Lycopene ­ the impact of supplementation on the skin aging process / Likopen ­ wplyw suplementacji na proces starzenia sie skóry.

The skin aging process is affected by multiple different factors (including sun exposure, smoking, poor diet) and reactive oxygen species (ROS). Under their influence, the skin becomes weaker, mainly elastin and collagen fibers are damaged. The amount of lipids is also reduced, leading to the death of the skin cells. The presence of free radicals also blocks the natural ability of the epidermis to regenerate. Each of these factors determines the acceleration of the signs of aging. To some extent, our body is able to deal with the free radicals by producing antioxidants. Regular supplementation is also a beneficial solution. Lycopene is a red pigment naturally found in tomatoes and is a known antioxidant. Among the carotenoids, it is the strongest singlet oxygen quencher and scavenger of peroxygen radicals, making it an important defense mechanism in the human body. The aim of this paper is to present the biological properties of lycopene in relation to its beneficial effect on the aging process of the skin.

Enhanced biological activity of liposomal methylated resveratrol analog 3'-hydroxy-3,4,5,4'-tetramethoxystilbene (DMU-214) in 3D patient-derived ovarian cancer model.

3'-hydroxy-3,4,5,4'-tetramethoxystilbene (DMU-214) belongs to methoxystilbenes family and is an active metabolite of 3,4,5,4'-tetramethoxystilbene (DMU-212). In several of our previous studies, the anti-apoptotic activity of DMU-214 was significantly higher than that of the parent compound, especially in ovarian cancer cells. Due to increased lipophilicity and limited solubility, methoxystilbenes require a solubilization strategy enabling DMU-214 administration to the aqueous environment. In this study, DMU-214-loaded liposomes were developed for the first time, and its antitumor activity was tested in the ovarian cancer model.First, several liposomal formulations of DMU-214 were obtained by the thin lipid film hydration method followed by extrusion and then characterized. The diameter of the resulting vesicles was in the range of 118.0-155.5 nm, and samples presented monodisperse size distribution. The release of DMU-214 from the studied liposomes was governed by the contribution of two mechanisms, Fickian diffusion and liposome relaxation.Subsequently, in vitro activity of DMU-214 in the form of a free compound or liposome-bound was studied, including commercial cell line SK-OV-3 and patient-derived ovarian cancer cells in monolayer and spheroid cell culture models. DMU-214 liposomal formulations were found to be more potent (had lower IC50 values) than the free DMU-214 both in the monolayer and, more significantly, in both examined spheroid models. The above results, with particular emphasis on the patient-derived ovarian cancer model, indicate the importance of further development of liposomal DMU-214 as a potential anticancer formulation for ovarian cancer treatment.

miR-218 affects the ECM composition and cell biomechanical properties of glioblastoma cells.

Glioblastoma (GBM) is the most common malignant brain tumour. GBM cells have the ability to infiltrate into the surrounding brain tissue, which results in a significant decrease in the patient's survival rate. Infiltration is a consequence of the low adhesion and high migration of the tumour cells, two features being associated with the highly remodelled extracellular matrix (ECM). In this study, we report that ECM composition is partially regulated at the post-transcriptional level by miRNA. Particularly, we show that miR-218, a well-known miRNA suppressor, is involved in the direct regulation of ECM components, tenascin-C (TN-C) and syndecan-2 (SDC-2). We demonstrated that the overexpression of miR-218 reduces the mRNA and protein expression levels of TN-C and SDC-2, and subsequently influences biomechanical properties of GBM cells. Atomic force microscopy (AFM) and real-time migration analysis revealed that miR-218 overexpression impairs the migration potential and enhances the adhesive properties of cells. AFM analysis followed by F-actin staining demonstrated that the expression level of miR-218 has an impact on cell stiffness and cytoskeletal reorganization. Global gene expression analysis showed deregulation of a number of genes involved in tumour cell motility and adhesion or ECM remodelling upon miR-218 treatment, suggesting further indirect interactions between the cells and ECM. The results demonstrated a direct impact of miR-218 reduction in GBM tumours on the qualitative ECM content, leading to changes in the rigidity of the ECM and GBM cells being conducive to increased invasiveness of GBM.

Down-regulation of tenascin-C inhibits breast cancer cells development by cell growth, migration, and adhesion impairment.

Tenascin-C (TNC) is an extracellular matrix (ECM) glycoprotein that plays an important role in cell proliferation, migration, and tumour invasion in various cancers. TNC is one of the main protein overexpressed in breast cancer, indicating a role for this ECM molecule in cancer pathology. In this study we have evaluated the TNC loss-off-function in breast cancer cells. In our approach, we used dsRNA sharing sequence homology with TNC mRNA, called ATN-RNA. We present the data showing the effects of ATN-RNA in MDA-MB-231 cells both in monolayer and three-dimensional culture. Cells treated with ATN-RNA were analyzed for phenotypic alterations in proliferation, migration, adhesion, cell cycle, multi-caspase activation and the involvement in epithelial to mesenchymal transition (EMT) processes. As complementary analysis the oncogenomic portals were used to assess the clinical implication of TNC expression on breast cancer patient's survival, showing the TNC overexpression associated with a poor survival outcome. Our approach applied first in brain tumors and then in breast cancer cell lines reveals that ATN-RNA significantly diminishes the cell proliferation, migration and additionally, reverses the mesenchymal cells phenotype to the epithelial one. Thus, TNC could be considered as the universal target in different types of tumors, where TNC overexpression is associated with poor prognosis.

Biological activity of N6-furfuryladenosine / Aktywnosc biologiczna N6-furfuryloadenozyny.

Cytokinins are a group of plant hormones which play an important role in plant growth and development. They produce various effects when applied to intact plants. They particularly stimulate protein synthesis and participate in cell cycle control. First discovered cytokinin was N6-furfuryladenine (kinetin). It is a strong inhibitor of proteins and nucleic acids oxidation in vitro and in vivo. Both kinetin and its ribosides (N6-furfuryladenosine, kinetin riboside) as natural compounds occur in the milk of coconuts on the nanomole level. Kinetin riboside selectively inhibits the proliferation of cancer cells and induce their apoptosis. This review focuses on the kinetin riboside occurrence, and primarily on its metabolism, and biological activity.

Let food be your medicine: nutraceutical properties of lycopene.

Currently, an increase in the awareness of a healthy lifestyle has been observed in society. People are seeking added health benefits from their dietary intake. Thus, functional foods with supplemented components that promote wellness are becoming popular. Lycopene is a carotenoid that gives vegetables and fruits their red color. Due to its chemical structure, lycopene acts as an antioxidant, which is the basis for its health-promoting properties. Oxidative stress is recognized as an important agent of many chronic diseases; thus, lycopene appears to be a universal medicine. Lycopene has the greatest antioxidant potential among carotenoids. Nutraceutical effects of lycopene have been reported for patients with cancer, infertility, metabolic syndrome and liver damage. Therefore, its supplementation can function as a proper causative treatment of disease. In this review, we highlight primary research and clinical trials involving lycopene and its impact on human health.

Nano-mediated delivery of double-stranded RNA for gene therapy of glioblastoma multiforme.

Glioblastoma multiforme (GBM) is the most common type of malignant gliomas, characterized by genetic instability, intratumoral histopathological variability and unpredictable clinical behavior. Disappointing results in the treatment of gliomas with surgery, radiation and chemotherapy have fueled a search for new therapeutic targets and treatment modalities. Here we report new approach towards RNA interference therapy of glioblastoma multiforme based on the magnetic nanoparticles delivery of the double-stranded RNA (dsRNA) with homological sequences to mRNA of tenascin-C (TN-C), named ATN-RNA. The obtained nanocomposite consisted of polyethyleneimine (PEI) coated magnetic nanoparticles conjugated to the dsRNA show high efficiency in ATN-RNA delivery, resulting not only in significant TN-C expression level suppressesion, but also impairing the tumor cells migration. Moreover, synthesized nanomaterials show high contrast properties in magnetic resonance imaging (MRI) and low cytotoxicity combining with lack of induction of interferon response. We believe that the present work is a successful combination of effective, functional, non-immunostimulatory dsRNA delivery system based on magnetic nanoparticles with high potential for further application in GBM therapy.

Synthesis, structural studies and biological properties of some phosphono-perfluorophenylalanine derivatives formed by SNAr reactions.

Several novel phosphono-perfluorophenylalanine derivatives, as mimetics of phenylalanine, were synthesized by subjecting diethyl (2-(perfluorophenyl)-1-(phenylamino)ethyl)-phosphonate to SNAr reactions with different types of nucleophiles such as thiols, amines and phenols. The structure of the products was confirmed using spectroscopic and spectrometric techniques. For two compounds X-ray single crystal diffraction analysis and DFT investigations were performed providing information in regard to the preferable conformation, hydrogen bonds and other interactions. The antiproliferative potency of some of the new phosphono-perfluorophenylalanine derivatives obtained as well as representatives of previously synthesized perfluorophenyl phosphonate analogues of phenylalanine was studied on selected glioma cell lines. Preliminary evaluation of the compounds drug likeness was examined with respect to Lipinski's and Veber's rules, and showed that they meet the criteria perfectly. MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) assay results demonstrated that the compounds exhibit moderate activity against the glioblastoma multiforme cell lines (T98G and U-118 MG). Moreover most of the studied SNAr reaction products displayed significantly higher inhibitory activity against both cancer cell lines than the parent diethyl (2-(perfluorophenyl)-1-(phenylamino)ethyl)phosphonate.

Synthesis and biological assay of new 2'-deoxyuridine dimers containing a 1,2,3-triazole linker. Part I.

We describe a simple method for the synthesis of modified dinucleosides containing pyrimidine nucleoside analogues (2'-deoxyuridine, thymidine and 5-fluoro-2'-deoxyuridine). Six different dimers with a 1,2,3-triazole linkage were obtained by azide-alkyne 1,3-dipolar cycloaddition (click reaction), starting from propargylated 2'-deoxyuridine and 5'-azido-nucleoside derivatives. Their cytotoxic activity was tested in five human cancer cell lines: cervical (HeLa), high grade gliomas (U-118 MG, U-87 MG, T98G), liver (HepG2), and normal human fibroblast cell line (MRC-5) using the sulforhodamine B (SRB) assay. The experiment showed that the obtained dimers with a 1,2,3-triazole moiety were very stable compounds, also in the physiological-like media, and had no anticancer activity.

New antiglioma zwitterionic pronucleotides with an FdUMP framework.

We have designed and synthesized new 5-fluoro-2'-deoxyuridine 5'-phosphate pronucleotides which can function as potential agents against the glioblastoma multiforme tumor. Their anti-malignant potency has been tested against T98G, U-118 MG, U-87 MG gliomas, HeLa, and Caco-2 cancer cell lines, using MRC-5 healthy cells as a reference. Five of the sixteen compounds (4c, 4f-i) exhibited significant anticancer potency and high selectivity indices (SI 12-66). It is likely that these zwitterionic pronucleotides may function in a similar manner to zwitterionic phospholipids, by inducing cell membrane charge disorder, making the cell permeable to bioactive agents. The most promising therapeutic pronucleotides 4c, 4f-h, have high intestinal-blood uptake potency (Caco-2 cell line), and may be considered as potential, orally administrated, anticancer drugs.

Searching for anti-glioma activity. Ribonucleoside analogues with modifications in nucleobase and sugar moieties.

Several ribonucleoside analogues with modifications in the nucleobase and sugar moiety have been screened for anti-glioma activity in the T98G glioma cell line using cervical (HeLa) cell line as reference human malignant cells, and lung fibroblast (MCR-5) cell line as non-cancerous reference cells. Among the investigated compounds, ribonucleosides containing 6-chloropurine (3), 7-guanine (5) and a pyrrolopyrimidine (18) as nucleobases, show promising anti-glioma activity with good selectivity indices, and can be considered as lead structures for further anti-cancer studies.

The Sequence and Structure Determine the Function of Mature Human miRNAs.

Micro RNAs (miRNAs) (19-25 nucleotides in length) belong to the group of non-coding RNAs are the most abundant group of posttranscriptional regulators in multicellular organisms. They affect a gene expression by binding of fully or partially complementary sequences to the 3'-UTR of target mRNA. Furthermore, miRNAs present a mechanism by which genes with diverse functions on multiple pathways can be simultaneously regulated at the post-transcriptional level. However, little is known about the specific pathways through which miRNAs with specific sequence or structural motifs regulate the cellular processes. In this paper we showed the broad and deep characteristics of mature miRNAs according to their sequence and structural motifs. We investigated a distinct group of miRNAs characterized by the presence of specific sequence motifs, such as UGUGU, GU-repeats and purine/pyrimidine contents. Using computational function and pathway analysis of their targeted genes, we were able to observe the relevance of sequence and the type of targeted mRNAs. As the consequence of the sequence analysis we finally provide the comprehensive description of pathways, biological processes and proteins associated with the distinct group of characterized miRNAs. Here, we found that the specific group of miRNAs with UGUGU can activate the targets associated to the interferon induction pathway or pathways prominently observed during carcinogenesis. GU-rich miRNAs are prone to regulate mostly processes in neurogenesis, whereas purine/pyrimidine rich miRNAs could be involved rather in transport and/or degradation of RNAs. Additionally, we have also analyzed the simple sequence repeats (SSRs). Their variation within mature miRNAs might be critical for normal miRNA regular activity. Expansion or contraction of SSRs in mature miRNA might directly affect its mRNA interaction or even change the function of that distinct miRNA. Our results prove that due to the specific sequence features, these molecules can also be involved in well-defined cellular processes depending on their sequence contents. The pathway mapping and theoretical gene target identification allowed us to create a biological framework to show the relevance of the specific miRNAs in regulation the distinct type of targets.

New 3'-O-aromatic acyl-5-fluoro-2'-deoxyuridine derivatives as potential anticancer agents.

New aromatic and aliphatic 3'-O-acyl-5-fluoro-2'-deoxyuridine derivatives were synthesized and evaluated as candidates for prodrugs against various cancer cell lines. As the most promising candidate for antimalignant therapeutics was found a dual-acting acyl derivative 7h, which apparently released not only the known anticancer nucleoside, 5-fluoro-2'-deoxyuridine (FdU), but also an additional active metabolite, acetylsalicylic acid, reinforcing thus therapeutic effect of FdU. Promising therapeutic indices showed also some aromatic dicarboxylic acids derivatives decorated with FdU esters (11 and 12).