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Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease associated by inflammation of the synovial tissue and autoantibody production. Oxidative stress and free radicals are known to be indirectly implicated in joint damage and cartilage destruction in RA. Several studies describe the presence of mitochondrial dysfunction in RA, but few of them follow the dynamics in energy parameters after therapy. The aim of our investigation is to evaluate the direct effect of JAK inhibitors on cellular metabolism (and under induced oxidative stress) in RA patients. Ten newly diagnosed RA patients were included in the study. Peripheral blood mononuclear cells (PBMCs) and plasma were isolated before and 6 months after therapy with JAK inhibitors. A real-time metabolic analysis was performed to assess mitochondrial function and cell metabolism in PBMCs. Sonographic examination, DAS28 and conventional clinical laboratory parameters were determined also prior and post therapy. A significant decrease in proton leak after therapy with JAK inhibitors was found. The increased production of ATP indicates improvement of cellular bioenergetics status. These findings could be related to the catalytic action of JAK inhibitors on oxidative phosphorylation which corresponds to the amelioration of clinical and ultra-sonographic parameters after treatment. Our study is the first to establish the dynamics of mitochondrial parameters in PBMCs from RA patients before and after in vivo therapy with JAK inhibitors. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. A growing body of evidence suggests that mitochondrial dysfunction and inflammation play a crucial role as a pathogenetic mechanism in PD. The glycoprotein YKL-40 (CHI3L1) is a potential biomarker involved in inflammation and tumor processes. The aim of the present study was to investigate the metabolic profile of PBMCs from PD patients and to search for a possible relationship between cellular bioenergetics and YKL-40. The study included 18 naïve PD patients and an age-matched control group (HC, n = 7). Patients were diagnosed according to the MDS-PD, the UPDRS, and the Hoen–Yahr scales. Mitochondrial activity was measured by a metabolic analyzer on isolated PBMCs from PD patients. Gene (qPCR) and protein (ELISA) expression levels of YKL40 were investigated. New data are reported revealing changes in the mitochondrial activity and YKL-40 levels in PD patients. Bioenergetic parameters showed increased respiratory reserve capacity in PD compared to HC. The protein levels of YKL-40 were threefold higher in PD. We found a correlation between the YKL-40 protein levels and basal respiration and between YKL-40 and ATP production. These observations suggest an interplay between YKL-40 and mitochondrial function in PD. We assume that the YKL-40 gene and protein levels in combination with changes in mitochondrial function might serve as an additional tool to monitor the clinical course of PD. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. It is characterized by the accumulation of α-Synuclein aggregates and the degeneration of dopaminergic neurons in substantia nigra in the midbrain. Although the exact mechanisms of neuronal degeneration in PD remain largely elusive, various pathogenic factors, such as α-Synuclein cytotoxicity, mitochondrial dysfunction, oxidative stress, and pro-inflammatory factors, may significantly impair normal neuronal function and promote apoptosis. In this context, neuroinflammation and autophagy have emerged as crucial processes in PD that contribute to neuronal loss and disease development. They are regulated in a complex interconnected manner involving most of the known PD-associated genes. This review summarizes evidence of the implication of neuroinflammation and autophagy in PD and delineates the role of inflammatory factors and autophagy-related proteins in this complex condition. It also illustrates the particular significance of plasma and serum immune markers in PD and their potential to provide a personalized approach to diagnosis and treatment. [ABSTRACT FROM AUTHOR]

The clinical trial aimed to study the effectiveness of a dietary supplement for respiratory system diseases therapy. Children underwent treatment during both acute and convalescent stages, and in addition to their primary treatment received the plant-based dietary supplement. The new plant-based dietary supplement with ingredients possessing synergetic properties was developed to supplement the normal diet and help correct metabolism disorders in the case of respiratory diseases. The ingredients for the new dietary supplement include echinacea purpurea, Vitamin C, rutin, zinc, and selenium. The consistent manufacturing process used to produce the new dietary supplement ensures that the contents are protected against adverse conditions, with the contents delivered and released at controlled rates and under specific conditions. The study of the effectiveness and the functional properties of the plant-based dietary supplement was undertaken. Children aged from 1 to 3 and treated for respiratory diseases were given ½ capsule twice a day, children aged from 3 to 7 took 1 capsule twice a day and children aged from 7 to 14 took 1 capsule three times a day as a supplement in addition to their primary medical treatment. At the same time, the children from the control group underwent only primary medical treatment. The clinical trial lasted from 10 to 14 days. During the clinical trial, regular laboratory tests and chest X-rays were carried out, and such symptoms of acute respiratory illnesses like nasal congestion, hyperaemia, sore throat, cough, wheeze as well as their duration were carefully studied. The consumption of the plant-based dietary supplement resulted in faster symptoms easing and helped relieve cough, wheeze, and nasal congestion. The data received indicates the boost to the immune response, strengthening of the immune system as a result of taking the plant-based dietary supplement. The plant-based dietary supplement is noted to be safe and it does not cause any adverse effects. The directions for use are developed. The mandatory State Registration is completed and the supplement is produced in the scientific research-to-production facilities of the Art-Life Scientific Production Association (Tomsk city). [ABSTRACT FROM AUTHOR]

In this paper, we introduce artificial boundary conditions for the linearized Green-- Naghdi system of equations. The derivation of such continuous (respectively, discrete) boundary conditions includes the inversion of Laplace transform (respectively, \scrZ -transform) and these boundary conditions are in turn nonlocal in time. In the case of continuous boundary conditions, the inversion is done explicitly. We consider two spatial discretizations of the initial system either on a staggered or on a collocated grid, both of interest from the practical point of view. We use a Crank--Nicolson time discretization. The proposed numerical scheme with the staggered grid permits explicit \scrZ - transform inversion, whereas the collocated grid discretization does not. A stable numerical procedure is proposed for this latter inversion. We test numerically the accuracy of the described method with standard Gaussian initial data and wave packet initial data which are more convenient to explore the dispersive properties of the initial set of equations. We used our transparent boundary conditions to solve numerically the problem of injecting propagating (planar) waves in a computational domain. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc) is a rare connective tissue disease characterized by vascular, immune and fibrotic abnormalities in the skin and in many internal organs. New biomarkers with predictive value associated with target organ involvement are needed. The up-regulation of IL-6 production is associated with the disease activity and in the development of cardiopulmonary manifestations in SSc patients. The protein YKL-40 is a promising and intensively investigated biomarker related to inflammatory and tumor diseases. The objective of the study was to investigate how serum levels of YKL-40 and IL-6 correlate with articular and periarticular involvement in patients with SSc assessed by high-frequency ultrasonography. 59 SSc patients (56 women, 3 men) and 23 age-matched healthy subjects (21 women and 2 men) were investigated for serum YKL-40 and IL-6 (by ELISA). All the patients and healthy controls underwent clinically and high-frequency ultrasound assessment of articular and periarticular structures. Joint involvement was scored according to the new US10SSc score. Clinical data about the SSc patients showed significantly higher mRSS in the dcSSc patients (p = 0.015). Clinical synovitis was diagnosed in 16.9% of all patients: 22.5% of the dcSSc group and 10.7% of the lcSSc group (p = 0.306). On the other hand, US synovitis was detected in a higher percentage: 44% of all SSc patients; 54.8% of the dcSSc group and 32% of the lcSSc patients (p = 0.116). Clinical tenosynovitis was established in 6.7% of all patients: 9.7% of the dcSSc group and 3.5% of the lcSSc group (p = 0.614). US tenosynovitis was detected at a higher rate: 27% of all patients; 32.25% of the dcSSc group and 21.4% of the lcSSc group (p = 0.393). Serum level of YKL-40 was significantly higher in SSc patients (115.62 ng/ml ± 89.51, median 86.76) compared to the healthy controls (46.28 ng/ml ± 18.91, median 44.02), p < 0.001. IL-6 level was also significantly higher in the patient group (27.60 ± 48.80 pg/ml; median 8.32) vs. the healthy controls (5.79 ± 2.46 pg/ml, median 5.52). In the patient subgroups, YKL-40 and IL-6 levels were significantly elevated in dcSSc compared to lcSSc patients: YKL-40 dcSSc (159.52 ng/ml ± 102.81; median 136.20 ng/ml) vs. lcSSc patients (89.31 ng/ml ± 50.36; median 68.03 ng/ml;), p < 0.001; IL-6 dcSSc patients (49.64 pg/ml ± 46.37; median 16.36 pg/ml) vs. lcSSc patients (13.22 pg/ml ± 8.95; median 8.65 pg/ml), p = 0.048. A statistically significant correlation of high magnitude (rs = 0.884, p < 0.001) was observed between YKL-40 and the ultrasound 10 Systemic sclerosis score (US10SSc) and between IL-6 and the US10SSc score (rs = 0.808, p < 0.001). Serum YKL-40 and IL-6 in combination with US may have a potential role in defining disease activity and stratification, predicting organ involvement, and in the prognosis of SSc. [ABSTRACT FROM AUTHOR]

High‐grade gliomas (HGG) are the most frequent brain tumors in adults. Glioblastoma multiforme (GBM) is their most aggressive form resistant to therapy. It was shown that inhibition of autophagy reduced GBM development and autophagy interfering agents are regarded as a new strategy to fight glioma cells. The lysosome‐associated membrane proteins (LAMPs) display differential expression particularly in cancer. There are few data on their expression and especially on their molecular profile. The aim of the present study is to investigate the expression of LAMP‐1 and LAMP‐2 genes and proteins in HGG. Newly diagnosed patients with HGG and healthy controls were examined by immunohistochemistry and qPCR for both protein and mRNA levels of LAMP‐1 and LAMP‐2. The transcriptional activity of LAMP‐1 in HGG was significantly higher compared to normal brain and to LAMP‐2. The two glycoproteins were detected in the cytosol of tumor cells with varying intensity, LAMP‐1 showing again enhanced expression. In conclusion, novel data on LAMP‐1 overexpression in HGG are presented suggesting involvement of this gene and protein in cell adhesion and tumor progression. These findings might help the elucidation of the complex biological role of the multifunctional LAMPs proteins and to predict novel therapeutic targets in lysosomes. [ABSTRACT FROM AUTHOR]

The aim of our study was to analyze the level of the glycoprotein YKL-40 in patients with active knee osteoarthritis (OA) and to search possible correlations with local inflammation and ultrasound (US) findings.Material and Methods: A prospective study with fifty consecutive patients with active knee OA (diagnosed based on the American College of Rheumatology criteria for OA with radiographic confirmation) was performed. Concentrations of YKL-40 in serum and synovial fluid were measured by ELISA. US examinations - Gray scale (GS) US and Power Doppler (PD) US - of the knee was performed according to international guidelines. The suprapatellar, medial and lateral parapatellar recesses were scanned in each knee to evaluate synovial hypertrophy and vascularization.Results: Forty women (mean age 61.50±11.33 years old) and 10 men (aged 68.50±6.60 years old) were enrolled. We found that the synovial level of the glycoprotein (237.80±104.08 ng/ml) was significantly higher compared to the serum concentration (112.83±60.61 ng/ml, p<0.001). The serum concentration in OA patients was higher comparing with age-matched healthy controls (84.19±11.39 ng/ml) (p<0.05). A statistically significant association between YKL- 40 in synovial fluid and serum levels was shown. We determined a moderately positive linear relationship between the synovial level of the glycoprotein and the serum concentration. No association between the levels of inflammatory markers - erythrocyte sedimentation rate and C-reactive protein - and YKL-40 concentrations was detected. Our study revealed a strong relationship between YKL-40 in synovial fluid and GS US and feeble with PD US. YKL-40 correlated with inflammatory activity in knee joints and neovascularization detected by US.Conclusions: YKL-40 is involved in the pathogenesis of OA synovitis. Evaluation of YKL-40 levels in parallel with US might provide more sensitive and reliable information for the diagnosis and understanding of OA. [ABSTRACT FROM AUTHOR]

YKL-40, also known as human cartilage glycoprotein 39, is a member of the 'mammalian chitinase-like proteins' family without chitinase activity. Increased serum concentrations are associated with inflammatory processes and several types of cancer. In this study, we evaluated YKL-40 levels in serum and synovial fluid of patients with rheumatoid arthritis in comparison with the ultrasonographic findings. YKL-40 levels were measured by enzyme-linked immunosorbent assay in 25 patients with active rheumatoid arthritis and in 40 healthy subjects. B mode and power Doppler were performed to determine synovial thickening and vascularization. Serum YKL-40 level in patients was significantly higher than the concentration in healthy controls ( P < 0.01). In patients with rheumatoid arthritis, the level of the glycoprotein in synovial fluid was remarkably elevated compared to the serum level ( P = 0.003). The B mode and power Doppler scores correlated to YKL-40 in serum and synovial fluid ( P = 0.07). Serum YKL-40 levels were related positively to serum markers of inflammation such as C-reactive protein ( P = 0.004) and erythrocyte sedimentation rate ( P = 0.003). This study is the first to demonstrate a relationship between YKL-40 levels and ultrasonographic examinations in Bulgarian patients with rheumatoid arthritis. The findings suggest that YKL-40 might be implicated in the pathogenesis of the disease and could indicate the level of joint inflammation. [ABSTRACT FROM AUTHOR]

Almost all transcribed human genes undergo alternative RNA splicing, which increases the diversity of the coding and non-coding cellular landscape. The resultant gene products might have distinctly different and, in some cases, even opposite functions. Therefore, the abnormal regulation of alternative splicing plays a crucial role in malignant transformation, development, and progression, a fact supported by the distinct splicing profiles identified in both healthy and tumor cells. Drug resistance, resulting in treatment failure, still remains a major challenge for current cancer therapy. Furthermore, tumor cells often take advantage of aberrant RNA splicing to overcome the toxicity of the administered chemotherapeutic agents. Thus, deciphering the alternative RNA splicing variants in tumor cells would provide opportunities for designing novel therapeutics combating cancer more efficiently. In the present review, we provide a comprehensive outline of the recent findings in alternative splicing in the most common neoplasms, including lung, breast, prostate, head and neck, glioma, colon, and blood malignancies. Molecular mechanisms developed by cancer cells to promote oncogenesis as well as to evade anticancer drug treatment and the subsequent chemotherapy failure are also discussed. Taken together, these findings offer novel opportunities for future studies and the development of targeted therapy for cancer-specific splicing variants. [ABSTRACT FROM AUTHOR]

Systemic sclerosis is a complex idiopathic disease originating from an intricate interplay between genetic susceptibility, environmental factors, and epigenetic modifications. This scoping review aims to map the advancements made regarding DNA methylation abnormalities and histone modifications in systemic sclerosis in the past decade. A literature search was conducted using three electronic databases (Scopus, Web of Science and PubMed) to identify relevant articles. A total of 44 studies were selected for this review, demonstrating the critical contribution of epigenetic perturbations in multiple cell types to disease pathogenesis. In conclusion, this scoping review has elucidated the significant discoveries made in the past decade regarding the role of DNA methylation and histone modifications in systemic sclerosis. Further progress in the field could lead to the development of novel treatment possibilities targeting epigenetic marks. [ABSTRACT FROM AUTHOR]

Objectives: Systemic sclerosis (SSc) is an autoimmune disease with incompletely revealed etiology and pathophysiology. There are still no specific and reliable biomarkers. Here we examined YKL-40 as a biomarker of inflammation and fibrosis, and suggest a possible mechanism for its regulation. Methods: Forty female patients with SSc (26 with diffuse cutaneous (dcSSc) and 14 with limited cutaneous SSc (lcSSc)) and 14 healthy female controls were enrolled in this cross-sectional study. Bioinformatic tools identified miR-214 binding site in the 30-untranslated region (3'UTR) of YKL-40 mRNA. Serum levels of YKL-40 were examined by ELISA, while YKL-40 mRNA and miR-214 was measured by qPCR. Results: The in silico analysis revealed several microRNAs (miRNAs) targeting YKL-40 mRNA, from which miR-214 was selected. YKL-40 serum levels were significantly higher in patients compared to controls (p=.0042). In contrary, miR-214 expression in plasma of SSc patients was significantly downregulated compared to controls (p=.0058). Receiver operating characteristic (ROC) and area under the curve (AUC) analysis showed that both serum YKL-40 and plasma miR-214 levels had good capacity to distinguish patients with SSc, dcSSc and lcSSc from healthy subjects. Conclusion: YKL-40 and miR-214 have different expression profile in SSc. Increased serum levels of YKL-40 could be associated with down-regulation of miR-214 expression in plasma. Both, YKL-40 concentrations and miR-214 plasma fold change values might serve as possible biomarkers in SSc. [ABSTRACT FROM AUTHOR]

At present it is well-defined that autophagy is a fundamental process essential for cell life but its pro-viral and anti-viral role has been stated out with the COVID pandemic. However, viruses in turn have evolved diverse adaptive strategies to cope with autophagy driven host defense, either by blocking or hijacking the autophagy machinery for their own benefit. The mechanisms underlying autophagy modulation are presented in the current review which summarizes the accumulated knowledge on the crosstalk between autophagy and viral infections, with a particular emphasizes on SARS-CoV-2. The different types of autophagy related to infections and their molecular mechanisms are focused in the context of inflammation. In particular, SARS-CoV-2 entry, replication and disease pathogenesis are discussed. Models to study autophagy and to formulate novel treatment approaches and pharmacological modulation to fight COVID-19 are debated. The SARS-CoV-2—autophagy interplay is presented, revealing the complex dynamics and the molecular machinery of autophagy. The new molecular targets and strategies to treat COVID-19 effectively are envisaged. In conclusion, our finding underline the importance of development new treatment strategies and pharmacological modulation of autophagy to fight COVID-19. [ABSTRACT FROM AUTHOR]

YKL-40 is a heparin- and chitin-binding glycoprotein that belongs to the family of glycosyl hydrolases but lacks enzymatic properties. It affects different (patho)physiological processes, including cancer. In different tumors, YKL-40 gene overexpression has been linked to higher cell proliferation, angiogenesis, and vasculogenic mimicry, migration, and invasion. Because, in colorectal cancer (CRC), the serological YKL-40 level may serve as a risk predictor and prognostic biomarker, we investigated the underlying mechanisms by which it may contribute to tumor progression and the clinical significance of its tissue expression in metastatic CRC. We demonstrated that high-YKL-40-expressing HCT116 and Caco2 cells showed increased motility, invasion, and proliferation. YKL-40 upregulation was associated with EMT signaling activation. In the AOM/DSS mouse model, as well as in tumors and sera from CRC patients, elevated YKL-40 levels correlated with high-grade tumors. In retrospective analyses of six independent cohorts of CRC patients, elevated YKL-40 expression correlated with shorter survival in patients with advanced CRC. Strikingly, high YKL-40 tissue levels showed a predictive value for a better response to cetuximab, even in patients with stage IV CRC and mutant KRAS, and worse sensitivity to oxaliplatin. Taken together, our findings establish that tissue YKL-40 overexpression enhances CRC metastatic potential, highlighting this gene as a novel prognostic candidate, a predictive biomarker for therapy response, and an attractive target for future therapy in CRC. [ABSTRACT FROM AUTHOR]

This work describes a method for synthesis, as well as in vitro antiproliferative and antibacterial investigation of 3-methyl-9'-fluorenespiro-5-hydantoin. The structure of the substituted fluorenylspirohydantoin derivative was verified by UV-Vis, FT-IR, Raman, 1H NMR and 13C NMR spectroscopy, and by using a combination of 2D NMR experiments, which included 1H-1H COSY, HMQC and HMBC sequences. The geometry of the compound was optimized by the B3LYP density functional with 6-31G(d) basis set and the 1H and 13C NMR spectra were predicted with the HF/6- 31G(d) calculations at the optimized geometry. The anticancer activity of the 3-methyl-9'-fluorenespiro-5-hydantoin was determined in suspension cell lines originating from tumors in humans (WERI-Rb-1). The cytotoxic effect was evaluated by WST-assay (Roche Applied Science). The antimicrobial effect of the compound against Gram-negative, Gram-positive bacteria and the yeast Candida albicans was investigated. [ABSTRACT FROM AUTHOR]

The analysis of Cartesian Perfectly Matched Layers (PMLs) in the context of time-domain electromagnetic wave propagation in a 3D unbounded anisotropic homogeneous medium modelled by a diagonal dielectric tensor is presented. Contrary to the 3D scalar wave equation or 2D Maxwell’s equations some diagonal anisotropies lead to the existence of backward waves giving rise to instabilities of the PMLs. Numerical experiments confirm the presented result. [ABSTRACT FROM AUTHOR]

Glial activation and related neuroinflammatory processes play a key role in the aging and progression of Alzheimer's disease (AD). CHI3L1 / YKL40 is a widely investigated chitinase in neurodegenerative diseases and recent studies have shown its involvement in aging and AD. Nevertheless, the biological function of CHI3L1 in AD is still unknown. Here, we collected microarray datasets from the National Center for Biotechnology Information (NCBI) brain samples of not demented healthy controls (NDHC) who died from causes not attributable to neurodegenerative disorders (n = 460), and of deceased patients suffering from Alzheimer's disease (AD) (n = 697). The NDHC and AD patients were stratified according to CHI3L1 expression levels as a cut-off. We identified two groups both males and females, subsequently used for our statistical comparisons: the high CHI3L1 expression group (HCEG) and the low CHI3L1 expression group (LCEG). Comparing HCEG to LCEG, we attained four signatures according to the sex of patients, in order to identify the healthy and AD brain cellular architecture, performing a genomic deconvolution analysis. We used neurological signatures (NS) belonging to six neurological cells populations and nine signatures that included the main physiological neurological processes. We discovered that, in the brains of NDHC the high expression levels of CHI3L1 were associated with astrocyte activation profile, while in AD males and females we showed an inflammatory profile microglia-mediated. The low CHI3L1 brain expression levels in NDHC and AD patients highlighted a neuronal activation profile. Furthermore, using drugs opposing CHI3L1 transcriptomic signatures, we found a specific drug profile for AD males and females characterized by high levels of CHI3L1 composed of fostamatinib, rucaparib, cephaeline, prednisolone, and dinoprostone. Brain levels of CHI3L1 in AD patients represent a biological signature that allows distinguishing between males and females and their likely cellular brain architecture. • Deconvolution method represents a new approach to define the brain cells' architecture AD. • CHI3L1 is a chitinase high modulated in neurodegenerative diseases and AD. • In AD brains the high expression levels of CHI3L1 were associated with an inflammatory profile. • Neuronal activation profile is significantly activated in AD patients with low CHI3L1 expression. • Anti-AD drugs identified by L1000FWD showed fostamatinib, rucaparib, cephaeline, prednisolone, and Dinoprostone. [ABSTRACT FROM AUTHOR]