Significance The first obstacle to human papillomavirus (HPV) is Toll-like receptors (TLRs). Research has revealed that TLR signaling demonstrating both tumor-suppressive and tumor-promoting effects Approach 2-ddCt value of m RNA TLR2, 3, 4 and 8 expressions after PDT in 121 women with HPV-related cervical lesions. Results TLR8 showed the most consistent reduction across all groups with the strongest suppression in cervical cancer cases. Conclusions TLR8 has the potential to serve as a novel earlier molecular immunological marker for the progression of HPV infection. TLR4 may represent an additional marker due to its reduced expression after PDT in cervical cancer.

Photodynamic therapy (PDT) is a minimally invasive treatment with low systemic toxicity and immunomodulatory effects, increasingly applied in managing HPV-associated cervical lesions. Toll-like receptors (TLRs) are critical in regulating immune responses in cervical pathology, yet their dynamics under PDT remain underexplored. This study investigates the effect of PDT on TLR2, TLR3, TLR4, and TLR8 expression in cervical epithelial cells ex vivo, considering lesion severity. The results reveal that TLR8 exhibited the most significant reduction across all groups 2 h after PDT, with the strongest suppression in patients with invasive cervical cancer. TLR4 expression decreased by 24% in HPV-infected patients and by 71% in those with cervical cancer, highlighting its potential role in modulating the inflammatory microenvironment post-PDT. TLR3 showed hyperexpression in LSIL and suppression in HSIL/CIN III, although changes were not statistically significant (p > 0.05). TLR2 expression remained unchanged, likely due to HPV type variability. These findings demonstrate that PDT effectively reduces hyperexpression of TLR8, TLR4, and TLR3 in early-stage cervical cancer, suggesting their potential as biomarkers for treatment efficacy. Further research incorporating HPV typing and advanced techniques like liquid biopsy is essential to refine our understanding of TLRs in PDT for HPV-associated cervical lesions.

BACKGROUND: Influenza infection is one of the most pressing global health problems. The problems of the formation of viral resistance to existing drugs and the immunosuppressive effect induced by the influenza virus are currently acute. A promising solution seems to be the creation of drugs whose action is based on inhibition of the activity of cellular genes through RNA interference. AIM: Evaluate the anti-influenza and immunomodulatory effect of small interfering RNAs directed to cellular genes in an in vivo model. METHODS: The study used the influenza virus strain A/California/7/09 (H1N1), BALB/c mouse. Small interfering RNA was administered and animals were infected intranasally. Changes in the cytokine profile and viral activity were assessed using molecular genetic and virological methods. RESULTS: In the lungs of mice with intranasal administration of all siRNA complexes, a decrease in the expression level of IL-1β and TNF-α was noted, but an increase in the expression of IL-1β and IL-6 in washings from the upper respiratory tract (URT) was noted. When using siRNA Nup98.1 and Nup98.1 / Nup205.1, a reliable increase in the expression of IL-10 in the lungs and URT by the third day was observed. Changes in expression were also noted in relation to TGF-β1. Reliable differences in the expression of pro- and anti-inflammatory cytokines were obtained. Based on this, the most active immunomodulatory effect of the used small interfering RNA complexes is shown in the upper respiratory tract and lungs, at the sites of their direct administration. CONCLUSION: The study presented data that small interfering RNAs directed to one or more cellular genes in an in vivo model can reliably lead to a decrease in viral reproduction, a change in the cytokine profile, as well as an increase in the survival rate of laboratory animals.

Recent studies suggest that immune response to pathogens may vary depending on changes in hormone levels. Toll-like receptors (TLRs) are the key components of the innate immune system and play a crucial role in HIV infection. Given the significant genetic diversity of HIV-1, this study examined the effect of female sex hormones on the several TLR2, TLR4, and TLR9 expression in human peripheral blood mononuclear cells (PBLs) isolated from different female donors and infected with different variants of HIV-1 subtypes A6 and B. Thus, high doses of hormones upregulated the TLR2 and TLR9 expression in PBLs infected only with v1.A6, which also correlated with an increased viral load: by 3.8 times (p = 0.0033) when cells were treated with estradiol and by 4.4 times (p = 0.006) when treated with progesterone. Hormones did not modulate TLRs expression in the cells infected with subtype B, with the exception of one donor. In PBLs from this donor infected with the v1.B variant, hormones upregulated TLRs expression, which also correlated with the increased viral load (1.3-fold increase (p = 0.0036)). Hence, it was shown that gonadal steroids can play an important role in HIV-1 replication and immune response to a pathogen. Moreover, it was shown that different isolates of the same subtype may have distinct biological properties. The detected diversity in the TLRs expression in infected PBLs from different donors indicates that host genetics may also play an important role in HIV susceptibility.

Purpose Photodynamic therapy (PDT) has emerged as a promising treatment modality for human papillomavirus (HPV) associated diseases, particularly cervical precancer and cancer, offering a non-invasive approach to disease management. Methods In this study, we conducted analysis of mRNA TLR-2, -3, -4, and − 8 expressions in cervical smears before and after PDT. A total of 1187 women underwent PDT, and the study focused on evaluating mRNA expression of TLRs 2/3/4/8 on 125 women. Results Our findings demonstrated that PDT triggers the activation of early markers of the antiviral innate immune response within two hours of treatment. This activation, in turn, induces a robust antiviral and antitumor immune response. Conclusion This study underscores the potential of PDT as a therapeutic strategy for HPV-associated diseases by harnessing its ability to activate the immune response. The observed reduction in the risk of cancer recurrence, coupled with the induction of an antiviral and antitumor immune response, highlights PDT as a promising approach in the treatment of cervical pathologies associated with HPV infection.

Purpose: to study the association of the polymorphic marker T786C of the eNOS gene with various stages of primary open-angle glaucoma (POAG).Materials and methods. Peripheral blood of 90 patients aged 56 to 89 yrs (ave. 71 yrs) with POAG stages I, II, III was tested. DNA was isolated using a set of ribosorbents (Synthol company); subsequently, a real-time PCR reaction was performed on a DT-96 amplifier using the set to determine the polymorphic marker T786C in the eNOS gene.Results. For all groups of patients, the frequency of occurrence of alleles and genotypes was calculated, and the relationship between the emergence of POAG and the presence of an unfavorable polymorphic marker was determined. The main changes were revealed at POAG stages II and III, whilst at stage I no effect of polymorphism T786C of the eNOS gene was observed.Conclusion. For the first time, a comparative assessment was made of the distribution of alleles and genotypes by the polymorphic marker T786C in the eNOS gene of patients with various POAG stages.

This study evaluates the oncolytic potential of the Moscow strain of reovirus against human metastatic melanoma and glioblastoma cells. The Moscow strain effectively infects and replicates within human melanoma cell lines and primary glioblastoma cells, while sparing non-malignant human cells. Infection leads to the selective destruction of neoplastic cells, mediated by functional viral replication. A positive correlation was identified between viral RNA accumulation and tumor cell death, with no replication observed in non-malignant cells. This study highlights the critical roles of cathepsins B, L, and S as mediators of the oncolytic process. The pharmacological inhibition of these enzymes significantly attenuated reovirus-induced cytotoxicity in melanoma and glioblastoma cells. Conversely, PKR production analysis revealed minimal activation in reovirus-infected tumor cells, suggesting that the hyperactivation of the RAS-signaling pathway and subsequent PKR inhibition do not directly contribute to the selective efficacy of reovirus. Moreover, infected tumor cells exhibited features of both apoptotic and non-apoptotic death, emphasizing the intricate mechanisms of reovirus-mediated oncolysis. These findings underscore the therapeutic promise of the Moscow strain of reovirus as a selective and potent oncolytic agent for targeting melanoma and glioblastoma cells.

Among respiratory viruses, the most serious complications are caused by influenza A and B viruses, as well as coronaviruses. Most studies determined the absolute content of interferons (IFNs) of different types in blood serum. However, serum IFN protein concentrations do not always reflect the level of antiviral protection. The purpose of this study was a comparative assessment of interferon status in patients with ARVI: influenza and the acute stage of COVID-19. Materials and methods. We used biomaterial in the form of whole blood samples from 113 patients with influenza and 110 patients in the acute phase of moderate COVID-19. The body’s antiviral defense during ARVI was assessed by determining the activity of type I and II interferons produced by blood leukocytes using the “Interferon status” method in a cell-virus system simulated in vitro. Results. This work reveals a statistically significant decrease in the biological activity of interferons produced by blood leukocytes in influenza and a deficiency of IFN activity in COVID-19, compared with reference values, and also shows possible prospects for the treatment of these nosologies with such immunoactive drugs as IFN inducers (cycloferon, Kagocel) and immunomodulators (ingavirin, multicomponent vaccine Immunovac-VP-4). Conclusion. The results of IFN activity are necessary to assess the antiviral potential of the body, especially with COVID-19, given the “novelty” of the infection, the severity and variety of its clinical manifestations. Today it is known that the SARS-CoV-2 virus is capable of penetrating not only into the epithelial cells of the upper respiratory tract, epithelial cells of the stomach and intestines, but also into the cells of the esophagus, heart, adrenal glands, bladder, brain, as well as into the vascular endothelium and macrophages. Coronavirus SARS-CoV-2 inhibits the expression of cellular genes, including innate immune genes, and has a negative effect on the IFN system. The use of IFN inducers and immunomodulators for influenza and COVID-19 has shown immunological feasibility and clinical promise.

Introduction. Rubella virus is an RNA-containing virus capable of infecting human cells and causing infectious disease. Infection of pregnant women with rubella virus can lead to abortion or congenital rubella syndrome (CRS), a set of long-term birth defects including incomplete fetal organ development and mental retardation. There is no specific treatment for rubella and CRS. The regulation of antiviral immune response and viral reproduction by long non-coding RNAs is currently under active investigation. In this study, we evaluated the changes in the expression profile of long non-coding RNAs in rubella virus-infected A549 epithelial by RNA sequencing. Materials and Methods. A549 cells were infected with a wild-type variant of laboratory strain C-77 of rubella virus with a multiplicity of infection of 1.0 infectious units per cell and incubated for 72 hours. Virus titres were determined by the CCID method in the sensitive RK-13 cell culture. 48 h after infection, the cell monolayer was lysed, RNA was isolated, and libraries were prepared for sequencing. Sequencing was performed on the NextSeq500 platform (Illumina, USA) in paired-end reading mode. Validation of the obtained RNA sequencing data was performed using quantitative real-time PCR. Results. Rubella virus replication affects the production of some long non-coding RNAs by altering their expression profile. Thus, upon infection of A549 epithelial cells with rubella virus, there was a significant increase in the expression of such long non-coding RNAs as GAS5, NEAT1, LUCAT1, MIR210HG, MEG3, EPB41L4A-AS1, ZFAS1, and SNHG 1, 7, 12, 29, 32. DANCR, IGFL2-AS1, IGFL2-AS1, MIR1915HG, and SNHG14 were most significantly decreased in expression. Gene ontology (GO)-analysis revealed that long non-coding RNAs are involved at different levels in the mechanisms of immune response, in particular, RNA processing and nucleic acid metabolism; therefore, up- and down-regulation of these molecules leads to modulation of human antiviral immune response in response to rubella virus infection. Conclusion. Thus, the regulation of long non-coding RNA production by rubella virus has been shown for the first time. Differentially expressed long non-coding RNAs can be used as prognostic and diagnostic biomarkers of viral diseases.

Today, the proportion of elderly and senile people is steadily growing throughout the world. The most important factors in the first line of immune defense of the mucous membranes of the upper respiratory tract are β-defensins, which are a group of secretory proteins with antimicrobial activity. The aim of this study was to study the expression of genes for antimicrobial peptides β-defensins and the composition of the microbiome of the mucous membranes of the upper respiratory tract in elderly people and long-livers with various aging phenotypes.The main study group included 67 centenarians and 49 elderly people, who were further divided into two subgroups depending on the course of aging (pathological and successful aging). Nucleic acids were isolated from nasopharyngeal scrapings and the expression levels of the DEFB1 and DEFB4 genes were determined using real-time polymerase chain reaction. The composition of the microbiota in nasopharyngeal swabs was determined by MALDI-TOF mass spectrometry.In analyzing the expression of the DEFB1 gene in elderly people and centenarians with successful and pathological aging phenotypes, no difference was revealed between the groups. Expression of the DEFB4 gene was increased in centenarians with pathological aging compared to centenarians with successful aging and in the elderly group. Excessive production of antimicrobial peptides is dual in nature; on the one hand, they provide the first line of defense against microorganisms, and on the other, they are cytotoxic to their own cells. An increase in the expression of the DEFB4 gene during aging may be due to an increase in the number of pathogen-associated molecular patterns, which can be one’s own microbiota and/or components of microbial metabolism. Analysis of the microbiota composition showed an increase in biodiversity in individuals with a successful aging phenotype compared to a pathological phenotype. Particular attention is paid to Staphylococcus spp., the species composition of which depends on the aging phenotype. In the pathological aging group, the frequency of St. aureus colonization is significantly higher than in the successful aging group.Thus, overexpression of the DEFB4 gene and changes in the composition of the microbiota of the mucous membranes of the upper respiratory tract may be one of the mechanisms explaining the increased susceptibility to infections in various aging phenotypes.

BackgroundBreast cancer (BC) mortality primarily stems from metastases rather than the primary tumor itself. Perioperative stress, encompassing both surgical and anesthetic factors, profoundly impacts the immune system, leading to alterations in neuroendocrine pathways and immune functions, potentially facilitating tumor progression and metastasis. Understanding the immunomodulatory effects of different anesthesia techniques is crucial for optimizing perioperative care in patients with BC. The neutrophil-to-lymphocyte ratio (NLR) serves as one of the key indicators of perioperative immune response.ObjectiveTo compare the effects of inhalation anesthesia (IA) and total intravenous anesthesia (TIVA) on perioperative immune response in BC surgery patients.MethodsIn this randomized, double-blind clinical trial, BC surgery patients were randomized to receive either TIVA with propofol or IA with sevoflurane. The primary endpoint was NLR assessment. Secondary immune parameters measured included natural killer cells, various T cell subsets, B cells, the immuno-regulatory index [T-helpers (CD3+CD4+)/cytotoxic T-cells (CD3+CD8+)], matrix metallopeptidases (MMP-9), complement components, and immunoglobulins, preoperatively and at 1 and 24 hours postoperatively.ResultsThe study included 98 patients (IA: 48, TIVA: 50). The baseline characteristics exhibited remarkable similarity across the groups. No significant difference in absolute NLR values was found between IA and TIVA groups at any time point (1 hour: p = 0.519, 24 hours: p = 0.333). Decreased IgA and IgM levels post-surgery suggested potential negative impacts of IA on humoral immunity compared to TIVA. CRP levels increased more by 24 hours (p = 0.044) in IA compared to TIVA. No significant differences were observed in natural killer cells, T cell subsets, B cells, MMP-9 levels or complement components between groups. Significant differences in the immuno-regulatory index between the TIVA and IA groups at one hour postoperatively (p = 0.033) were not maintained at 24 hours.ConclusionWhile there were no notable differences in NLR among the types of anesthesia, the observed disparities in immunoglobulin content and C-reactive protein levels between groups suggest that we cannot dismiss the potential immunosuppressive effects of inhalational anesthesia in breast cancer surgeries. Further investigation needed to clarify the impact of various anesthesia methods on immune function and their implications for long-term cancer outcomes.

Psoriasis is an immune-mediated autoimmune inflammatory skin disease with a prevalence of 2 to 3% worldwide. In the psoriasis development and pathogenesis an important role is played by disorders in the immune system. Disruption of the innate and adaptive immune response mechanisms with the involvement of keratinocytes leads to the initiation and maintenance of inflammation. Immune reactions are activated in the skin, in which various cells participate (macrophages, dendritic cells, mast cells, innate immune lymphoid cells, melanocytes, keratinocytes, Langerhans cells and γδT cells; T and B cells; epithelial endothelial and stromal cells of the skin), each of which expresses pattern recognition receptors that respond to pathogens and cell damage itself. Many of these receptors, in particular toll-like receptors and NOD-like receptors play an important role in the pathogenesis of psoriasis. The associated innate receptors signaling cascades that activate in the skin cells may become potential targets for the treatment of this disease. To date, there are several approved drugs for biological therapy of psoriasis. The study of the role of the innate immune cells receptors in inflammatory skin pathologies requires further exploration and new developments.

Due to the developing resistance and intolerance to antiretroviral drugs, there is an urgent demand for alternative agents that can suppress the viral load in people living with human immunodeficiency virus (HIV). Recently, there has been increased interest in agents of marine origin such as, in particular, fucoidans to suppress HIV replication. In the present study, the anti-HIV-1 activity of fucoidans from the brown algae Alaria marginata, Alaria ochotensis, Laminaria longipes, Saccharina cichorioides, Saccharina gurianovae, and Tauya basicrassa was studied in vitro. The studied compounds were found to be able to inhibit HIV-1 replication at different stages of the virus life cycle. Herewith, all fucoidans exhibited significant antiviral activity by affecting the early stages of the virus–cell interaction. The fucoidan from Saccharina cichorioides showed the highest virus-inhibitory activity by blocking the virus’ attachment to and entry into the host’s cell, with a selectivity index (SI) > 160.

(1) Background: Impacted third molar extraction with a scalpel and rotary instruments is one of the most traumatic surgeries in dentistry. Therefore, it is necessary to discover less traumatic methods and instruments to reduce the risk of postoperative complications. (2) Methods: This study is reported in accordance with the CONSORT guidelines. The study aim is to assess the effectiveness of an Er:YAG laser with a wavelength of 2.94 μm, cutting and rotating instruments in the extraction of lower third molars in comparison with the traditional instruments using clinical and radiology parameters. In the control group, the impacted third molars were extracted with the traditional instruments, like scalpel and rotary instruments; in the test group, the impacted third molars were extracted with an Er:YAG laser. As per the inclusion and exclusion criteria, we enrolled 60 patients who were randomly assigned into two groups (Er:YAG laser group and control group). The efficacy of the Er:YAG laser was assessed by postoperative pain, collateral swelling, mouth opening, and radiology parameters such as radiographic infrabony defects and radiographic bone height after tooth extraction. (3) Results: The results showed that the clinical postoperative parameters like pain, collateral swelling, and mouth opening were less pronounced in the Er:YAG laser group than those in the control group (p < 0.001). According to the data of the radiology parameters (RBH and RID), the regeneration of the socket after extraction was better in the laser group than in the control group (p < 0.001). (4) Conclusions: Based on the obtained results of clinical and radiology parameters assessment, it was shown that third molar extraction using an Er:YAG laser is a less traumatic method than extraction using a scalpel and rotary instruments.

Background: The mechanisms of the formation of immunological competence against tuberculosis (TB), and especially those associated with HIV co-infection, remain poorly understood. However, there is an urgent need for risk recurrence predictive biomarkers, as well as for predictors of successful treatment outcomes. The goal of the study was to identify possible immunological markers of TB recurrence in individuals with HIV/TB co-infection. Methods: The plasma levels of IFN-γ, TNF-α, IL-10, and IL-1β (cytokines which play important roles in the immune activation and protection against Mycobacterium tuberculosis) were measured using ELISA EIA-BEST kits. The cytokine concentrations were determined using a standard curve obtained with the standards provided by the manufacturer of each kit. Results: A total of 211 individuals were enrolled in the study as follows: 62 patients with HIV/TB co-infection, 52 with HIV monoinfection, 52 with TB monoinfection, and 45 healthy donors. Out of the 62 patients with HIV/TB, 75.8% (47) of patients were newly diagnosed with HIV and TB, and 24.2% (15) displayed recurrent TB and were newly diagnosed with HIV. Decreased levels of IFN-γ, TNF-α, and IL-10 were observed in patients with HIV/TB when compared with HIV and TB patients. However, there was no difference in IFN-γ, TNF-α, or IL-10 secretion between both HIV/TB groups. At the same time, an almost 4-fold decrease in Il-1β levels was detected in the HIV/TB group with TB recurrence when compared with the HIV/TB group (p = 0.0001); a 2.8-fold decrease when compared with HIV patients (p = 0.001); and a 2.2-fold decrease with newly diagnosed TB patients (p = 0.001). Conclusions: Significantly decreased Il-1β levels in HIV/TB patients’ cohort with secondary TB indicate that this cytokine can be a potential biomarker of TB recurrence.

Herpes simplex viruses type 1 (HSV-1) and type 2 (HSV-2) are widespread human pathogens that establish chronic latent infections leading to recurrent episodes. Current treatments are limited, necessitating the development of novel antiviral strategies. This study aimed to assess the antiviral efficacy of novel topical formulations containing interferon alpha-2b (IFN α-2b) against HSV-1 and HSV-2. The formulations, Oftalmoferon® forte (eye drops) and Interferon Vaginal Tablets, demonstrated potent antiviral effects against HSV-1 and HSV-2 in Vero cells, respectively, with concentration-dependent inhibition of viral replication. Subsequently, their efficacy was tested in animal models: HSV-1 keratitis in the rabbit eye model and HSV-2 genital herpes in mice. Oftalmoferon® forte effectively treated HSV-1 keratitis, reducing clinical symptoms and ulcerations compared to virus control. Interferon Vaginal Tablets showed promising results in controlling HSV-2 genital herpes in mice, improving survival rates, reducing clinical signs, weight loss and viral replication. The novel IFN α-2b formulations exhibited significant antiviral activity against HSV infections in cell culture and animal models. These findings suggest the potential of these formulations as alternative treatments for HSV infections, particularly in cases resistant to current therapies. Further studies are warranted to optimize treatment regimens and assess clinical efficacy in humans.

The indicators of innate immunity and the composition of the microbiome in the nasopharyngeal mucosa in centenarians with different aging phenotypes were analyzed. A significant increase in the expression of pattern-recognizing receptor genes (TLR2, TLR4, and NLRP3) and proinflammatory cytokines (IL1B, IL18) was shown in the group of centenarians with pathological aging phenotype. In centenarians with successful aging phenotype, increased diversity of the microbiome composition was observed. At the same time, a moderate inverse correlation was found between an increase in the growth of the commensal bacterium Streptococcus salivarius and a decrease in the expression of proinflammatory cytokine genes IL1B and IL18. These findings can serve as biomarkers for the timely identification of the phenotype of aging in senile and elderly people.