BACKGROUND: Modern trends in reconstructive surgery involve the use of free perforator flaps to reduce the donor site morbidity. The course of perforator vessels has a great anatomic variability and demands detailed knowledge of the anatomical relationships and the variability of the course of the perforators. The numerous modifications to perforator nomenclature proposed by various authors resulted in confusion rather than simplification. In our study, we focused on the hypothesis that a septocutaneous perforator traverses from the given source vessel to the deep fascia adherent to but not to within the septum itself. METHODS: Sixty-nine septocutaneous perforators from three different limb donor sites (lateral arm flap, anterolateral thigh flap, and radial forearm free flap) were collected from the gross pathology specimens of 14 fresh cadavers. The gross picture and the cross-sections with the histological cross-sections on different levels were examined to determine the position of the vessel to the septal tissue. RESULTS: Of the observed 69 septal perforators, 61 (88.5%) perforators were adherent to but not within the septum. The remaining eight (12.5%) perforators passed through the septum. All these eight perforators were found in multiple different cross-section levels (2 of 19 in lateral arm flap, 3 of 27 in anterolateral thigh flap, and 3 of 23 in radial forearm free flap). CONCLUSION: Although septocutaneous vessels appear identical macroscopically, microscopically two types of vessels with paraseptal and intraseptal pathways are observed. The majority of these vessels are merely adherent to the septum having a paraseptal pathway, while a minority are within the septum and are "true" septocutaneous perforators. It is advisable to dissect with a piece of the septum in order to avoid damage or injury to the perforator.

• MeSH
• lidé MeSH
• mrtvola MeSH
• perforátorový lalok * krevní zásobení   MeSH
• předloktí krevní zásobení   chirurgie   MeSH
• stehno krevní zásobení   MeSH
• volné tkáňové laloky * krevní zásobení   MeSH
• zákroky plastické chirurgie * metody   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Antagonizing the aryl hydrocarbon receptor (AhR) is a highly pertinent pharmacotherapeutic strategy. To overcome the drawbacks of existing AhR antagonists, novel molecules that can selectively target canonical and noncanonical AhR pathways are urgently needed. Recent reports on the structures and functions of cytosolic and nuclear AhR-protein complexes have allowed for understanding structural determinants for intrinsic activity and functional selectivity of AhR ligands. This new information regarding AhR surface interactions has opened new avenues for the development of novel AhR antagonists. Achievable strategies include the negative allosteric modulation of AhR and the disruption of AhR-protein and AhR-DNA interfaces using peptidomimetics or small molecules. Here, we discuss such novel approaches that may lead to new AhR-targeted therapeutics.

• Klíčová slova
• AhR receptor, allosteric modulation, antagonism, functional selectivity,
• MeSH
• lidé MeSH
• ligandy MeSH
• receptory aromatických uhlovodíků * antagonisté a inhibitory   metabolismus   chemie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• ligandy MeSH
• receptory aromatických uhlovodíků * MeSH

Aryl hydrocarbon receptor (AhR) is a ligand-dependent transcriptional factor that is activated by a plethora of exogenous and endogenous compounds, including environmental pollutants, drugs, and microbial metabolites. The AhR plays an important role in modulating immunity. Current findings suggest that AhR activation serves as a mechanism for evasion of host antiviral immune response and promotes viral replication. This review will focus on AhR's role in RNA virus infection because they show high mutation rates compared with DNA viruses, and therefo pose one of the greatest threats to humans in terms of potential pandemic risk. Indeed, they include human immunodeficiency virus (HIV), influenza A virus (IAV), coronaviruses (CoVs), Zika virus, and others. Understanding the mechanisms by which AhR influences the immune response to these viruses is critical for developing effective therapeutic strategies. By focusing on the interplay between AhR signaling and RNA virus infections, this review aims to contribute to the growing body of knowledge regarding host-pathogen interactions and the implications for antiviral immunity.

• Klíčová slova
• Aryl hydrocarbon receptor, RNA virus, antiviral immunity, viral infection,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Monocyclic monoterpenoids carvones have been recently identified as atypical negative allosteric modulators of aryl hydrocarbon receptor (AhR). In the current work, we performed AhR antagonist activity screening of 100 natural and synthetic monoterpenoids, and their analogues. Using SAR approach, structural determinants of AhR antagonist activity were assigned, including CO presence/position, planarity, and C3/C5-alkylation. Applying pyramidal selection criteria, including absence of residual agonist activity, no cytotoxicity, strong antagonist potency, and pan-antagonism against diverse AhR agonists, we distilled four lead AhR antagonists (carvacrol, o-cresol, 3-methyl-S-carvone, EN-2). Whereas 3-methyl-S-carvone and EN-2 were non-competitive AhR pan-antagonists, carvacrol and o-cresol were ligand-selective AhR antagonists acting by unclear mechanism. We characterized in detail the effects of lead compounds at cellular functions of AhR, including AhR nuclear translocation, AhR dimerization with ARNT, and the expression of AhR-regulated genes. As a proof of concept, effects of monoterpenoids in the murine macrophages were investigated.

• Klíčová slova
• Allosteric binding, Aryl hydrocarbon receptor, Monoterpenoids, Therapeutic targeting,
• MeSH
• lidé MeSH
• molekulární struktura MeSH
• monoterpeny * farmakologie   chemie   chemická syntéza   MeSH
• myši MeSH
• receptory aromatických uhlovodíků * metabolismus   antagonisté a inhibitory   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• monoterpeny * MeSH
• receptory aromatických uhlovodíků * MeSH

This study compared the risk of nodal metastasis progression in the submandibular area when using submental flap contralateral (SFC) or submental flap ipsilateral (SFI) relative to the tumor side. Thirty patients underwent treatment for squamous cell carcinoma of the oral cavity. Submental flap ipsilateral and SFC were used in 14 and 16 patients, respectively. After unilateral supraomohyoid neck dissection (levels I-III), the SFC group showed a significantly higher total number of positive lymph nodes removed (P = 0.014). In addition, the number of positive lymph nodes in the IB region was significantly higher in the SFC group compared with the SFI group (P = 0.001). Tumour relapse was the same in both groups (SFI: n = 4/SFC: n = 4). The authors' results suggest that SFC can be adequately used to reconstruct oral cavity defects because, after rerouting, the rotation arc reaches the upper incisors and covers the arc of SFI rotation in the oral cavity. Moreover, with SFC, a complete neck block dissection and more radical tumor resection can be achieved without limitations.

• Publikační typ
• časopisecké články MeSH

The novel diiron amine complexes [Fe2Cp2(CO)(NH2R')(μ-CO){μ-CN(Me)(Cy)}]CF3SO3 [R' = H, 3; Cy, 4; CH2CH2NH2, 5; CH2CH2NMe2, 6; CH2CH2(4-C6H4OMe), 7; CH2CH2(4-C6H4OH), 8; Cp = η5-C5H5, Cy = C6H11 = cyclohexyl] were synthesized in 49-92 % yields from [Fe2Cp2(CO)2(μ-CO){μ-CN(Me)(Cy)}]CF3SO3, 1a, using a straightforward two-step procedure. They were characterized by IR and multinuclear NMR spectroscopy, and the structure of 7 was confirmed through X-ray diffraction analysis. Complexes 3-8 and the acetonitrile adducts [Fe2Cp2(CO)(NCMe)(μ-CO){μ-CN(Me)(R)}]CF3SO3 (R = Cy, 2a; Me, 2b; Xyl = 2,6-C6H3Me2, 2c) were assessed for their water solubility, octanol-water partition coefficient and stability in physiological-like solutions. The in vitro antiproliferative activity of 2a-c and 3-8 was tested on seven human cancer cell lines (A2780, A2780R, PC3, A549, MCF7, HOS and HT-29), while the selectivity was evaluated using normal MRC-5 cells. Overall, the complexes exhibited variable cytotoxicity, with IC50 values reaching the low micromolar range for 3, 7 and 8 in A2780 and A2780R cells, along with significant selectivity. Targeted experiments covered cell cycle modification, induction of cell death, mitochondrial membrane potential, ROS production and interaction with DNA and bovine serum albumin (BSA) as a model protein. The interaction of 3 with BSA was further investigated through computational studies. Results showed a negligible increase in intracellular ROS levels (except for 2b) and insignificant changes in mitochondrial membrane potential.

• Klíčová slova
• Bioorganometallic chemistry, Cellular effects, Diiron complexes, In vitro cytotoxicity, Labile ligand,
• MeSH
• aminy chemie   farmakologie   MeSH
• komplexní sloučeniny chemie   farmakologie   chemická syntéza   MeSH
• lidé MeSH
• ligandy MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• proliferace buněk * účinky léků   MeSH
• protinádorové látky * farmakologie   chemie   chemická syntéza   MeSH
• screeningové testy protinádorových léčiv * MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• železo chemie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• aminy MeSH
• komplexní sloučeniny MeSH
• ligandy MeSH
• protinádorové látky * MeSH
• železo MeSH

A series of eight gold(I) N-heterocyclic carbene (NHC) complexes [Au(IMes)(Ln)] based on 1,3-bis(2,4,6-trimethylphenyl)imidazole-2-ylidene (IMes) and 7-azaindole derivatives (HLn), where n = 1-8 for HL1 = 5-fluoro-7-azaindole, HL2 = 5-bromo-7-azaindole, HL3 = 3-chloro-7-azaindole, HL4 = 3-iodo-7-azaindole, HL5 = 5-bromo-3-chloro-7-azaindole, HL6 = 5-bromo-3-iodo-7-azaindole, HL7 = 4-chloro-2-methyl-7-azaindole and HL8 = 7-azaindole, was prepared, characterised and studied for their in vitro anti-cancer and anti-inflammatory effects. The complexes showed significant cytotoxicity on human ovarian cancer cell lines (A2780, IC50 ≈ 8-19 μM and A2780R, IC50 ≈ 8-19 μM) and lowered toxicity in normal HaCat and MRC-5 cells. Cellular effects of the selected complexes 1 and 7 were evaluated in A2780 cells using flow cytometry. Moreover, the time-dependent cellular uptake in A2780 cells, a shotgun proteomic analysis, an ESI-MS study of hydrolysis and interactions with l-cysteine and reduced glutathione (GSH) were performed. Complexes 1 and 7 revealed remarkable anti-inflammatory effects via inhibition of NF-κB activity in human endothelial cells.

• Klíčová slova
• A2780, Anti-inflammatory, Cellular effects, Cytotoxicity, Gold, NHC, Proteomics,
• MeSH
• antiflogistika * farmakologie   chemie   MeSH
• antioxidancia * farmakologie   chemie   MeSH
• apoptóza * účinky léků   MeSH
• endoteliální buňky pupečníkové žíly (lidské) účinky léků   MeSH
• endoteliální buňky účinky léků   metabolismus   cytologie   MeSH
• heterocyklické sloučeniny * chemie   MeSH
• komplexní sloučeniny * chemie   farmakologie   MeSH
• lidé MeSH
• methan * analogy a deriváty   chemie   farmakologie   MeSH
• nádorové buněčné linie MeSH
• protinádorové látky farmakologie   chemie   MeSH
• zlato * chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antiflogistika * MeSH
• antioxidancia * MeSH
• carbene MeSH Prohlížeč
• heterocyklické sloučeniny * MeSH
• komplexní sloučeniny * MeSH
• methan * MeSH
• protinádorové látky MeSH
• zlato * MeSH

Chronic intestinal inflammation significantly contributes to the development of colorectal cancer and remains a pertinent clinical challenge, necessitating novel therapeutic approaches. Indole-based microbial metabolite mimics Felix Kopp Kortagere 6 (FKK6), which is a ligand and agonist of the pregnane X receptor (PXR), was recently demonstrated to have PXR-dependent anti-inflammatory and protective effects in a mouse model of dextran sodium sulfate (DSS)-induced acute colitis. Here, we examined the therapeutic potential of FKK6 in a mouse model (C57BL/6 FVB humanized PXR mice) of colitis-associated colon cancer (CAC) induced by azoxymethane and DSS. FKK6 (2 mg/kg) displayed substantial antitumor activity, as revealed by reduced size and number of colon tumors, improved colon histopathology, and decreased expression of tumor markers (c-MYC, β-catenin, Ki-67, and cyclin D) in the colon. In addition, we carried out a chronic toxicity (30 days) assessment of FKK6 (1 mg/kg and 2 mg/kg) in C57BL/6 mice. Histological examination of tissues, biochemical blood analyses, and immunohistochemical staining for Ki-67 and γ-H2AX showed no difference between FKK6-treated and control mice. Comparative metabolomic analyses in mice exposed for 5 days to DSS and administered with FKK6 (0.4 mg/kg) revealed no significant effects on several classes of metabolites in the mouse fecal metabolome. Ames and micronucleus tests showed no genotoxic and mutagenic potential of FKK6 in vitro. In conclusion, anticancer effects of FKK6 in azoxymethane/DSS-induced CAC, together with FKK6 safety data from in vitro tests and in vivo chronic toxicity study, and comparative metabolomic study, are supportive of the potential therapeutic use of FKK6 in the treatment of CAC. SIGNIFICANCE STATEMENT: Microbial metabolite mimicry proposes that chemical mimics of microbial metabolites that serve to protect hosts against aberrant inflammation in the gut could serve as a new paradigm for the development of drugs targeting inflammatory bowel disease if, like the parent metabolite, is devoid of toxicity but more potent against the microbial metabolite receptor. We identified a chemical mimic of Felix Kopp Kortagere 6, and we propose that Felix Kopp Kortagere 6 is devoid of toxicity yet significantly reduces tumor formation in an azoxymethane-dextran sodium sulfate model of murine colitis-induced colon cancer.

• Klíčová slova
• Colon cancer, Inflammation, Microbial metabolites, Pregnane X receptor,
• MeSH
• azoxymethan MeSH
• chronická nemoc MeSH
• indoly * terapeutické užití   farmakologie   MeSH
• kolitida farmakoterapie   komplikace   chemicky indukované   MeSH
• kolorektální nádory * farmakoterapie   patologie   metabolismus   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• síran dextranu MeSH
• zánět * farmakoterapie   komplikace   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• azoxymethan MeSH
• indoly * MeSH
• síran dextranu MeSH

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor, which plays numerous and pivotal roles in human physiology and pathophysiology. Therefore, pharmacotherapeutic targeting of the AhR is a highly pertinent issue. The identification of new AhR ligands and the characterization of the interactions between the AhR ligands and AhR protein requires appropriate methodology. In spite the AhR is monomeric intracellular soluble receptor, the full-length human AhR protein has not been crystallized so far, and its isolation in a form applicable in the binding assays is highly challenging. Recent advances, including crystallization of AhR fragments, recombinant protein technologies, and cryogenic electron microscopy, allowed for exploitation of diverse experimental techniques for studying interactions between ligands and the AhR. In the current paper, we review existing AhR ligand binding assays, including their description, applicability and limitations.

• Klíčová slova
• aryl hydrocarbon receptor, interactions, ligands, protein binding,
• MeSH
• lidé MeSH
• ligandy MeSH
• receptory aromatických uhlovodíků * metabolismus   chemie   genetika   MeSH
• transkripční faktory bHLH * metabolismus   chemie   MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• AHR protein, human MeSH Prohlížeč
• ligandy MeSH
• receptory aromatických uhlovodíků * MeSH
• transkripční faktory bHLH * MeSH

The new diiron complexes [Fe2Cp2(CO)(L)(μ-CO){μ-CN(Me)(Cy)}]CF3SO3 (L = pyridine, 3a; 4-aminopyridine, 3b; 4-dimethylaminopyridine, 3c; 4-trifluoromethylpyridine, 3d; nicotinic acid, 4; Cp = η5-C5H5, Cy = C6H11 = cyclohexyl) were synthesized in moderate to high yields using two distinct synthetic routes from the precursors 1 (L = CO, for 4) and 2 (L = NCMe, for 3a-d), respectively. All products were characterized by IR and multinuclear NMR spectroscopy, and the structures of 3b and 3d were ascertained by X-ray diffraction studies. The behavior of the complexes in aqueous solutions (solubility, Log Pow, stability) was assessed using NMR and UV-Vis methods. The in vitro antiproliferative activity of 3a-c and 4 was evaluated against seven human cancer cell lines (A2780, A2780R, A549, MCF-7, PC3, HOS and HT-29) and one normal cell line (MRC-5), following 24 h of incubation (MTT test). Overall, 3-4 demonstrated stronger cytotoxicity than cisplatin, with 3c emerging as the most potent compound. The activity seems primarily linked to the inhibition of metabolic processes in the cancer cells, including depletion of reactive oxygen species (ROS) levels. However, subtle differences have been observed between the complexes, with 4 exerting its cytotoxicity through a distinct multimodal mechanism.

• Klíčová slova
• Bioorganometallic chemistry, Cellular effects, Diiron complexes, In vitro cytotoxicity, Metals in medicine, Pyridine ligand,
• MeSH
• komplexní sloučeniny * chemie   farmakologie   chemická syntéza   MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• ligandy MeSH
• nádorové buněčné linie MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky * farmakologie   chemie   chemická syntéza   MeSH
• pyridiny * chemie   farmakologie   MeSH
• screeningové testy protinádorových léčiv MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• komplexní sloučeniny * MeSH
• ligandy MeSH
• protinádorové látky * MeSH
• pyridine MeSH Prohlížeč
• pyridiny * MeSH