growth inhibition
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The glycoprotein clusterin (CLU) is involved in cell proliferation and DNA damage repair and is highly expressed in tumor cells. Here, we aimed to investigate the effects of CLU dysregulation on two human astrocytic cell lines: CCF-STTG1 astrocytoma cells and SV-40 immortalized normal human astrocytes. We observed that suppression of CLU expression by RNA interference inhibited cell proliferation, triggered the DNA damage response, and resulted in cellular senescence in both cell types tested. To further investigate the underlying mechanism behind these changes, we measured reactive oxygen species, assessed mitochondrial function, and determined selected markers of the senescence-associated secretory phenotype. Our results suggest that CLU deficiency triggers oxidative stress-mediated cellular senescence associated with pronounced alterations in mitochondrial membrane potential, mitochondrial mass, and expression levels of OXPHOS complex I, II, III and IV, indicating mitochondrial dysfunction. This report shows the important role of CLU in cell cycle maintenance in astrocytes. Based on these data, targeting CLU may serve as a potential therapeutic approach valuable for treating gliomas.
- MeSH
- astrocyty * metabolismus patologie MeSH
- klusterin * metabolismus genetika MeSH
- lidé MeSH
- membránový potenciál mitochondrií * fyziologie MeSH
- mitochondrie * metabolismus MeSH
- nádorové buněčné linie MeSH
- oxidační stres fyziologie MeSH
- oxidativní fosforylace MeSH
- poškození DNA MeSH
- proliferace buněk * MeSH
- reaktivní formy kyslíku metabolismus MeSH
- stárnutí buněk * fyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Impaired fibroblast growth factor receptor (FGFR) signaling is associated with many human conditions, including growth disorders, degenerative diseases, and cancer. Current FGFR therapeutics are based on chemical inhibitors of FGFR tyrosine kinase activity (TKIs). However, FGFR TKIs are limited in their target specificity as they generally inhibit all FGFRs and other receptor tyrosine kinases. In the search for specific inhibitors of human FGFR1, we identified VZ23, a DNA aptamer that binds to FGFR1b and FGFR1c with a KD of 55 nM and 162 nM, respectively, but not to the other FGFR variants (FGFR2b, FGFR2c, FGFR3b, FGFR3c, FGFR4). In cells, VZ23 inhibited the activation of downstream FGFR1 signaling and FGFR1-mediated regulation of cellular senescence, proliferation, and extracellular matrix homeostasis. Consistent with the specificity toward FGFR1 observed in vitro, VZ23 did not inhibit FGFR2-4 signaling in cells. We show that the VZ23 inhibits FGFR1 signaling in the presence of cognate fibroblast growth factor (FGF) ligands and its inhibitory activity is linked to its capacity to form unusual G-quadruplex structure. Our data suggest that targeting FGFR1 with DNA aptamers could be an effective alternative to TKIs for treating impaired FGFR1 signaling in human craniosynostoses.
- Publikační typ
- časopisecké články MeSH
During development, tooth germs undergo various morphological changes resulting from interactions between the oral epithelium and ectomesenchyme. These processes are influenced by the extracellular matrix, the composition of which, along with cell adhesion and signaling, is regulated by metalloproteinases. Notably, these include matrix metalloproteinases (MMPs), a disintegrin and metalloproteinases (ADAMs), and a disintegrin and metalloproteinases with thrombospondin motifs (ADAMTSs). Our analysis of previously published scRNAseq datasets highlight that these metalloproteinases show dynamic expression patterns during tooth development, with expression in a wide range of cell types, suggesting multiple roles in tooth morphogenesis. To investigate this, Marimastat, a broad-spectrum inhibitor of MMPs, ADAMs, and ADAMTSs, was applied to ex vivo cultures of mouse molar tooth germs. The treated samples exhibited significant changes in tooth germ size and morphology, including an overall reduction in size and an inversion of the typical bell shape. The cervical loop failed to extend, and the central area of the inner enamel epithelium protruded. Marimastat treatment also disrupted proliferation, cell polarization, and organization compared with control tooth germs. In addition, a decrease in laminin expression was observed, leading to a disruption in continuity of the basement membrane at the epithelial-mesenchymal junction. Elevated hypoxia-inducible factor 1-alpha gene (Hif-1α) expression correlated with a disruption to blood vessel development around the tooth germs. These results reveal the crucial role of metalloproteinases in tooth growth, shape, cervical loop elongation, and the regulation of blood vessel formation during prenatal tooth development.NEW & NOTEWORTHY Inhibition of metalloproteinases during tooth development had a wide-ranging impact on molar growth affecting proliferation, cell migration, and vascularization, highlighting the diverse role of these proteins in controlling development.
- MeSH
- faktor 1 indukovatelný hypoxií - podjednotka alfa metabolismus genetika MeSH
- inhibitory matrixových metaloproteinas farmakologie MeSH
- kyseliny hydroxamové farmakologie MeSH
- metaloproteasy metabolismus genetika MeSH
- moláry embryologie růst a vývoj metabolismus enzymologie MeSH
- morfogeneze MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- odontogeneze * MeSH
- proliferace buněk * MeSH
- vývojová regulace genové exprese MeSH
- zubní zárodek embryologie metabolismus enzymologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Bacillus is well known for producing a wide range of compounds that inhibit microbial phytopathogens. From this perspective, we were interested in evaluating the biocontrol potential of 5 plant growth-promoting rhizobacteria Bacillus species (PGPR-Bacillus) on 21 microbial pectinolytic plant pathogens isolated from previous studies. Phytopathogenicity and in vivo biocontrol potential of PGPR curative and preventive treatments were investigated from this angle. Overall, the pathogenicity test on healthy tomato, zucchini, and mandarin showed low rot to no symptoms for all PGPR strain culture treatments. Conversely, zucchini pre-treated with PGPR strains B. circulans and B. cereus for 72 h showed no signs of soft rot and remained healthy when in vitro contaminated with phytopathogens (Neisseria cinerea and Pichia anomala). Additionally, the PGPR-Bacillus strains were shown to be effective in mitigating the symptoms of soft rot in tomatoes, zucchini, and oranges using in vivo curative treatment. It is true that the majority of pectinolytic phytopathogenic strains exhibited antibiotic resistance. In vivo tests revealed that PGPR-Bacillus cell culture was effective against plant pathogens. Thus, PGPR-Bacillus can be considered a potential biocontrol agent for pectinolytic plant pathogens.
- MeSH
- antibióza * MeSH
- Bacillus * fyziologie MeSH
- biologická kontrola škůdců * metody MeSH
- biologická ochrana * MeSH
- Citrus mikrobiologie růst a vývoj MeSH
- nemoci rostlin * mikrobiologie prevence a kontrola MeSH
- pektiny metabolismus MeSH
- půdní mikrobiologie MeSH
- Solanum lycopersicum mikrobiologie růst a vývoj MeSH
- vývoj rostlin MeSH
- Publikační typ
- časopisecké články MeSH
Apple replant disease (ARD) is a significant factor restricting the healthy development of the apple industry. Biological control is an important and sustainable method for mitigating ARD. In this study, a strain of Paenibacillus polymyxa GRY-11 was isolated and screened from the rhizosphere soil of healthy apple trees in old apple orchards in Shandong Province, China, and the effects of strain GRY-11 on soil microbial community and ARD were studied. The result showed that P. polymyxa GRY-11 could effectively inhibit the growth of the main pathogenic fungi that caused ARD, and the inhibition rates of the strain against Fusarium moniliforme, Fusarium proliferatum, Fusarium solani, and Fusarium oxysporum were 80.00%, 71.60%, 75.00%, and 70.00%, respectively. In addition, the fermentation supernatant played an active role in suppressing the growth of pathogenic fungi. The results of the pot experiment showed that the bacterial fertilizer of the GRY-11 promoted the growth of Malus hupehensis seedlings, improved the activity of protective enzymes in plant roots, enhanced the soil enzyme content, and optimized the soil microbial environment. In general, the GRY-11 can be used as an effective microbial preparation to alleviate ARD. Our study offers novel perspectives for the prevention of ARD.
- MeSH
- antibióza MeSH
- biologická kontrola škůdců * MeSH
- biologická ochrana * MeSH
- Fusarium růst a vývoj MeSH
- houby růst a vývoj MeSH
- kořeny rostlin mikrobiologie MeSH
- Malus * mikrobiologie růst a vývoj MeSH
- nemoci rostlin * mikrobiologie prevence a kontrola MeSH
- Paenibacillus polymyxa * izolace a purifikace fyziologie genetika klasifikace MeSH
- půdní mikrobiologie MeSH
- rhizosféra MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Čína MeSH
Present study was aimed to develop an efficient microbial consortium for combating Alternaria blight disease in cumin. The research involved isolating biocontrol agents against Alternaria burnsii, characterizing their biocontrol and growth promotion traits, and assessing compatibility. A pot experiment was conducted during rabi season of 2022-2023 to evaluate the bioefficacy of four biocontrol agents (1F, 16B, 31B, and 223B) individually and in consortium, focusing on disease severity, plant growth promotion, and defense responses in cumin challenged with A. burnsii. Microbial isolates 1F, 16B, 31B, and 223B significantly inhibited A. burnsii growth in dual plate assays (~ 86%), displaying promising biocontrol and plant growth promotion activities. They were identified as Trichoderma afroharzianum 1F, Aneurinibacillus aneurinilyticus 16B, Pseudomonas lalkuanensis 31B, and Bacillus licheniformis 223B, respectively. The excellent compatibility was observed among all selected biocontrol agents. Cumin plants treated with consortia of 1F + 16B + 31B + 223B showed least percent disease index (32.47%) and highest percent disease control (64.87%). Consortia of biocontrol agents significantly enhanced production of secondary metabolites (total phenol, flavonoids, antioxidant, and tannin) and activation of antioxidant-defense enzymes (POX, PPOX, CAT, SOD, PAL, and TAL) compared to individual biocontrol treatment and infected control. Moreover, consortium treatments effectively reduced electrolyte leakage over the individual biocontrol agent and infected control treatment. The four-microbe consortium significantly enhanced chlorophyll (154%), carotenoid content (88%), plant height (78.77%), dry weight (72.81%), and seed yield (104%) compared to infected control. Based on these findings, this environmentally friendly four-microbe consortium may be recommended for managing Alternaria blight in cumin.
Hormón grelín bol objavený pomerne nedávno (r. 1999). Dnes ho vnímame najmä ako jeden z dôležitých regulátorov príjmu potravy. Okrem svojej primárnej funkcie (zvyšovanie hladiny rastového hormónu) je výrazne pleiotropný: navodzuje pocit hladu, resp. chuti do jedla, participuje na vnímaní chutí, organizmus pripravuje na príjem potravy (zvyšuje motilitu a sekréciu žalúdka), má mnohé metabolické účinky – znižuje sekréciu inzulínu, brzdí lipolýzu, indukuje lipogenézu atď. Biologický polčas grelínu je krátky, preto v prípade liečebného používania prichádzajú do úvahy skôr jeho syntetické analógy – agonisty. Aktuálne sa grelín, jeho agonisty ani antagonisty v liečbe rutinne nepoužívajú (okrem anamorelínu – analógu grelínu v Japonsku), hoci s nimi prebiehajú klinické štúdie. Na základe už existujúcich poznatkov sa dá odôvodnene predpokladať, že by mohli byť efektívne pri liečbe viacerých významných patológií, ako sú sarkopénia, kachexia, obezita, Alzheimerova a Parkinsonova choroba, koronárna artériová a chronická obličková choroba a ďalšie patologické stavy s vysokou prevalenciou v séniu. V našom písomníctve zatiaľ neboli publikované informácie, ktoré by sa špecifickejšie týkali vzťahu grelínu a veku. V tomto článku ponúkame jeden z možných pohľadov na túto oblasť.
The hormone ghrelin was discovered relatively recently (in 1999). Today, we perceive it mainly as one of the important regulators of food intake. In addition to its primary function (increasing the level of growth hormone), it is significantly pleiotropic: it induces a feeling of hunger, or rather appetite, participates in the perception of tastes, prepares the body for food intake (increases motility and secretion of the stomach), has many metabolic effects – reduces insulin secretion, inhibits lipolysis, induces lipogenesis, etc. The biological half-life of ghrelin is short, therefore, in the case of therapeutic use, its synthetic analogues – agonists are more likely to be considered. Currently, ghrelin, its agonists or antagonists are not routinely used in treatment (except for anamorelin – a ghrelin analogue in Japan), although clinical trials are underway with them. Based on existing knowledge, it can be reasonably assumed that they could be effective in the treatment of several important pathologies, such as sarcopenia, cachexia, obesity, Alzheimer’s and Parkinson’s diseases, coronary artery and chronic kidney disease and other pathological conditions with a high prevalence in elderly. In our literature, there has not yet been published information that would specifically relate to the relationship between ghrelin and age. In this article, we offer one possible insight into this area.
Plicní arteriální hypertenze (PAH) je vzácné, ale závažné onemocnění, které je nevyléčitelné a progredující. I přes pokrok ve farmakologické léčbě PAH je morbidita i mortalita nemocných s PAH nadále vysoká. Jedním z nových léků, který mění prognózu nemocných, je sotatercept. Tento lék inhibuje signální dráhu transformujícího růstového faktoru β (transforming growth factor β, TGF-β), což vede k ovlivnění regulace růstu a diferenciace buněk plicních arteriol. Tento lék může zásadním způsobem pozitivně ovlivnit nejen symptomy, ale i celkovou mortalitu nemocných. Výsledky studií STELLAR a ZENITH ukázaly, že sotatercept významně zlepšuje vzdálenost, kterou jedinec ujde při šestiminutovém testu chůzí (six-minute walk test, 6MWT), snižuje riziko klinického zhoršení PAH a má pozitivní vliv na hemodynamiku PAH. Na základě provedených studií došlo k změně v léčebném schématu nemocných s PAH, kde sotatercept hraje významnou roli v kombinační farmakologické terapii.
Pulmonary arterial hypertension (PAH) is a rare but serious disease that is incurable and progressive. Despite advances in the pharmacological treatment of PAH, morbidity and mortality in PAH remain high One new drug that is changing the prognosis of patients is sotatercept. This drug inhibits the transforming growth factor β (TGFβ) signaling pathway, leading to an effect on the regulation of growth and differentiation of pulmonary arteriolar cells. This drug can have a major positive impact not only on symptoms but also on overall mortality. The results of the STELLAR and ZENITH trials showed that sotatercept improves the distance an individual walks in a six-minute walk test (6MWT), reduces the risk of clinical worsening of PAH and has a positive effect on the hemodynamics of PAH. Based on the studies conducted, there has been a change in the treatment regimen of PAH patients, with sotatercept playing a significant role in combination therapy.
A new group of potent histone deacetylase inhibitors (HDACis) capable of inhibiting cell growth and affecting cell-cycle progression in Tohoku Hospital Pediatrics-1 (THP-1) monocytic leukaemia cells was synthesized. The inhibitors belong to a series of hydroxamic acid derivatives. We designed and synthesized a series of 22 N-hydroxycinnamamide derivatives, out of which 20 are new compounds. These compounds contain various substituted anilides as the surface recognition moiety (SRM), a p-hydroxycinnamate linker, and hydroxamic acids as the zinc-binding group (ZBG). The whole series of synthesized hydroxamic acids inhibited THP-1 cell proliferation. Compounds 7d and 7p, which belong to the category of derivatives with the most potent antiproliferative properties, exert a similar effect on cell-cycle progression as vorinostat and induce apoptosis in THP-1 cells. Furthermore, compounds 7d and 7p were demonstrated to inhibit HDAC class I and II in THP-1 cells with comparable potency to vorinostat and increase acetylation of histones H2a, H2b, H3, and H4. Molecular modelling was used to predict the probable binding mode of the studied HDACis in class I and II histone deacetylases in terms of Zn2+ ion chelation by the hydroxamate group.
- MeSH
- apoptóza * účinky léků MeSH
- buněčný cyklus účinky léků MeSH
- histondeacetylasy metabolismus MeSH
- inhibitory histondeacetylas * farmakologie chemická syntéza chemie MeSH
- kyseliny hydroxamové * farmakologie chemická syntéza chemie MeSH
- kyseliny kumarové * farmakologie chemie chemická syntéza MeSH
- lidé MeSH
- molekulární struktura MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- protinádorové látky * farmakologie chemická syntéza chemie MeSH
- screeningové testy protinádorových léčiv MeSH
- simulace molekulového dockingu MeSH
- THP-1 buňky MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and Burkholderia cenocepacia are considered emerging pathogens classified as a public health problem due to extensive antimicrobial resistance. Therefore, the discovery of new therapeutic strategies has become crucial. This study aimed to evaluate the antimicrobial activity of gallic acid and methyl gallate against non-fermenting bacteria. The study included five clinical isolates of Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and Burkholderia cenocepacia. The minimum inhibitory concentrations of gallic acid and methyl gallate were determined by the broth microdilution method. Growth curves, metabolic activity, and biofilm formation of each bacterial strain in the presence or absence of phenolic compounds were performed. Finally, the therapeutic efficacy of the compounds was evaluated using an in vivo model. Gallic acid and methyl gallate showed antibacterial activity against bacterial strains in a concentration range of 64 to 256 μg/mL, both compounds reduced bacterial growth and metabolic activity of the strains, even at subinhibitory concentrations. Only, methyl gallate exhibited activity to inhibit the formation of bacterial biofilms. Moreover, gallic acid and methyl gallate increased larval survival by up to 60% compared to 30% survival of untreated larvae in a bacterial infection model in Galleria mellonella. Our results highlight the potential of gallic acid and methyl gallate as therapeutic alternatives for infections by emerging non-fermentative bacteria.
