Abstract
Follicular regulatory T (Tfr) cells play various roles in immune responses, contributing to both positive and negative regulation of foreign antigen-specific B cell responses, control over ...autoreactive antibody responses and autoimmunity, and B cell class-switching to IgE and allergy development. Studies conducted on mice uncovered various subsets of CXCR5+FoxP3+CD4+ Tfr cells that could differently contribute to immune regulation. Moreover, recent studies of human Tfr cells revealed similar complexity with various subsets of follicular T cells of different origins and immunosuppressive and/or immunostimulatory characteristics. In this review we will overview and compare Tfr subsets currently identified in mice and humans and will discuss their origins and antigen specificity, as well as potential modes of action and contribution to the control of the autoimmune and allergic reactions.
Graphical Abstract
Graphical Abstract
Introduction
B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL) is the most common neoplasm in children. One of the long known recurrent rearrangements in BCP‐ALL is ...t(1;19)(q23;p13.3)/TCF3::PBX1. However, other TCF3 gene rearrangements were also described that are associated with significant difference in ALL prognosis.
Methods
The current study aimed to analyze the spectrum of TCF3 gene rearrangements in children in Russian Federation. A cohort of 203 patients with BCP‐ALL was selected based on FISH screening and was studied by karyotyping, FISH, RT‐PCR and high throughput sequencing.
Results
T(1;19)(q23;p13.3)/TCF3::PBX1 is the most common aberration in TCF3‐positive pediatric BCP‐ALL (87.7%), with its unbalanced form prevailing. It resulted from TCF3::PBX1 exon 16‐exon 3 fusion junction (86.2%) or unconventional exon 16‐exon 4 junction (1.5%). Rarer events included t(12;19)(p13;p13.3)/TCF3::ZNF384 (6.4%) and t(17;19)(q21‐q22;p13.3)/TCF3::HLF (1.5%). The latter translocations demonstrated high molecular heterogeneity and complex structure—four distinct transcripts were shown for TCF3::ZNF384 and each patient with TCF3::HLF had a unique transcript. These features hamper TCF3 rearrangement primary detection by molecular methods and brings FISH screening to the fore. A case of novel TCF3::TLX1 fusion in a patient with t(10;19)(q24;p13) was also discovered. Survival analysis within the national pediatric ALL treatment protocol demonstrated the severe prognosis of TCF3::HLF compared to both TCF3::PBX1 and TCF3::ZNF384.
Conclusion
So, high molecular heterogeneity of TCF3 gene rearrangement in pediatric BCP‐ALL was demonstrated and a novel fusion gene TCF3::TLX1 was described.
To date, the 'one bug-one drug' approach to antiviral drug development cannot effectively respond to the constant threat posed by an increasing diversity of viruses causing outbreaks of viral ...infections that turn out to be pathogenic for humans. Evidently, there is an urgent need for new strategies to develop efficient antiviral agents with broad-spectrum activities. In this paper, we identified camphene derivatives that showed broad antiviral activities in vitro against a panel of enveloped pathogenic viruses, including influenza virus A/PR/8/34 (H1N1), Ebola virus (EBOV), and the Hantaan virus. The lead-compound
, with pyrrolidine cycle in its structure, displayed antiviral activity against influenza virus (IC
= 45.3 µM), Ebola pseudotype viruses (IC
= 0.12 µM), and authentic EBOV (IC
= 18.3 µM), as well as against pseudoviruses with Hantaan virus Gn-Gc glycoprotein (IC
= 9.1 µM). The results of antiviral activity studies using pseudotype viruses and molecular modeling suggest that surface proteins of the viruses required for the fusion process between viral and cellular membranes are the likely target of compound
. The key structural fragments responsible for efficient binding are the bicyclic natural framework and the nitrogen atom. These data encourage us to conduct further investigations using bicyclic monoterpenoids as a scaffold for the rational design of membrane-fusion targeting inhibitors.
In the present work we studied the antiviral activity of the home library of monoterpenoid derivatives using the pseudoviral systems of our development, which have glycoproteins of the SARS-CoV-2 ...virus strains Wuhan and Delta on their surface. We found that borneol derivatives with a tertiary nitrogen atom can exhibit activity at the early stages of viral replication. In order to search for potential binding sites of ligands with glycoprotein, we carried out additional biological tests to study the inhibition of the re-receptor-binding domain of protein S. For the compounds that showed activity on the pseudoviral system, a study using three strains of the infectious SARS-CoV-2 virus was carried out. As a result, two leader compounds were found that showed activity on the Wuhan, Delta, and Omicron strains. Based on the biological results, we searched for the potential binding site of the leader compounds using molecular dynamics and molecular docking methods. We suggested that the compounds can bind in conserved regions of the central helices and/or heptad repeats of glycoprotein S of SARS-CoV-2 viruses.
Respiratory syncytial virus (RSV) causes acute respiratory infections, thus, posing a serious threat to the health of infants, children, and elderly people. In this study, we have discovered a series ...of potent RSV entry inhibitors with the (-)-borneol scaffold. The active compounds 3b, 5a, 5c, 7b, 9c, 10b, 10c, and 14b were found to exhibit activity against RSV A strain A2 in HEp-2 cells. The most active substances, 3b (IC50 = 8.9 μM, SI = 111) and 5a (IC50 = 5.0 μM, SI = 83), displayed more potency than the known antiviral agent Ribavirin (IC50 = 80.0 μM, SI = 50). Time-of-addition assay and temperature shift studies demonstrated that compounds 3b, 5a, and 6b inhibited RSV entry, probably by interacting with the viral F protein that mediated membrane fusion, while they neither bound to G protein nor inhibited RSV attachment to the target cells. Appling procedures of molecular modeling and molecular dynamics, the binding mode of compounds 3b and 5a was proposed. Taken together, the results of this study suggest (-)-borneol esters to be promising lead compounds for developing new anti-RSV agents.
Due to the ability of influenza virus to develop drug resistance, the search for novel antivirals is an important goal of medical science and health care systems. We assessed the ability of the ...influenza virus to develop resistance to the hemagglutinin inhibitor camphecene and characterized laboratory-selected resistant strains. We showed by electron microscopy that camphecene decreases the number of virions fusing their envelopes with endosomal membranes. A 160-fold decrease in virus susceptibility was observed after six passages in cells. This was associated with the emergence of a V458L mutation in the HA2 subunit of HA and with a decrease in viral pathogenicity. Molecular modeling predicts that this substitution results in a more stable HA molecule compared to wild-type HA; and an altered camphecene-binding site. Therefore, despite the relatively rapid development of resistance, camphecene remains promising as a potential antiviral due to the low pathogenicity of resistant viruses that may arise.
A series of compounds containing a 1,7,7-trimethylbicyclo2.2.1heptane fragment were evaluated for their antiviral activity against influenza A virus strain A/Puerto Rico/8/34 (H1N1)
in vitro
. The ...most potent antiviral compound proved to be a quaternary ammonium salt based on (-)-borneol, 10a. In
in vitro
experiments, compound 10a inhibited influenza A viruses (H1, H1pdm09, and H3 subtypes), with an IC
50
value of 2.4-16.8 µM (depending on the virus), and demonstrated low toxicity (CC
50
= 1311 µM). Mechanism-of-action studies for compound 10a revealed it to be most effective when added at the early stages of the viral life cycle. In direct haemolysis inhibition tests, compound 10a was shown to decrease the membrane-disrupting activity of influenza A virus strain A/Puerto Rico/8/34. According to molecular modelling results, the lead compound 10a can bind to different sites in the stem region of the viral hemagglutinin.
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A chemical library was constructed based on the scaffold of camphecene (2-(E)-((1R,4R)-1,7,7-trimethylbicyclo2.2.1heptan-2-ylidene-aminoethanol). The modifications included ...introduction of mono-and bicyclic heterocyclic moieties in place of the terminal hydroxyl group of camphecene. All compounds were tested for cytotoxicity and anti-viral activity against influenza virus A/Puerto Rico/8/34 (H1N1) in MDCK cells. Among 15 tested compounds 11 demonstrated a selectivity index (SI) higher than 10 and IC50 values in the micromolar range. The antiviral activity and toxicity were shown to strongly depend on the nature of the heterocyclic substituent. Compounds 2 and 14 demonstrated the highest virus-inhibiting activity with SIs of 106 and 183, and bearing pyrrolidine and piperidine moieties, correspondingly. Compound 14 was shown to interfere with viral reproduction at early stages of the viral life cycle (0–2 h post-infection). Taken together, our data suggest potential of camphecene derivatives in particular and camphor-based imine derivatives in general as effective anti-influenza compounds.
In this work, a library of (+)‐camphor and (−)‐fenchone based N‐acylhydrazones, amides, and esters, including para‐substituted aromatic/hetaromatic/cyclohexane ring was synthesized, with potent ...orthopoxvirus inhibitors identified among them. Investigations of the structure‐activity relationship revealed the significance of the substituent at the para‐position of the aromatic ring. Also, the nature of the linker between a hydrophobic moiety and aromatic ring was clarified. Derivatives with p‐Cl, p‐Br, p‐CF3, and p‐NO2 substituted aromatic ring and derivatives with cyclohexane ring showed the highest antiviral activity against vaccinia virus, cowpox, and ectromelia virus. The hydrazone and the amide group were more favourable as a linker for antiviral activity than the ester group. Compounds 3 b and 7 e with high antiviral activity were examined using the time‐of‐addition assay and molecular docking study. The results revealed the tested compounds to inhibit the late processes of the orthopoxvirus replication cycle and the p37 viral protein to be a possible biological target.
With orthopoxviruses (OPXVs) posing a growing threat to human health, it is urgent that novel compounds against OPXV be developed. This study reports on the synthesis of a library of monoterpenoid derivatives. The synthesized compounds were tested against vaccinia virus, cowpox, and ectromelia virus. The time‐of‐addition assay and molecular docking study were performed to identify a possible biological target.
Direct measurements of aggregation forces in piconewton range between two red blood cells in pair rouleau are performed under physiological conditions using double trap optical tweezers. Aggregation ...and disaggregation properties of healthy and pathologic (system lupus erythematosis) blood samples are analyzed. Strong difference in aggregation speed and behavior is revealed using the offered method which is proposed to be a promising tool for SLE monitoring at single cell level.
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