Inhibition of soluble epoxide hydrolase (sEH) appears to be promising for the treatment of many diseases. Studies have focused on the beneficial effects of epoxyeicosatrienoic acids (EETs), which are sEH substrates. However, our recent studies have shown that the sEH activity is crucial for the proper intestinal cell differentiation. In this recent study, we investigated the impact of TPPU, an inhibitor of sEH, on the colon cancer cell lines Caco2 and HT-29. We analysed the changes in the expression of the cytoskeletal protein ezrin and the phosphorylated protein kinase p38 (p-p38). Our results showed a decrease in ezrin expression in differentiated cells and an increase in p-p38 expression after TPPU treatment. Immunocytochemical staining revealed a higher staining intensity of p-p38 in the nuclei of HT-29 cells following TPPU treatment. Immunohistochemical staining was performed on human samples of normal colon tissue, grade 2 tumours, and embryonal/foetal tissues. The staining intensity of ezrin in tumours was reduced in the surface area compared to the crypts. Additionally, we observed the translocation of p-p38 expression from the cytoplasm to the nucleus during differentiation. The tumour samples exhibited higher levels of p-p38 in the cytoplasm, similar to normal undifferentiated tissue. To observe the disruption of the cytoskeleton after TPPU treatment, confocal microscopy was used. It was found that β-actin associated with ezrin forms clusters under the plasma membranes. All of these results are significant because sEH inhibitors are being tested in clinical trials, but they could cause an unexpected adverse effects.

• MeSH
• buněčná diferenciace * účinky léků   MeSH
• buňky HT-29 MeSH
• Caco-2 buňky MeSH
• cytoskeletální proteiny * metabolismus   MeSH
• epoxid hydrolasy * antagonisté a inhibitory   metabolismus   MeSH
• fenylmočovinové sloučeniny farmakologie   MeSH
• inhibitory enzymů farmakologie   MeSH
• lidé MeSH
• mitogenem aktivované proteinkinasy p38 metabolismus   MeSH
• nádory tračníku * farmakoterapie   patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Several Ranunculaceae species are used in folk medicine to eliminate pathologies associated with oxidative stress as well as parasitic infections; however, a number of studies confirming their pharmacological properties is limited. In this study, 19 ethanolic extracts obtained from 16 Ranunculaceae species were assayed for in vitro antioxidant, antiproliferative, and antiparasitic potential. The maximum antioxidant potential in both oxygen radical absorbance capacity (ORAC) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays was observed for Aconitum toxicum extract [half-maximal inhibitory concentration (IC50) 18.7 and 92.6 μg/mL]. Likewise, Anemone transsilvanica extract exerted the most promising antiproliferative activity against Caco-2 (IC50 46.9 μg/mL) and HT29 (IC50 70.2 μg/mL) cell lines in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Additionally, a dual antioxidant and cytotoxicity effect was demonstrated for Aconitum moldavicum and Caltha palustris extracts. Whilst the efficacy of extracts was modest against Trypanosoma brucei (IC50 ranging from 88.8 to 269.3 μg/mL), several extracts exhibited high potency against Leishmania infantum promastigotes (Aconitum vulparia IC50 18.8 μg/mL). We also tested them against the clinically relevant intracellular stage and found extract of A. vulparia to be the most effective (IC50 29.0 ± 1.1 μg/mL). All tested extracts showed no or low toxicity against FHs 74Int normal cell line (IC50 ranging from 152.9 to >512 μg/mL). In conclusion, we suggest the above-mentioned plant extracts as potential candidates for development of novel plant-based antioxidant and/or antiproliferative and/or antileishmanial compounds.

• MeSH
• antioxidancia * farmakologie   chemie   MeSH
• antiparazitární látky farmakologie   chemie   MeSH
• buňky HT-29 MeSH
• Caco-2 buňky MeSH
• léčivé rostliny chemie   MeSH
• lidé MeSH
• proliferace buněk * účinky léků   MeSH
• Ranunculaceae chemie   MeSH
• rostlinné extrakty * farmakologie   chemie   MeSH
• tradiční lékařství MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Rumunsko MeSH

A wide range of articles describe the role of different probiotics in the prevention or treatment of various diseases. However, currently, the focus is shifting from whole microorganisms to their easier-to-define components that can confer similar or stronger benefits on the host. Here, we aimed to describe polysaccharide B.PAT, which is a surface antigen isolated from Bifidobacterium animalis ssp. animalis CCDM 218 and to understand the relationship between its structure and function. For this reason, we determined its glycerol phosphate-substituted structure, which consists of glucose, galactose, and rhamnose residues creating the following repeating unit: To fully understand the role of glycerol phosphate substitution on the B.PAT function, we prepared the dephosphorylated counterpart (B.MAT) and tested their immunomodulatory properties. The results showed that the loss of glycerol phosphate increased the production of IL-6, IL-10, IL-12, and TNF-α in bone marrow dendritic cells alone and after treatment with Lacticaseibacillus rhamnosus GG. Further studies indicated that dephosphorylation can enhance B.PAT properties to suppress IL-1β-induced inflammatory response in Caco-2 and HT-29 cells. Thus, we suggest that further investigation of B.PAT and B.MAT may reveal distinct functionalities that can be exploited in the treatment of various diseases and may constitute an alternative to probiotics.

• MeSH
• bakteriální polysacharidy farmakologie   chemie   izolace a purifikace   MeSH
• Bifidobacterium animalis * chemie   MeSH
• buňky HT-29 MeSH
• Caco-2 buňky MeSH
• cytokiny metabolismus   MeSH
• dendritické buňky účinky léků   imunologie   metabolismus   MeSH
• fosforylace účinky léků   MeSH
• imunologické faktory farmakologie   chemie   izolace a purifikace   MeSH
• Lacticaseibacillus rhamnosus chemie   MeSH
• lidé MeSH
• myši MeSH
• probiotika farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Because of synergism between tubulin and HDAC inhibitors, we used the pharmacophore fusion strategy to generate potential tubulin-HDAC dual inhibitors. Drug design was based on the introduction of a N-hydroxyacrylamide or a N-hydroxypropiolamide at the 5-position of the 2-aroylbenzo[b]furan skeleton, to produce compounds 6a-i and 11a-h, respectively. Among the synthesized compounds, derivatives 6a, 6c, 6e, 6g, 11a, and 11c showed excellent antiproliferative activity, with IC50 values at single- or double-digit nanomolar levels, against the A549, HT-29, and MCF-7 cells resistant towards the control compound combretastatin A-4 (CA-4). Compounds 11a and 6g were also 10-fold more active than CA-4 against the Hela cell line. When comparing the inhibition of tubulin polymerization versus the HDAC6 inhibitory activity, we found that 6a-g, 6i, 11a, 11c, and 11e, although very potent as inhibitors of tubulin assembly, did not have significant inhibitory activity against HDAC6.

• MeSH
• benzofurany * farmakologie   chemie   chemická syntéza   MeSH
• buňky HT-29 MeSH
• HeLa buňky MeSH
• histondeacetylasa 6 antagonisté a inhibitory   metabolismus   MeSH
• inhibitory histondeacetylas farmakologie   chemická syntéza   chemie   MeSH
• kyseliny hydroxamové * farmakologie   chemie   chemická syntéza   MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• modulátory tubulinu * farmakologie   chemická syntéza   chemie   MeSH
• nádorové buněčné linie MeSH
• proliferace buněk * účinky léků   MeSH
• protinádorové látky * farmakologie   chemická syntéza   chemie   MeSH
• screeningové testy protinádorových léčiv MeSH
• tubulin * metabolismus   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Hyaluronan, a linear glycosaminoglycan comprising D-N-acetylglucosamine and D-glucuronic acid, is the main component of the extracellular matrix. Its influence on cell proliferation, migration, inflammation, signalling, and other functions, depends heavily on its molecular weight and chemical modification. Unsaturated HA oligosaccharides are available in defined length and purity. Their potential therapeutic utility can be further improved by chemical modification, e. g., reduction. No synthesis of such modified oligosaccharides, either stepwise or by hyaluronan cleavage, has been reported yet. Here we show a three-step synthesis (esterification, depolymerization and reduction) of unsaturated even numbered hyaluronan oligosaccharides with carboxylates and the reducing terminus reduced to an alcohol. Particular oligosaccharides were synthesised. The modified oligosaccharides are not cleaved by mammalian or bacterial hyaluronidase and do not affect the growth of mouse and human fibroblasts. Further, MTT and NRU viability tests showed that they inhibit the growth of human colon carcinoma cells HT-29 by 20-50 % in concentrations 500-1000 μg/mL. Interestingly, this effect takes place regardless of CD44 receptor expression and was not observed with unmodified HA oligosaccharides. These compounds could serve as enzymatically stable building blocks for biologically active substances.

• MeSH
• antigeny CD44 metabolismus   MeSH
• buňky HT-29 MeSH
• cytostatické látky * farmakologie   chemie   chemická syntéza   MeSH
• fibroblasty účinky léků   MeSH
• hyaluronoglukosaminidasa * metabolismus   antagonisté a inhibitory   MeSH
• kyselina hyaluronová * chemie   farmakologie   MeSH
• lidé MeSH
• myši MeSH
• oligosacharidy * chemie   farmakologie   MeSH
• proliferace buněk * účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND/AIM: Colorectal cancer (CRC) is one of the most widespread malignancies. One of the alternative therapeutic methods appears to be photodynamic therapy (PDT). MATERIALS AND METHODS: This study investigated the efficiency of 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrin zinc (ZnTPPS4) and chloro-aluminum phthalocyanine disulfonate (ClAlPcS2) with two commercial photosensitive compounds 5,10,15,20-tetrakis(1-methylpyridinium-4-yl)porphyrin (TMPyP) and tetramethylthionine chloride (methylene blue, MB) in PDT for CRC in vitro. In addition to the study of the photodynamic effect on the viability of the colorectal carcinoma cell line HT29, cellular uptake, ROS production, and DNA damage were investigated. RESULTS: All photosensitizers showed good accumulation within HT29 cells, high efficiency in killing the cells, and a concentration-dependent increase in the production of ROS. CONCLUSION: PDT using ZnTPPS4 and ClAlPcS2 may be effective in the treatment of CRC, achieving a similar photocytotoxic effect at much lower concentrations compared to MB.

• MeSH
• adenokarcinom * farmakoterapie   metabolismus   patologie   MeSH
• buňky HT-29 MeSH
• fotochemoterapie * metody   MeSH
• fotosenzibilizující látky * farmakologie   MeSH
• indoly * farmakologie   MeSH
• kolorektální nádory * farmakoterapie   patologie   metabolismus   MeSH
• lidé MeSH
• metaloporfyriny * farmakologie   MeSH
• organokovové sloučeniny * farmakologie   MeSH
• poškození DNA účinky léků   MeSH
• reaktivní formy kyslíku * metabolismus   MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Magnetic polymer nanocomposites are inherently multifunctional and harbor assorted physiochemical actions for applications thereof as novel drug nanocarriers. Herein, Fe3O4-nanoparticles were supported on rice straw cellulose for 5-fluorouracil carrier abbreviated as MC/5-FU for potential colorectal cancer treatments. Several analyses indicated the multifunctional properties of MC/5-FU bionanocomposites. Transmission and scanning electron microscopy study demonstrated that Fe3O4 nanofillers covered the cellulose matrix. The drug release from MC/5-FU was evaluated under various pH and temperature conditions, showing the maximum release at pH 7.4 and 44.2 °C. In in vitro anticancer assay, MC/5-FU exhibited enhanced selectivity and anticancer actions against 2D monolayer and 3D tumour spheroid models colorectal cancer cells. The anticancer effects of MC/5-FU with magnetic targeting and heat induction were also examined. This easily synthesized MC/5-FU indicated the potential in application as a low-cost drug formulation for colorectal cancer treatments.

• MeSH
• buňky HT-29 MeSH
• celulosa chemie   MeSH
• fluoruracil chemie   farmakologie   MeSH
• HCT116 buňky MeSH
• kolorektální nádory farmakoterapie   metabolismus   MeSH
• lékové transportní systémy metody   MeSH
• lidé MeSH
• magnetické jevy MeSH
• magnetické nanočástice oxidů železa chemie   MeSH
• mikroskopie elektronová rastrovací metody   MeSH
• nanokompozity chemie   MeSH
• nosiče léků chemie   MeSH
• polymery chemie   MeSH
• protinádorové látky farmakologie   MeSH
• uvolňování léčiv MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

From 98 Lactobacillus strains, isolated from Algerian homemade cheeses, 14 (B1-B14) were selected based on their anti-Escherichia coli and anti-Staphylococcus aureus activities. These strains were also tested towards Listeria monocytogenes 161 and Salmonella Typhimurium LT2 and further investigated for their resistance to simulated gastrointestinal digestion, cell surface properties, ability to adhere to HT-29 cells, cholesterol lowering, antioxidant activity, and technological traits. Five isolates (B9, B13, B18, B19, and B38) were active against L. monocytogenes and Salmonella. From them, three isolates, identified as Lactobacillus brevis (B9, B13, and B38) by MALDI-TOF spectrometry and 16S rDNA sequencing, exhibited high tolerance to pancreatic juice, bile salts and acidic juices, high percentages of hydrophobicity (87, 92, and 81%, respectively), auto-aggregation (61, 68, and 72%, respectively), and adherence to HT-29 cells (79, 84, and 74%, respectively), which testify on their potential of colonization of the human intestine. On the other way, the strains B9 and B13 manifested the most relevant antioxidant activity and cholesterol-lowering ability, respectively. L. brevis strains showed low acidifying and good proteolytic activities with noticeable heat tolerance. The results gathered in this study highlighted the richness of Algerian artisanal cheeses on new lactobacilli strains with an excellent probiotic potential and demonstrated that L. brevis, largely used as nonstarter in cheese manufacture, could be exploited also as a probiotic for human use.

• MeSH
• antibióza MeSH
• bakteriální adheze MeSH
• buňky HT-29 MeSH
• Escherichia coli fyziologie   MeSH
• Levilactobacillus brevis * izolace a purifikace   fyziologie   MeSH
• lidé MeSH
• Listeria monocytogenes * fyziologie   MeSH
• potravinářská mikrobiologie * MeSH
• probiotika * izolace a purifikace   metabolismus   MeSH
• RNA ribozomální 16S genetika   MeSH
• Staphylococcus aureus fyziologie   MeSH
• sýr * mikrobiologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Camptothecin (CPT), an alkaloid, was first discovered from plants and has potent anti-tumor activity. Since then, CPT analogs (namely Irinotecan and Topotecan) have been approved by the FDA for cancer treatments. Curcumin, on the other hand, is a widely used photosensitizer in photodynamic therapy (PDT) treatment. In our previous work, we have reported a straightforward strategy to construct a drug self-delivery system in which two-molecular species Irinotecan and Curcumin can self-assembly into a complex of ion pairs, namely ICN, through intermolecular non-covalent interactions. We found that ICN has slightly better chemotherapy efficacy than its individual components with much fewer side effects. In this paper, we aim to combine the chemotherapy and the PDT of ICN to further improve its anti-tumor performance. The efficient cellular uptake of ICNs was observed by confocal microscopy. Dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay was used to detect the generation of singlet oxygen species. We found that the cell viability was 9% with both chemotherapy and PDT, and 31% with chemotherapy alone for the case with an ICN concentration of 10 μM, which demonstrated that the anti-tumor efficacy against the HT-29 cancer cell line was enhanced substantially with the combination therapy strategy. The study with an in vivo mouse model has further verified that the chemo-PDT dual therapy can inhibit tumor growth by 84% and 18.8% comparing with the control group and the chemotherapy group, respectively. Our results demonstrated that the new strategy using self-assembly and carrier-free nanoparticles with their chemo-PDT dual therapy may provide new opportunities to develop future combinatorial therapy methods in treating cancer.

• MeSH
• apoptóza účinky léků   účinky záření   MeSH
• buňky HT-29 MeSH
• diarylheptanoidy chemie   MeSH
• fotochemoterapie metody   MeSH
• intracelulární prostor účinky léků   metabolismus   účinky záření   MeSH
• kamptothecin chemie   farmakologie   MeSH
• kombinovaná terapie MeSH
• lidé MeSH
• protinádorové látky chemie   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

ACE2 was observed as the cell surface receptor of the SARS-CoV-2 virus. Interestingly, we also found ACE2 positivity inside the cell nucleus. The ACE2 levels changed during cell differentiation and aging and varied in distinct cell types. We observed ACE2 depletion in the aortas of aging female mice, similarly, the aging caused ACE2 decrease in the kidneys. Compared with that in the heart, brain and kidneys, the ACE2 level was the lowest in the mouse lungs. In mice exposed to nicotine, ACE2 was not changed in olfactory bulbs but in the lungs, ACE2 was upregulated in females and downregulated in males. These observations indicate the distinct gender-dependent properties of ACE2. Differentiation into enterocytes, and cardiomyocytes, caused ACE2 depletion. The cardiomyogenesis was accompanied by renin upregulation, delayed in HDAC1-depleted cells. In contrast, vitamin D2 decreased the renin level while ACE2 was upregulated. Together, the ACE2 level is high in non-differentiated cells. This protein is more abundant in the tissues of mouse embryos and young mice in comparison with older animals. Mostly, downregulation of ACE2 is accompanied by renin upregulation. Thus, the pathophysiology of COVID-19 disease should be further studied not only by considering the ACE2 level but also the whole renin-angiotensin system.

• MeSH
• angiotensin-konvertující enzym 2 metabolismus   MeSH
• buněčná diferenciace fyziologie   MeSH
• buňky A549 MeSH
• buňky HT-29 MeSH
• COVID-19 epidemiologie   patologie   virologie   MeSH
• HEK293 buňky MeSH
• lidé MeSH
• myši MeSH
• pandemie MeSH
• regulace genové exprese fyziologie   MeSH
• renin-angiotensin systém fyziologie   MeSH
• renin metabolismus   MeSH
• SARS-CoV-2 patogenita   MeSH
• sexuální faktory MeSH
• stárnutí fyziologie   MeSH
• věkové faktory MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH