Prospects for the Use of Marine Sulfated Fucose-Rich Polysaccharides in Treatment and Prevention of COVID-19 and Post-COVID-19 Syndrome.

Symptoms of the new coronavirus infection that appeared in 2019 (COVID-19) range from low fever and fatigue to acute pneumonia and multiple organ failure. The clinical picture of COVID-19 is heterogeneous and involves most physiological systems; therefore, drugs with a wide spectrum of mechanism of action are required. The choice of the treatment strategy for post-COVID-19 syndrome is still a challenge to be resolved. Polysaccharides with a high fucose content derived from seaweed and marine animals can form the basis for the subsequent development of promising agents for the treatment of COVID-19 and post-COVID-19 syndrome. This class of biopolymers is characterized by a variety of biological activities, including antiviral, antithrombotic, anticoagulant, hemo-stimulating, anti-inflammatory and immune-regulatory. Low molecular weight derivatives of these polysaccharides, as well as synthetic oligosaccharides with a sufficient amount and sulfation type may be considered as the most promising compounds due to their better bioavailability, which undoubtedly increases their therapeutic potential.

Erratum to: Prospects for the Use of Marine Sulfated Fucose-Rich Polysaccharides in Treatment and Prevention of COVID-19 and Post-COVID-19 Syndrome.

[This corrects the article DOI: 10.1134/S1068162022060152.].

Secretome of Mesenchymal Bone Marrow Stem Cells: Is It Immunosuppressive or Proinflammatory?

Mesenchymal stem cells (MSC) are characterized by tolerogenic potential and therefore, are used in the treatment of autoimmune diseases such as graft-versus-host disease (GVHD) reactions after allogeneic hematopoietic cell transplantation to improve the transplant functions, as well as for the therapy and prevention of cytokine storm in COVID-19 patients and some other conditions. However, MSC can exhibit proinflammatory activity, which causes risks for their clinical use. We studied the cytokine profile of bone marrow MSC culture and demonstrate intensive production of IL-6, IL-8, and chemokine MCP-1, which participate in the pathogenesis of cytokine storm and GVHD. At the same time, no anti-inflammatory IL-4 and IL-10 were detected. To reduce the risks of MSC application in the GVHD therapeutic protocols, further studies of the conditions promoting generation of MSC with tolerogenic potential and approved clinical standards of MSC use are required.

Experimental evaluation of combined immunotherapy for tumors.

The minimal vaccination dose of tumor cells was determined on experimental models. The effectiveness of antitumor immunotherapy with activated natural killer cells or dendritic cell vaccine (monotherapy or combined treatment) was evaluated in vivo. The inhibition of tumor growth was more pronounced after combination therapy with activated natural killer cells and dendritic cell-based vaccine. Our results indicate that the effectiveness of antitumor immunotherapy increases in simultaneous modulation of both immune components (innate and adaptive immunity).

[Influence of regulatory T cells on the functioning of natural killer cells during cancer immunotherapy].

One of the common arguments against cancer immunotherapy based on natural killer (NK) cells activated in the presence of interleukin-2 (IL-2) is the probability of the activation of regulatory T cells (Tregs) by IL-2 besides NK cells. Thus, we have monitored numbers of FoxP3+CD4+CD25+ T cells in the samples of healthy volunteers' peripheral blood mononuclear cells (PBMCs) cultured with or without IL-2. We observed marked increase in the percentages of the CD4+CD25+ T cells in the presence of IL-2. Proportions of Foxp3+CD4+CD25+ T cells feebly increased, remained on the same level or even decreased compared to PBMCs cultured without exogenous IL-2. Based on the absence of FoxP3 expression, most of the CD4+CD25+ T cells purified from IL-2 activated PBMCs were not Tregs, but activated Th cells. Moreover, the addition of the purified supposed Tregs to samples of activated NK cells never inhibited their cytotoxic reactions.

Use of recombinant interleukin-2 for intrapleural therapy of tumor-associated pleurisy.

Clinical efficiency of low dose Roncoleukin was studied in 30 patients with metastatic exudative pleurisy. Intrapleural therapy proved to be highly effective (overall effect reached 84%), was well tolerated, and improved patients' quality of life.

[Adoptive immunotherapy of malignancies].

The results of the studies show that mononuclear leukocytes isolated from human peripheral blood, malignant effusions, and surgically removed spleen can be generated into lymphokine-activated killers (LAK) characterized by high anti-tumor activity. LAKs may be used foradoptive immunotherapy of malignant effusions and the prevention of tumor recurrence in oncological patients after radical surgery.

[Comparative characteristic of the methods of immunocytochemistry and immunomagnetic separation for detection of cytokeratin-positive cells in bone marrow and lymph nodes].

Comparative study of cytokeratin-positive (CK+) cells, isolated from bone marrow and lymph node micrometastases in patients with lung and esophageal cancer, was performed using the methods of immunocytochemistry and immunomagnetic separation. It was found that immunocytochemical analysis permitted the detection of CK+ cells in the smears of bone marrow of oncologic patients. All the samples of bone marrow with immunocytochemically demonstrated CK+ cells, contained also the cellular complexes marked by magnetic spheres. The method of positive immunomagnetic separation has some advantages for the intraoperative diagnosis. However, when either method was applied, among CK+ cells in bone marrow and lymph nodes some false-positive, questionable cellular forms and hemopoietic cells expressing epithelial markers were found. Theses results suggest that for verification of micrometastases in these organs, an additional study using the standard staining of the slides, is required.

Selective antitumor activity of lymphokine-activated killer cells in vitro.

We compared cytotoxic activity of blood mononuclear leukocytes from healthy donors and lymphokine-activated killer cells generated from them towards tumor and normal cells. Lymphokine-activated killer cells exhibited higher (in comparison with blood mononuclear leukocytes) killer activity towards tumor cells. Lymphokine-activated cells and mononuclear leukocytes had no lytic effect on non-transformed eukaryotic cells. Hence, we demonstrated selective cytotoxic activity of effector cells (lymphokine-activated killers) towards tumor cells of different origin (but not normal cells).

Combined effect of cisplatin and lymphokine-activated killer cells on A549 cells of non-small cell lung cancer.

We studied the ability of lymphokine-activated killer cells to lyse A549 human non-small cell lung cancer cells after preincubation with cisplatin. Lymphokine-activated killer cells obtained after incubation of human blood lymphocytes with interleukin-2 were characterized by high expression of natural killer cell antigens and activation molecules. Lymphokine-activated killer cells produced potent cytotoxic effect on intact A549 cells and lysed tumor cells survived after treatment with cisplatin in concentrations of IC50 and IC30. Cisplatin in noncytotoxic concentrations did not increase lytic activity of lymphokine-activated killer cells.

Effect of "Profetal" on differentiation and functional activity of human mononuclear leukocytes.

The effect of "Profetal", a preparation containing human alpha-fetoprotein, on proliferative activity and differentiation of mononuclear leukocytes isolated from donor peripheral blood was studied in cultures with serum-free media. The results suggest that human alpha-fetoprotein in effective doses stimulates proliferation and blast transformation of cultured peripheral blood mononuclear leukocytes with the formation of CD34+/CD45+ hemopoietic precursor cells. This phenomenon of ex vivo generation of hemopoietic precursor cells using human alpha-fetoprotein can be important for clinical oncology, specifically, for the development of adaptive cell therapies.

Cytotoxic activity of lymphocytes isolated from mouse liver involved into tumor process.

We studied cytotoxic activity and immunophenotype of mononuclear cells isolated from the liver of mice after implantation of ovarian cancer cells into the liver parenchyma. The isolated cells exhibited higher natural killer cell activity and possessed higher cytotoxic potential against autologous tumor cells compared to spleen lymphocytes. The ratio of CD3+ lymphocytes and natural killer cells was high in the liver with tumor metastases. Lymphoid cells were practically absent in the liver of intact animals. Natural killer cells and T cells from liver tumor tissue play an important role in antitumor immunity and can be used for local and regional adjuvant immunotherapy of liver metastases.

[Morphological and functional characteristics of lymphokine-activated killer cells generated from the mononuclear cells of human peripheral blood].

The aim of this research was to study the morphological, functional and immunophenotypical characteristics of lymphokine-activated killer cells (LAKC) generated from the mononuclear cells (MNC) of healthy donors' peripheral blood at different time intervals after the cultivation with interleukin-2 (IL-2). LAKC had the appearance of large lymphoid cells of prolymphocyte and immunoblast type with highly pyroninophilic cytoplasm and electrone-microscopic features indicative of synthetic activity. LAKC were shown to intensely express activation antigens and adhesion molecules on their surface and to posess high cytotoxic potential in respect to tumor cells. Time-course of LAKC surface antigen expression corresponded to the changes of a proportion of activated cellular forms, generated from MNC of healthy donors' peripheral blood by incubation with IL-2. On the basis of these experimental findings, the usage of 3-5-day culture of LAKC could be recommended for the immunotherapy of malignant tumors.

[Morphological characteristics and immunophenotype of dendritic cells generated from monocytes of human peripheral blood]. / Morfologicheskie osobennosti i immunofenotip dendritnykh kletok, poluchennykh iz monotsitov perifericheskoi krovi cheloveka.

Morphological features and immunophenotype of mature dendritic cells (DC) generated from the monocytes of healthy donor blood after culture with GM-CSF and IL-4 with the addition of TNF, were studied using light and electron microscopy, as well as flow-cytometry. It was shown that DC were characterized by a number of morphological features such as: large size, eccentrically located nucleus, highly developed system of extensions, large vacuolated cytoplasm, prominent and activated Golgi complex and ribosomal apparatus. Mature DC are characterized by active surface expression of MHC and co-stimulatory molecules (MHC I, MHC II, CD40, CD80, CD86).

[Effect of MESNA on intracellular accumulation of doxorubicin and its interaction with DNA]. / Issledovanie vliianiia MESNA na vnutrikletochnoe nakoplenie i vzaimodeistvie doksorubitsina s DNK.

The effect of MESNA, an uroprotector (sodium 2-mercaptoethane sulfonate) on intracellular accumulation of doxorubicin and its interaction with DNA was studied in the cultures of the cells of human ovary carcinoma (CaOV) and normal epithelial kidney cells of green monkeys (VERO). The study was performed with methods developed by the authors. The results showed that MESNA had no effect on the qualitative and quantitative characteristics of the indicated processes in both the types of the doxorubicin sensitive cells. It was concluded that with the combined use of doxorubicin and phosphamide or cyclophosphane the use of MESNA for lowering the urotoxic action of oxazophosphorines had no effect on the biological efficacy of doxorubicin. The necessity of studying the possible modifying effect of MESNA in the cultures of doxorubicin resistant cells and in vivo is indicated.