Development of FluoAHRL: A Novel Synthetic Fluorescent Compound That Activates AHR and Potentiates Anti-Inflammatory T Regulatory Cells

Aryl Hydrocarbon Receptor (AHR) ligands, upon binding, induce distinct gene expression profiles orchestrated by the AHR, leading to a spectrum of pro- or anti-inflammatory effects. In this study, we designed, synthesized and evaluated three indole-containing potential AHR ligands (FluoAHRL: AGT-4, AGT-5 and AGT-6). All synthesized compounds were shown to emit fluorescence in the near-infrared. Their AHR agonist activity was first predicted using in silico docking studies, and then confirmed using AHR luciferase reporter cell lines. FluoAHRLs were tested in vitro using mouse peritoneal macrophages and T lymphocytes to assess their immunomodulatory properties. We then focused on AGT-5, as it illustrated the predominant anti-inflammatory effects. Notably, AGT-5 demonstrated the ability to foster anti-inflammatory regulatory T cells (Treg) while suppressing pro-inflammatory T helper (Th)17 cells in vitro. AGT-5 actively induced Treg differentiation from naïve CD4+ cells, and promoted Treg proliferation, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) expression and interleukin-10 (IL-10) production. The increase in IL-10 correlated with an upregulation of Signal Transducer and Activator of Transcription 3 (STAT3) expression. Importantly, the Treg-inducing effect of AGT-5 was also observed in human tonsil cells in vitro. AGT-5 showed no toxicity when applied to zebrafish embryos and was therefore considered safe for animal studies. Following oral administration to C57BL/6 mice, AGT-5 significantly upregulated Treg while downregulating pro-inflammatory Th1 cells in the mesenteric lymph nodes. Due to its fluorescent properties, AGT-5 could be visualized both in vitro (during uptake by macrophages) and ex vivo (within the lamina propria of the small intestine). These findings make AGT-5 a promising candidate for further exploration in the treatment of inflammatory and autoimmune diseases.This research was funded by the Ministry of Science, Technological Development and Innovations of the Republic of Serbia No. 451-03-66/2024-03/200007, Serbian Clinical Immunology Fund New Castle, UK. Also, this study has been supported by the European Regional Development Fund of the European Union and Greek national funds through the Operational Program Competitiveness, Entrepreneurship and Innovation, under the call RESEARCH—CREATE—INNOVATE (project code: TAEDK-06189/Τ2EDK-0326, Acronym: Glioblastoma). Pedro Moura-Alves, Sérgio Marinho and Inês Castro-Almeida were funded by the European Union’s Horizon 2020 research and innovation programme under grant agreement No 951921 (ImmunoHUB). Graphical abstract was created by BioRender.com

Implications of serial measurements of natriuretic peptides in heart failure: insights from BIOSTAT‐CHF

No abstract available

Decoding the historical tale: COVID-19 impact on haematological malignancy patients-EPICOVIDEHA insights from 2020 to 2022

The COVID-19 pandemic heightened risks for individuals with hematological malignancies due to compromised immune systems, leading to more severe outcomes and increased mortality. While interventions like vaccines, targeted antivirals, and monoclonal antibodies have been effective for the general population, their benefits for these patients may not be as pronounced.Peer reviewe

Changes in plasma brain natriuretic peptide levels during exercise stress echocardiography tests in patients with idiopathic dilated cardiomyopathy with or without preserved left ventricular contractile reserve

Introduction: The study of importance of left ventricular contractile reserve presence and changes plasma brain natriuretic peptide levels (BNP) during exercise in patinets with idiopathic dilated cardiomyopathy is very popular today, but these two parametres have rarely been interconnected. The study of response BNP during echocardiography stress tests in patients with idiopathic dilated cardiomyopathy with or without preserved left ventricular contractile reserve. We studied 55 consecutive patients with idiopathic dilated cardiomyopathy (mean age 54.98 ± 9.84, 49 (89.1%) male) treated in the outpatient clinic for heart failure at the Institute of Cardiovascular Diseases 'Dedinje'. All the patients underwent the echocardiography stress test. Contractile reserve was assessed by measuring of the changes of the left ventricle ejection fraction basally and in the first minute after the strongest stress. Level of BPN was measured at rest, in the first minute and after 20 minutes of maximal exercise stress. Following the kinetics of BNP level during stress testing, we find that in patients with preserved left ventricular contractile reserve BNP level is rising at maximum load achieved (Mediana (IQR) - 59 (22-113) vs. 91 (37-135) vs. 78 (30-159) ng/L, p<0.001), whereas in patients without preserved left ventricular contractile reserve BNP level does not change significantly (Mediana (IQR) - 89 (50-322) vs. 119.5 (61.3-321.8) vs. 136 (72- 281), p=0.102). The increase in BNP in the peak load compared to its value at rest was positively correlated with preserved contractile reserve (r=0.38, p=0.009), better WMSI at rest (r=-0.28, p=0.04), greater difference in the double product (r=0.40, p=0.002), as well as the work accomplished on the test (r = 0.47, p <0.001), and longer duration of the test (r = 0.43, p = 0.001). The increase in BNP during physical exercise in patients with idiopathic dilated cardiomyopathy suggests a preserved contractile reserve of the left ventricle

Blastic plasmacytoid dendritic cell neoplasm of the uterus

© 2020, Serbia Medical Society. All rights reserved. Introduction Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and very aggressive hematological malignancy derived from precursor of the plasmacytoid dendritic cell. We present a case with cervix uteri involvement without skin lesions, which is, to the best of our knowledge, the first case of BPDCN localized in the cervix. Case outline A 66-year-old previously healthy women initially presented with a four-week history of vaginal bleeding. Gynecologic examination revealed a tumorous bleeding formation on cervix uteri. Except paleness of the skin, physical examination results were normal. Complete blood counts showed anemia and thrombocytopenia. Computed tomography scans showed an expansive tumorous formation at the level of the isthmus and cervix uteri, 60 × 42 mm in size. Cervical biopsy was done and final pathohistological diagnosis was BPDCN. Karyotype analysis results from the bone marrow aspiration specimen demonstrated tetrasomy of chromosome 2 and monosomy of chromosome 16. The patient did not accept treatment and died two months after the initial diagnosis was established. Conclusion Attributes such as aggressive clinical course of BPDCN, demonstrated unusual localization, infrequency, and the absence of consensus about standard treatment options, demand constructive clinical reasoning and tight cooperation between medical professionals of various fields

UPLC Method for Determination of Moxonidine and Its Degradation Products in Active Pharmaceutical Ingredient and Pharmaceutical Dosage Form

A simple, rapid, isocratic, stability-indicating reverse phase ultra-performance liquid chromatographic (RP-UPLC) method was developed and validated for the routine analysis of moxonidine in the presence of its degradation products in active pharmaceutical ingredient and pharmaceutical dosage forms. Forced degradation studies were performed according to the guidance of International Conference for Harmonization and were used to evaluate moxonidine intrinsic stability. The drug was subjected to acid, neutral and base hydrolysis as well as to oxidative, thermal and photolytic decomposition in both solution and solid state. The drug appeared to be unstable towards acid and base hydrolysis. To achieve desirable conditions for UPLC analysis, the method development was done with the assistance of experimental design and multivariate optimization methodology by means of Derringer's desirability function. Stress samples were analyzed according to the experimental plan for fractional factorial screening design and Box-Behnken optimization design. The chromatographic separation was achieved on a C-18 Hypersil Gold aq. column (100 mm x 2.1 mm, 1.9 mu m) with the mobile phase consisting of methanol-ammonium acetate buffer (10 mM, pH 3.43) mixture (0.9:99.1, v/v) pumped at a flow rate of 870 mu L min(-1) and detection wavelength of 255 nm. The UPLC-MS and UPLC-MS/MS analyses were further used to characterize the found degradation products. The validation of the proposed method was also performed considering selectivity, linearity, accuracy, precision, limit of detection and limit of quantification, and the results indicated that the method fulfilled all required criteria. The method was successfully applied to the analysis of commercial tablets