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BACKGROUND: SOT201 and its murine surrogate mSOT201 are novel cis-acting immunocytokines consisting of a humanized/murinized/, Fc-silenced anti-programmed cell death protein 1 (PD-1) monoclonal antibody (mAb) fused to an attenuated human interleukin (IL)-15 and the IL-15Rα sushi+ domain. Murine mPD1-IL2v is a conjugate of a murinized, Fc silenced anti-PD-1 mAb bearing human IL-2 with abolished IL-2Rα binding. These immunocytokines spatiotemporally reinvigorate PD-1+ CD8+ tumor-infiltrating lymphocytes (TILs) via cis-activation and concomitantly activate the innate immunity via IL-2/15Rβγ signaling. METHODS: Human peripheral blood mononuclear cell and cell lines were used to evaluate cis/trans activity of SOT201. Anti-PD-1 mAb responsive (MC38, CT26) and resistant (B16F10, CT26 STK11 KO) mouse tumor models were used to determine the anticancer efficacy, and the underlying immune cell activity was analyzed via single-cell RNA sequencing and flow cytometry. The expansion of tumor antigen-specific CD8+ T cells by mSOT201 or mPD1-IL2v and memory CD8+ T-cell generation in vivo was determined by flow cytometry. RESULTS: SOT201 delivers attenuated IL-15 to PD-1+ T cells via cis-presentation, reinvigorates exhausted human T cells and induces higher interferon-γ production than pembrolizumab in vitro. mSOT201 administered as a single dose exhibits strong antitumor efficacy with several complete responses in all tested mouse tumor models. While mPD1-IL2v activates CD8+ T cells with a 50-fold higher potency than mSOT201 in vitro, mSOT201 more effectively reactivates effector exhausted CD8+ T cells (Tex), which demonstrate higher cytotoxicity, lower exhaustion and lower immune checkpoint transcriptional signatures in comparison to mPD1-IL2v in MC38 tumors in vivo. This can be correlated with a higher rate of complete responses in the MC38 tumor model following mSOT201 treatment when compared with mPD1-IL2v. mSOT201 increased the relative number of tumor antigen-specific CD8+ T cells, and unlike mPD1-IL2v stimulated greater expansion of adoptively transferred ovalbumin-primed CD8+ T cells simultaneously limiting the peripheral CD8+ T-cell sink, leading to the development of memory CD8+ T cells in vivo. CONCLUSIONS: SOT201 represents a promising therapeutic candidate that preferentially targets PD-1+ TILs, delivering balanced cytokine activity for reviving CD8+ Tex cells in tumors. SOT201 is currently being evaluated in the Phase I clinical study VICTORIA-01 (NCT06163391) in patients with advanced metastatic cancer.
- MeSH
- antigeny CD279 * antagonisté a inhibitory MeSH
- CD8-pozitivní T-lymfocyty imunologie MeSH
- inhibitory kontrolních bodů farmakologie MeSH
- interleukin-15 * genetika farmakologie MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Cyanobacterial harmful blooms (CyanoHABs) pose a global ecological problem, and their lipopolysaccharides (LPS) are among the bioactive compounds they release. Previous studies on CyanoHAB-LPS from single cyanobacterial species have shown varying bioactivities in different in vitro cell models. In this study, we isolated LPS from 19 CyanoHAB samples collected at 18 water bodies in the Czech Republic over two consecutive seasons. The proportions of cyanobacteria, Gram-negative bacteria (G-), and other bacteria in the biomass were determined by qPCR, while the cyanobacterial genera were identified using light microscopy. In vitro models of keratinocytes (HaCaT), the intestinal epithelium (co-culture of differentiated Caco-2 cells and peripheral blood mononuclear cells - PBMC), and PBMC alone were treated with isolated LPS at concentrations of 50, 100, and 1 μg/ml, respectively. The endotoxin activities of these concentrations were within the range measured in the aquatic environment. Approximately 85-90% of the samples displayed biological activity. However, the potency of individual LPS effects and response patterns varied across the different in vitro models. Furthermore, the observed activities did not exhibit a clear correlation with the taxonomic composition of the phytoplankton community, the relative share of microbial groups in the biomass, endotoxin activity of the LPS, or LPS migration and staining pattern in SDS-PAGE. These findings suggest that the effects of CyanoHAB-LPS depend on the specific composition and abundance of various LPS structures within the complex environmental sample and their interactions with cellular receptors.
- MeSH
- biomasa MeSH
- Caco-2 buňky MeSH
- leukocyty mononukleární MeSH
- lidé MeSH
- lipopolysacharidy * toxicita MeSH
- sinice * MeSH
- škodlivý vodní květ MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Neurosteroids are investigated as effective antidotes for the poisoning induced by tetramethylenedisulfotetramine (TMDT) as well as treatments for epileptic spasms during infancy. Both these conditions are quite resistant to pharmacotherapy; thus, a search for new treatments is warranted. METHODS: In this study, we determined the efficacy of two novel neurosteroids, pregnanolone glutamate (PAG) and pregnanolone pyroglutamate (PPG), and tested these drugs in doses of 1-10 mg/kg (ip) against the TMDT syndrome and in our rodent model of infantile spasms. RESULTS: Only PPG in doses 5 and 10 mg/kg suppressed the severity of the TMDT syndrome and TMDT-induced lethality, while the 1 mg/kg dose was without an effect. Interestingly, the 1 mg/kg dose of PPG in combination with 1 mg/kg of diazepam was also effective against TMDT poisoning. Neither PAG nor PPG were effective against experimental spasms in the N-methyl-D-aspartate (NMDA)-triggered model of infantile spasms. CONCLUSIONS: While evidence suggests that PAG can act through multiple actions which include allosteric inhibition of NMDA-induced and glycine receptor-evoked currents as well as augmentation of ɣ-aminobutyric acid subtype A (GABAA) receptor-induced currents, the agent appears to neither have the appropriate mechanistic signature for activity in the infantile spasm model, nor the adequate potency, relative to PPG, for ameliorating the TMDT syndrome. The full mechanisms of action of PPG, which may become a potent TMDT antidote either alone or in combination with diazepam are yet unknown and thus require further investigation.
- MeSH
- diazepam farmakologie MeSH
- hlodavci MeSH
- křeče u dětí * chemicky indukované farmakoterapie MeSH
- kyselina glutamová MeSH
- kyselina pyrrolidonkarboxylová MeSH
- N-methylaspartát toxicita terapeutické užití MeSH
- neurosteroidy * MeSH
- neurotoxické syndromy * MeSH
- pregnanolon škodlivé účinky MeSH
- spasmus MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Aryl hydrocarbon receptor (AHR) plays pivotal roles in intestinal physiology and pathophysiology. Intestinal AHR is activated by numerous dietary, endogenous, and microbial ligands. Whereas the effects of individual compounds on AHR are mostly known, the effects of real physiological mixtures occurring in the intestine have not been studied. Using reporter gene assays and RT-PCR, we evaluated the combinatorial effects (3520 combinations) of 11 microbial catabolites of tryptophan (MICTs) on AHR. We robustly (n = 30) determined the potencies and relative efficacies of single MICTs. Synergistic effects of MICT binary mixtures were observed between low- or medium-efficacy agonists, in particular for combinations of indole-3-propionate and indole-3-lactate. Combinations comprising highly efficacious agonists such as indole-3-pyruvate displayed rather antagonist effects, caused by saturation of the assay response. These synergistic effects were confirmed by RT-PCR as CYP1A1 mRNA expression. We also tested mimic multicomponent and binary mixtures of MICTs, prepared based on the metabolomic analyses of human feces and colonoscopy aspirates, respectively. In this case, AHR responsiveness did not correlate with type of diet or health status, and the indole concentrations in the mixtures were determinative of gross AHR activity. Future systematic research on the synergistic activation of AHR by microbial metabolites and other ligands is needed.
- MeSH
- cytochrom P-450 CYP1A1 genetika metabolismus MeSH
- indoly metabolismus farmakologie MeSH
- lidé MeSH
- ligandy MeSH
- messenger RNA metabolismus MeSH
- propionáty MeSH
- pyruváty MeSH
- receptory aromatických uhlovodíků * metabolismus MeSH
- střeva MeSH
- tryptofan * metabolismus farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články 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.
DNA-dependent DNA and RNA polymerases are important modulators of biological functions such as replication, transcription, recombination, or repair. In this work performed in cell-free media, we studied the ability of selected DNA polymerases to overcome a monofunctional adduct of the cytotoxic/antitumor platinum-acridinylthiourea conjugate [PtCl(en)(L)](NO3)2 (en = ethane-1,2-diamine, L = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea) (ACR) in its favored 5'-CG sequence. We focused on how a single site-specific ACR adduct with intercalation potency affects the processivity and fidelity of DNA-dependent DNA polymerases involved in translesion synthesis (TLS) and repair. The ability of the G(N7) hybrid ACR adduct formed in the 5'-TCGT sequence of a 24-mer DNA template to inhibit the synthesis of a complementary DNA strand by the exonuclease-deficient Klenow fragment of DNA polymerase I (KFexo-) and human polymerases eta, kappa, and iota was supplemented by thermodynamic analysis of the polymerization process. Thermodynamic parameters of a simulated translesion synthesis across the ACR adduct were obtained by using microscale thermophoresis (MST). Our results show a strong inhibitory effect of an ACR adduct on enzymatic TLS: there was only small synthesis of a full-length product (less than 10%) except polymerase eta (~20%). Polymerase eta was able to most efficiently bypass the ACR hybrid adduct. Incorporation of a correct dCMP opposite the modified G residue is preferred by all the four polymerases tested. On the other hand, the frequency of misinsertions increased. The relative efficiency of misinsertions is higher than that of matched cytidine monophosphate but still lower than for the nonmodified control duplex. Thermodynamic inspection of the simulated TLS revealed a significant stabilization of successively extended primer/template duplexes containing an ACR adduct. Moreover, no significant decrease of dissociation enthalpy change behind the position of the modification can contribute to the enzymatic TLS observed with the DNA-dependent, repair-involved polymerases. This TLS could lead to a higher tolerance of cancer cells to the ACR conjugate compared to its enhanced analog, where thiourea is replaced by an amidine group: [PtCl(en)(L)](NO3)2 (complex AMD, en = ethane-1,2-diamine, L = N-[2-(acridin-9-ylamino)ethyl]-N-methylpropionamidine).
- MeSH
- adukty DNA chemie MeSH
- DNA-dependentní DNA-polymerasy metabolismus MeSH
- interkalátory chemie MeSH
- lidé MeSH
- močovina analogy a deriváty chemie MeSH
- oprava DNA * MeSH
- organoplatinové sloučeniny chemie MeSH
- poškození DNA * MeSH
- replikace DNA MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
INTRODUCTION: The emergence and spread of antibiotic resistance among pathogenic bacteria drives the search for alternative antimicrobial therapies. Bacteriocins represent a potential alternative to antibiotic treatment. In contrast to antibiotics, bacteriocins are peptides or proteins that have relatively narrow spectra of antibacterial activities and are produced by a wide range of bacterial species. Bacteriocins of Escherichia coli are historically classified as microcins and colicins, and, until now, more than 30 different bacteriocin types have been identified and characterized. AREAS COVERED: We performed bibliographical searches of online databases to review the literature regarding bacteriocins produced by E. coli with respect to their occurrence, bacteriocin role in bacterial colonization and pathogenicity, and application of their antimicrobial effect. EXPERT OPINION: The potential use of bacteriocins for applications in human and animal medicine and the food industry includes (i) the use of bacteriocin-producing probiotic strains, (ii) recombinant production in plants and application in food, and (iii) application of purified bacteriocins.
- MeSH
- antibakteriální látky biosyntéza izolace a purifikace farmakologie MeSH
- bakteriociny biosyntéza izolace a purifikace farmakologie MeSH
- Escherichia coli metabolismus MeSH
- koliciny biosyntéza izolace a purifikace farmakologie MeSH
- lidé MeSH
- probiotika farmakologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Herein, we describe the rapid synthesis of a focused library of trisubstituted imidazo[4,5-b]pyridines and imidazo[4,5-c]pyridines from 2,4-dichloro-3-nitropyridine using the combination of solution-phase/solid-phase chemistry as new potential anti-inflammatory agents in the treatment of autoimmune diseases. Structure-activity relationship studies, followed by the structure optimization, provided hit compounds (17 and 28) which inhibited phosphodiesterase 4 (PDE4) with IC50 values comparable to rolipram and displayed different inhibitory potency against phosphodiesterase 7 (PDE7). Among them, compound 17 showed a beneficial effect in all the studied animal models of inflammatory and autoimmune diseases (concanavalin A-induced hepatitis, lipopolysaccharide-induced endotoxemia, collagen-induced arthritis, and MOG35-55-induced encephalomyelitis). In addition, compound 17 showed a favorable pharmacokinetic profile after intraperitoneal administration; it was characterized by a fast absorption from the peritoneal cavity and a relatively long terminal half-life in rats. It was found to penetrate brain barrier in mice. The performed experiments sheds light on the impact of PDE7A inhibition for the efficacy of PDE4 inhibitors in these disease conditions.
- MeSH
- antiflogistika chemie farmakokinetika farmakologie terapeutické užití MeSH
- autoimunitní nemoci farmakoterapie MeSH
- cyklické nukleotidfosfodiesterasy, typ 7 antagonisté a inhibitory MeSH
- imidazoly chemie farmakokinetika farmakologie terapeutické užití MeSH
- inhibitory fosfodiesteras chemie farmakokinetika farmakologie terapeutické užití MeSH
- inhibitory fosfodiesterasy 4 chemie farmakokinetika farmakologie terapeutické užití MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední BALB C MeSH
- potkani Wistar MeSH
- pyridiny chemie farmakokinetika farmakologie terapeutické užití MeSH
- zánět farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Selective agonism of the estrogen receptor (ER) subtypes, ERα and ERβ, has historically been difficult to achieve due to the high degree of ligand-binding domain structural similarity. Multiple efforts have focused on the use of classical organic scaffolds to model 17β-estradiol geometry in the design of ERβ selective agonists, with several proceeding to various stages of clinical development. Carborane scaffolds offer many unique advantages including the potential for novel ligand/receptor interactions but remain relatively unexplored. We synthesized a series of para-carborane estrogen receptor agonists revealing an ERβ selective structure-activity relationship. We report ERβ agonists with low nanomolar potency, greater than 200-fold selectivity for ERβ over ERα, limited off-target activity against other nuclear receptors, and only sparse CYP450 inhibition at very high micromolar concentrations. The pharmacological properties of our para-carborane ERβ selective agonists measure favorably against clinically developed ERβ agonists and support further evaluation of carborane-based selective estrogen receptor modulators.
- MeSH
- beta receptor estrogenů agonisté MeSH
- estrogeny chemická syntéza chemie farmakologie MeSH
- HEK293 buňky MeSH
- lidé MeSH
- molekulární struktura MeSH
- sloučeniny boru chemická syntéza chemie farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
There is a limited number of studies about the constituents of Hypericum olympicum subsp. olympicum and its genotoxic and cytotoxic potency. We examined the possible antigenotoxic/genotoxic properties of methanolic extract of H. olympicum subsp. olympicum (HOE) on human lymphocytes by employing sister chromatid exchange, micronucleus and comet assay and analyzed its chemical composition by GCxGC-TOF/MS. The anti-growth activity against MCF-7 and MDA-MB-231 cell lines was assessed by using the ATP viability assay. Cell death mode was investigated with fluorescence staining and ELISA assays. The major components of the flower and trunk were determined as eicosane, heptacosane, 2-propen-1-ol, hexahydrofarnesyl acetone and α-muurolene. HOE caused significant DNA damage at selected doses (250-750 µg/ml) while chromosomal damage was observed at higher concentrations (500 and 750 µg/ml). HOE demonstrated anti-growth activity in a dose-dependent manner between 3.13-100 µg/ml. Pyknotic nuclei were observed at 100 µg/ml concentration of HOE in both cell lines. In conclusion, HOE demonstrated cytotoxic effects in a cell type-dependent manner, however its genotoxic effects were observed at relatively higher doses.
- MeSH
- buněčná smrt účinky léků MeSH
- chromatografie MeSH
- fluorescenční spektrometrie MeSH
- inhibitory růstu MeSH
- lidé MeSH
- lymfocyty účinky léků MeSH
- nádorové buněčné linie * účinky léků MeSH
- nádory prsu terapie MeSH
- statistika jako téma MeSH
- třezalka * chemie toxicita MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
