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.
- MeSH
- azoxymethan toxicita MeSH
- chronická nemoc MeSH
- indoly farmakologie terapeutické užití MeSH
- kolitida farmakoterapie chemicky indukované metabolismus patologie MeSH
- kolorektální nádory * farmakoterapie metabolismus patologie MeSH
- modely nemocí na zvířatech * MeSH
- molekulární mimikry MeSH
- myši inbrední C57BL * MeSH
- myši MeSH
- nádory asociované s kolitidou patologie farmakoterapie metabolismus MeSH
- síran dextranu toxicita MeSH
- zánět farmakoterapie metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
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
Background: Complex nasal defects most often arise due to oncological resection or severe trauma. Traditional methods of two-stage nose reconstruction using a forehead flap with a skin graft have often resulted in collapse and deformity of the nose with a very compromised outcome over time. These techniques were gradually replaced by new procedures consistently reconstructing the intranasal lining, most often with flaps from the nasal septum. These methods reconstruct the cartilaginous and bony support of the nose as well, while the skin cover of the nose is, nowadays, in large defects, reconstructed in three stages. Evaluation of the topic: The options for intranasal lining reconstruction are as follows: a composite graft, a turnover flap covered with a local flap, advancement of the residual lining (bipedicle vestibular mucosa flap), a folded forehead flap, a prelaminated forehead flap, the use of another local flap (a forehead, nasolabial, facial artery myomucosal flap), a hinged turnover flap, a septal mucoperichondrial hinged flap, a composite septal chondromucosal pivot flap, a turbinate flap and microvascular free flaps (a radial forearm flap, a helix free flap, a kite flap, a dorsalis pedis free flap, a temporoparietal free flap, a postauricular free flap). Thanks to the abundant vascular supply of the face, the risk of ischemia and infection is mitigated, allowing most complex nasal defects to be reconstructed by using local flaps to restore all layers of the nose. Local tissues retain ideal quality, coloration, and texture, are reliable, and usually result in esthetically acceptable morbidity of the donor area. If the inner lining defect is extensive, it must be reconstructed by free microvascular tissue transfer. If other than intranasal flaps are used in the reconstruction of the internal lining, it is preferable to postpone the reconstruction of the supporting framework until the second stage while thinning the flaps used; otherwise, there is a high risk of obturation of the nasal airways. Conclusion: The results of modern reconstruction dramatically improved after the introduction of three-stage nasal reconstruction and emphasizing the reconstruction of all layers of the nose. Therefore, a quality inner lining is the basis for the construction of the new nose.
Background: Lymphovenous anastomosis (LVA) and vascularized lymph node transfer (VLNT) are both accepted microsurgical treatment options for lymphedema. This article summarises and analyses recent data on outcomes associated with LVA and VLNT for lymphedema treatment at varying degrees of severity. Methods: Literature research was conducted in the PubMed and Embase Ovid database to extract articles published through March 2024. The included studies report data on objective and subjective improvement in lymphedema after physiological surgical procedures as LVA and VLNT. Extracted data comprised number of patients, affected limbs, staging of the disease, duration of the follow up period, objective and subjective improvement and percentage of discontinuation of compression garments. Results: A total of 23 articles were included in this article, representing 1,944 patients suffering from either primary or secondary lymphedema. The lymphedema stages were classified by classification of International Society of Lymphedema (ISL stage) or Campisi stage and range from stage I to III, as well as prophylactic indication for surgery. The follow-up duration ranged from 3 months to 8 years. Objective improvement was achieved in 82.76–100% and measured in circumferential reduction rate and reduction of cellulitis episodes. In 80–100% of the patient’s subjective improvement was seen, which was measured in quality of life and personal feedback. The percentage of patients able to discontinue the use of compression garments ranges from 0 to 100%, while others were able to reduce the total time of wearing. Conclusion: LVA and VLNT are both safe and effective techniques for the surgical treatment of lymphedema in several stages. LVA should be preferred if the lymph vessels preserved its patency, otherwise VLNT might be the therapy of choice. Combinations of various procedures with an appropriate postoperative treatment plan might lead to improved patient outcomes.
Volné laloky jsou považovány za zlatý standard v rekonstrukčních operacích anatomicky i funkčně složitých defektů v oblasti hlavy a krku. Jedná se o časově, technicky i logisticky náročné operace vyžadující multioborovou spolupráci. Materiál a metodika: Do retrospektivní klinické studie byli zahrnuti pacienti, kteří podstoupili rekonstrukci onkochirurgického defektu v oblasti hlavy a krku volným lalokem na Klinice otorinolaryngologie a chirurgie hlavy a krku FN u sv. Anny v Brně v letech 2000–2022. Výsledky: Do studie bylo zařazeno celkem 158 pacientů, u nichž bylo provedeno 162 rekonstrukčních operací volným lalokem. Typ laloku: fasciokutánní předloketní lalok 62 (38,3 %); fasciokutánní laterální pažní lalok 16 (9,9 %); muskulokutánní lalok z širokého zádového svalu 79 (48,8 %), jiný: 5 (3,1 %). Komplikace: Revize pro poruchu prokrvení laloku: 30 (18,5 %); parciální nekróza laloku: 5 (3,12 %); totální nekróza laloku: 2 (1,2 %). Úspěšnost přihojení laloku 98,8 %. Závěr: Úspěšnost přihojení volných laloků je srovnatelná s předními zahraničními centry zabývajícími se komplexní onkochirurgickou péčí o nádory hlavy a krku. Předpokladem úspěšného programu je kvalitní mezioborová spolupráce, vhodná selekce pacientů, vysoká erudice chirurgického týmu a standardizované postupy pooperační péče.
Free flaps are considered as the gold standard in reconstructive surgery for anatomically and functionally complex defects in the head and neck region. These surgeries are time-consuming and technically demanding, requiring interdisciplinary cooperation. Materials and methods: The retrospective clinical study included patients who underwent free flap reconstruction of oncological defects in the head and neck region at the Department of Otorhinolaryngology and Head and Neck Surgery, St. Anne’s University Hospital in Brno, between 2000 and 2022. Results: A total of 158 patients underwent 162 free flap reconstructive surgeries. Flap types: radial forearm fasciocutaneous flap 62 (38.3%); lateral arm fasciocutaneous flap 16 (9.9%); latissimus dorsi musculocutaneous flap 79 (48.8%); and other 5 (3.1%). Complications: Revision for vascular compromise: 30 (18.5%); partial flap necrosis: 5 (3.12%); total flap necrosis: 2 (1.2%); and flap survival rate 98.8%. Conclusion: The flap survival rate is comparable to leading international centers for head and surgery. Key factors for a successful program include high-quality interdisciplinary cooperation, appropriate patient selection, high level of surgical skills, and standardized postoperative care protocols.
- MeSH
- chirurgické laloky chirurgie klasifikace transplantace MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory hlavy a krku * chirurgie diagnóza MeSH
- otorinolaryngologické chirurgické výkony metody MeSH
- retrospektivní studie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- volné tkáňové laloky * chirurgie klasifikace transplantace MeSH
- výsledek terapie MeSH
- zákroky plastické chirurgie metody MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
Volné laloky jsou dnes zlatým standardem pro rekonstrukci onkologických defektů hlavy a krku. Lokální laloky mají díky své barvě a struktuře nezastupitelnou úlohu při rekonstrukci menších defektů, defektů nosu, očních víček a uší. Regionální stopkované laloky se obvykle používají při rekonstrukci hlavy a krku jako laloky druhé volby. Rutinně používané lokální laloky jsou V-Y posuvný lalok, transpoziční lalok, rotační lalok a jeho forma Bilobed flap. Z regionálních laloků se nejčastěji používají submentální lalok, supraklavikulární lalok, infrahyoidní myokutánní lalok, FAMM flap, stopkovaný pektorální lalok, stopkovaný lalok svalu latissimus dorsi, trapézový myokutánní lalok a paramediánní lalok čela. Lokální a regionální laloky by měly být zvažovány za primární metodu rekonstrukce hlavy a krku u pacientů s přidruženými komorbiditami, s deplecí cév na krku nebo je lze použít v kombinaci s volnými laloky či jako záchrannou rekonstrukci po selhání volného laloku. Stejně tak je lze užít jako záchrannou rekonstrukci v důsledku recidivy onkologického onemocnění. Stále však patří k základnímu vybavení chirurga hlavy a krku.
Free flaps are now the gold standard for reconstruction of oncological defects of the head and neck. Local flaps have an irreplaceable role due to their colour and texture in the reconstruction of smaller defects, and defects of the nose, eyelids, and ears. Regional pedicled flaps are usually used in head and neck reconstruction as second choice flaps. Routinely used local flaps are V-Y advancement flap, transposition flap, rotation flap, and its form bilobed flap. Of the regional flaps, the most commonly used are the submental flap, supraclavicular flap, infrahyoid myocutaneous flap, facial artery musculomucosal flap (FAMM), pedicled pectoralis major flap, pedicled latissimus dorsi flap, trapezius myocutaneous flap, and paramedian forehead flap. Local and regional flaps should be considered as a primary method of head and neck reconstruction in patients with associated comorbidities and neck vascular depletion or they can be used in combination with free flaps or as salvage reconstruction following free flap failure. Similarly, they can be used as a salvage reconstruction due to recurrence of oncological dis ease. However, they still belong to the basic armentarium of the head and neck surgeon,
- MeSH
- chirurgické laloky * chirurgie klasifikace transplantace MeSH
- hlava chirurgie MeSH
- krk chirurgie MeSH
- lidé MeSH
- otorinolaryngologické chirurgické výkony * metody MeSH
- volné tkáňové laloky chirurgie klasifikace transplantace MeSH
- zákroky plastické chirurgie metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem 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.
- 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
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.
- 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
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.
