sodium pyrophosphate from high-moor pine-peat moss-cotton grass peat improves humoral immune response of C57BL/6 mice, stimulates the production of TNFα, IL-1β, and IL-12 by the animal peritoneal macrophages and the production of IFNγ and TNFα by donor peripheral blood mononuclears, causing no changes in the production of IL-10 in vitro.

The role of signaling molecules in synthesis of humoral regulators of granulocytopoiesis by the hematopoietic microenvironmental cells during stress was analyzed using specific inhibitors. The major role in stimulation of the synthesis of granulocytic CSF during stressful stimulation is played by PI3K/Akt signaling cascade. Nuclear transcription factor NF-κB plays an auxiliary role in the regulation of functional activity of the bone marrow mononuclears. However, this factor affects the synthesis of granulocytic CSF by CD4 + cells of the bone marrow in response to stressful stimulation. Different degree and specific character of involvement of the signaling proteins in the regulation of the production of humoral factors determining colony-stimulating activity are explained by changes in functional state of monocyte-derived macrophages in different periods of stress response.

The involvement of the studied signal cascades in the regulation of erythropoietin production by bone marrow nuclears under conditions of immobilization stress depends on the type of the hemopoiesis-inducing microenvironment cells and the period of blood system reaction to stress exposure. Secretory activity of monocytes is regulated mainly by PI3K improving cell resistance to disturbances. The functional role of signal cascades involved in the production of erythropoietin by T cells is determined by the stage of the common adaptation syndrome.

We studied activation of macrophages with humic acids extracted from peat of large deposits in the Tomsk region by two extraction methods: by hydroxide or sodium pyrophosphate. Humic acid of lowland peat types containing large amounts of aromatic carbon, phenolic and alcohol groups, carbohydrate residues and ethers, irrespectively of the extraction methods contained LPS admixture that probably determines their activating properties. Humic acid of upland peat types characterized by high content of carbonyl, carboxyl, and ester groups enhance NO production and reduce arginase expression, but these effects were minimized when sodium hydroxide was used as an extraction solvent. Pyrophosphate samples of the upland peat types were characterized by aromaticity and diversity of functional groups and have a significant advantage because of they induce specific endotoxin-independent stimulating action on antigen presenting cells.

The leading role in the regulation of erythropoietic activity of adherent bone marrow cells under conditions of post-hemorrhagic anemia is played by classical MAP kinase pathway (ERK pathway). Erythropoietin is not the decisive factor in the formation of erythropoietic activity of adherent cells. PI3K, MAPK/ERK 1/2, and p38-signaling proteins are not the main regulators of local production of erythropoietin after 30% loss of circulating blood volume.

Course treatment with IFN-α2b immobilized on polyethylene glycol stimulates phagocytic activity of peritoneal macrophages and neutrophils, enhances humoral immune response in CBA/CaLac mice, stimulates IL-4 synthesis, and suppresses IFN-γ production by mitogenstimulated splenocytes from experimental animals.

A screening study of biological activity of native humic acids isolated from peat was performed; several physical and chemical parameters of their structures were studied by UV- and infrared spectroscopy. Spectroscopy yielded similar shape of light absorption curves of humic acids of different origin, which can reflect similarity of general structural principles of these substances. Alkaline humic acids have more developed system of polyconjugation, while molecular structures of pyrophosphate humic acids were characterized by higher aromaticity and condensation indexes. Biological activity of the studied humic acids was assessed by NO-stimulating capacity during their culturing with murine peritoneal macrophages in a wide concentration range. It was shown that due to dose-dependent enhancement of NO production humic acids can change the functional state of macrophages towards development of pro-inflammatory properties. These changes were associated with high activity of humic acids isolated by pyrophosphate extraction, which allows considering effects of isolation method on biological activity.

Screening study of the effects of sweet flag (Acorus calamus L.) rhizome and clover (Trifolium pratense L.) aerial part on the production of NO by mouse macrophages was carried out. The polysaccharides were separated by ion exchange chromatography into fractions differing by monomeric composition and ramification type and were used in concentrations of 20, 40, and 100 μg/ml. Four fractions of Acorus calamus L. (PSF-101, PSF-102, PSF-103, and PSF-105), used in different concentrations, moderately stimulated nitrite production by macrophages. Three of five Trifolium pratense L. polysaccharides (PS62-3, PS62-4, and PS62-5) exhibited a significant specific effect on NO production. Rhamnogalactouronans from clover PS63-3 in all concentrations and from PS62-5 in a concentration of 100 μg/ml exhibited the highest activity, comparable to the NO-stimulatory activity of the reference LPS, while polysaccharide PS62-3 in a concentration of 40 μg/ml exhibited even higher activity.

PI3- and MAP-kinase signaling pathways duplicate and interchange each other in production of agents that determine total erythropoietic activity under conditions of balanced erythropoiesis. The alternative p38-dependent MAP-kinase pathway is the major regulator of erythropoietic activity of adherent bone marrow cells. Blockade of PI3K and p38 signaling pathways stimulated production of erythropoietin by cells that do not produce it constitutively.

The role of JNK-mediated signal pathway and participation of p53 transcription factor in stimulation of mesenchymal precursor cell function by the fibroblast growth factor was studied. The levels of fibroblast colony- and cluster formation and proliferative activity of mesenchymal precursors increased in response to JNK and p53 specific inhibitors. JNK and p53 blockers did not change the rate of fibroblast growth factor-induced progenitor element differentiation.

Specific JNK and p53 inhibitors stimulated the formation of fibroblast colonies (CFU-F) and clusters (ClFU-F) and increased proliferative activity of mesenchymal progenitor cells. No effects of inhibitors of JNK and p53 on differentiation of progenitor elements were revealed.

The involvement of PI3K, ERK and p38-dependent signaling system in the regulation of functional activity of erythroid precursors after blood loss (30% of circulating volume) was studied. We demonstrated the important role of PI3K and p38 in the suppression of differentiation of erythroid precursors the contribution of p38 to stimulation of mitotic activity of erythroid CFU, which maintains the growth potential of the precursors at the optimal physiological level. The classical MAPK/ERK-kinase pathway does not determine the proliferative and differentiation status of erythroid CFU.

A preclinical study of the immunocorrection action of the sum of active substances isolated from ethereal-oil plants Coluria geoides (Pall.) Ledeb. (Rosaceae family) with respect to experimental immunodeficiency showed that preparations relieve symptoms of immunodeficiency caused by the administration of cyclophosphan: suppressed synthesis of anti-erythrocyte antibodies (agglutinine) and proliferative processes in the spleen. Under the influence of C. geoides preparations, the absolute numbers of cariocytes and antibody forming cells in spleen significantly increased (compared to the group of animals with experimental immunodeficiency) and in some cases reached the background level. The drugs studied produced a more pronounced stimulating effect on the synthesis of specific immunoglobulins and proliferation of antibody forming cells of spleen as compared to the effect of Echinacea tincture. Preparation C-2 (extract from underground organs and grass of C. geoides obtained by percolation method with 70% ethanol) is most promising for in-depth research and the development of new effective drugs with immunocorrecting properties.

The effects of extracts from licorice (Glycyrrhisa glabra), great nettle (Urtica dioica), common burdock (Arctium lappa), and bur marigold (Bidens tripartite) on the humoral and cellular immune response and nonspecific resistance in mice were studied. Burdock and bur marigold extracts stimulated the humoral immune response, nettle and licorice extracts stimulated cellular response and nonspecific resistance, their effects being superior to those of pharmacopoeial Echinacea purpurea tincture.

Poetam and anaferon (pediatric formulation) administered in combination with iron preparation to patients with anemia induce pronounced positive shifts in metabolic and morphological status of mature erythrocytes: the number of sulfhydryl groups and lipoprotein complexes in cell membranes and dry weight of erythrocytes increased, while the number of forms at different stages of degeneration decreased.

Immune reactions of the progeny of female Wistar rats injected with paclitaxel a single MPD of 1 and 3 months before mating with intact males were studied. Thymic hyperplasia was detected in the progeny of female rats mated 1 month after treatment. Disorders in the antibody-specific and antibody-nonspecific mechanisms of the immune response were detected in the progeny of females mated with intact males 3 months after cytostatic treatment.

Natural suppressor cells from the bone marrow of intact animals and mice with Th1- and Th2-dependent immune response largely suppressed the production of Th1 (IFN-gamma, IL-2) and Th2 cytokines (IL-4). Antiproliferative activity of natural suppressor cells from intact and immunized animals was mediated by NO. Proliferation of Th1 cells was suppressed greater than that of Th2 cells. This selective effect of natural suppressor cells on the proliferation of target lymphocytes was due to higher stimulatory potential of Th1 cells (in comparison with Th2) towards natural suppressor cells.

We studied the content of hemopoietic precursor cells in the bone marrow, production of IL-1, IL-3, and colony-stimulating and erythropoietic activities by bone marrow cells under conditions of chronic stress. It was shown that in mice subjected to 15-h immobilization no hyperplasia of the bone marrow developed against the background of increased content of committed erythro- and granulomonocytopoietic precursors and enhanced production of short-distant humoral regulators of hemopoiesis, which reflects dysregulation of hemopoietic cells proliferation and differentiation processes in stressed animals.

The influence of a dry extract from Bergenia crassifolia (Fritsch) on the specific immune response parameters was studied under extremal conditions of model immunodepressive states induced by immobilization stress or cyclophosphamide injections. The drug produced normalizing effect on the content of antibody-forming cells in the spleen of experimental mice under the conditions of humoral response stimulation by antigen and in both immunodepression models. The bergenia extract decreases expression of inflammatory processes under delayed hypersensitivity reaction conditions, by preventing the accumulation of T-lymphocytes in the inflammation focus and reducing the ability of cells to produce anti-inflammatory cytokines.

Baikal skullcap extract was introduced into cytostatic therapy of mice with Lewis lung carcinoma. This extract potentiated the antimetastatic effect of cyclophosphamide in mice with grafted tumors. Combined treatment with cyclophosphamide and extract of Baikal skullcap modulated cytotoxic activity of natural killer cells and peritoneal macrophages during tumor growth.

We studied the effects of antibodies against interferon-gamma, erythropoietin, and tumor necrosis factor-alpha in ultralow doses on the production of endogenous interferon-gamma. Course peroral treatment with potentiated antibodies to interferon-gamma in various dilutions produced similar changes in experimental animals. The treatment stimulated spontaneous production of endogenous interferon-gamma by mouse lymphocytes. It should be emphasized that antibodies to other cytokines in ultralow doses did not stimulate interferon-gamma production. These data illustrate the specificity of action of antibodies to endogenous regulators in ultralow doses.

Mice of different strains can be classified by the intensity of humoral immune reaction to thymus-dependent antigen as high, moderate, and low responders. High and moderate responders (CBA/CaLac, DBA/1, BALB/c) are characterized by high sensitivity of the productive phase of humoral immune response and phagocytic activity of macrophages to immobilization stress. In low responders (C57BL/6, CC57W) stress only slightly affected the productive phase of the humoral immune response, but activity of peritoneal macrophages decreased. These differences in the reactions of the immune system of inbred mice after immobilization stress reflect different reactions of the immune system to extreme factors.

T cells were most sensitive to cyclophosphamide in DBA/2 mice, while in C57Bl/6 mice both T and B cells were sensitive. The formation of antibody-producing cells and the production of specific antibodies were delayed in DBA/2 mice immunized after pretreatment with antitumor drug. Accumulation of antibody-producing cells in the spleen was more active in immunized C57Bl/6 mice treated with cyclophosphamide compared to animals not treated with cyclophosphamide.

We studied the effects of ultralow doses of anti-idiotypic antibodies to human gamma-interferon on humoral immune response in experimental animals immunized with a thymus-dependent antigen, delayed-type hypersensitivity, and phagocytic activity of neutrophils in the peritoneal exudate. This preparation stimulated the humoral immune response and activated phagocytosis, but had no effect on functional activity of T cells.

We studied immunotropic properties of antibodies to human interferon-gamma in homeopathic doses. The effects of these antibodies on the ratio between the counts of T helper (CD4+) and T suppressor cells (CD8+), production of interleukin-1 and interleukin-2, and functional activity of natural killer cells were evaluated. Potentiated antibodies slightly decreased the number of CD8+ cells in the spleen of experimental animals. After the addition to cultured human mononuclear cells the preparation produced a moderate comitogenic effect, stimulated proliferation of T and B lymphocytes, increased spontaneous and induced production of interleukin-1, and enhanced functional activity of natural killer cells (under certain conditions).

The responses of immunocompetent cells to thymus-dependent antigen differ in mice of different strains. Immunization stimulated phagocytic activity of peritoneal macrophages in CBA/CaLac, DBA/2, and BALB/c mice and suppressed it in CC57W mice. By the formation of antibody-producing cells in the spleen in response to thymus-dependent antigen DBA/2 and CBA/CaLac mice can be classified as high responders, BALB/c mice as medium-responders, and C57Bl/6 and CC57W mice as low responders.