Marcela Dvorakova

Anti-inflammatory activity of natural stilbenoids: A review

Graphical abstract Figure. No caption available. ABSTRACT Resveratrol and other natural stilbenoids, including piceatannol, pterostilbene, and gnetol, are well‐known anti‐inflammatory compounds with indisputable activity in vitro as well as in vivo. Their molecular targets include inducible nitric oxide synthase, cyclooxygenases, leukotrienes, nuclear factor kappa B, tumor necrosis factor &agr;, interleukins and many more. This anti‐inflammatory activity together with their antioxidant activity is believed to stand behind their other positive health effects against cancer, cardiovascular and neurodegenerative diseases or diabetes. Thus, they are nowadays commercially marketed as nutraceuticals. Naturally, they are present in wine, grapes or berries. However, there is a rigorous debate about the real effect of these compounds on human health. It is argued that the concentration of stilbenoids in food and beverages is too low to have any therapeutic potential and this concentration is further reduced by their low bioavailability and extensive metabolism. Therefore, this review focuses on in vitro, in vivo, preclinical as well as clinical data available for various natural stilbenoids and summarizes the anti‐inflammatory targets on molecular level, compares the relevance of the experimental studies, discusses the metabolism of stilbenoids and the potential activity of their metabolites and relates this knowledge to human health. Moreover, the ways to augment stilbenoidsí efficacy are suggested with special focus on multitargeted therapy and nanocarriers.

Impact of Wines and Wine Constituents on Cyclooxygenase-1, Cyclooxygenase-2, and 5-Lipoxygenase Catalytic Activity

Cyclooxygenases and lipoxygenases are proinflammatory enzymes; the former affects platelet aggregation, vasoconstriction, vasodilatation and later the development of atherosclerosis. Red wines from Georgia and central and western Europe inhibited cyclooxygenase-1 (COX-1) activity in the range of 63–94%, cyclooxygenase-2 (COX-2) activity in the range of 20–44% (tested at a concentration of 5 mL/L), and 5-lipoxygenase (5-LOX) activity in the range of 72–84% (at a concentration of 18.87 mL/L). White wines inhibited 5-LOX in the range of 41–68% at a concentration of 18.87 mL/L and did not inhibit COX-1 and COX-2. Piceatannol (IC50 = 0.76 μM) was identified as a strong inhibitor of 5-LOX followed by luteolin (IC50 = 2.25 μM), quercetin (IC50 = 3.29 μM), and myricetin (IC50 = 4.02 μM). trans-Resveratrol was identified as an inhibitor of COX-1 (IC50 = 2.27 μM) and COX-2 (IC50 = 3.40 μM). Red wine as a complex mixture is a powerful inhibitor of COX-1, COX-2, and 5-LOX, the enzymes involved in eicosanoid biosynthetic pathway.

Redox and non-redox mechanism of in vitro cyclooxygenase inhibition by natural quinones.

In this study, ten anthra-, nine naphtho-, and five benzoquinone compounds of natural origin and five synthetic naphthoquinones were assessed, using an enzymatic in vitro assay, for their potential to inhibit cyclooxygenase-1 and -2 (COX-1 and COX-2), the key enzymes of the arachidonic acid cascade. IC₅₀ values comparable with COX reference inhibitor indomethacin were recorded for several quinones (primin, alkannin, diospyrin, juglone, 7-methyljuglone, and shikonin). For some of the compounds, we suggest the redox potential of quinones as the mechanism responsible for in vitro COX inhibition because of the quantitative correlation with their pro-oxidant effect. Structure-relationship activity studies revealed that the substitutions at positions 2 and 5 play the key roles in the COX inhibitory and pro-oxidant actions of naphthoquinones. In contrast, the redox mechanism alone could not explain the activity of primin, embelin, alkannin, and diospyrin. For these four quinones, molecular modeling suggested similar binding modes as for conventional nonsteroidal anti-inflammatory drugs (NSAIDs).

Diffuse parenchymal lung disease as first clinical manifestation of GATA-2 deficiency in childhood

BackgroundGATA-2 transcription factor deficiency has recently been described in patients with a propensity towards myeloid malignancy associated with other highly variable phenotypic features: chronic leukocytopenias (dendritic cell-, monocyto-, granulocyto-, lymphocytopenia), increased susceptibility to infections, lymphatic vasculature abnormalities, and sensorineural deafness. Patients often suffer from opportunistic respiratory infections; chronic pulmonary changes have been found in advanced disease.Case presentationWe present a case of a 17-year-old previously healthy Caucasian male who was admitted to the hospital with fever, malaise, headache, cough and dyspnea. A chest X-ray revealed bilateral interstitial infiltrates and pneumonia was diagnosed. Despite prompt clinical improvement under antibiotic therapy, interstitial changes remained stable. A high resolution computer tomography showed severe diffuse parenchymal lung disease, while the patient’s pulmonary function tests were normal and he was asymptomatic. Lung tissue biopsy revealed chronic reparative and resorptive reaction with organizing vasculitis. At the time of the initial presentation to the hospital, serological signs of acute infection with Epstein-Barr virus (EBV) were present; EBV viremia with atypical serological response persisted during two-year follow up. No other infectious agents were found. Marked monocytopenia combined with B-cell lymphopenia led to a suspicion of GATA-2 deficiency. Diagnosis was confirmed by detection of the previously published heterozygous mutation in GATA2 (c.1081 C > T, p.R361C). The patient’s brother and father were both carriers of the same genetic defect. The brother had no clinically relevant ailments despite leukocyte changes similar to the index patient. The father suffered from spondylarthritis, and apart from B-cell lymphopenia, no other changes within the leukocyte pool were seen.ConclusionWe conclude that a diagnosis of GATA-2 deficiency should be considered in all patients with diffuse parenchymal lung disease presenting together with leukocytopenia, namely monocyto-, dendritic cell- and B-lymphopenia, irrespective of severity of the clinical phenotype. Genetic counseling and screening for GATA2 mutations within the patient’s family should be provided as the phenotype is highly variable and carriers without apparent immunodeficiency are still in danger of developing myeloid malignancy. A prompt recognition of this rare condition helps to direct clinical treatment strategies and follow-up procedures.

Histone deacetylase inhibitors for the treatment of cancer stem cells

Tiny populations of tumor cells are present in solid and hematologic malignancies and are responsible for cancer development, metastasis and limited response to therapy; these are referred to as cancer stem cells (CSCs). CSCs are resistant to standard cancer treatments and are the main cause of tumor relapse. Therefore, the development of new therapeutics to overcome the resistance of CSCs is greatly required. It is known that epigenetic histone modifications (acetylation/deacetylation) play a crucial role in cancer development through regulation of gene expression. Deacetylation of histone and non-histone proteins controls cell proliferation, metabolism and apoptosis as well as DNA repair and differentiation. Thus, histone deacetylase inhibitors (HDACis) are a promising group of anti-cancer agents, showing the ability to induce growth arrest or apoptosis in tumor cells. In this review, we summarize the current knowledge about the prospects of HDACis utilization in the treatment of CSCs.

Biotransformation of (1S)-2-Carene and (1S)-3-Carene by Picea abies Suspension Culture

Biotransformation of (1S)-2-carene and (1S)-3-carene by Picea abies suspension culture led to the formation of oxygenated products. (1S)-2-Carene was transformed slowly and the final product was identified as (1S)-2-caren-4-one. On the other hand, the transformation of (1S)-3-carene was rapid and finally led to the formation of (1S)-3-caren-5-one and (1S)-2-caren-4-one as equally abundant major products. The time-course of the reaction indicates that some products abundant at the beginning of the reaction (e.g. (1S,3S,4R)-3,4-epoxycarane and (1R)-p-mentha-1(7),2-dien-8-ol) were consumed by a subsequent transformations. Thus, a precise selection of the biotransformation time may be used for a production of specific compounds.

beta-1,2,3-Triazolyl-Nucleosides as Nicotinamide Riboside Mimics

The synthesis of a series of pyridine- and piperidine-substituted 1,2,3-triazolides linked to a riboside moiety is described. The presence of a triazolide substituent on the pyridine moiety permitted the facile reduction of the latter under mild hydrogenation conditions. These analogues were modelled as to define their similarity to nicotinamide riboside and quantify their ability to bind NAD-dependent protein deacetylases.

Triazolide Strigolactone Mimics Influence Root Development in Arabidopsis

Strigolactones are the most recently recognized class of phytohormones, which are also known to establish plant symbiosis with arbuscular mycorhizal fungi or induce germination of parasitic plants. Their relatively complex structures and low stability urgently calls for simple derivatives with maintained biological function. We have prepared a series of triazolide strigolactone mimics and studied their ability to affect root development of Arabidopsis thaliana. The strigolactone mimics significantly induced root elongation and lateral root formation while resembling the effect of the reference compound GR24.

Increased Ginsenosides Production by Elicitation of In vitro Cultivated Panax Ginseng Adventitious Roots

Ginsenosides, which belong to group of triterpenoid saponins, are considered to be main constituents responsible for the biological effects of ginseng drug. Effect of organic and inorganic elicitors and other additives on the ginsenoside biosynthesis and biomass production by the in vitro cultivated adventitious root cultures of Korean ginseng was investigated in present study. Elicitation potential of natural mixtures (coconut water, pineapple extract, casein hydrolyzate, yeast extract, malt extract), organic elicitors (putrescine, spermidine, spermine, jasmonic acid), inorganic ions (calcium) and their complexes with organic acids (titanium ascorbate, titanium citrate) was tested. Changes in concentration of 9 main ginsenosides (Re, Rg1 , Rf, Rg2 , Rb1 , Rb2 , Rc, Rg3 and Rd) were monitored using HPLC-PDA and LC/MS/MS techniques. Jasmonic acid was the most effective elicitor of ginsenoside production (about 3.5 mg/g of DW in comparison with 1.4 mg/g of DW in control); however, its application (similar to spermine) was followed with significant reduction of the biomass growth. Among tested additives, casein hydrolyzate showed the highest increase of the ginsenoside content (2.2 mg/g DW) together with no effect on the growth of the culture. Both tested titanium complexes showed slight inhibition of the saponin accumulation in comparison with untreated control.

Resorcinol-Type Strigolactone Mimics as Potent Germinators of the Parasitic Plants Striga hermonthica and Phelipanche ramosa

Strigolactones are a particular class of plant metabolites with diverse biological functions starting from the stimulation of parasitic seed germination to phytohormonal activity. The expansion of parasitic weeds in the fields of developing countries is threatening the food supply and calls for simple procedures to combat these weeds. Strigolactone analogues represent a promising approach for such control through suicidal germination, i.e., parasitic seed germination without the presence of the host causing parasite death. In the present work, the synthesis of resorcinol-type strigolactone mimics related to debranones is reported. These compounds were highly stable even at alkaline pH levels and able to induce seed germination of parasitic plants Striga hermonthica and Phelipanche ramosa at low concentrations, EC50 ≈ 2 × 10-7 M ( Striga) and EC50 ≈ 2 × 10-9 M ( Phelipanche). On the other hand, the mimics had no significant effect on root architecture of Arabidopsis plants, suggesting a selective activity for parasitic seed germination, making them a primary target as suicidal germinators.