Hepatitis C virus (HCV) is one of the basic culprits behind chronic liver disease, which may result in cirrhosis and hepatocarcinoma. In spite of the extensive research conducted, a vaccine against ...HCV has not been yet created. We have obtained human mesenchymal stem cells (hMSCs) and used them for expressing the HCV NS5A protein as a model vaccination platform. Sixteen hMSC lines of a different origin were transfected with the pcNS5A-GFP plasmid to obtain genetically modified MSCs (mMSCs). The highest efficiency was obtained by the transfection of dental pulp MSCs. C57BL/6 mice were immunized intravenously with mMSCs, and the immune response was compared with the response to the pcNS5A-GFP plasmid, which was injected intramuscularly. It was shown that the antigen-specific lymphocyte proliferation and the number of IFN-γ-synthesizing cells were two to three times higher after the mMSC immunization compared to the DNA immunization. In addition, mMSCs induced more CD4+ memory T cells and an increase in the CD4+/CD8+ ratio. The results suggest that the immunostimulatory effect of mMSCs is associated with the switch of MSCs to the pro-inflammatory phenotype and a decrease in the proportion of myeloid derived suppressor cells. Thus, the possibility of using human mMSCs for the creation of a vaccine against HCV has been shown for the first time.
Despite the development of efficient anti–human immunodeficiency virus-1 (HIV-1) therapy, HIV-1 associated pathogens remain a major clinical problem. Human cytomegalovirus (CMV) is among the most ...common HIV-1 copathogens and one of the main causes of persistent immune activation associated with dysregulation of the immune system, cerebrovascular and cardiovascular pathologies, and premature aging. Here, we report on the development of dual-targeted drugs with activity against both HIV-1 and CMV. We synthesized seven compounds that constitute conjugates of molecules that suppress both pathogens. We showed that all seven compounds exhibit low cytotoxicity and efficiently inhibited both viruses in cell lines. Furthermore, we chose a representative compound and demonstrated that it efficiently suppressed replication of HIV-1 and CMV in human lymphoid tissue ex vivo coinfected with both viruses. Further development of such compounds may lead to the development of dual-targeted anti-CMV/HIV-1 drugs.
•We synthetized seven dual-targeted anti-CMV/HIV heterodimers.•AZT or 3 TC were used as anti HIV molecules while 1-ω-(phenoxy)alkyluracil derivatives were used as anti CMV molecules.•These compounds inhibited CMV and HIV respectively in WS1 and MT-4 cell cultures.•Both AZT and 3 TC-based heterodimers inhibited CMV and HIV replication in coinfected human lymphoid tissues.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We report an "inversed" Arbuzov reaction of the fullerene derivatives C
60
Ar
5
Cl with trialkyl phosphites P(OR)
3
producing alkylated fullerene derivatives C
60
Ar
5
R (R = Me, Et, iPr,
n
Bu) with ...almost quantitative yields. This reaction provides a convenient synthetic route for the preparation of a large variety of functionalized fullerene derivatives with tailored properties,
e.g.
water-soluble compounds demonstrating promising antiviral activities against HCMV, HSV1, HIV and several influenza virus strains.
We report an "inversed" Arbuzov reaction of C
60
Ar
5
Cl with P(OR)
3
producing C
60
Ar
5
R with an excellent selectivity.
Introduction. SARS-CoV-2 infection causes immune disorders that create conditions for the reactivation of human herpesviruses (HHVs). However, the estimates of the HHVs effect on the course and ...outcome of COVID-19 are ambiguous. Аim – to study the possible relationship between the HHV reactivation and the adverse outcome of COVID-19. Materials and methods. Postmortem samples from the brain, liver, spleen, lymph nodes and lungs were obtained from 59 patients treated at the Moscow Infectious Diseases Hospital No.1 in 2021–2023. The group 1 comprised 39 patients with fatal COVID-19; group 2 (comparison group) included 20 patients not infected with SARS-CoV-2 who died from various somatic diseases. HHV DNA and SARS-CoV-2 RNA were determined by PCR. Results. HHV DNA was found in autopsy samples from all patients. In group 1, EBV was most often detected in lymph nodes (94%), HHV-6 in liver (68%), CMV in lymph nodes (18%), HSV in brain (16%), VZV in lung and spleen (3% each). The detection rates of HHVs in both groups was similar. Important differences were found in viral load. In patients with COVID-19, the number of samples containing more than 1,000 copies of HHV DNA per 100,000 cells was 52.4%, in the comparison group – 16.6% (p 0.002). An association has been established between the reactivation of HSV and HHV-6 and the severity of lung damage. Reactivation of EBV correlated with increased levels of liver enzymes. Conclusion. Reactivation of HHVs in patients with fatal COVID-19 was associated with severe lung and liver damages, which indicates a link between HHV reactivation and COVID-19 deaths.
Aim. To carry out a comparative analysis of the cytotoxic and antiviral properties of synthesized tellurium derivatives in model cellular systems of infections caused by herpes simplex virus and ...cytomegalovirus.Material and Methods. 4 organo‐tellurium compounds were studied using primary and continuous cell cultures in various infection schemes.Results. For each biological model studied, different thresholds of cytotoxicity concentration (TCD50 acute CC50 and CD50 CC50) were identified. Tellurium derivatives with methoxyphenyl and ethoxyphenyl ethene exhibit virus‐neutralizing activity, preventing the penetration of herpes simplex virus virions into sensitive cells. HTI (SI selectivity index) for these compounds was 84 and 77, respectively.Conclusion. The manifestation of the cytotoxic effect of all tellurium‐containing organic compounds for transplanted cells lies in a lower concentration than for primary cells. The data obtained in the analysis of antiviral activity showed that the derivatives have therapeutic properties against HSV infection in cell culture.
Pathogenic variants in the GJB2 gene, encoding connexin 26, are known to be a major cause of hearing impairment (HI). More than 300 allelic variants have been identified in the GJB2 gene. Spectrum ...and allelic frequencies of the GJB2 gene vary significantly among different ethnic groups worldwide. Until now, the spectrum and frequency of the pathogenic variants in exon 1, exon 2 and the flanking intronic regions of the GJB2 gene have not been described thoroughly in the Sakha Republic (Yakutia), which is located in a subarctic region in Russia. The complete sequencing of the non-coding and coding regions of the GJB2 gene was performed in 393 patients with HI (Yakuts-296, Russians-51, mixed and other ethnicities-46) and in 187 normal hearing individuals of Yakut (n = 107) and Russian (n = 80) populations. In the total sample (n = 580), we revealed 12 allelic variants of the GJB2 gene, 8 of which were recessive pathogenic variants. Ten genotypes with biallelic recessive pathogenic variants in the GJB2 gene (in a homozygous or a compound heterozygous state) were found in 192 out of 393 patients (48.85%). We found that the most frequent GJB2 pathogenic variant in the Yakut patients was c.-23+1G>A (51.82%) and that the second most frequent was c.109G>A (2.37%), followed by c.35delG (1.64%). Pathogenic variants с.35delG (22.34%), c.-23+1G>A (5.31%), and c.313_326del14 (2.12%) were found to be the most frequent among the Russian patients. The carrier frequencies of the c.-23+1G>A and с.109G>A pathogenic variants in the Yakut control group were 10.20% and 2.80%, respectively. The carrier frequencies of с.35delG and c.101T>C were identical (2.5%) in the Russian control group. We found that the contribution of the GJB2 gene pathogenic variants in HI in the population of the Sakha Republic (48.85%) was the highest among all of the previously studied regions of Asia. We suggest that extensive accumulation of the c.-23+1G>A pathogenic variant in the indigenous Yakut population (92.20% of all mutant chromosomes in patients) and an extremely high (10.20%) carrier frequency in the control group may indicate a possible selective advantage for the c.-23+1G>A carriers living in subarctic climate.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Euchromatic segments of the X chromosomes of placental mammals are the most conservative elements of the karyotype, only rarely subjected to either inter- or intrachromosomal rearrangements. Here, ...using microdissection-derived set of region-specific probes of Terricola savii we detailed the evolutionary rearrangements found in X chromosomes in 20 vole species (Arvicolinae, Rodentia). We show that the evolution of X chromosomes in this taxon was accompanied by multiple para- and pericentric inversions and centromere shifts. The contribution of intrachromosomal rearrangements to the karyotype evolution of Arvicolinae species was approximately equivalent in both the separate autosomal conserved segments and the X chromosomes. Intrachromosmal rearrangements and structural reorganization of the X chromosomes was likely accompanied by an accumulation, distribution, and evolution of repeated sequences.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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