Although information about the occurrence and distribution of retinoids in the environment is scarce, cyanobacterial water blooms have been identified as a significant source of these small molecules. Despite the confirmed presence of retinoids in the freshwater blooms dominated by cyanobacteria and their described teratogenic effects, reliable identification of retinoid producers and the mechanism of their biosynthesis is missing. In this study, the cultures of several taxonomically diverse species of axenic cyanobacteria were confirmed as significant producers of retinoid-like compounds. The consequent bioinformatic analysis suggested that the enzymatic background required for the biosynthesis of all-trans retinoic acid from retinal is not present across phylum Cyanobacteria. However, we demonstrated that retinal conversion into other retinoids can be mediated non-enzymatically by free radical oxidation, which leads to the production of retinoids widely detected in cyanobacteria and environmental water blooms, such as all-trans retinoic acid or all-trans 5,6epoxy retinoic acid. Importantly, the production of these metabolites by cyanobacteria in association with the mass development of water blooms can lead to adverse impacts in aquatic ecosystems regarding the described teratogenicity of retinoids. Moreover, our finding that retinal can be non-enzymatically converted into more bioactive retinoids, also in water, and out of the cells, increases the environmental significance of this process.

• Klíčová slova
• aldehyde dehydrogenases, biosynthesis, cyanobacteria, reactive oxygen species, retinoids,
• MeSH
• ekosystém MeSH
• retinoidy analýza   metabolismus   toxicita   MeSH
• sinice * metabolismus   MeSH
• teratogeny * toxicita   MeSH
• tretinoin toxicita   MeSH
• voda metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• retinoidy MeSH
• teratogeny * MeSH
• tretinoin MeSH
• voda MeSH

Cyanobacterial blooms represent a worldwide problem in freshwater as well as marine ecosystems as producers of various toxic compounds. This study provides environmentally important information about the common presence of mixtures of retinoids in various water bodies associated with the occurrence of cyanobacterial blooms dominated by many different species. The study documents, for the first time, that retinoids are produced by environmental cyanobacterial blooms dominated by species belonging to different genera such as Microcystis, Dolichospermum, Planktothrix, Woronichinia, Pseudanabaena and others. Samples of biomass of cyanobacterial blooms and their surrounding water were collected from seventeen independent freshwater bodies across the Czech Republic during summer 2015. Retinoid-like activity was detected by an in vitro reporter gene bioassay in water samples from 8 out of 17 localities with a maximal activity of 263 ng all-trans retinoic acid equivalent (REQ)/L. In comparison, in vitro assessment of biomass extracts documented retinoid-like activity at 11 out of 17 localities with a maximal retinoid-like activity of 867 ng REQ/g dry mass (dm). Individual retinoids were detected by chemical analyses in all water samples and in 16 out of 17 biomass samples with 4keto-retinal and all-trans 5,6epoxy retinoic acid being detected in aquatic ecosystems for the first time. Further, all-trans 4keto retinoic acid and retinal were the most commonly detected compounds in both types of samples. With respect to retinoid-like activity, a large proportion was explained in some samples by contributions of individual detected retinoids calculated from their concentrations and relative potencies. However, results also indicate that other unknown compounds with a retinoic acid receptor-mediated mode of action were present. The revealed widespread production of retinoids by cyanobacterial blooms dominated by diverse species across various aquatic ecosystems and their common presence in both biomass and surrounding water raises concern namely because some retinoids belong to the most potent teratogens. These compounds need to be taken into consideration in the assessment of risks associated with massive cyanobacterial blooms.

• Klíčová slova
• Cyanobacteria, Retinoid-like activity, Retinoids, Water bloom,
• MeSH
• ekosystém MeSH
• Microcystis * MeSH
• retinoidy MeSH
• sinice * MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• retinoidy MeSH

Retinoids represent a popular group of differentiation inducers that are successfully used in oncology for treatment of acute promyelocytic leukemia in adults and of neuroblastoma in children. The therapeutic potential of retinoids is based on their key role in the regulation of cell differentiation, growth, and apoptosis, which provides a basis for their use both in cancer therapy and chemoprevention. Nevertheless, patients treated with retinoids often exhibit or develop resistance to this therapy. Although resistance to retinoids is commonly categorized as either acquired or intrinsic, resistance as a single phenotypic feature is usually based on the same mechanisms that are closely related or combined in both of these types. In this review, we summarize the most common changes in retinoid metabolism and action that may affect the sensitivity of a tumor cell to treatment with retinoids. The availability of retinoids can be regulated by alterations in retinol metabolism or in retinoid intracellular transport, by degradation of retinoids or by their efflux from the cell. Retinoid effects on gene expression can be regulated via retinoid receptors or via other molecules in the transcriptional complex. Finally, the role of small-molecular-weight inhibitors of altered cell signaling pathways in overcoming the resistance to retinoids is also suggested.

• Klíčová slova
• cell differentiation, differentiation therapy, mechanisms of resistance, retinoids,
• MeSH
• biologický transport účinky léků   MeSH
• buněčná diferenciace účinky léků   MeSH
• chemorezistence účinky léků   MeSH
• genetická transkripce účinky léků   MeSH
• lidé MeSH
• receptory kyseliny retinové metabolismus   MeSH
• retinoidy metabolismus   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• receptory kyseliny retinové MeSH
• retinoidy MeSH

Retinoids are natural and synthetic compounds related to retinoic acid that act through interaction with two basic types of nuclear receptors: retinoic acid receptors (RARalpha, RARbeta and RARgamma) and retinoid X receptors (RXRalpha, RXRbeta and RXRgamma) as ligand-activated, DNA-binding, transacting, transcription-modulating proteins involved in a general molecular mechanism responsible for transcriptional responses in target genes. Function of retinoids in organisms affecting broad spectrum of various biochemical and molecular biology reactions is unimaginable without fully functional nuclear receptors--retinoid inducible transcription factors. Retinoic acids exert tumour-suppressive activity due to their antiproliferative and apoptosis-inducing effects. A number of novel retinoids and rexinoids acting through cognate nuclear receptors have been tested both in vitro and in vivo, using cell culture or animal models for breast cancer. This article briefly summarizes the role and properties of nuclear retinoid/rexinoid receptors as well as selected effects of retinoic acids or selected synthetic retinoids and rexinoids with respect to their potential use in chemoprevention of breast cancer.

• MeSH
• antikarcinogenní látky terapeutické užití   MeSH
• fenretinid terapeutické užití   MeSH
• lidé MeSH
• nádory prsu prevence a kontrola   MeSH
• receptory cytoplazmatické a nukleární metabolismus   fyziologie   MeSH
• regulace genové exprese účinky léků   fyziologie   MeSH
• retinoidní X receptory účinky léků   fyziologie   MeSH
• retinoidy farmakologie   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• antikarcinogenní látky MeSH
• fenretinid MeSH
• receptory cytoplazmatické a nukleární MeSH
• retinoidní X receptory MeSH
• retinoidy MeSH

Retinoids are newly detected compounds in aquatic ecosystems associated with cyanobacterial water blooms. Their potential health risks are only scarcely described despite numerous detections of all-trans retinoic acid (ATRA) and its derivatives in the environment. Besides the known teratogen ATRA there is only little or no information about their potency and namely their effects in vivo. We characterize ATRA and 8 other retinoids reported to occur in the environment for their bioactivity and teratogenicity using four in vitro reporter gene assays and zebrafish (Danio rerio) embryotoxicity assay. Our results document the ability of these compounds to interfere with retinoid signalling and cause teratogenicity at environmentally relevant levels with EC50 values at nM (hundreds of ng/L) levels and teratogenic indexes ranging from 2.8 (9cis retinoic acid) to 15.8 (retinal). The relative potency of individual compounds for teratogenicity ranged from 0.059 (retinal) to 0.96 (5,6-epoxy ATRA) when compared to ATRA. An environmentally relevant mixture of retinoids was tested showing good predictability of teratogenicity from the in vitro activities and additive toxicity of the mixture. The high teratogenicity of the newly described compounds associated with cyanobacteria presents a concern for developmental stages due to high conservation of the retinoid signalling across vertebrates.

• Klíčová slova
• In vitro, RAR, Retinoids, Teratogenicity, Zebrafish,
• MeSH
• chemické látky znečišťující vodu * toxicita   MeSH
• dánio pruhované genetika   MeSH
• ekosystém MeSH
• Microcystis * MeSH
• retinoidy toxicita   MeSH
• sinice * MeSH
• teratogeny toxicita   MeSH
• tretinoin toxicita   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• chemické látky znečišťující vodu * MeSH
• retinoidy MeSH
• teratogeny MeSH
• tretinoin MeSH

BACKGROUND: Retinoids, rexinoids and their biologically active derivatives are involved in a complex arrangement of physiological and developmental responses in many tissues of higher vertebrates. Both retinoids and rexinoids are either natural or synthetic compounds related to retinoic acids that act through interaction with two basic types of nuclear receptors belonging to the nuclear receptor superfamily: All-trans retinoic acid receptors (RARalpha, RARbeta, and RARgamma) and retinoid X receptors (RXRalpha, RXRbeta and RXRgamma) as retinoid-inducible transcription factors. AIM: Summarization of selected effects of biologically active natural or synthetic retinoids and rexinoids and their exploitation in chemoprevention of various types of cancer. RESULTS: Retinoid receptors play a role as ligand-activated, DNA-binding, trans-acting, transcription-modulating proteins involved in a general molecular mechanism responsible for transcriptional responses in target genes. They exert both beneficial and detrimental activity; they have tumour-suppressive activity but on the other hand they are teratogenic. A number of nuclear receptor selective retinoids and rexinoids, have been successfully tested using a variety of cell lines or animal models. Retinoids inhibit carcinogenesis, suppress premalignant epithelial lesions and tumour growth and invasion in a variety of tissues. CONCLUSIONS: Natural and synthetic retinoids exert important biological effects due to their antiproliferative and apoptosis-inducing effects. They are also known to cause redifferentiation or to prevent further dedifferentiation of various tumour tissues.

• MeSH
• lidé MeSH
• nádory patofyziologie   prevence a kontrola   MeSH
• receptory cytoplazmatické a nukleární fyziologie   MeSH
• receptory kyseliny retinové fyziologie   MeSH
• retinoidní X receptory fyziologie   MeSH
• retinoidy fyziologie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• receptory cytoplazmatické a nukleární MeSH
• receptory kyseliny retinové MeSH
• retinoidní X receptory MeSH
• retinoidy MeSH

For decades, retinoids and their synthetic derivatives have been well established anticancer treatments due to their ability to regulate cell growth and induce cell differentiation and apoptosis. Many studies have reported the promising role of retinoids in attaining better outcomes for adult or pediatric patients suffering from several types of cancer, especially acute myeloid leukemia and neuroblastoma. However, even this promising differentiation therapy has some limitations: retinoid toxicity and intrinsic or acquired resistance have been observed in many patients. Therefore, the identification of molecular markers that predict the therapeutic response to retinoid treatment is undoubtedly important for retinoid use in clinical practice. The purpose of this review is to summarize the current knowledge on candidate markers, including both genetic alterations and protein markers, for retinoid resistance and sensitivity in human malignancies.

• Klíčová slova
• Acute myeloid leukemia, Breast carcinoma, Cell differentiation, Neuroblastoma, Pancreatic ductal adenocarcinoma, Predictive biomarkers, Retinoid resistance, Retinoid sensitivity, Retinoids,
• MeSH
• antitumorózní látky fytogenní chemie   farmakologie   terapeutické užití   MeSH
• biologické markery MeSH
• buněčná diferenciace účinky léků   MeSH
• chemorezistence MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• management nemoci MeSH
• nádory diagnóza   farmakoterapie   genetika   metabolismus   MeSH
• prognóza MeSH
• receptory kyseliny retinové chemie   metabolismus   MeSH
• retinoidy chemie   farmakologie   terapeutické užití   MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antitumorózní látky fytogenní MeSH
• biologické markery MeSH
• receptory kyseliny retinové MeSH
• retinoidy MeSH

The metabolism of steroids and retinoids has been studied in detail for a long time, as these compounds are involved in a broad spectrum of physiological processes. Many enzymes participating in the conversion of such compounds are members of the short-chain dehydrogenase/reductase (SDR) superfamily. Despite great effort, there still remain a number of poorly characterized SDR proteins. According to various bioinformatics predictions, many of these proteins may play a role in the metabolism of steroids and retinoids. Dehydrogenase/reductase (SDR family) member 7 (DHRS7) is one such protein. In a previous study, we determined DHRS7 to be an integral membrane protein of the endoplasmic reticulum facing the lumen which has shown at least in vitro NADPH-dependent reducing activity toward several eobiotics and xenobiotics bearing a carbonyl moiety. In the present paper pure DHRS7 was used for a more detailed study of both substrate screening and an analysis of kinetics parameters of the physiologically important substrates androstene-3,17-dione, cortisone and all-trans-retinal. Expression patterns of DHRS7 at the mRNA as well as protein level were determined in a panel of various human tissue samples, a procedure that has enabled the first estimation of the possible biological function of this enzyme. DHRS7 is expressed in tissues such as prostate, adrenal glands, liver or intestine, where its activity could be well exploited. Preliminary indications show that DHRS7 exhibits dual substrate specificity recognizing not only steroids but also retinoids as potential substrates and could be important in the metabolism of these signalling molecules.

• Klíčová slova
• Carbonyl reduction, DHRS7, Metabolism, Retinoids, SDR, Steroids,
• MeSH
• androstendion metabolismus   MeSH
• cirkulární dichroismus MeSH
• fylogeneze MeSH
• kinetika MeSH
• kortison metabolismus   MeSH
• lidé MeSH
• oxidoreduktasy chemie   genetika   metabolismus   MeSH
• regulace genové exprese enzymů MeSH
• retinaldehyd metabolismus   MeSH
• steroidy metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• androstendion MeSH
• DHRS7 protein, human MeSH Prohlížeč
• DHRS7c protein, human MeSH Prohlížeč
• kortison MeSH
• oxidoreduktasy MeSH
• retinaldehyd MeSH
• steroidy MeSH

Some psoriasis forms can be successfully treated with topical medicaments; serious and extensive forms cannot be cured without systemic treatment with retinoids (etretinate, acitretin, tazarotene) or with immunosuppressives (methotrexate, cyclosporine A, tacrolimus, SDZ 281-240). Immunotherapy and nucleotide analogues are being newly introduced, a number of potentially effective substances interfering with pathogenetic mechanisms participating in the emergence and self-prolongation of psoriasis are in the stage of research and clinical trials, and gene therapy possibilities are being investigated. The development and testing of drugs serving therapy for psoriasis correlates with the development of knowledge about the origins of the disease and the mechanisms of how antipsoriatics in current use as well as the new potential ones work.

• MeSH
• fotochemoterapie MeSH
• imunosupresiva terapeutické užití   MeSH
• lidé MeSH
• psoriáza farmakoterapie   MeSH
• retinoidy terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• imunosupresiva MeSH
• retinoidy MeSH

Natural retinoids and curcuminoids are known for their broad spectrum of biological properties, such as antioxidant, anti-inflammatory, antitumor, and so forth. In this work, a convenient synthesis of aromatic retinoids and curcuminoids from vinyl or allyl ketones, and the corresponding alcohols, using olefin metathesis as a key reaction, was elaborated. The best yields and diastereoselectivities were obtained from allylic or homoallylic alcohols by employing the two-step cross-metathesis/oxidation procedure. The synthesized analogues were tested for their antiproliferative activity on human cancer cell lines of various origin (leukemia CEM, adenocarcinoma MCF7, cervical carcinoma HeLa) as well as for their antioxidant and anti-inflammatory activity in vitro. All examined derivatives exhibited strong anti-inflammatory activity in vitro without affecting cell viability. They also showed strong cytotoxicity against leukemia cell line CEM, except for 18 and 35. The antioxidant activity of the tested compounds was rather weak.

• Klíčová slova
• anti-inflammatory activity, antitumor agents, curcuminoids, metathesis, retinoids,
• Publikační typ
• časopisecké články MeSH