Vol 16, No 2 (2024)
- Year: 2024
- Published: 21.08.2024
- Articles: 9
- URL: https://actanaturae.ru/2075-8251/issue/view/884
Reviews
Molecular Mechanisms of Drosophila Hematopoiesis
Abstract
As а model organism, the fruit fly (Drosophila melanogaster) has assumed a leading position in modern biological research. The Drosophila genetic system has a number of advantages making it a key model in investigating the molecular mechanisms of metazoan developmental processes. Over the past two decades, significant progress has been made in understanding the molecular mechanisms regulating Drosophila hematopoiesis. This review discusses the major advances in investigating the molecular mechanisms involved in maintaining the population of multipotent progenitor cells and their differentiation into mature hemocytes in the hematopoietic organ of the Drosophila larva. The use of the Drosophila hematopoietic organ as a model system for hematopoiesis has allowed to characterize the complex interactions between signaling pathways and transcription factors in regulating the maintenance and differentiation of progenitor cells through the signals from the hematopoietic niche, autocrine and paracrine signals, and the signals emanated by differentiated cells.
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Research Articles
EVALUATION OF THE HER2/NEU EXPRESSION IN THE TISSUE OF METASTATIC AXILLARY LYMPH NODES IN BREAST CANCER PATIENTS USING THE [99mTs]TC-(HE)3-G3
Abstract
Anatomical visualization and molecular typing of tumor tissue of regional metastatic lymph nodes (mALN) in patients with breast cancer, it is an important clinical problem in modern oncology. According to the results of previous studies, the [99mTc]Tc-(HE)3-G3 has proven itself as a promising diagnostic agent that allows differentiating the status of the HER2/neu receptor of a primary breast tumor (p<0.05, Mann-Whitney test). In this regard, the purpose of this study is to explore the possibilities of using [99mTc]Tc-(HE)3-G3 to type the status of HER2/neu in patients with breast cancer. The study was conducted on clinical material including 20 patients with breast cancer (T2-4N1-3M0-1) before the systemic therapy (10 patients with overexpression of HER2/neu in metastases of axillary lymph nodes and 10 patients with negative) who underwent SPECT/CT scan 4 hours after injection of [99mTc]Tc-(HE)3-G3. Morphological and immunohistochemical studies of tumor tissue of metastatic axillary lymph nodes were performed in all patients with an assessment of HER2/neu status. Based on the results of our analysis, we found that the use of the mALN -to-contralateral and mALN-to-LDM ratios 4 hours after injection of [99mTc]Tc-(HE)3-G3 should be considered for typing the status of HER2/neu in mALN in breast cancer patients (p<0.05, Mann-Whitney test). At the same time, for the low/background parameter, the sensitivity and specificity indicators were 80% with a threshold value > 12.25.
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Experimental Use of Common Marmosets (Callithrix jacchus) in Preclinical Trials of Antiviral Vaccines
Abstract
Common marmoset (Callithrix jacchus, CM) is a New World primate species that is of interest for preclinical trials of immunobiological products. In this study, we describe the approaches to long-term laboratory breeding and maintenance of CMs. We also establish the reference values of the main complete blood count and serum chemistry parameters evaluated during preclinical trials of immunobiological products and describe the histological characteristics of CM lymphoid organs during the development of post-vaccination immune response. We show that CMs bred in laboratory conditions excluding background infectious pathology are a relevant model that allows for a high degree of reliability in characterizing the safety and immunogenicity profile of antiviral vaccines during preclinical trials.
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Dihydroquercetin-Loaded Liposomes Change Fibrous Tissue Distribution in the Bleomycin-Induced Fibrosis Model
Abstract
The effects of the antioxidant dihydroquercetin (DHQ) were studied in a model of pulmonary fibrosis. DHQ penetration into the lesion was facilitated by encapsulation into liposomes. Pulmonary fibrosis was modeled in rats by intratracheal injection of bleomycin. For the first 7 days, the rats in the treatment group received a liposomal emulsion with DHQ, while in the comparator group rats received saline. In the control group, intact rats did not receive any exposure. Thirty days after the initiation, lung function and the pathological lesion volume were assessed by 7T 1H MRI and the lungs were taken for histologic examination. The proportion of fibrous tissue was counted by Masson’s trichrome staining. Both experimental groups were characterized by a significant functional pulmonary deficiency, with low mortality and a small lesion area. In the rats treated with DHQ, the distribution of fibrous tissue was significantly altered. Significantly more fibrous tissue was found in the center of the lesion, while significantly less was in the interstitial space of alveoli. Lung density at the same time was lower in the treated lungs. Dihydroquercetin encapsulated in liposomes affects the mechanisms of bleomycin-induced pulmonary fibrosis progression in rats. While accelerated fibrosis of the lesion can restrict inflammatory processes, delayed fibrosis of the interstitium can further improve the functional state of the lungs.
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7-Methylguanine Inhibits Colon Cancer Growth in vivo
Abstract
7-Methylguanine (7-MG) is a natural inhibitor of poly(ADP-ribose) polymerase 1 and tRNA-guanine transglycosylase, the enzymatic activity of which is central for the proliferation of cancer cells. Recently, a number of preclinical tests have demonstrated the safety of 7-MG and a regimen of intragastric administration was established in mice. In the present work, the pharmacological activity of 7-MG was studied in BALB/c and BALB/c nude mice with transplanted tumors. It was found that 7-MG effectively penetrates tumor tissue and suppresses colon adenocarcinoma growth in the Akatol model, as well as in a xenograft model with human HCT116 cells.
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LPS-Induced Acute Lung Injury: Analysis of the Development and Suppression by the TNF-α-Targeting Aptamer
Abstract
Acute lung injury (ALI) is a specific form of lung inflammation characterized by diffuse alveolar damage, noncardiogenic pulmonary edema, as well as a pulmonary and systemic inflammation. The pathogenesis of ALI involves a cascade inflammatory response accompanied by an increase in the local and systemic levels of proinflammatory cytokines and chemokines. The development of molecular tools targeting key components of cytokine signaling appears to be a promising approach in ALI treatment. The development of lipopolysaccharide (LPS)-induced ALI, as well as the feasibility of suppressing it by an aptamer targeting the proinflammatory cytokine TNF-α, was studied in a mouse model. The TNF-α level was shown to increase significantly and remain steadily high during the development of ALI. LPS-induced morphological signs of inflammation in the respiratory system become most pronounced 24 h after induction. Intranasal administration of TNF-α-targeting aptamers conjugated with polyethylene glycol (PEG-aptTNF-α) to mice with ALI reduced the intensity of inflammatory changes in lung tissue. Assessment of the levels of potential TNF-α target genes (Usp18, Traf1, and Tnfaip3) showed that their expression levels in the lungs increase during ALI development, while declining after the application of PEG-aptTNF-α. Therefore, topical use of TNF-α-targeting aptamers may be an efficient tool for treating ALI and other inflammatory lung diseases.
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A Vector Nanoplatform for the Bioimaging of Deep-Seated Tumors
Abstract
Today, in preclinical studies, optical bioimaging based on luminescence and fluorescence is indispensable in studying the development of neoplastic transformations, the proliferative activity of the tumor, its metastatic potential, as well as the therapeutic effect of antitumor agents. In order to expand the capabilities of optical imaging, sensors based on the bioluminescence resonance energy transfer (BRET) mechanism and, therefore, independent of an external light source are being developed. A targeted nanoplatform based on HER2-specific liposomes whose internal environment contains a genetically encoded BRET sensor was developed in this study to visualize deep-seated tumors characterized by overexpression of human epidermal growth factor receptor type 2 (HER2). The BRET sensor is a hybrid protein consisting of the highly catalytic luciferase NanoLuc (an energy donor) and a LSSmKate1 red fluorescent protein with a large Stokes shift (an energy acceptor). During the bioimaging of disseminated intraperitoneal tumors formed by HER2-positive SKOV3.ip1cells of serous ovarian cystadenocarcinoma, it was shown that the developed system is applicable in detecting deep-seated tumors of a certain molecular profile. The developed system can become an efficient platform for optimizing preclinical studies of novel targeted drugs.
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An Attenuated and Highly Immunogenic Variant of the Vaccinia Virus
Abstract
The vaccinia virus (VACV) has been used for prophylactic immunization against smallpox for many decades. However, the VACV-based vaccine had been highly reactogenic. Therefore, after the eradication of smallpox, the World Health Organization in 1980 recommended that vaccination against this infection be discontinued. As a result, there has been a rise in the occurrence of orthopoxvirus infections in humans in recent years, with the most severe being the 2022 monkeypox epidemic that reached all continents. Thus, it is crucial to address the pressing matter of developing safe and highly immunogenic vaccines for new generations to combat orthopoxvirus infections. In a previous study, we created a LAD strain by modifying the LIVP (L) VACV strain, which is used as a first-generation smallpox vaccine in Russia. This modification involved introducing mutations in the A34R gene to enhance extracellular virion production and deleting the A35R gene to counteract the antibody response to the viral infection. In this study, a strain LADA was created with an additional deletion in the DNA of the LAD strain ati gene. This ati gene directs the production of a major non-virion immunogen. The findings indicate that the LADA VACV variant exhibits lower levels of reactogenicity in BALB/c mice during intranasal infection, as compared to the original L strain. Following intradermal immunization with a 105 PFU dose, both the LAD and LADA strains were found to induce a significantly enhanced cellular immune response in mice when compared to the L strain. At the same time, the highest level of virus-specific IFN-γ producing cells for the LAD variant was detected on the 7th day post-immunization (dpi), whereas for LADA, it was observed on 14 dpi. The LAD and LADA strains induced significantly elevated levels of VACV-specific IgG compared to the original L strain, particularly between 28 and 56 dpi. The vaccinated mice were intranasally infected with the cowpox virus at a dose of 460 LD50 to assess the protective immunity at 62 dpi. The LADA virus conferred complete protection to mice, with the LAD strain providing 70% protection and the parent strain L offering protection to only 60% of the animals.
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