Effects of flavonoids on glycosaminoglycan synthesis: implications for substrate reduction therapy in Sanfilippo disease and other mucopolysaccharidoses

Sanfilippo disease (mucopolysaccharidosis type III, MPS III) is a severe metabolic disorder caused by accumulation of heparan sulfate (HS), one of glycosaminoglycans (GAGs), due to a genetic defect resulting in a deficiency of GAG hydrolysis. This disorder is characterized as the most severe neurological form of MPS, revealing rapid deterioration of brain functions. Among therapeutic approaches for MPS III, one of the most promising appears to be the substrate reduction therapy (SRT). Genistein (5, 7-dihydroxy-3- (4-hydroxyphenyl)-4H-1-benzopyran-4-one) is an isoflavone that has been used in SRT for MPS III. In this report, we tested effects of other flavonoids (apigenin, daidzein, kaempferol and naringenin) on GAG synthesis. Their cytotoxicity and anti-proliferation features were also tested. We found that daidzein and kaempferol inhibited GAG synthesis significantly. Moreover, these compounds were able to reduce lysosomal storage in MPS IIIA fibroblasts. Interestingly, although genistein is believed to inhibit GAG synthesis by blocking the tyrosine kinase activity of the epidermal growth factor receptor, we found that effects of other flavonoids were not due to this mechanism. In fact, combinations of various flavonoids resulted in significantly more effective inhibition of GAG synthesis than the use of any of these compounds alone. These results, together with results published recently by others, suggest that combination of flavonoids can be considered as a method for improvement of efficiency of SRT for MPS III

Synthesis of antimicrobial silver nanoparticles through a photomediated reaction in an aqueous environment

Rafał Banasiuk,1,* Joanna E Frackowiak,2,* Marta Krychowiak,1 Marta Matuszewska,1 Anna Kawiak,1 Magdalena Ziabka,3 Zofia Lendzion-Bielun,4 Magdalena Narajczyk,5 Aleksandra Krolicka1 1Department of Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, 2Department of Pathophysiology, Medical University of Gdansk, Gdansk, 3Faculty of Materials Science and Ceramics, Department of Ceramics and Refractories, AGH-University of Science and Technology, Kraków, 4Institute of Chemical and Environment Engineering, West Pomeranian University of Technology, Szczecin, 5Faculty of Biology, Laboratory of Electron Microscopy, University of Gdansk, Gdansk, Poland *These authors contributed equally to this work Abstract: A fast, economical, and reproducible method for nanoparticle synthesis has been developed in our laboratory. The reaction is performed in an aqueous environment and utilizes light emitted by commercially available 1 W light-emitting diodes (λ =420 nm) as the catalyst. This method does not require nanoparticle seeds or toxic chemicals. The irradiation process is carried out for a period of up to 10 minutes, significantly reducing the time required for synthesis as well as environmental impact. By modulating various reaction parameters silver nanoparticles were obtained, which were predominantly either spherical or cubic. The produced nanoparticles demonstrated strong antimicrobial activity toward the examined bacterial strains. Additionally, testing the effect of silver nanoparticles on the human keratinocyte cell line and human peripheral blood mononuclear cells revealed that their cytotoxicity may be limited by modulating the employed concentrations of nanoparticles. Keywords: antimicrobial activity, green synthesis, nanocubes, nanospheres&nbsp

Silver Nanoparticles as Chlorhexidine and Metronidazole Drug Delivery Platforms: Their Potential Use in Treating Periodontitis [Corrigendum]

Steckiewicz KP, Cieciórski P, Barcińska E, et al. Int J Nanomedicine. 2022;17:495–517. Our authors have advised that the funding source number listed in the Acknowledgment section on page 513 was incorrect. The sentence should read from “This work was supported by PRELUDIUM grant 2017/27/N/NZ7/0267 from the Polish National Science Centre…” to “This work was supported by PRELUDIUM grant 2017/27/N/NZ7/02675 from the Polish National Science Centre…” The authors apologize for this oversight

Salicylic acid can reduce infection symptoms caused by Dickeya solani in tissue culture grown potato (Solanum tuberosum L.) plants

The potential for control of Dickeya solani infections in potato by elicitation of in vitro grown potato plants with salicylic acid (SA) was investigated by selective plating and confocal laser scanning macroscopy (CLSM). In replicated experiments potato plants grown on medium supplemented with 25 or 50 μM of SA were evaluated for the phytotoxic effects. Potato plants grown on medium supplemented with SA and inoculated with GFP-tagged D. solani were investigated for blackleg development and colonization of potato plants by the bacteria. Three days after inoculation, colonization of roots by D. solani was observed in 100 % control plants grown on medium without SA but not in plants grown on medium supplemented with 50 μM SA. After 14 days, 100 % of control plants showed severe disease symptoms, whereas plants grown on medium supplemented with 50 μM SA and inoculated with bacteria did not express any symptoms. After 14 days bacteria were found inside 100 % stems of control plants in densities of ca. 103–104 cfu g−1 and inside ca. 10–15 % stems of plants treated with 50 μM SA in densities similar to these in the control plants. The GFP-tagged bacteria were macroscopically detected on the surface of the roots of control plants but not on the surface of the plants treated with 50 μM SA 14 days after inoculation. The implications of SA treatments on plant fitness and disease development are discussed.</p

Genistein in Sanfilippo disease: A randomized controlled crossover trial

Objective: Sanfilippo disease (mucopolysaccharidosis type III [MPS III]) is a rare neurodegenerative metabolic disease caused by a deficiency of 1 of the 4 enzymes involved in the degradation of heparan sulfate (HS), a glycosaminoglycan (GAG). Genistein has been proposed as potential therapy but its efficacy remains uncertain. We aimed to determine the efficacy of genistein in MPS III. Methods: Thirty patients were enrolled. Effects of genistein were determined in a randomized, crossover, placebocontrolled intervention with a genistein-rich soy isoflavone extract (10mg/kg/day of genistein) followed by an openlabel extension study for patients who were on genistein during the last part of the crossover. Results: Genistein resulted in a significant decrease in urinary excretion of total GAGs (p 0.02, slope = 0.68mg GAGs/mmol creatinine/mo) and in plasma concentrations of HS (p 0.01, slope = 15.85ng HS/ml/mo). No effects on total behavior scores or on hair morphology were observed. Parents or caregivers could not predict correctly during which period of the crossover a patient was on genistein. Interpretation: Genistein at 10mg/kg/day effectively reduces urinary excretion of GAGs and plasma HS concentration in patients with MPS III. However, the absolute reduction in GAGs and in HS is small and values after 12 months of treatment remain within the range as observed in untreated patients. No clinical efficacy was detected. Substantially higher doses of genistein might be more effective as suggested by recent studies in animal models. ANN NEUROL 2012; 71: 110-12

Spontaneous mutations in hlyD and tuf genes result in resistance of Dickeya solani IPO 2222 to phage ϕD5 but cause decreased bacterial fitness and virulence in planta

Abstract Lytic bacteriophages able to infect and kill Dickeya spp. can be readily isolated from virtually all Dickeya spp. containing environments, yet little is known about the selective pressure those viruses exert on their hosts. Two spontaneous D. solani IPO 2222 mutants (0.8% of all obtained mutants), DsR34 and DsR207, resistant to infection caused by lytic phage vB_Dsol_D5 (ΦD5) were identified in this study that expressed a reduced ability to macerate potato tuber tissues compared to the wild-type, phage-susceptible D. solani IPO 2222 strain. Genome sequencing revealed that genes encoding: secretion protein HlyD (in mutant DsR34) and elongation factor Tu (EF-Tu) (in mutant DsR207) were altered in these strains. These mutations impacted the DsR34 and DsR207 proteomes. Features essential for the ecological success of these mutants in a plant environment, including their ability to use various carbon and nitrogen sources, production of plant cell wall degrading enzymes, ability to form biofilms, siderophore production, swimming and swarming motility and virulence in planta were assessed. Compared to the wild-type strain, D. solani IPO 2222, mutants DsR34 and DsR207 had a reduced ability to macerate chicory leaves and to colonize and cause symptoms in growing potato plants