New 1,3,4-Oxadiazole Derivatives of Pyridothiazine-1,1-Dioxide with Anti-Inflammatory Activity

Numerous studies have confirmed the coexistence of oxidative stress and inflammatory processes. Long-term inflammation and oxidative stress may significantly affect the initiation of the neoplastic transformation process. Here, we describe the synthesis of a new series of Mannich base-type hybrid compounds containing an arylpiperazine residue, 1,3,4-oxadiazole ring, and pyridothiazine-1,1-dioxide core. The synthesis was carried out with the hope that the hybridization of different pharmacophoric molecules would result in a synergistic effect on their anti-inflammatory activity, especially the ability to inhibit cyclooxygenase. The obtained compounds were investigated in terms of their potencies to inhibit cyclooxygenase COX-1 and COX-2 enzymes with the use of the colorimetric inhibitor screening assay. Their antioxidant and cytotoxic effect on normal human dermal fibroblasts (NHDF) was also studied. Strong COX-2 inhibitory activity was observed after the use of TG6 and, especially, TG4. The TG11 compound, as well as reference meloxicam, turned out to be a preferential COX-2 inhibitor. TG12 was, in turn, a non-selective COX inhibitor. A molecular docking study was performed to understand the binding interaction of compounds at the active site of cyclooxygenases.     

Computer-Aided Search for 5-Arylideneimidazolone Anticancer Agents Able To Overcome ABCB1-Based Multidrug Resistance

ABCB1 modulation is an interesting strategy in the search for new anticancer agents that can overcome multidrug resistance (MDR). Hence, 17 new 5-arylideneimidazolones containing an amine moiety, as potential ABCB1 inhibitors, were designed, synthesized, and investigated. The series was tested in both parental (PAR) and multidrug-resistant (MDR) ABCB1-overexpressing T-lymphoma cancer cells using cytotoxicity assays. The ABCB1-modulating activity was examined in rhodamine 123 accumulation tests, followed by Pgp-Glo™ Assay to determine the influence of the most active compounds on ATPase activity. Lipophilic properties were assessed both, in silico and experimentally (RP-TLC). Pharmacophore-based molecular modelling toward ABCB1 modulation was performed. The studies allowed the identification of anticancer agents (p-fluorobenzylidene derivatives) more potent than doxorubicin, with highly selective action on MDR T-lymphoma cells (selectivity index >40). Most of the investigated compounds showed ABCB1-modulating action; in particular, two 5-benzyloxybenzylidene derivatives displayed activity nearly as strong as that of tariquidar.     

Antimicrobial Resistance and Whole-Genome Characterisation of High-Level Ciprofloxacin-Resistant Salmonella Enterica Serovar Kentucky ST 198 Strains Isolated from Human in Poland

Background: Salmonella Kentucky belongs to zoonotic serotypes that demonstrate that the high antimicrobial resistance and multidrug resistance (including fluoroquinolones) is an emerging problem. To the best of our knowledge, clinical S. Kentucky strains isolated in Poland remain undescribed. Methods: Eighteen clinical S. Kentucky strains collected in the years 2018–2019 in Poland were investigated. All the strains were tested for susceptibility to 11 antimicrobials using the disc diffusion and E-test methods. Whole genome sequences were analysed for antimicrobial resistance genes, mutations, the presence and structure of SGI1-K (Salmonella Genomic Island and the genetic relationship of the isolates. Results: Sixteen of 18 isolates (88.9%) were assigned as ST198 and were found to be high-level resistant to ampicillin (>256 mg/L) and quinolones (nalidixic acid MIC ≥ 1024 mg/L, ciprofloxacin MIC range 6–16 mg/L). All the 16 strains revealed three mutations in QRDR of GyrA and ParC. The substitutions of Ser83 → Phe and Asp87 → Tyr of the GyrA subunit and Ser80→Ile of the ParC subunit were the most common. One S. Kentucky isolate had qnrS1 in addition to the QRDR mutations. Five of the ST198 strains, grouped in cluster A, had multiple resistant determinants like blaTEM1-B, aac(6′)-Iaa, sul1 or tetA, mostly in SGI1 K. Seven strains, grouped in cluster B, had shorter SGI1-K with deletions of many regions and with few resistance genes detected. Conclusion: The results of this study demonstrated that a significant part of S. Kentucky isolates from humans in Poland belonged to ST198 and were high-level resistant to ampicillin and quinolones.     

Anti-Inflammatory Activity of Oat Beta-Glucans in a Crohn’s Disease Model: Time- and Molar Mass-Dependent Effects

Background: The incidence of Crohn’s disease (CD) is increasing worldwide, and it has currently become a serious public health issue in society. The treatment of CD continues throughout a patient’s lifetime, and therefore, it is necessary to develop new, effective treatment methods, including dietotherapy. The present study aimed to determine the effects of consumption of oat beta-glucans with different molar mass on colon inflammation (colitis) in the early stages of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced CD in an animal model. Methods: Sprague–Dawley rats (control and TNBS-induced CD) were divided into three dietary groups and fed for 3 days (reflecting acute inflammation) or 7 days (reflecting remission) with a feed containing 1% low (βGl) or high (βGh) molar mass oat beta-glucan or a feed without this polysaccharide. The level of colon inflammatory markers and the expression of cytokines and their receptor genes were measured by ELISA and RT-PCR methods, respectively. Results: Acute inflammation or remission (3 or 7 days after TNBS administration, respectively) stages of experimentally induced CD were characterized by an increase in the level of inflammatory markers (IL-1, IL-6, IL-10, IL-12, TNF-α, CRP, MPO, COX, and PGE2) and the disruption of some cytokine signaling pathways as well as macro- and microscopic changes of colon tissue. The consumption of oat beta-glucans reduced the level of inflammatory markers and recovered the signaling pathways and histological changes, with stronger effects of βGl after 7 days of colitis. Conclusions: Dietary oat beta-glucans can reduce colitis at the molecular and organ level and accelerate CD remission.     

Palm Oil-Rich Diet Affects Murine Liver Proteome and S-Palmitoylome

Palmitic acid (C16:0) is the most abundant saturated fatty acid in animals serving as a substrate in synthesis and β-oxidation of other lipids, and in the modification of proteins called palmitoylation. The influence of dietary palmitic acid on protein S-palmitoylation remains largely unknown. In this study we performed high-throughput proteomic analyses of a membrane-enriched fraction of murine liver to examine the influence of a palm oil-rich diet (HPD) on S-palmitoylation of proteins. HPD feeding for 4 weeks led to an accumulation of C16:0 and C18:1 fatty acids in livers which disappeared after 12-week feeding, in contrast to an accumulation of C16:0 in peritoneal macrophages. Parallel proteomic studies revealed that HPD feeding induced a sequence of changes of the level and/or S-palmitoylation of diverse liver proteins involved in fatty acid, cholesterol and amino acid metabolism, hemostasis, and neutrophil degranulation. The HPD diet did not lead to liver damage, however, it caused progressing obesity, hypercholesterolemia and hyperglycemia. We conclude that the relatively mild negative impact of such diet on liver functioning can be attributed to a lower bioavailability of palm oil-derived C16:0 vs. that of C18:1 and the efficiency of mechanisms preventing liver injury, possibly including dynamic protein S-palmitoylation.     

Analysis of indole compounds in edible Basidiomycota species after thermal processing

Methanolic extracts of processed fruiting bodies of six edible mushroom species (Basidiomycota) - Armillaria mellea, Boletus badius, Boletus edulis, Cantharellus cibarius, Lactarius deliciosus collected from natural habitats and Pleurotus ostreatus of commercial origin - were analysed for the presence of non-hallucinogenic indole compounds. Thermal processing was designed in such a way that it mimicked conditions used for cooking of mushroom dishes, since only a narrow group of mushrooms can be eaten raw, while indole compounds are thermolabile. All processed extracts were shown to contain l-tryptophan (up to 8.92 mg/100 g dw). The contents of the remaining compounds, 5-methyltryptophan, tryptamine, melatonin, indoleacetonitrile and indole, varied in different species (from 0.71 to 6.55 mg/100 g dw). Extract of processed C. cibarius fruiting bodies contained l-tryptophan, 5-methyltryptophan, tryptamine, melatonin, indoleacetonitrile and indole (1.96-4.94 mg/100 g dw) whereas l-tryptophan (2.78 mg/100 g dw) and tryptamine (2.77 mg/100 g dw) were the only indole compounds identified in the processed fruiting bodies of A. mellea.     

Influence of Unmodified and β-Glycerophosphate Cross-Linked Chitosan on Anti-Candida Activity of Clotrimazole in Semi-Solid Delivery Systems

The combination of an antifungal agent and drug carrier with adjunctive antimicrobial properties represents novel strategy of complex therapy in pharmaceutical technology. The goal of this study was to investigate the unmodified and ion cross-linked chitosan’s influence on anti-Candida activity of clotrimazole used as a model drug in hydrogels. It was particularly crucial to explore whether the chitosans’ structure modification by β-glycerophosphate altered its antifungal properties. Antifungal studies (performed by plate diffusion method according to CLSI reference protocol) revealed that hydrogels obtained with chitosan/β-glycerophosphate displayed lower anti-Candida effect, probably as a result of weakened polycationic properties of chitosan in the presence of ion cross-linker. Designed chitosan hydrogels with clotrimazole were found to be more efficient against tested Candida strains and showed more favorable drug release profile compared to commercially available product. These observations indicate that novel chitosan formulations may be considered as promising semi-solid delivery system of clotrimazole.     

Synthesis of polymer membranes of different porosity and their application for phenol removal from liquid phase

Preparation of polymeric membranes based on polyethersulfone (PES) modified by adding different amounts of a pore-forming agent (PVP) is presented, and potential application of the membranes obtained for removal of phenol from the liquid phase is examined. The addition of various amounts of PVP has been shown to bring about changes in the content of the surface oxygen groups, but has no significant effect on the chemical character of the groups and acidic groups dominate. Filtration by phenol solution leads to significant changes in the total content of surface oxides; however, the acidic groups remain dominant. Membranes characterized by higher porosity exhibited more stable and higher rejection ratio for phenol removal. Although all the membranes were characterized by similar rejection ratios for phenol removal, the cake resistance (Rc) and pore resistance (Rp) values were found to depend significantly on the structure and porosity of the membrane applied for filtration.