The aryl hydrocarbon receptor (AhR) is a cytosolic ligand-activated transcription factor integral to various physiological and pathological processes. Among its diverse ligands, indole-based compounds have garnered attention due to their significant biological activity and potential therapeutic applications. This study explores the activation of AhR by structurally diverse halogenated indoles. We evaluated the transcriptional activity of AhR and cell viability in the human LS174T-AhR-luc reporter cell line. Among the tested compounds, 4-FI, 7-FI, 6-BrI, 7-BrI, 6-Cl-2-ox, 5-Br-2-ox, and 6-Br-2-ox activated AhR in a concentration-dependent manner, displaying high efficacy and potency. Molecular docking analysis revealed moderate binding affinities of these compounds to the PAS-B domain of AhR, corroborated by competitive radioligand binding assays. Functional assays showed that halogenated indoles induce the formation of AhR-ARNT heterodimer and enhance the binding of the AhR to the CYP1A1 promoter. Additionally, 4-FI and 7-FI exhibited anti-inflammatory properties in Caco-2 cell models, highlighting their potential for therapeutic applications. This study underscores the significance of the type and position of halogen moiety in indole scaffold, suggesting their potential as candidates for developing therapeutics drugs to treat conditions such as inflammatory bowel disease via AhR activation.
- MeSH
- cytochrom P-450 CYP1A1 metabolismus MeSH
- halogenace MeSH
- indoly * chemie farmakologie MeSH
- lidé MeSH
- molekulární struktura MeSH
- receptory aromatických uhlovodíků * metabolismus chemie MeSH
- simulace molekulového dockingu * MeSH
- transkripční faktory bHLH MeSH
- viabilita buněk účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The Department of Plastic and Aesthetic Surgery, St. Anne‘s University Hospital in Brno, and Faculty of Medicine of Masaryk University, Brno, has a long history of surgical treatment of lymphedema and elephantiasis, which started in 1970s. There were many types of surgeries described and performed at our department – starting with prof. Bařinka‘s radical operation of elephantiasis, then lower limb end-to-side lymphovenous anastomosis pulled through the wall to the great saphenous vein, and genital lymphedema reduction. We call this era “the first period” of surgical lymphedema treatment. “The second period” started in 2016 by using free flaps with lymph nodes or vascularized lymph nodes and using microsurgical techniques of end-to-end, end-to-side and side-to-end lymphovenous anastomoses to the subcutaneous veins of a small calibre, which then drain the lymph into the blood stream. “The third period” started 2 years ago after the visit of prof. Yang from Taiwan – we started to use the method of single stitch end-to-side anastomosis to big subcutaneous veins like the great saphenous vein or the cephalic vein.
- Klíčová slova
- Bařinkova operace,
- MeSH
- anastomóza chirurgická klasifikace metody MeSH
- dějiny 20. století MeSH
- dějiny 21. století MeSH
- elefantiáza chirurgie diagnóza terapie MeSH
- lidé MeSH
- lymfedém * chirurgie diagnóza terapie MeSH
- výsledek terapie MeSH
- zákroky plastické chirurgie * dějiny klasifikace metody MeSH
- Check Tag
- dějiny 20. století MeSH
- dějiny 21. století MeSH
- lidé MeSH
- Publikační typ
- přehledy MeSH
- Geografické názvy
- Česká republika MeSH
Introduction: Skin malignancy is one of the most common reasons for seeking out a plastic surgery clinic. This article presents an overview of the therapeutic results at Department of Plastic and Aesthetic Surgery Brno and includes an algorithm according to which we proceed in the treatment of patients with skin malignancy. Material and methods: Retrospective analysis of data for the year 2022, including a set of 791 patients with a total of 1,117 procedures to remove skin malignancy. The representation of cutaneous malignancy was as follows – basalioma (51%), squamous cell carcinoma (14%), and other malignancies including precancerous lesions were represented in 35%. Age, sex, a character and a number of procedures (excision, re-excision, controlled excision), and the histological results of resected specimens (with a sufficient margin or ingrowth) were evaluated. Based on the analysis of the patient cohort, an algorithm is presented to guide the surgical management of the patient. Results: Patients’ age ranged from 26 to 102 years. There was a discrete male predominance in the cohort (51%). Tumour localization was most frequently on the skin of the face, cleavage, and extremities. Regarding the spectrum of procedures, excision accounted for the largest proportion (83%). Re-excision accounted for the rest of the procedures (10%), controlled excision was performed in 6% and excisional biopsy accounted for 1%. Primary sanative excision with a histologically sufficient margin was performed in 96%. In the group of controlled excisions, 59% were sanative. Overall, 73% of patients in our cohort underwent a single operation only to remove a cutaneous malignancy. Conclusion: The results of the therapy and the algorithm of the care for patients with skin malignancy can be evaluated as successful based on the analysis performed. The determination of the surgical strategy according to the algorithm appears to be effective. The authors recommend its use in practice, especially with the current trend of the increasing incidence of skin malignancies and the desire to improve the effectiveness of surgical interventions.
- MeSH
- bazocelulární karcinom chirurgie patologie terapie MeSH
- lidé MeSH
- management nemoci MeSH
- nádory kůže * chirurgie patologie terapie MeSH
- retrospektivní studie MeSH
- směrnice pro lékařskou praxi jako téma MeSH
- spinocelulární karcinom chirurgie patologie terapie MeSH
- výsledek terapie MeSH
- zákroky plastické chirurgie * metody MeSH
- Check Tag
- lidé MeSH
- Geografické názvy
- Česká republika MeSH
Two copper(II) complexes containing diplacone (H4dipl), a naturally occurring C-geranylated flavanone derivative, in combination with bathophenanthroline (bphen) or 1,10-phenanthroline (phen) with the composition [Cu3(bphen)3(Hdipl)2]⋅2H2O (1) and {[Cu(phen)(H2dipl)2]⋅1.25H2O}n (2) were prepared and characterized. As compared to diplacone, the complexes enhanced in vitro cytotoxicity against A2780 and A2780R human ovarian cancer cells (IC50 ≈ 0.4-1.2 μM), human lung carcinoma (A549, with IC50 ≈ 2 μM) and osteosarcoma (HOS, with IC50 ≈ 3 μM). Cellular effects of the complexes in A2780 cells were studied using flow cytometry, covering studies concerning cell-cycle arrest, induction of cell death and autophagy and induction of intracellular ROS/superoxide production. These results uncovered a possible mechanism of action characterized by the G2/M cell cycle arrest. The studies on human endothelial cells revealed that complexes 1 and 2, as well as their parental compound diplacone, do possess anti-inflammatory activity in terms of NF-κB inhibition. As for the effects on PPARα and/or PPARγ, complex 2 reduced the expression of leukocyte adhesion molecules VCAM-1 and E-selectin suggesting its dual anti-inflammatory capacity. A wide variety of Cu-containing coordination species and free diplacone ligand were proved by mass spectrometry studies in water-containing media, which might be responsible for multimodal effect of the complexes.
- MeSH
- antiflogistika farmakologie chemie MeSH
- antitumorózní látky * farmakologie chemie chemická syntéza MeSH
- autofagie účinky léků MeSH
- flavanony * farmakologie chemie MeSH
- komplexní sloučeniny * farmakologie chemická syntéza chemie MeSH
- lidé MeSH
- měď * chemie farmakologie MeSH
- nádorové buněčné linie MeSH
- proliferace buněk * účinky léků MeSH
- reaktivní formy kyslíku metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Based on the mimicry of microbial metabolites, functionalized indoles were demonstrated as the ligands and agonists of the pregnane X receptor (PXR). The lead indole, FKK6, displayed PXR-dependent protective effects in DSS-induced colitis in mice and in vitro cytokine-treated intestinal organoid cultures. Here, we report on the initial in vitro pharmacological profiling of FKK6. FKK6-PXR interactions were characterized by hydrogen-deuterium exchange mass spectrometry. Screening FKK6 against potential cellular off-targets (G protein-coupled receptors, steroid and nuclear receptors, ion channels, and xenobiotic membrane transporters) revealed high PXR selectivity. FKK6 has poor aqueous solubility but was highly soluble in simulated gastric and intestinal fluids. A large fraction of FKK6 was bound to plasma proteins and chemically stable in plasma. The partition coefficient of FKK6 was 2.70, and FKK6 moderately partitioned into red blood cells. In Caco2 cells, FKK6 displayed high permeability (A-B: 22.8 × 10-6 cm.s-1) and no active efflux. These data are indicative of essentially complete in vivo absorption of FKK6. The data from human liver microsomes indicated that FKK6 is rapidly metabolized by cytochromes P450 (t1/2 5 min), notably by CYP3A4. Two oxidized FKK6 derivatives, including DC73 (N6-oxide) and DC97 (C19-phenol), were detected, and these metabolites had 5-7 × lower potency as PXR agonists than FKK6. This implies that despite high intestinal absorption, FKK6 is rapidly eliminated by the liver, and its PXR effects are predicted to be predominantly in the intestines. In conclusion, the PXR ligand and agonist FKK6 has a suitable pharmacological profile supporting its potential preclinical development.
A bis(chalcone) molecule (H2L) was synthesized via Aldol's condensation from terephthalaldehyde and 2'-hydroxyacetophenone and it was used as bridging ligand for the preparation of five dinuclear copper(II) complexes of the composition [Cu(NN)(μ-L)Cu(NN)](NO3)2⋅nH2O (n = 0-2) (1-5), where NN stands for a bidentate N-donor ligand such as phen (1,10-phenanthroline, 1), bpy (2,2'-bipyridine, 2), mebpy (5,5'-dimethyl-2,2'-dipyridine, 3), bphen (bathophenanthroline, 4) and nphen (5-nitro-1,10-phenanthroline, 5). The compounds were characterized by different suitable techniques to confirm their purity, composition, and structure. Moreover, the products were evaluated for their in vitro cytotoxicity on a panel of human cancer cell lines: ovarian (A2780), ovarian resistant to cisplatin (A2780R), prostate (PC3), osteosarcoma (HOS), breast (MCF7) and lung (A549), and normal fibroblasts (MRC-5), showing significant cytotoxicity in most cases, with IC50 ≈ 0.35-7.8 μM. Additionally, the time-dependent cytotoxicity and cellular uptake of copper, together with flow cytometric studies concerning cell-cycle arrest, induction of cell death and autophagy and induction of intracellular ROS/superoxide production in A2780 cells, were also performed. The results of biological testing on A2780 cells pointed out a possible mechanism of action characterized by the G2/M cell cycle arrest and induction of apoptosis by triggering the intrinsic signalling pathway associated with the damage of mitochondrial structure and depletion of mitochondrial membrane potential. SYNOPSIS: Dinuclear Cu(II) complexes bearing a bridging bis(chalcone) ligand revealed high in vitro cytotoxicity, initiated A2780 cell arrest at G2/M phase and efficiently triggered intrinsic pathway of apoptosis.
- MeSH
- antitumorózní látky * farmakologie chemie MeSH
- apoptóza MeSH
- chalkon * farmakologie MeSH
- chalkonoidy * farmakologie MeSH
- komplexní sloučeniny * farmakologie chemie MeSH
- lidé MeSH
- ligandy MeSH
- měď chemie MeSH
- nádorové buněčné linie MeSH
- nádory vaječníků * MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Two cationic [Cu2(L1-2)2](ClO4)2 (1, 2), and four neutral doubly bridged-phenoxido-copper(II) complexes [Cu2(L3-4)2] (3, 4) and [Cu2(L5-6)2(H2O)]‧2H2O (5, 6) as well as 1D polymeric catena-[Cu(L7)] (7), where HL1-2 and H2L3-7 represent tripodal tetradentate pyridyl or aliphatic-amino groups based 2,4-disubstituted phenolates, were synthesized and thoroughly characterized by various spectroscopic methods and single crystal X-ray analysis. The molecular structures of the complexes exhibited diverse geometrical environments around the central Cu(II) atoms. The in vitro antiproliferative activity of the isolated complexes and selected parent free ligands were screened against some human cancer cell lines (A2780, A2780R, PC-3, 22Rv1, MCF-7). The most promising cytotoxicity against cancer cells were obtained for 1-6, while complex 6 was found as the best performing as compared to the reference drug cisplatin. The cytotoxicity study of complex 6 was therefore extended to wider variety of cancer cell lines (HOS, A549, PANC-1, CaCo2, HeLa) and results revealed its significant cytotoxicity on all investigated human cancer cells. The cell uptake study showed that cytotoxicity of 6 (3 μM concentration and 24 h of incubation) against A2780 cells was almost independent from the intracellular levels of copper. The effect of complexes 4, 6 and 7 on cell cycle of A2780 cells indicates that the mechanism of action in these complexes is not only different from that of cisplatin but also different among them. Complex 7 was able to induce apoptosis in A2780 cells, while complexes 4 and 6 did not and on the other hand, they showed considerable effect on autophagy induction and there are some clues that these complexes were able to induce cuproptosis in A2780 cells.
- MeSH
- antitumorózní látky * farmakologie chemie MeSH
- Caco-2 buňky MeSH
- cisplatina MeSH
- komplexní sloučeniny * farmakologie chemie MeSH
- krystalografie rentgenová MeSH
- lidé MeSH
- ligandy MeSH
- měď chemie MeSH
- molekulární struktura MeSH
- nádorové buněčné linie MeSH
- nádory vaječníků * MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
AIMS: The objective of this study was to compare bone invasion type with histopathological, clinical and immunohistochemical prognostic factors. METHODS: The study included 49 patients who were treated for oral squamous cell carcinoma. Of which, 30 patients, with presence of bone invasion on histopathology, were divided according to the type of bone invasion (erosive, infiltrative, mixed). Each invasion type was compared to microvascular density using the CD34 marker. RESULTS: The bone invasion was observed in 30 out of 49 patients (61.22%). On McNemar's test, statistically significant association was observed between bone invasion types and histopathological grade. In contrast, no significant correlation was observed between bone invasion type, and tumour volume or nodal metastases. In tumours with bone invasion of the infiltrative type, higher frequency of locoregional relapses was observed. The 5-year survival, since diagnosis, was approximately 60% in the erosive group, 40% in the mixed group, and merely 15% in the infiltrative group. CONCLUSION: Peritumoural microvascular density was not significantly related to bone invasion types. Whereas, a significantly higher intratumoural microvascular density was observed in infiltrative type of the bone invasion, when compared to the erosive and mixed type.
- MeSH
- lidé MeSH
- lokální recidiva nádoru patologie MeSH
- nádory hlavy a krku * MeSH
- nádory úst * MeSH
- orofarynx patologie MeSH
- prognóza MeSH
- spinocelulární karcinom * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
OBJECTIVE: The extent to which tryptophan (Trp) metabolism alterations explain or influence the outcome of inflammatory bowel diseases (IBDs) is still unclear. However, several Trp metabolism end-products are essential to intestinal homeostasis. Here, we investigated the role of metabolites from the kynurenine pathway. DESIGN: Targeted quantitative metabolomics was performed in two large human IBD cohorts (1069 patients with IBD). Dextran sodium sulphate-induced colitis experiments in mice were used to evaluate effects of identified metabolites. In vitro, ex vivo and in vivo experiments were used to decipher mechanisms involved. Effects on energy metabolism were evaluated by different methods including Single Cell mEtabolism by profiling Translation inHibition. RESULTS: In mice and humans, intestinal inflammation severity negatively correlates with the amount of xanthurenic (XANA) and kynurenic (KYNA) acids. Supplementation with XANA or KYNA decreases colitis severity through effects on intestinal epithelial cells and T cells, involving Aryl hydrocarbon Receptor (AhR) activation and the rewiring of cellular energy metabolism. Furthermore, direct modulation of the endogenous tryptophan metabolism, using the recombinant enzyme aminoadipate aminotransferase (AADAT), responsible for the generation of XANA and KYNA, was protective in rodent colitis models. CONCLUSION: Our study identified a new mechanism linking Trp metabolism to intestinal inflammation and IBD. Bringing back XANA and KYNA has protective effects involving AhR and the rewiring of the energy metabolism in intestinal epithelial cells and CD4+ T cells. This study paves the way for new therapeutic strategies aiming at pharmacologically correcting its alterations in IBD by manipulating the endogenous metabolic pathway with AADAT.
- MeSH
- idiopatické střevní záněty * farmakoterapie MeSH
- kolitida * chemicky indukované farmakoterapie metabolismus MeSH
- lidé MeSH
- myši MeSH
- střeva MeSH
- tryptofan metabolismus MeSH
- zánět MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Xenobiotic receptors, such as the pregnane X receptor, regulate multiple host physiologic pathways including xenobiotic metabolism, certain aspects of cellular metabolism, and innate immunity. These ligand-dependent nuclear factors regulate gene expression via genomic recognition of specific promoters and transcriptional activation of the gene. Natural or endogenous ligands are not commonly associated with this class of receptors; however, since these receptors are expressed in a cell-type specific manner in the liver and intestines, there has been significant recent effort to characterize microbially derived metabolites as ligands for these receptors. In general, these metabolites are thought to be weak micromolar affinity ligands. This journal anniversary minireview focuses on recent efforts to derive potentially nontoxic microbial metabolite chemical mimics that could one day be developed as drugs combating xenobiotic receptor-modifying pathophysiology. The review will include our perspective on the field and recommend certain directions for future research. SIGNIFICANCE STATEMENT: Xenobiotic receptors (XRs) regulate host drug metabolism, cellular metabolism, and immunity. Their presence in host intestines allows them to function not only as xenosensors but also as a response to the complex metabolic environment present in the intestines. Specifically, this review focuses on describing microbial metabolite-XR interactions and the translation of these findings toward discovery of novel chemical mimics as potential drugs of the future for diseases such as inflammatory bowel disease.
