Dendrimer Structure Diversity and Tailorability as a Way to Fight Infectious Diseases

Dendrimers represent a distinct class of polymers—highly branched and uniform, with a relatively small size when compared to their mass. They are composed of the core, from which branched polymeric dendrons diverge and they are end‐capped with selected terminal groups. Recently, dendrimers have attracted considerable attention from medicinal chemists, mostly due to their well‐defined and easy‐to‐modify structure. This chapter aims to compile dendrimer applications and activities especially for prevention and fighting off infections caused by bacteria and fungi, viruses, and parasites/protozoa. Our goal in this review is to discuss selected modifications of dendrimers of potential value for pharmaceutical chemistry

Tryptophan pathway abnormalities in a murine model of hereditary glaucoma

Background: It has been shown that a possible pathogenetic mechanism of neurodegenera-tion in the mouse model of glaucoma (DBA/2J) may be an alteration of kynurenic acid (KYNA) in the retina. This study aimed to verify the hypothesis that alterations of tryptophan (TRP) metabolism in DBA/2J mice is not limited to the retina. Methods: Samples of the retinal tissue and serum were collected from DBA/2J mice (6 and 10 months old) and control C57Bl/6 mice of the same age. The concentration of TRP, KYNA, kynurenine (KYN), and 3-hydroxykynurenine (3OH-K) was measured by HPLC. The activity of indoleamine 2,3-dioxygenase (IDO) was also determined as a KYN/TRP ratio. Results: TRP, KYNA, L-KYN, and 3OH-K concentration were significantly lower in the retinas of DBA/2J mice than in C57Bl/6 mice. 3OH-K concentration was higher in older mice in both strains. Serum TRP, L-KYN, and KYNA concentrations were lower in DBA/2J than in age-matched controls. However, serum IDO activity did not differ significantly between compared groups and strains. Conclusions: Alterations of the TRP pathway seem not to be limited to the retina in the murine model of hereditary glaucoma

Tryptophan and Kynurenine Pathway Metabolites in Animal Models of Retinal and Optic Nerve Damage: Different Dynamics of Changes

Kynurenines, products of tryptophan (TRP) metabolism, display neurotoxic (e.g., 3-hydroxykynurenine; 3-HK), or neuroprotective (e.g., kynurenic acid; KYNA) properties. Imbalance between the enzymes constituting the kynurenine pathway (KP) plays a role in several disease, including neurodegeneration. In this study, we track changes in concentrations of tryptophan and its selected metabolites after damage to retinal ganglion cells and link this data with expression of KP enzymes. Brown-Norway rats were subjected to intravitreal N-methyl-D-aspartate (NMDA) injection or partial optic nerve crush (PONC). Retinas were collected 2 and 7 days after the completion of PONC or NMDA injection. Concentrations of TRP, kynurenine (KYN), and KYNA were determined by high performance liquid chromatography (HPLC). Data on gene expression in the rat retina were extracted from GEO, public microarray experiments database. Two days after NMDA injection concentration of TRP decreased, while KYN and KYNA increased. At day 7 compared to day 2 decrease of KYN, KYNA and further reduction of TRP concentration were observed, but on day 7 KYN concentration was still elevated when compared to controls. At day 2 and 7 after NMDA injection no statistically significant alterations of 3-HK were observed. TRP and 3-HK concentration was higher in PONC group than in controls. However, both KYN and KYNA were lower. At day seven concentration of TRP, 3-HK, and KYN was higher, whereas concentration of KYNA declined. In vivo experiments showed that retinal damage or optic nerve lesion affect TRP metabolism via KP. However, the pattern of changes in metabolite concentrations was different depending on the model. In particular, in PONC KYNA and KYN levels were decreased and 3-HK elevated. These observations correspond with data on expression of genes encoding KP enzymes assessed after optic nerve crush or transection. After intraorbital optic nerve crush downregulation of KyatI and KyatIII between 24 h and 3 days after procedure was observed. Kmo expression was transiently upregulated (12 h after the procedures). After intraorbital optic nerve transsection (IONT) Kmo expression was upregulated after 48 h and 7 days, KyatI and KyatIII were downregulated after 12, 48 h, 7 days and upregulated after 15 days. Collected data point to the conclusion that development of therapeutic strategies targeting the KP could be beneficial in diseases involving retinal neurodegeneration

Overexpression of human kynurenine-3-monooxygenase protects against 3-hydroxykynurenine-mediated apoptosis through bidirectional non-linear feedback

Kynurenine 3-monooxygenase (KMO) is a critical regulator of inflammation. The preferred KMO substrate, kynurenine, is converted to 3-hydroxykynurenine (3HK), and this product exhibits cytotoxicity through mechanisms that culminate in apoptosis. Here, we report that overexpression of human KMO with orthotopic localisation to mitochondria creates a metabolic environment during which the cell exhibits increased tolerance for exogenous 3HK-mediated cellular injury. Using the selective KMO inhibitor Ro61-8048, we show that KMO enzyme function is essential for cellular protection. Pan-caspase inhibition with Z-VAD-FMK confirmed apoptosis as the mode of cell death. By defining expression of pathway components upstream and downstream of KMO, we observed alterations in other key kynurenine pathway components, particularly tryptophan-2,3-dioxygenase upregulation, through bidirectional nonlinear feedback. KMO overexpression also increased expression of inducible nitric oxide synthase (iNOS). These changes in gene expression are functionally relevant, because siRNA knockdown of the pathway components kynureninase and quinolinate phosphoribosyl transferase caused cells to revert to a state of susceptibility to 3HK-mediated apoptosis. In summary, KMO overexpression, and importantly KMO activity, have metabolic repercussions that fundamentally affect resistance to cell stress

Level of vitamin 25 (OH) D and B group vitamins and functional efficiency among the chronically ill elderly in domiciliary care - a pilot study

Introduction and objective. Deficits of vitamin resources constitute a significant public health problem, especially among the elderly population. The aim of the research was to determine the level of vitamin 25 (OH) D and vitamins from group B in the chronically ill elderly in domiciliary care, depending on functional capacity and coexisting diseases. Materials and method. The pilot study included 137 patients staying in long-term domiciliary care. Samples of the participants’ venous blood was obtained for laboratory tests. Centrifuged serum was used to determine the level of the following biochemical parameters: vitamin 25 (OH)D, B12, folic acid and total protein, albumin, triglycerides, total cholesterol and HDL cholesterol. Assessment of the functional status of patients was made by using the Barthel scale. Results. More than 3⁄4 of the patients with functional deficit (according to Barthel’s score 0–85 points) were deficient in vitamin 25 (OH)D, while folic acid values were below the reference values in more than half of the patients. Respondents with lower functional efficiency were characterised by a reduced average value of vitamin 25 (OH)D and folic acid. Conclusions. The studied group of the chronically ill elderly was characterised by a deficiency of vitamin D3 and folic acid. Subjects with a functional impairment deficit show a reduced mean value of vitamin 25 (OH)D and folic acid in the blood serum, compared to the group of patients with higher mobility

An evaluation of the genetic conditioning of evoking pain

Introduction and objective. Pain is an integral element of the pathogenic process and sometimes determines its course. Disorders in pain sensation, as well as its lack, the pain threshold, and variability in sensation of the same pain stimuli as more or less intensive by different persons, may be genetically conditioned. The aim of the study is to examine genes in pathogenesis of chronic pain. Materials and method. The study was conducted in a specially selected group of 31 persons: study group – 20 patients with chronic pain, and control group – 11 healthy individuals who did not experience pain. The control group of 11 healthy persons, compared with the study group, was the catalyst for determining the relative quantification (RQ) of gene expression. Biological material in the form of venous blood was collected from the study participants into the tubes containing anticoagulant EDTA KE/2.7 ml (ethylenediaminetetraacetic acid), preventing extracorporeal blood clotting. Results. Analysis of expression of the examined genes showed over-expression of the DRD1 gene in patients experiencing chronic pain, which means that in these patients an increased number of dopamine D1 receptors encoded by this gene should be expected. The dopamine D1 receptor is a G-protein-coupled receptor which regulates (stimulates or inhibits) adenyl cyclase – the enzyme responsible for synthesis of cyclic AMP (cAMP). An increase in the concentration of cAMP in neurons enhances the sensation of pain. Conclusions. The genes (DRD1, COMT, OPRK1, HCN2) have a significant role in the pathogenesis of chronic pain in various diseases; they can also influence the perception of pain. Knowledge of these genes can contribute to the development of effective methods of combating pain

Different expression of CD180, CD284 and CD14 receptors on the CD19+ subpopulation of normal and B-CLL lymphocytes.

Numerous experimental data indicate that B-CLL development and progression are influenced by antigenic pressure. It can not be excluded that these antigens may originate from bacteria and viruses. Toll like receptors (TLRs) interact with pathogen associated molecular patterns as part of innate immunity. TLRs are currently used to target different subclasses of B-cell leukemia, and TLR agonists are being evaluated in clinical trials. It is little known regarding the repertoire and function of TLR in B-CLL. The aim of the study was to assess the CD180, CD284 and mCD14 levels in CD19+ subpopulation of B-CLL peripheral blood lymphocytes and compare them with respective levels in the normal B-cells of adult volunteers, before and after LPS stimulation. We investigated the percentage of the CD19+CD180+, CD19+CD284+, CD19+CD14+ cells and the mean fluorescence intensity (MFI) of CD180, CD284 and CD14 antigens among CD19+ B-CLL as well as in the normal B cells for comparison. MFI analysis revealed that CD180, CD284 and CD14 expression was higher on normal B cells then on CD19+ B-CLL (MFI CD180: 99.16 vs. 25.3, MFI CD284: 7.37 vs. 5.79 and MFI CD14 25.07 vs. 8.32). After 24-hour LPS activation of B-cells, CD180 MFI appeared to decrease, in both healthy and B-CLL patients. CD284 MFI in healthy controls decreased after LPS stimulation while slight increase of MFI was observed in leukemic cells. CD14 MFI in leukemic cells was moderately higher after LPS in comparison to CD14 MFI without LPS stimulation, whereas CD14 MFI in normal CD19+ cells after LPS stimulation decreased over three times. Variations observed in expression of both normal and leukemic receptors may be due to their different sensitivity to antigenic stimulation