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The adsorption of biomolecules on biomaterial surfaces can promote their integration with surrounding tissue without changing their bulk properties. For biomaterials in bone reconstruction, the promotion of osteogenic differentiation and reduction of inflammation are desirable. Fibrillar coatings are interesting because of fibrils’ high surface area-volume ratio, aiding adsorption and adhesion. Fibrils also serve as a matrix for the immobilization of biomolecules with biological activity, such as the phenolic compound phloroglucinol (PG), the subunit of marine polyphenols. The aim of this work was to investigate the influence of PG coatings on fibroblast- and osteoblast-like cells to increase the osseointegration of titanium implants. Collagen fibril coatings, containing PG at low and high concentrations, were produced on titanium alloy (Ti6Al4V) scaffolds generated by additive manufacturing (AM). These coatings, especially PG-enriched coatings, reduced hydrophobicity and modulated the behavior of human osteosarcoma SaOS-2 and mouse embryonic fibroblast 3T3 cell lines. Both osteoblastic and fibroblastic cells spread and adhered well on PG-enriched coatings. Coatings significantly reduced the inflammatory response. Moreover, osteogenic differentiation was promoted by collagen coatings with a high PG concentration. Thus, the enrichment of collagen fibril coatings with PG is a promising strategy to improve Ti6Al4V implants for bone contact in orthopedics and dentistry and is worthy of further investigation.

New unsymmetrical bisacridines (UAs) demonstrated high activity not only against a set of tumor cell lines but also against human tumor xenografts in nude mice. Representative UA compounds, named C-2028, C-2045 and C-2053, were characterized in respect to their physicochemical properties and the following studies aimed to elucidate the role of metabolic transformations in UAs action. We demonstrated with phase I and phase II enzymes in vitro and in tumors cells that: (i) metabolic products generated by cytochrome P450 (P450), flavin monooxygenase (FMO) and UDP-glucuronosyltransferase (UGT) isoenzymes in noncellular systems retained the compound’s dimeric structures, (ii) the main transformation pathway is the nitro group reduction with P450 isoenzymes and the metabolism to N-oxide derivative with FMO1, (iii), the selected UGT1 isoenzymes participated in the glucuronidation of one compound, C-2045, the hydroxy derivative. Metabolism in tumor cells, HCT-116 and HT-29, of normal and higher UGT1A10 expression, respectively, also resulted in the glucuronidation of only C-2045 and the specific distribution of all compounds between the cell medium and cell extract was demonstrated. Moreover, P4503A4 activity was inhibited by C-2045 and C-2053, whereas C-2028 affected UGT1A and UGT2B action. The above conclusions indicate the optimal strategy for the balance among antitumor therapeutic efficacy and drug resistance in the future antitumor therapy.

Referring to our previous laboratory results related to the tyrosinase and urease inhibition by pyrazolo[4,3-e][1,2,4]triazine sulfonamides, we examined here in silico the mechanism of action at the molecular level of the investigated pyrazolotriazine sulfonamides by the molecular docking method. The studied compounds being evaluated for their cytotoxic effect against cancer cell lines (MCF-7, K-562) and for recombinant Abl and CDK2/E kinase inhibitory potency turned out to be inactive in these tests. The pyrazolotriazines were also investigated with respect to their lipophilicity and plasma protein binding using HPLC chromatography in isocratic conditions. The observed small affinity for plasma proteins could be advantageous in the potential in vivo studies. Moreover, the compounds were sensitive to metabolic transformations with phase I enzymes, which led to the hydroxylation and dealkylation products, whereas phase II transformations did not occur.

Background Age-driven immune signals cause a state of chronic low-grade inflammation and in consequence affect bone healing and cause challenges for clinicians when repairing critical-sized bone defects in elderly patients. Methods Poly(l-lactide-co-ɛ-caprolactone) (PLCA) scaffolds are functionalized with plant-derived nanoparticles from potato, rhamnogalacturonan-I (RG-I), to investigate their ability to modulate inflammation in vitro in neutrophils and macrophages at gene and protein levels. The scaffolds’ early and late host response at gene, protein and histological levels is tested in vivo in a subcutaneous rat model and their potential to promote bone regeneration in an aged rodent was tested in a critical-sized calvaria bone defect. Significant differences were tested using one-way ANOVA, followed by a multiple-comparison Tukey’s test with a p value ≤ 0.05 considered significant. Results Gene expressions revealed PLCA scaffold functionalized with plant-derived RG-I with a relatively higher amount of galactose than arabinose (potato dearabinated (PA)) to reduce the inflammatory state stimulated by bacterial LPS in neutrophils and macrophages in vitro. LPS-stimulated neutrophils show a significantly decreased intracellular accumulation of galectin-3 in the presence of PA functionalization compared to Control (unmodified PLCA scaffolds). The in vivo gene and protein expressions revealed comparable results to in vitro. The host response is modulated towards anti-inflammatory/ healing at early and late time points at gene and protein levels. A reduced foreign body reaction and fibrous capsule formation is observed when PLCA scaffolds functionalized with PA were implanted in vivo subcutaneously. PLCA scaffolds functionalized with PA modulated the cytokine and chemokine expressions in vivo during early and late inflammatory phases. PLCA scaffolds functionalized with PA implanted in calvaria defects of aged rats downregulating pro-inflammatory gene markers while promoting osteogenic markers after 2 weeks in vivo. Conclusion We have shown that PLCA scaffolds functionalized with plant-derived RG-I with a relatively higher amount of galactose play a role in the modulation of inflammatory responses both in vitro and in vivo subcutaneously and promote the initiation of bone formation in a critical-sized bone defect of an aged rodent. Our study addresses the increasing demand in bone tissue engineering for immunomodulatory 3D scaffolds that promote osteogenesis and modulate immune responses.

Implant failures are primarily related to bacterial infections and inflammation. Nanocoating of implant devices with organic molecules is a method used for improving their integration into host tissues and limiting inflammation. Bioengineered plant-derived rhamnogalacturonan-Is (RG-Is) from pectins improve tissue regeneration and exhibit anti-inflammatory properties. Therefore, the aim of this study is to evaluate the in vitro effect of RG-I nanocoating on human gingival primary fibroblast (HGF) activity and proinflammatory response following Porphyromonas gingivalis (P. gingivalis) infection. Infected HGFs were incubated on tissue culture polystyrene (TCPS) plates coated with unmodified RG-I isolated from potato pectin (PU) and dearabinanated RG-I (PA). HGF morphology, proliferation, metabolic activity, and expression of genes responsible for extracellular matrix (ECM) turnover and proinflammatory response were examined. Following the P. gingivalis infection, PU and PA significantly promoted HGF proliferation and metabolic activity. Moreover, gene expression levels of IL1B, IL8, TNFA, and MMP2 decreased in the infected cells cultured on PU and PA, whereas the expression of COL1A1, FN1, and FGFR1 was upregulated. The results indicate that RG-Is are promising candidates for nanocoating of an implant surface, can reduce inflammation, and enhance implant integration, particularly in medically compromised patients with chronic inflammatory diseases such as periodontitis and rheumatoid arthritis. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3475-3481, 2017.

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