Multipotent antioxidant
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Alzheimer's disease is debilitating neurodegenerative disorder in the elderly. Current therapy relies on administration of acetylcholinesterase inhibitors (AChEIs) -donepezil, rivastigmine, galantamine, and N-methyl-d-aspartate receptor antagonist memantine. However, their therapeutic effect is only short-term and stabilizes cognitive functions for up to 2 years. Given this drawback together with other pathological hallmarks of the disease taken into consideration, novel approaches have recently emerged to better cope with AD onset or its progression. One such strategy implies broadening the biological profile of AChEIs into so-called multi-target directed ligands (MTDLs). In this review article, we made comprehensive literature survey emphasising on donepezil template which was structurally converted into plethora of MTLDs preserving anti-cholinesterase effect and, at the same time, escalating the anti-oxidant potential, which was reported as a crucial role in the pathogenesis of the Alzheimer's disease.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- Alzheimerova nemoc farmakoterapie metabolismus MeSH
- antioxidancia chemie farmakologie MeSH
- cholinesterasové inhibitory chemie farmakologie MeSH
- indany chemie farmakologie MeSH
- lidé MeSH
- molekulární struktura MeSH
- piperidiny chemie farmakologie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
A novel series of 6-chlorotacrine-scutellarin hybrids was designed, synthesized and the biological activity as potential anti-Alzheimer's agents was assessed. Their inhibitory activity towards human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE), antioxidant activity, ability to cross the blood-brain barrier (BBB) and hepatotoxic profile were evaluated in vitro. Among these compounds, hybridK1383, bearing two methylene tether between two basic scaffolds, was found to be very potenthAChE inhibitor (IC50= 1.63 nM). Unfortunately, none of the hybrids displayed any antioxidant activity (EC50≥ 500 μM). Preliminary data also suggests a comparable hepatotoxic profile with 6-Cl-THA (established on a HepG2 cell line). Kinetic studies performed onhAChE with the most active compound in the study,K1383, pointed out to a mixed, non-competitive enzyme inhibition. These findings were further corroborated by docking studies.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- aktivace enzymů účinky léků MeSH
- Alzheimerova nemoc enzymologie MeSH
- apigenin chemie MeSH
- butyrylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory chemická syntéza chemie farmakologie MeSH
- glukuronáty chemie MeSH
- hematoencefalická bariéra metabolismus MeSH
- lidé MeSH
- racionální návrh léčiv MeSH
- simulace molekulového dockingu MeSH
- takrin analogy a deriváty chemie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The aim of this study was to examine whether mesenchymal stem cells (MSCs) and/or corneal limbal epithelial stem cells (LSCs) influence restoration of an antioxidant protective mechanism in the corneal epithelium and renewal of corneal optical properties changed after alkali burns. The injured rabbit corneas (with 0.25 N NaOH) were untreated or treated with nanofiber scaffolds free of stem cells, with nanofiber scaffolds seeded with bone marrow MSCs (BM-MSCs), with adipose tissue MSCs (Ad-MSCs), or with LSCs. On day 15 following the injury, after BM-MSCs or LSCs nanofiber treatment (less after Ad-MSCs treatment) the expression of antioxidant enzymes was restored in the regenerated corneal epithelium and the expressions of matrix metalloproteinase 9 (MMP9), inducible nitric oxide synthase (iNOS), α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), and vascular endothelial factor (VEGF) were low. The central corneal thickness (taken as an index of corneal hydration) increased after the injury and returned to levels before the injury. In injured untreated corneas the epithelium was absent and numerous cells revealed the expressions of iNOS, MMP9, α-SMA, TGF-β1, and VEGF. In conclusion, stem cell treatment accelerated regeneration of the corneal epithelium, restored the antioxidant protective mechanism, and renewed corneal optical properties.
- MeSH
- alkálie MeSH
- antioxidancia terapeutické užití MeSH
- buněčná diferenciace účinky léků MeSH
- chemické popálení enzymologie genetika patologie terapie MeSH
- imunohistochemie MeSH
- králíci MeSH
- limbus corneae cytologie MeSH
- matrixová metaloproteinasa 9 metabolismus MeSH
- mezenchymální kmenové buňky cytologie účinky léků MeSH
- ochranné látky farmakologie terapeutické užití MeSH
- pachymetrie rohovky MeSH
- regulace genové exprese účinky léků MeSH
- rohovkový epitel patologie MeSH
- superoxiddismutasa metabolismus MeSH
- synthasa oxidu dusnatého, typ II metabolismus MeSH
- transformující růstový faktor beta genetika metabolismus MeSH
- transplantace mezenchymálních kmenových buněk * MeSH
- tukové buňky cytologie účinky léků MeSH
- vaskulární endoteliální růstový faktor A metabolismus MeSH
- zákal rohovky komplikace terapie MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A series of antioxidants was designed and synthesized based on conjugation of the hepatoprotective flavonolignan silybin with l-ascorbic acid, trolox alcohol or tyrosol via a C12 aliphatic linker. These hybrid molecules were prepared from 12-vinyl dodecanedioate-23-O-silybin using the enzymatic regioselective acylation procedure with Novozym 435 (lipase B) or with lipase PS. Voltammetric analyses showed that the silybin-ascorbic acid conjugate exhibited excellent electron donating ability, in comparison to the other conjugates. Free radical scavenging, antioxidant activities and cytoprotective action were evaluated. The silybin-ascorbic acid hybrid exhibited the best activities (IC50 = 30.2 μM) in terms of lipid peroxidation inhibition. The promising protective action of the conjugate against lipid peroxidation can be attributed to modulated electron transfer abilities of both the silybin and ascorbate moieties, but also to the hydrophobic C12 linker facilitating membrane insertion. This was supported experimentally and theoretically by density functional theory (DFT) and molecular dynamics (MD) calculations. The results presented here can be used in the further development of novel multipotent antioxidants and cytoprotective agents, in particular for substances acting at an aqueous/lipid interface.
- MeSH
- antioxidancia chemie metabolismus farmakologie MeSH
- buněčná membrána metabolismus MeSH
- buňky Hep G2 MeSH
- cytoprotekce účinky léků MeSH
- flavonolignany chemie metabolismus farmakologie MeSH
- játra cytologie účinky léků metabolismus MeSH
- lidé MeSH
- lipasa metabolismus MeSH
- molekulární konformace MeSH
- peroxidace lipidů účinky léků MeSH
- silymarin chemie MeSH
- simulace molekulární dynamiky MeSH
- transport elektronů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Melatonin představuje klíčový hormon produkovaný epifýzou, který je intenzivně zkoumán ve vztahu k neurodegenerativním onemocněním v posledních letech. Kritický je zejména úbytek jeho hladiny ve stáří. Data z klinických studií ukazují na jeho pozitivní vlastnosti ve vztahu ke kvalitě spánku, protizánětlivý a antioxidační potenciál, hojně jsou rovněž diskutovány jeho neuroprotektivní vlastnosti. Předkládaná práce shrnuje poznatky základního výzkumu z oblasti medicinální chemie melatoninu. Zvláštní důraz je kladen na deriváty tohoto hormonu, které cílí na řadu patologických mechanismů neurodegenerativních chorob současně.
Melatonin is a key regulatory hormone produced mainly in the pineal gland. In the recent years, melatonin contribution to neurodegenerative disorders has dramatically increased when inspecting its favorable pharmacological profile. Its levels were found to be decreased during aging. Data from clinical studies point out to its positive outcome not only in improving the quality of sleep but it also exerts anti-inflammatory and antioxidant profile. Moreover, it was found as an effective neuroprotective agent. Current study summarizes the experimental data from basic research of medicinal chemistry field devoted to melatonin. Particular emphasis is directed toward melatonin derivatives with multipotent profile affecting concomitantly several pathological hallmarks of the neurodegenerative disorders.
- MeSH
- acetylcholinesterasa MeSH
- Alzheimerova nemoc farmakoterapie MeSH
- antioxidancia MeSH
- kurkumin terapeutické užití MeSH
- lidé MeSH
- melatonin * fyziologie terapeutické užití MeSH
- neurodegenerativní nemoci * farmakoterapie MeSH
- stárnutí MeSH
- techniky in vitro MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
The search for novel drugs to address the medical needs of Alzheimer's disease (AD) is an ongoing process relying on the discovery of disease-modifying agents. Given the complexity of the disease, such an aim can be pursued by developing so-called multi-target directed ligands (MTDLs) that will impact the disease pathophysiology more comprehensively. Herewith, we contemplated the therapeutic efficacy of an amiridine drug acting as a cholinesterase inhibitor by converting it into a novel class of novel MTDLs. Applying the linking approach, we have paired amiridine as a core building block with memantine/adamantylamine, trolox, and substituted benzothiazole moieties to generate novel MTDLs endowed with additional properties like N-methyl-d-aspartate (NMDA) receptor affinity, antioxidant capacity, and anti-amyloid properties, respectively. The top-ranked amiridine-based compound 5d was also inspected by in silico to reveal the butyrylcholinesterase binding differences with its close structural analogue 5b. Our study provides insight into the discovery of novel amiridine-based drugs by broadening their target-engaged profile from cholinesterase inhibitors towards MTDLs with potential implications in AD therapy.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- Alzheimerova nemoc * farmakoterapie metabolismus MeSH
- aminochinoliny terapeutické užití MeSH
- butyrylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory * farmakologie terapeutické užití chemie MeSH
- lidé MeSH
- ligandy MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The purpose of this study was to investigate whether rabbit bone marrow-derived mesenchymal stem cells (MSCs) effectively decrease alkali-induced oxidative stress in the rabbit cornea. The alkali (0.15 N NaOH) was applied on the corneas of the right eyes and then rinsed with tap water. In the first group of rabbits the injured corneas remained untreated. In the second group MSCs were applied on the injured corneal surface immediately after the injury and eyelids sutured for two days. Then the sutures were removed. In the third group nanofiber scaffolds seeded with MSCs (and in the fourth group nanofibers alone) were transferred onto the corneas immediately after the injury and the eyelids sutured. Two days later the eyelid sutures were removed together with the nanofiber scaffolds. The rabbits were sacrificed on days four, ten or fifteen after the injury, and the corneas were examined immunohistochemically, morphologically, for the central corneal thickness (taken as an index of corneal hydration) using an ultrasonic pachymeter and by real-time PCR. Results show that in untreated injured corneas the expression of malondialdehyde (MDA) and nitrotyrosine (NT) (important markers of lipid peroxidation and oxidative stress) appeared in the epithelium. The antioxidant aldehyde dehydrogenase 3A1 (ALDH3A1) decreased in the corneal epithelium, particularly in superficial parts, where apoptotic cell death (detected by active caspase-3) was high. (In control corneal epithelium MDA and NT are absent and ALDH3A1 highly present in all layers of the epithelium. Cell apoptosis are sporadic). In injured untreated cornea further corneal disturbances developed: The expressions of matrix metalloproteinase 9 (MMP9) and proinflammatory cytokines, were high. At the end of experiment (on day 15) the injured untreated corneas were vascularized and numerous inflammatory cells were present in the corneal stroma. Vascular endothelial growth factor (VEGF) expression and number of macrophages were high. The results obtained in injured corneas covered with nanofiber scaffolds alone (without MSCs) or in injured corneas treated with MSCs only (transferred without scaffolds) did not significantly differ from the results found in untreated injured corneas. In contrast, in the injured corneas treated with MSCs on nanofiber scaffolds, ALDH3A1 expression remained high in the epithelium (as in the control cornea) and positive expression of the other immunohistochemical markers employed was very low (MMP9) or absent (NT, MDA, proinflammatory cytokines), also similarly as in the control cornea. Corneal neovascularization and the infiltration of the corneal stroma with inflammatory cells were significantly suppressed in the injured corneas treated with MSCs compared to the untreated injured ones. The increased central corneal thickness together with corneal opalescency appearing after alkali injury returned to normal levels over the course of ten days only in the injured corneas treated with MSCs on nanofiber scaffolds. The expression of genes for the proinflammatory cytokines corresponded with their immunohistochemical expression. In conclusion, MSCs on nanofiber scaffolds protected the formation of toxic peroxynitrite (detected by NT residues), lowered apoptotic cell death and decreased matrix metalloproteinase and pro-inflammatory cytokine production. This resulted in reduced corneal inflammation as well as neovascularization and significantly accelerated corneal healing.
- MeSH
- alkálie toxicita MeSH
- chemické popálení patologie chirurgie MeSH
- hojení ran MeSH
- králíci MeSH
- mezenchymální kmenové buňky cytologie MeSH
- modely nemocí na zvířatech MeSH
- nanovlákna terapeutické užití MeSH
- oxidační stres * MeSH
- poranění rohovky MeSH
- rohovka patologie chirurgie MeSH
- tkáňové podpůrné struktury * MeSH
- transplantace mezenchymálních kmenových buněk metody MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
Ischemic diseases are characterized by reduced blood supply to a tissue or an organ due to obstruction of blood vessels. The most serious and most common ischemic diseases include ischemic heart disease, ischemic stroke, and critical limb ischemia. Revascularization is the first choice of therapy, but the cell therapy is being introduced as a possible way of treatment for no-option patients. One of the possibilities of cell therapy is the use of mesenchymal stem cells (MSCs). MSCs are easily isolated from bone marrow and can be defined as non-hematopoietic multipotent adult stem cells population with a defined capacity for self-renewal and differentiation into cell types of all three germ layers depending on their origin. Since 1974, when Friedenstein and coworkers (Friedenstein et al. 1974) first time isolated and characterized MSCs, MSC-based therapy has been shown to be safe and effective. Nevertheless, many scientists and clinical researchers want to improve the success of MSCs in regenerative therapy. The secret of successful cell therapy may lie, along with the homing, in secretion of biologically active molecules including cytokines, growth factors, and chemokines known as MSCs secretome. One of the intracellular signalling mechanism includes the activity of phosphatidylinositol-3-kinase (phosphoinositide 3-kinase) (PI3K) - protein kinase B (serine-threonine protein kinase Akt) (Akt) pathway. This PI3K/Akt pathway plays key roles in many cell types in regulating cell proliferation, differentiation, apoptosis, and migration. Pre-conditioning of MSCs could improve efficacy of signalling mechanism.
- MeSH
- fosfatidylinositol-3-kinasy metabolismus MeSH
- fyziologická neovaskularizace MeSH
- ischemie metabolismus terapie MeSH
- kinázy asociované s rho metabolismus MeSH
- lidé MeSH
- mezenchymální kmenové buňky metabolismus MeSH
- oxid dusnatý metabolismus MeSH
- oxidační stres MeSH
- protoonkogenní proteiny c-akt metabolismus MeSH
- transplantace mezenchymálních kmenových buněk * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
In this study, spherical or hexagonal NaYF4:Yb,Er nanoparticles (UCNPs) with sizes of 25 nm (S-UCNPs) and 120 nm (L-UCNPs) were synthesized by high-temperature coprecipitation and subsequently modified with three kinds of polymers. These included poly(ethylene glycol) (PEG) and poly(N,N-dimethylacrylamide-co-2-aminoethylacrylamide) [P(DMA-AEA)] terminated with an alendronate anchoring group, and poly(methyl vinyl ether-co-maleic acid) (PMVEMA). The internalization of nanoparticles by rat mesenchymal stem cells (rMSCs) and C6 cancer cells (rat glial tumor cell line) was visualized by electron microscopy and the cytotoxicity of the UCNPs and their leaches was measured by the real-time proliferation assay. The comet assay was used to determine the oxidative damage of the UCNPs. An in vivo study on mice determined the elimination route and potential accumulation of UCNPs in the body. The results showed that the L- and S-UCNPs were internalized into cells in the lumen of endosomes. The proliferation assay revealed that the L-UCNPs were less toxic than S-UCNPs. The viability of rMSCs incubated with particles decreased in the order S-UCNP@Ale-(PDMA-AEA) > S-UCNP@Ale-PEG > S-UCNPs > S-UCNP@PMVEMA. Similar results were obtained in C6 cells. The oxidative damage measured by the comet assay showed that neat L-UCNPs caused more oxidative damage to rMSCs than all coated UCNPs while no difference was observed in C6 cells. An in vivo study indicated that L-UCNPs were eliminated from the body via the hepatobiliary route; L-UCNP@Ale-PEG particles were almost eliminated from the liver 96 h after intravenous application. Pilot fluorescence imaging confirmed the limited in vivo detection capabilities of the nanoparticles.
- MeSH
- krysa rodu rattus MeSH
- mezenchymální kmenové buňky * metabolismus účinky léků cytologie MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nanočástice chemie MeSH
- oxidační stres účinky léků MeSH
- polyethylenglykoly chemie MeSH
- velikost částic MeSH
- viabilita buněk účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Protective effects of electromagnetic fields (EMFs) against oxygen and glucose deprivation (OGD)-induced human mesenchymal stem cell (MSC) death were studied. Cell survival, intracellular calcium and ROS/RNS levels were measured after culturing MSCs for 3 h under OGD with or without EMF exposure. The survival rate of cells cultured under OGD condition was significantly reduced compared to control cells, while cells cultured in OGD with 10 Hz/1 mT EMF exposure had higher survival ratio than that in equivalent non-exposed cells. This protective effect of EMF was not observed at different frequency/intensity combinations such as 10 Hz/0.01 mT, 10 Hz/0.1 mT, 50 Hz/1 mT and 100 Hz/1 mT. ROS/RNS levels of cells cultured under OGD conditions significantly increased compared to the control level while 10 Hz/1 mT EMF alleviated this effect. Intracellular calcium levels in OGD group were higher than control while those in OGD plus 10 Hz/1 mT EMF group were significantly lower than OGD group. Addition of Ca2+ chelator promoted protective effects of EMF against OGD-induced MSC death. Our results suggest that 10 Hz/1 mT EMF exposure protects MSCs from OGD-induced cell death and the underlying mechanisms of the protection are reduction of intracellular levels of Ca2+ and ROS/RNS.
- MeSH
- buněčná smrt účinky záření MeSH
- elektromagnetická pole * MeSH
- mezenchymální kmenové buňky metabolismus patologie MeSH
- oxidační stres MeSH
- reaktivní formy dusíku škodlivé účinky MeSH
- reaktivní formy kyslíku škodlivé účinky MeSH
- techniky in vitro MeSH
- vápníkové kanály MeSH
- Publikační typ
- práce podpořená grantem MeSH