IntroductionCoronavirus Disease 2019 (COVID-19) may affect many organs and may be responsible for numerous complications including cardiovascular problems.Material and methodsWe analysed consecutive patients (n=51) admitted to the cardiology department between 1st October 2020 and 31st January 2021 due to symptoms, which might have reflected cardiovascular complications following COVID-19.ResultsThe complications after Covid-19 appeared after 1-4 months after disease recovery.ConclusionsDiabetes, elevated level of CRP and troponin, heart rate variability parameters and worsening of left ventricular ejection fraction are related to the severity of cardiovascular complications following the COVID-19 infection.

Fludarabine, a nucleoside analogue antimetabolite, has complicated pharmacokinetics requiring facilitated transmembrane transport and intracellular conversion to triphosphate nucleotide form (Ara-FATP), causing it to be susceptible to emergence of drug resistance. We are testing a promising strategy to improve its clinical efficacy by direct delivery of Ara-FATP utilizing a biocompatible glycodendrimer nanocarrier system. Here, we present results of a proof-of-concept experiment in several in vitro-cultured leukemic cell lines (CCRF, THP-1, U937) using noncovalent complexes of maltose-modified poly(propyleneimine) dendrimer and fludarabine triphosphate. We show that Ara-FATP has limited cytotoxic activity toward investigated cells relative to free nucleoside (Ara-FA), but complexation with the glycodendrimer (which does not otherwise influence cellular metabolism) drastically increases its toxicity. Moreover, we show that transport via hENT1 is a limiting step in Ara-FA toxicity, while complexation with dendrimer allows Ara-FATP to kill cells even in the presence of a hENT1 inhibitor. Thus, the use of glycodendrimers for drug delivery would allow us to circumvent naturally occurring drug resistance due to decreased transporter activity. Finally, we demonstrate that complex formation does not change the advantageous multifactorial intracellular pharmacodynamics of Ara-FATP, preserving its high capability to inhibit DNA and RNA synthesis and induce apoptosis via the intrinsic pathway. In comparison to other nucleoside analogue drugs, fludarabine is hereby demonstrated to be an optimal candidate for maltose glycodendrimer-mediated drug delivery in antileukemic therapy.

PurposeFourth-generation poly(propylene imine) dendrimers fully surface-modified by maltose (dense shell, PPI-m DS) were shown to be biocompatible in cellular models, which is important for their application in drug delivery. We decided to verify also their inherent bioactivity, including immunomodulatory activity, for potential clinical applications. We tested their effects on the THP-1 monocytic cell line model of innate immunity effectors.MethodsTo estimate the cytotoxicity of dendrimers the reasazurin assay was performed. The expression level of NF-κB targets: IGFBP3, TNFAIP3 and TNF was determined by quantitative real-time RT-PCR. Measurement of NF-κB p65 translocation from cytoplasm to nucleus was conducted with a high-content screening platform and binding of NF-κB to a consensus DNA probe was determined by electrophoretic mobility shift assay. The cytokine assay was performed to measure protein concentration of TNFalpha and IL-4.ResultsWe found that PPI-m DS did not impact THP-1 viability and growth even at high concentrations (up to 100 μM). They also did not induce expression of genes for important signaling pathways: Jak/STAT, Keap1/Nrf2 and ER stress. However, high concentrations of 4th generation PPI-m DS (25–100 μM), but not their 3rd generation counterparts, induced nuclear translocation of p65 NF-κB protein and its DNA-binding activity, leading to NF-κB-dependent increased expression of mRNA for NF-κB targets: IGFBP3, TNFAIP3 and TNF. However, no increase in pro-inflammatory cytokine secretion was detected.ConclusionWe conclude that maltose-modified PPI dendrimers of specific size could exert a modest immunomodulatory effect, which may be advantageous in clinical applications (e.g. adjuvant effect in anti-cancer vaccines).

It is well documented that inflammatory chemokines play a significant role in the development of multiple sclerosis (MS) and its model, experimental autoimmune encephalomyelitis (EAE). Recently, the involvement of homeostatic (or lymphoid) chemokines in the pathogenesis of autoimmune diseases has become an object of intensive study. In this work, quantitative analysis of CCL19, CCL21 and CCR7 expression in the central nervous system (CNS), as well as in inflammatory mononuclear cells isolated from several organs during the first attack, remission and the second attack of chronic-relapsing EAE (ChREAE), was performed. Using real-time PCR, RNAse Protection Assay and immunohistochemistry, the expression of both chemokines, as well as of their common receptor CCR7, was analyzed in the brain, spleen, lymph nodes and peripheral blood mononuclear cells. Increased expression of CCL19 and CCL21 was observed mostly in mononuclear inflammatory cells isolated from the CNS during active ChREAE. At the same time the expression of CCR7 in blood mononuclear leukocytes was reduced. This observation extends our current knowledge about the possible role of chemokines CCL19, CCL21 and their receptor CCR7 in the pathogenesis of ChREAE and, by extension, MS.