of the study is to evaluate the efficacy, safety, and immunogenicity of divozilimab (DIV), anti-CD20 monoclonal antibody, in patients with systemic sclerosis (SS). . Patients with SS according to ACR/EULAR (American College of Rheumatology/European Alliance of Associations for Rheumatology) 2013 criteria with modified Rodnan skin score (mRSS) ≥10 and ≤20 and forced vital capacity (FVC) ≥40% from the due took part in the study. Infusions of DIV 250 mg were administered on weeks 0 and 2, and DIV 500 mg on week 24 with the subsequent use in open mode, starting from week 48. This publication presents data obtained for 48 weeks of trial (before the DIV infusion at week 48). Primary endpoint was the change in the mRSS from baseline to week 48. The dynamic of FVC was estimated as the secondary endpoint. The safety evaluation included the frequency and profile of adverse events and adverse reactions (ARs). Immunogenicity was assessed by detection of binding and neutralizing anti-drug antibodies on weeks 2, 24, and 48. : The patients (151) were randomized into two groups: DIV (n = 76) and placebo (n = 75). The most were female; the median duration of the disease was about 3-4 years. The initial value of the mRSS was 14 and 13 points in DIV and Placebo groups, respectively. The change of mRSS from baseline to week 48 was -5.8 ± 1.1 points in DIV group and -2.7 ± 1.0 points in placebo group (adjusted mean difference (AMD) with 95% confidence interval -3.1 (-4.5; -1.7); p < 0.0001). The lung function was stable in patients treated with DIV. A comparable safety profile of DIV and placebo was demonstrated. The most frequent ARs were infusion reactions and a decrease in the number of lymphocytes. There were no severe and serious ARs in DIV group. All infusion reactions were mild and moderate. 5.3% (4/76) patients in DIV group had binding antibodies without neutralizing activity. : Divozilimab has demonstrated a significant decrease in severity of skin fibrosis, a positive effect on the respiratory function, and a favorable safety profile, which allows it to be considered as a promising therapeutic option for SS.
The aim of the study was to analyze the effectiveness and tolerability of subcutaneous methotrexate (sc MTX) (METHORTRIT; sc ROMPHARM Company) in RA patients with high disease activity with rapid dose escalation, to assess their quality of life (QOL) in real clinical practice. -The study included 105 patients, mostly women, with a reliable diagnosis of RA with high disease activity (DAS28 ≥ 5.1) aged 18 years and older and ineffectiveness of previous oral MT therapy for at least 6 months or who had not received MT. sc MTX therapy was started at a dose of 15 mg /weekly. During the first month of therapy, a rapid escalation of the scMTX dose of 2.5 mg/week was performed once a week until the dose of 22.5 mg/week was reached; then, with insufficient response, the dose of sc MTX could be increased to 25 mg/week. The evaluation of the effectiveness of therapy, functional status, and QOL was carried out after 4-12-18-24 weeks. -After a rapid escalation of the sc MTX dose during the first month of the study, at all stages of follow-up, a rapid decrease in disease activity was noted for all standard indices (DAS28 from 5.8 ± 0.75 to 2.93 ± 1.05; CDAI from 30.13 ± 8.33 to 7.08 ± 6.07; SDAI from 32.78 ± 9.64 to 7.48 ± 6.53) and the activity index, which was evaluated by the patients themselves (RAPID-3 from 16.18 ± 4.6 to 5.56 ± 4.66), p ≤ 0.05. The number of patients with high disease activity according to DAS28 decreased by 2 times by the 4th week of therapy (to 46.2%), after 12 weeks they remained 13.3%, and by 24 weeks high activity remained only in 4.4% of patients. There was a marked decrease in pain from 65.6 ± 13.07 to 20.5 ± 17.1 mm in VAS (p < 0.001), which contributed to an improvement in the functional state: the HAQ index decreased on average from 1.47 ± 0.65 to 0.64 ± 052 points. Population indices of functional status (HAQ ≤ 0.5) by the 24th week of therapy were observed in 48.9% of patients. A decrease in the level of fatigue (from 6.25 ± 7.04 to 1.81 ± 1.71 cm according to VAS, p < 0.001) was accompanied by a decrease in anxiety (from 7.47 ± 4.03 to 2.36 ± 2.72, p < 0.001) and depression (from 7.77 ± 3.84 to 2.50 ± 2.56, p < 0.001), as well as improved sleep. By the 24th week of the study, 45% of patients had population-based indices of QOL according to the EQ-5D index. Glucocorticoids (GC) were completely eliminated in 2/3 of the patients. Patients who did not receive GC had lower disease activity by 24 weeks in all indices: DAS 28 (2.7 ± 0.1 and 3.4± 0.2, respectively), CDAI (6.0 ± 0.3 and 10.2 ± 0.1), SDAI (6.4 ± 0.2 and 10.9 ± 0.3), p < 0.05. Patients receiving and not receiving GC had the same number of adverse reactions (p > 0.05); however, the number of infections in patients receiving GC was significantly higher (9.5%-0.0, respectively, p = 0.009). The need for nonsteroidal anti-inflammatory drugs (NSAIDs) at the beginning of the study was in 93.2% of patients on average 21.1 days per month; after 24 weeks, the need for NSAIDs was in 54.4% of patients on average 3.8 days per month. In general, the safety profile of MTX was acceptable. -With high RA activity, the tactics of starting therapy with sc MTX at a dose of 15 mg per week and a rapid escalation of its dose of 2.5 mg weekly to 22.5-25 mg/week, allows achieving therapy goals by 3 months in 17.8% of patients, and by 6 months in 64.5%, to quickly improve the QOL, reduce the level of pain, reduce the dose of GC by 3 months of therapy or completely cancel them, and reduce the need for NSAIDs by 7 times with an acceptable level of therapy safety.
The aim to evaluate the effectiveness of long-term therapy with Russian rituximab (RTX) biosimilar in Sjögren's disease (SjD) in real-life clinical practice. MATERIALS AND METHODS : The retrospective study included 53 patients with SjD (Russian 2001 criteria and ACR/EULAR (American College of Rheumatology/European Alliance of Associations for Rheumatology) 2016 criteria), observed at the Nasonova Research Institute of Rheumatology from 2017 to 2024 and receiving long-term RTX therapy (Russian biosimilar Acellbia®, BIOCAD). The signs of clinical and laboratory activity of the disease, stomatological and ophthalmological tests, as well as the incidence of new systemic manifestations and lymphomas were assessed dynamically. RESULTS : The median duration of RTX therapy was 27 [19; 55] months, and the median total dose was 4 [3.5; 5.5] g. Before the therapy, 13 (25%) patients had recurrent parotitis, which was relieved in all patients during the therapy. Persistent enlargement of the salivary glands was observed in 10 (20.4%) patients, in 9 of them it was relieved. A significant increase in stimulated saliva flow was found (from 1.5 [0.5; 3] to 2.4 [1.4; 3.5] mL; p = 0.002), an increase in salivation was found in 51% of patients, stabilization in 28.6%, and deterioration in 20.4%. When assessing the ultrasound dynamics of the salivary glands, the size of hypoechoic avascular lesions significantly decreased (from 1.8 [1.3; 2.3] to 1.3 [1.1; 1.5] mm; p<0.001), and according to the ultrasound activity index, stabilization was noted in 67.4% of patients, improvement in 27.9%, and deterioration in 4.7% of patients. When assessing the dynamics of sialography, the size of cavities significantly decreased (from 1.5 [1.5; 2.5] to 1.0 [0; 1.5] mm; p < 0.001), and according to the assessment of sialographic stages, stabilization was noted in 67.5% of patients, improvement in 32.5% of patients, and deterioration was not noted in any patient. When assessing the lacrimal glands function, a significant increase in lacrimation was found according to the stimulated Schirmer's test (from 6 [3.75; 12] to 8 [5; 15] mm; p = 0.005); an increase in lacrimation was noted in 38% of patients, stabilization in 40.6%, and a decrease in 21.4%. When assessing the tear break-up time, a tendency towards its increase was noted, but statistically insignificant (from 5 [3.75; 9.25] to 5.5 [4; 9] sec; p = 0.35). Corneal epitheliopathy during the therapy was relieved in 44% and persisted in 56% of patients; worsening of corneal epitheliopathy during the treatment was observed in a few patients, while no cases of ulcer formation or perforation of the cornea were recorded. During the therapy, a significant decrease in the levels of erythrocyte sedimentation rate, gamma globulins, IgG, IgA, IgM, rheumatoid factor, an increase in the C3 complement level, and the elimination of monoclonal gammopathy were observed, while the dynamics of the C4 complement level and cryoglobulinemia were multidirectional. The median duration of B lymphocyte depletion was 5 [4; 6] months, constant depletion could be maintained only in 59.6% of patients. During the therapy, the SjD systemic activity index (ESSDAI, EULAR Sjögren's Syndrome Disease Activity Index) significantly decreased (from 5 [2; 8] to 1 [0; 3] points; p<0.001), and minimal clinically important improvement of this index was achieved in 66.6% of patients. During the observation, one patient developed a new skin lesion (lupus chilblain); no other new systemic manifestations or lymphomas were registered. CONCLUSIONS : According to our retrospective study conducted in real-life clinical practice, long-term therapy with Russian RTX biosimilar in most cases (60-80%) led to stabilization or improvement of SjD manifestations. RTX can be used to treat not only systemic but also glandular manifestations of the disease. Given the lack of an optimal response to RTX therapy in a number of SjD patients, it is necessary to study the effectiveness of drugs that lead to a deeper depletion of B lymphocytes.
-Background Interleukin (IL)-6 plays an important role in the pathogenesis of comorbid rheumatoid arthritis (RA) depression. IL-6 inhibitors used to treat patients with RA may also have an antidepressant effect. - of this study is to evaluate the effectiveness of 24-week IL-6 inhibitor therapy with olokizumab (OKZ) in combination with or without psychopharmacotherapy (PPT) in patients with moderate to high RA activity. - A total of 125 patients with RA were included, 102 (81.6%) of them were women. The average age of the patients was 48.5 ± 12.6 years; the majority of the patients (86.4%) had high RA activity and had shown ineffectiveness with stable 12-week therapy using conventional synthetic disease modifying antirheumatic drugs (csDMARDs). Additionally, 34 (27.2%) patients had shown inefficiency with one or more biological DMARDs. According to the International Classification of Diseases, 10th revision (ICD-10), a psychiatrist diagnosed varying severity of depression (chronic or recurrent) in all patients during a semi-structured interview. At week 0, all patients were randomized using sequential numbers in a 2:2:1 ratio into one of three groups: in group 1, patients received csDMARDs + OKZ 64 mg subcutaneously once every 4 weeks (q4w) (n = 49); in group 2, patients received csDMARDs + OKZ 64 mg subcutaneously q4w along with PPT (n = 51); in group 3, patients received csDMARDs + PPT (n = 25). The study duration was 24 weeks. The severity of depression was assessed using the PHQ-9 (Patient Health Questionnaire 9) and MADRS (Montgomery-Asberg Depression Rating Scale) scales, and anxiety was assessed using the HAM-A (Hamilton Anxiety Rating Scale) scale. Projective experimental psychological techniques were also used. - After 12 and 24 weeks of therapy, a significant decrease in the severity of depression and anxiety was observed in all patients' groups. However, the differences between the final and initial values of the scales filled in by a psychiatrist were statistically significantly greater (p < 0.001) in the groups of patients receiving PPT: in group 2 (ΔMADRS24-0 = -20.2 ± 6.57; ΔHAM-A24-0 = -13.2 ± 5.68) and group 3 (ΔMADRS24-0 = -17.8 ± 4.73; ΔHAM-A24-0 = -13.4 ± 4.41), compared with the group 1 (ΔMADRS24-0 = -5.42 ± 7.14; ΔHAM-A24-0 = -4.58 ± 6.80). There were no significant differences between the groups according to the PHQ-9 depression questionnaire (in group 1, ΔPHQ-924-0 = -4.89 ± 4.87; in group 2, ΔPHQ-924-0 = -6.73 ± 4.97; in group 3, ΔPHQ-924-0 = -7.26 ± 5.58, respectively), despite a greater decrease in the severity of depression observed in the groups with PPT. According to a semi-structured interview with a psychiatrist and in accordance with the criteria of ICD-10 the proportion of patients without depression 24 weeks after the start of therapy was significantly higher in the groups receiving PPT: 84.3% in group 2, 100% in group 3, and 16.3% in group 1. - n patients with moderate/high RA activity and comorbid depression, OKZ without PPT can lead to a decrease in the severity of depression or, less often, to a complete regression of depressive symptoms, mainly in patients with minor depression. OKZ therapy without PPT also reduces the severity of anxiety, but does not eliminate it completely. The combination of OKZ and PPT is optimal for achieving complete regression of depression and anxiety in this category of RA patients.
High genome variability of the 7th cholera pandemic agent, V. cholerae El Tor, led to emergence of genovariants with a distinct set of altered genes. The aim of the work was to analyze the dynamics of changes in pathogenicity, epidemicity, as well as drug resistance and phylogeny in toxigenic strains of V. cholerae El Tor isolated in Russia and endemic regions during three waves of ongoing pandemic. We used whole-genome nucleotide sequences of 155 strains, obtained by us (42) and taken from the NCBI Genbank (113). DNA sequencing was performed on Ion PGM platform. Phylogenetic relations were determined based on the Bayesian analysis of core SNPs obtained using Snippy 4.6 software package. Antibiotic resistance was assessed using the disk diffusion test. SNP data revealed that the studied strains (1970-2023) can be divided into three clusters. A clear correlation between each-cluster strain genotype and relevant isolation timing was observed. Separation of genetically altered cluster II and III strains isolated during the 2nd and 3rd waves of the pandemic from typical cluster I strains is associated with the acquisition of new DNA regions and mutations in pathogenicity and drug resistance genes. Due to different combination of mutations, cluster III strains are genetically heterogeneous. Genome comparison showed that this diversity increased dramatically during the 3rd wave, which led to emergence of new genovariants with higher pathogenic and epidemic potential. It is demonstrated that antibiotic resistance in strains both from endemic regions and Russia over the past 30 years (1993-2023) has undergone significant changes. The changing drug resistance clearly correlated with the occurrence of mutations in various pathogenicity genes. It is shown that, over the past two decades, the agent genome underwent a rather rapid change resulting in emergence of various genovariants. A change in the pathogen variants in Russia has been established. Strains combining genetic markers of hyper-virulence and multiple drug resistance are of particular concern. Genome variability of the strains identified points at a need for constant genomic surveillance to obtain data on altering epidemically important properties for timely generation of new diagnostic and preventive means.
The lipid envelope of the influenza A virus contains two major types of protein spikes formed by the transmembrane hemagglutinin trimers (HA, MW 80 kDa) and neuraminidase tetramers (NA, MW 55 kDa), in quantities of 500 and 120, respectively. The third transmembrane protein, M2 (MW 14 kDa), forms tetramers of ion channels in quantities of about 10-20 per virion. Modeling of the molecular structure using the AlphaFold software tool showed a novel model for a heterocomplex of HA0-M2 proteins, in which the M2 tetramer located inside the HA0 trimer like a "matryoshka doll." Similar models of the HA0-M2 heterocomplex were obtained for the A/Aichi/2/68 (H3N2) and A/WSN/33 (H1N1) viruses. The resulting HA0-M2 heterocomplex possessed a high structural complementarity of the macromolecular interfaces (ipTM = 0.65), had no structural clashes of atoms in the molecular interfaces (clash score = 0.0), and exhibited stable and reliable intermolecular topology with a high ranking score of 0.79. The constructed model allows to explain the phenomenon of blocking the function of M2 ion channels by the rigid conformation of the uncleaved HA0 protein and, in contrast, the activation of M2 channels after (i) specific point proteolysis of HA0 into HA1 (55 kDa) and HA2 (25 kDa) subunits and (ii) exposure to acidic pH of 4.0-5.5, leading to the disclosure of the 3D structure of the HA1/2 molecule and the opening of the M2 channel.
to compare the efficacy and safety of different doses of colchicine (0.5 mg/day vs. 1.0 mg/day) used for the prevention of arthritis attacks in gout patients during the initiation of urate-lowering therapy. -The study included 96 patients diagnosed with gout. Patients were randomized into three groups: those receiving colchicine 0.5 mg/day, those receiving colchicine 1 mg/day, and those without anti-inflammatory therapy. All participants were prescribed febuxostat 80 mg/day. The duration of the observation period was 6 months. The frequency and severity of arthritis attacks, as well as the incidence of adverse events, were compared. -Patients who did not receive colchicine experienced arthritis attacks more frequently compared to those receiving colchicine 0.5 mg/day (p = 0.03) and 1 mg/day (p = 0.007). In the groups receiving colchicine 0.5 and 1.0 mg/day, the frequency of attacks did not differ significantly (p = 0.6), nor did the proportion of patients who did not experience arthritis attacks (18 (56%) and 22 (69%), respectively, p = 0.3). Among the patients not taking colchicine, 9 (28%) did not develop arthritis attacks (p = 0.02 compared to those taking 0.5 mg/day and p = 0.001 for 1 mg/day). The administration of colchicine 1 mg/day (but not 0.5 mg/day) was associated with lower pain intensity on the visual analog scale (VAS) during arthritis attacks compared to the non-therapy group (p = 0.04). The frequency of adverse events was comparable across the groups. -The use of colchicine 0.5 mg/day for the prevention of arthritis attacks in gout patients is justified due to the absence of differences in efficacy compared to the higher dose. However, prescribing colchicine 1 mg/day also demonstrates a good safety profile and may be considered for the prevention of arthritis attacks.
-The aim of the study was to obtain data on the safety of netakimab (NTK) in a population of patients with ankylosing spondylitis (AS), including various somatic diseases, as well as to assess treatment retention during 2 years of observation in real world clinical practice. MATERIALS AND METHODS: -Patients were recruited for the study from August 2020 to December 2021 at 23 centers in the Russian Federation. The study included 137 patients who were prescribed netakimab therapy before enrollment. Clinical and medical history data for the first visit were entered retrospectively, and following visits at 12, 24, 52, 76, and 104 weeks of therapy were collected within the study. The average age of the patients 42.3 years, 34.3% of them with previous biologics therapy. RESULTS: -Median observation period was 104 weeks (range 1-137 weeks). At the end of the analyzed period (104 weeks of therapy), 85.5% (95% confidence interval (95% CI): 79.7-91.8) of patients continued treatment with netakimab. Retention on NTK therapy was slightly better in "bio-naïve" vs patients who received biologics earlier: 88.7% (95% CI: 82.3-95.5) and 78.9% (95% CI: 67.5-92.2), respectively, without significant differences between groups (p = 0.16). As many as 21 (15.3%) patients withdrew from study before visit 6. The main end-of-study reasons were lost to follow-up (7 (5.1%) patients) and treatment inefficacy (6 (4.4%) patients). The BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) and ASDAS-CRP (Ankylosing Spondylitis Disease Activity Score with C-reactive protein) showed statistically significant decreases from baseline: by 3 times during the first 3 months of therapy and 2 times decrease during the first year of treatment. This trend continued in the second year of treatment, although with a lower rate of reduction. By week 104 of therapy, 52.9% (95% CI: 47.3-58.4) reached low disease activity (1.3 ≤ ASDAS < 2.1), 21.3% (95% CI: 12.8-29.8) had inactive disease (ASDAS < 1.3). Netakimab was well tolerated by patients: AEs, related to therapy according to the investigator's opinion, were reported in 8 (6.0%) patients. CONCLUSIONS: -In real-world clinical practice, 85.5% of patients continued treatment with Netakimab at the end of 104 weeks. By 104 weeks 74% patients had low disease activity or inactive disease. Netakimab was well tolerated by most of patients.
The evolutionarily conserved transcription factor ENY2 is a component of several distinct complexes that regulate various stages of gene expression: the SAGA transcription coactivator, the THO transcription elongation complex involved in mRNA processing, and the TREX-2 complex responsible for mRNA export from the nucleus to the cytoplasm. Previous works in D. melanogaster have shown that SAGA associates with the histone locus body (HLB) biomolecular condensate, where histone mRNA transcription and processing take place, whereas TREX-2 interacts with histone mRNA and is involved in its export from the nucleus to the cytoplasm. This study demonstrates that ENY2 is a component of the HLB. ENY2 is present at the histone locus on D. melanogaster polytene chromosomes. ENY2 associates with the chromatin of the histone gene cluster as part of the SAGA coactivator complex and the THO transcription elongation complex, which also interacts with histone gene chromatin. ENY2 and subunits of the SAGA, THO, and TREX-2 complexes interact with FLASH, a specific constituent structural component of the HLB. Thus, ENY2 is present at the HLB biomolecular condensate and participates in histone gene expression as part of three functionally diverse complexes: SAGA, THO, and TREX-2.
This study is aimed to evaluate the prebiotic potential of plant polysaccharides of various structural types and origins, including acacia gum arabinogalactan, beech wood xylan, apple pectin enriched in homogalacturonan, flaxseed mucilage (containing arabinoxylan, and rhamnogalacturonan I), and chicory inulin. All carbohydrate samples varied in their monosaccharide composition and molecular weight distribution. The prebiotic activity of the polysaccharides was assessed using in vitro models under anaerobic conditions with the Bifidobacterium bifidum 791 and Lactobacillus acidophilus n.v. Ep 317/402. It was found that adding various polysaccharides to the nutrient media intensified lactic acid production, increased the biomass yield of bifidobacteria and lactobacilli, and influenced the rate and extent of substrate assimilation. The lower molecular weight inulin (4.2 kDa) and arabinogalactan (115 kDa) supported higher biomass yields in both strains. The viable cell count of Bifidobacterium bifidum 791 (colony-forming units per mL) increased by 3.5, 12.3, 110.5, 128.1, and 215.8% compared to the control upon the addition of beech wood xylan, flaxseed mucilage polysaccharides, apple pectin, inulin, and acacia arabinogalactan, respectively. For L. acidophilus n.v. Ep 317/402, the addition of the same polysaccharides increased the biomass yield by 1.5, 7.7, 64.6, 69.2, and 207.7%, respectively, versus the control. Flaxseed mucilage, composed of rhamnogalacturonan I (3400 kDa) and arabinoxylan (1330 kDa), supported a high biomass yield in both cultures. Based on this research, it can be concluded that flaxseed mucilage promoted probiotic growth in a manner similar to, and often more effectively than, the established prebiotic inulin. Due to the availability of flaxseeds, simple mucilage extraction process, and the limited existing research, flaxseed polysaccharide complex emerges as a promising candidate for further development as a prebiotic supplement.
A comparative structural-phylogenetic and expression analysis of the SNAT1 and SNAT2 genes of tomato Solanum lycopersicum and garlic Allium sativum was performed. It was shown that the SNAT1 and SNAT2 are intron-rich and intronless genes, respectively, and may have different evolutionary origins. It was predicted that, unlike the chloroplast protein SNAT1, SNAT2 has features of chloroplast-mitochondrial localization. The highest expression level of SNAT1 and SNAT2 was detected (in silico and qRT-PCR) in leaves, while in roots and mature storage organs it was significantly lower; SNAT2 was not expressed in garlic roots and bulbs. It was found that the expression level of SNAT2 in tomato plant organs is higher than the expression level of SNAT1, while for garlic the opposite ratio was observed.
Aging is a key challenge for modern society. In particular, brain aging is accompanied by chronic inflammation, depletion of energy potential, and an increased level of oxidative stress, with changes in blood composition playing a special role in this process. Recent studies also show that aging progresses non-linearly throughout life. Primates are genetically and anthropometrically the closest laboratory animals to humans, thus representing the most accurate model for research. This study establishes baseline values for biochemical parameters (including the state of the body's antioxidant system), cellular-hematological, and genomic indicators in aging primates of various species, sexes, and ages from the Kurchatov Complex of Medical Primatology. In aging males, the concentration of lipid peroxidation products was lower than in females of the same age and species. Analysis of antioxidant defense parameters indicates a more stable redox balance in old cynomolgus macaques of both sexes, which may be associated with their lower aggressiveness and high adaptability. The biochemical profile analysis in aging rhesus macaques revealed that females exhibit elevated levels of all measured parameters. In aging cynomolgus macaques, there are fewer sex-related differences in blood composition characteristics compared to rhesus macaques. It can be noted that under the housing conditions of the primates at the nursery of the Kurchatov Complex of Medical Primatology, several types of aging based on blood parameters can be observed within the same age category across different species and sexes.
MLN4924 (pevonedistat), a selective inhibitor of the NEDD8-activating enzyme, has inhibitory effects on various tumors by blockade of the neddylation pathway. Conversely, recent studies show that low-dose MLN4924 exerts pro-survival effects in both cancer cells and neurons, however, its actions on SH-SY5Y cells remain unclear. In this study, the effects of low-dose MLN4924 in SH-SY5Y cells were assessed by CCK-8 and Transwell assay, respectively. SH-SY5Y cells were transfected with enhanced green fluorescent protein plasmid to further observe neurite changes. The expression of SOCS3, p-JAK2 and p-STAT3 were analyzed by Western blot, and the potential interaction between MLN4924 and SOCS3 was explored via in silico molecular docking. Our results showed that 0.1 μM MLN4924 significantly enhanced SH-SY5Y cell viability and migration while concurrently reducing neurite outgrowth. The expression level of SOCS3 was significantly increased in the MLN4924 treatment group compared with the control group, but the phosphorylation levels of JAK2 and STAT3 showed no changes. Molecular docking further predicted that Glu63 of SOCS3 serves as a key residue for MLN4924 binding. Together, low-dose MLN4924 enhances SH-SY5Y cell viability and migration by targeting SOCS3 signaling, independent of JAK2/STAT3 signaling.
Ferroptosis is considered a promising strategy for inducing the death of tumor cells. However, the effectiveness of known ferroptosis inducers, such as erastin, is in some cases limited, which stimulates the search for new combined application strategies. In this study, the combined effect of erastin and docosahexaenoic acid (DHA) on prostate cancer cells was examined over time. It was shown that the combination of these agents is more toxic compared to their separate use for all tumor cells considered. At the same time, known ferroptosis inhibitors, ferrostatin-1 and deferoxamine, effectively prevented cell death, indicating the specificity of the mechanism of action. Transcriptomic analysis of cell lines differing in sensitivity to the combination revealed activation of antioxidant systems in more resistant cells (in particular, pronounced expression of the NQO1 and GCLM genes responsible for the reduction of quinones to hydroquinones and the synthesis of glutathione, respectively). The obtained results indicate the high synergistic potential of the erastin-DHA combination for ferroptosis induction and open new possibilities for the development of combined approaches to the therapy of resistant tumors.
Rhamnogalacturonans I (RGs-I) are complex, multifunctional pectic polysaccharides found in plant cell walls and seed mucilages. Their structure varies based on the source, tissue type, and growth stage. This study investigates the structural peculiarities of different functional types of RG-I from flax, focusing on NMR analysis of RGs-I from seed mucilage, primary cell walls of hypocotyls, and tertiary cell walls of fibers. RG-I from flaxseed mucilage features single-residue side chains of Galp and Fucp, with 55% Rhap substitution at the rare O-3 position, no homogalacturonan, and the presence of acetyl groups. Primary cell wall RG-I includes homogalacturonan (up to 50% of the total backbone), 54% Rhap substitution at O-4, and short β-(1 → 4)-galactan and α-(1 → 5)-arabinan side chains (averaging 2-3 residues), with 17% represented by single Ara and Gal units, along with acetyl, feruloyl, and benzoyl groups. The tertiary cell wall RG-I has a pure backbone without homogalacturonan and the highest Rhap substitution at O-4 (72%) by long galactan side chains (up to 92 residues). Modifications of this RG-I in the cell wall suggest the removal of acetyl groups and trimming of galactan chains (47% reduced to a single residue; longer side chains of up to 16 residues remaining). This research provides insights into the structural diversity of RG-I within a single plant, contributing to the understanding of their functional roles in plant growth and development.
Boron Neutron Capture Therapy (BNCT) is one of the innovative methods for treating oncological diseases. Its selectivity is based on the targeted delivery of the boron-10 isotope to tumor cells, followed by neutron irradiation, the 10B(n, α)7Li reaction occurs with a local release of 2.79 MeV of energy. Budding boron delivery agents are nanoscale systems. This study evaluated in vitro cytotoxicity, accumulation, and retention of elemental boron nanoparticles, synthesized by laser ablation and laser fragmentation, in U87 and BT474 tumor cells and BJ-5ta fibroblasts. It was shown that both types of nanoparticles exhibit low cytotoxicity at therapeutically relevant concentrations. Boron accumulation was maximal after 24 h of incubation and was significantly higher in tumor cells, especially in the BT474 cell line, compared to fibroblasts. The obtained data indicate the promise of these nanoparticles as boron delivery agents for BNCT.
Genetic predisposition without doubt is one of the risk factors of cancer initiation. It is known that single nucleotide polymorphisms (SNP) of genes that maintain the genome stability, including SNP of DNA repair, may contribute to the initiation of carcinogenesis. Single-nucleotide polymorphisms of genes that support genome stability, including SNP of DNA repair genes, can contribute to cancer initiation. Polymorphism of the excision repair gene OGG1 causes interest of leading scientific groups from various countries. It is assumed that there is relationship between the rs1052133 polymorphism in the gene and predisposition to cancer initiation. The objective of this study was to establish association between rs1052133 polymorphism of base excision repair gene OGG1 and the risk of cancer initiation in people chronically exposed to ionizing radiation. Residents (888 people) of the Techa riverside settlements, chronically exposed to low or medium dose radiation from the Techa River and the East-Urals Radioactive Trace were included in the study. The study allowed researchers to establish that exposed to chronic radiation people, carriers of the rs1052133*G allele, have increased risk of malignant neoplasm initiation: OR = 1.38; 95% CI [1.05-1.83], p = 0.023. The multifactorial synergistic interactions between the dose to the red bone marrow and the rs1052133 polymorphism of the OGG1 gene was found: Testing Balanced Accuracy (TBA) = 0.56; Cross Validation Consistency (CVC) = 10/10; p = 0.01). The study found that the rs1052133 polymorphism may be considered as genetical marker of risk of cancer initiation in people chronically exposed to radiation with doses ranged from 0.74 to 3507.07 mGy (average 523.10 ± 33.89 mGy). It was found that the presence of the rs1052133*G in combination with radiation exposure can modify the risk of solid cancers initiation, as it is indicated by the synergistic relationship between the SNP and the radiation dose.
The study proposes an experimental approach to determining the rates of individual stages of a reaction catalyzed by bacterial luciferase, based on the tryptophan fluorescence of the protein and the stopped-flow technique. The relationship between the fluorescence intensity of tryptophan residues in luciferase and the presence of substrates and reaction products in the active site of the enzyme is substantiated. The non-steady-state kinetics of bioluminescence in the reaction of two bacterial luciferases with aliphatic aldehydes of different chain lengths, as well as the kinetics of enzyme fluorescence intensity during the reaction, were analyzed. The obtained results confirmed the relationship between the rate of the two kinetic stages of enzyme luminescence and the processes of flavin substrate binding and enzyme activity recovery after the catalytic act.
Boundary elements in the Drosophila Bithorax complex partition the Abd-B regulatory landscape into autonomous domains that require insulation and boundary bypass. We surveyed Large Boundary Complex (LBC) occupancy across Abd-B boundaries and detected binding at Fab-7 and Fab-8, but not at Fab-6 or at Mcp (the boundary between Abd-B and abd-A). Despite lacking LBC binding, Fab-6 supports boundary bypass, demonstrating that bypass can occur without LBC. Fab-7 and Fab-8 share two conserved motifs ("green" and "blue"); however, mutational analysis shows that neither motif is required for LBC recruitment. These findings reveal selective, context-dependent LBC occupancy at Abd-B boundaries and imply that additional factor(s) and/or higher-order sequence organization underlie bypass activity. Thus, LBC is not universally required for boundary bypass, and its recruitment to Fab-7/8 is independent of the shared "green/blue" motifs.
The patterns of radiation adaptive response (RAR) induction and transgenerational genomic instability in mice following exposure to carbon ions (12C) with a linear energy transfer (LET) of ~39 keV/μm and to X‑rays with a LET of ~2 keV/μm at a dose of 10 cGy were studied. Low doses of 12C, as well as X‑rays, induce RAR, the magnitude of which depends on the quality of the challenge radiation. In the first- and second- generation offspring of males irradiated 12C at a dose of 10 cGy, an increased spontaneous level of cytogenetic damage and the absence of RAR in the first generation were detected, in contrast to the offspring of males after irradiation with X‑rays.