Guanine-rich sequences can form G-quadruplexes (G4) in living cells, making these structures promising anti-cancer targets. Compounds able to recognize these structures have been investigated as potential anticancer drugs; however, no G4 binder has yet been approved in the clinic. Here, we describe G4 ligands structure-activity relationships, in vivo effects as well as clinical trials. Addressing G4 ligand characteristics, targeting challenges, and structure-activity relationships, this review provides insights into the development of potent and selective G4-targeting molecules for therapeutic applications.
- MeSH
- antitumorózní látky * farmakologie terapeutické užití MeSH
- G-kvadruplexy * MeSH
- lidé MeSH
- ligandy MeSH
- nádory * farmakoterapie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
AIMS: Neuroinflammation is a prominent hallmark in several neurodegenerative diseases (NDs). Halting neuroinflammation can slow down the progression of NDs. Improving the efficacy of clinically available non-steroidal anti-inflammatory drugs (NSAIDs) is a promising approach that may lead to fast-track and effective disease-modifying therapies for NDs. Here, we aimed to utilize the L-type amino acid transporter 1 (LAT1) to improve the efficacy of salicylic acid as an example of an NSAID prodrug, for which brain uptake and intracellular localization have been reported earlier. MAIN METHODS: Firstly, we confirmed the improved LAT1 utilization of the salicylic acid prodrug (SA-AA) in freshly isolated primary mouse microglial cells. Secondly, we performed behavioural rotarod, open field, and four-limb hanging tests in mice, and a whole-brain proteome analysis. KEY FINDINGS: The SA-AA prodrug alleviated the lipopolysaccharide (LPS)-induced inflammation in the rotarod and hanging tests. The proteome analysis indicated decreased neuroinflammation at the molecular level. We identified 399 proteins linked to neuroinflammation out of 7416 proteins detected in the mouse brain. Among them, Gps2, Vamp8, Slc6a3, Slc18a2, Slc5a7, Rgs9, Lrrc1, Ppp1r1b, Gnal, and Adcy5/6 were associated with the drug's effects. The SA-AA prodrug attenuated the LPS-induced neuroinflammation through the regulation of critical pathways of neuroinflammation such as the cellular response to stress and transmission across chemical synapses. SIGNIFICANCE: The efficacy of NSAIDs can be improved via the utilization of LAT1 and repurposed for the treatment of neuroinflammation. This improved brain delivery and microglia localisation can be applied to other inflammatory modulators to achieve effective and targeted CNS therapies.
- MeSH
- antiflogistika nesteroidní * farmakologie MeSH
- intracelulární signální peptidy a proteiny metabolismus MeSH
- kyselina salicylová farmakologie MeSH
- lipopolysacharidy MeSH
- mikroglie metabolismus MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- neurodegenerativní nemoci * metabolismus MeSH
- neurozánětlivé nemoci * farmakoterapie MeSH
- prekurzory léčiv * farmakologie MeSH
- proteom metabolismus MeSH
- zánět farmakoterapie metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
AIM: We aimed to determine whether the sodium/glucose cotransporter family member SGLT3, a proposed glucose sensor, is expressed in the intestine and/or kidney, and if its expression is altered in mouse models of obesity and in humans before and after weight-loss surgery. MAIN METHODS: We used in-situ hybridization and quantitative PCR to determine whether the Sglt3 isoforms 3a and 3b were expressed in the intestine and kidney of C57, leptin-deficient ob/ob, and diabetic BTBR ob/ob mice. Western blotting and immunohistochemistry were also used to assess SGLT3 protein levels in jejunal biopsies from obese patients before and after weight-loss Roux-en-Y gastric bypass surgery (RYGB), and in lean healthy controls. KEY FINDINGS: Sglt3a/3b mRNA was detected in the small intestine (duodenum, jejunum and ileum), but not in the large intestine or kidneys of mice. Both isoforms were detected in epithelial cells (confirmed using intestinal organoids). Expression of Sglt3a/3b mRNA in duodenum and jejunum was significantly lower in ob/ob and BTBR ob/ob mice than in normal-weight littermates. Jejunal SGLT3 protein levels in aged obese patients before RYGB were lower than in lean individuals, but substantially upregulated 6 months post-RYGB. SIGNIFICANCE: Our study shows that Sglt3a/3b is expressed primarily in epithelial cells of the small intestine in mice. Furthermore, we observed an association between intestinal mRNA Sglt3a/3b expression and obesity in mice, and between jejunal SGLT3 protein levels and obesity in humans. Further studies are required to determine the possible role of SGLT3 in obesity.
- MeSH
- dospělí MeSH
- down regulace MeSH
- exprese genu MeSH
- hmotnostní úbytek MeSH
- inzulin metabolismus MeSH
- inzulinová rezistence MeSH
- jejunum metabolismus MeSH
- leptin nedostatek metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- messenger RNA genetika metabolismus MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- obezita genetika metabolismus MeSH
- protein - isoformy MeSH
- střevní sliznice metabolismus MeSH
- tenké střevo metabolismus MeSH
- transkriptom MeSH
- transportní proteiny pro sodík a glukosu biosyntéza genetika metabolismus MeSH
- žaludeční bypass MeSH
- zvířata MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
AIMS: This study aimed to explore the antioxidant properties and neuroprotective effects of Esc-1GN. MAIN METHODS: FRAP assay and ABTS, DPPH, and NO radicals radical scavenging assays were performed to investigated the Antioxidant activities of Esc-1GN in vitro. Hydrogen peroxide (H2O2)-induced cell damage model was used to determine the neuroprotective effects of Esc-1GN. Carrageenan-injected inflamed paw model was performed to analysis the antioxidant and anti-inflammatory properties of Esc-1GN in vivo. KEY FINDINGS: Esc-1GN scavenged the ABTS, DPPH, and NO radicals and reduced Fe3+ in a concentration-dependent manner. Moreover, Esc-1GN exhibited neuroprotective activity by decreasing malondialdehyde and reactive oxygen species accumulation, restoring endogenous antioxidant enzyme activity, and inhibiting H2O2-induced cell cycle arrest and apoptosis in PC12 cells. Esc-1GN significantly reversed the dysregulation of MAPK, AKT and NF-κB signaling caused by H2O2. In vivo, Esc-1GN decreased MDA, COX-2, NO, TNF-α, IL-6, and Il-1β levels and increased SOD, CAT activity and GSH level in carrageenan-injected inflamed paw tissues. SIGNIFICANCE: These findings suggest that Esc-1GN might serve as a potential antioxidant agent with therapeutic potential in human neurodegenerative diseases.
AIMS: To elucidate the role of alveolar macrophages (AM) in the pathogenesis of hypoxic pulmonary hypertension (HPH), we tested the effects of sustained hypoxia on AM polarization and on the formation of superoxide by AM in vivo and in vitro. MAIN METHODS: Rat AM were obtained by bronchoalveolar lavage. 4-day exposure to hypoxia (10% O2) was carried out in vivo (rats in isobaric hypoxic chamber, controls kept in air) or in vitro (control AM in 21% O2 and 5% CO2). Superoxide production was measured by luminol-orthovanadate chemiluminescence, AM polarization was detected immunocytochemically. To ascertain the effect of substances contained in the alveolar environment, we cultivated cells also in the presence of non-cellular components of the bronchoalveolar lavage fluid (BALF) either from controls or from rats exposed to 4 days of hypoxia. KEY FINDINGS: In vivo, but not in vitro, hypoxia increased AM superoxide production. Both types of hypoxia polarized AM into M2 (pro-proliferative) type. While the presence of control BALF attenuated superoxide production in AM cultivated in normoxia, BALF from the hypoxia-exposed rats had no effect. In AM cultivated in hypoxia, superoxide production was not altered by control BALF and elevated by BALF obtained from hypoxic rats. SIGNIFICANCE: Hypoxia does not influence superoxide production by AM directly but rather by modulating their milieu and their sensitivity to external influences.
- MeSH
- alveolární makrofágy metabolismus patologie MeSH
- bronchoalveolární lavážní tekutina chemie MeSH
- hypoxie patofyziologie MeSH
- krysa rodu rattus MeSH
- kultivované buňky MeSH
- potkani Wistar MeSH
- superoxidy metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
AIMS: Increased plasma soluble endoglin concentrations (sEng) are frequently detected in metabolic disorders accompanied with hypercholesterolemia in serum, but effect of sEng on the cholesterol biochemistry is unknown. Cholesterol and bile acids (BA) are important products of liver metabolism with numerous functions within the organism. Turnover of these substances requires precise regulation due to potential toxicities during their cumulation. In this study, we hypothesized that high sEng levels affect cholesterol homeostasis and BA turnover in mice liver. MAIN METHODS: Nine-month-old transgenic male mice overexpressing human sEng and wild-type mice underwent plasma, bile, stool, and organ samples analysis by analytical, qRT-PCT and Western blot methods. KEY FINDINGS: sEng mice demonstrated decreased plasma total and LDL cholesterol concentrations due to upregulation of hepatic Sr-b1 and Ldlr receptors, increased liver cholesterol content, and increased Abcg8-mediated cholesterol efflux into bile. sEng also increased conversion of cholesterol into bile acids (BA) via upregulation of Cyp7a1 and increased Mdr1 expression. Plasma concentrations of BA were increased in sEng mice due to their enhanced reabsorption via ileum. Increased hepatic disposition of BA led to their increased biliary excretion coupled with choleretic activity. SIGNIFICANCE: For the first time, we have shown that high sEng plasma levels affect cholesterol and BA homeostasis on the basis of complex liver and intestinal effects. The significance of these findings for pathophysiology of diseases associated with increased sEng concentrations remains to be elucidated in prospective studies.
- MeSH
- cholesterol krev metabolismus MeSH
- endoglin krev fyziologie MeSH
- feces MeSH
- homeostáza * MeSH
- játra metabolismus MeSH
- myši transgenní MeSH
- myši MeSH
- oxidační stres MeSH
- přenašeče organických aniontů závislé na sodíku metabolismus MeSH
- protein SREBP2 metabolismus MeSH
- receptory LDL metabolismus MeSH
- symportéry metabolismus MeSH
- upregulace MeSH
- zánět krev MeSH
- žlučové kyseliny a soli krev metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
AIMS: Neuroinflammatory changes in the central nervous system are widely involved in the initiation and maintenance of neuropathic pain after peripheral nerve injury. The present study investigated how losartan treatment may affect the development of neuropathic pain and neuroinflammation. MAIN METHODS: The effect of losartan treatment on the development of peripheral neuropathy was studied in L5 spinal nerve ligation (SNL) model in rats with systemic (100 mg/kg) or intrathecal (10 μl/ 20 μM solution) application of losartan. Electronic von Frey filament and plantar test were used to determine pain thresholds to mechanical and thermal stimulations. At the 7th post-operative day, CD68-positive cells in DRG and dorsal roots were quantified by immunohistochemistry and western blot analyses were used to compare the expression levels of neuroinflammatory markers in lumbar spinal cord (SC). KEY FINDINGS: Our data confirmed the presence of SNL-evoked heat hyperalgesia and mechanical allodynia. Losartan application blocked the SNL-induced hypersensitivity to thermal stimuli but failed to prevent mechanical allodynia. No significant difference between systemic and i.t. administration of losartan was observed. Immunohistochemistry confirmed the presence of infiltrated macrophages in the ipsilateral DRG that was significantly attenuated with the losartan treatment. Western blot SC tissue analysis revealed that systemic treatment with losartan prevented SNL-induced upregulation of CCR2, TNFα, TNFR1, and OX42 while its effect on CCL2 and AT1R expression was not significant. SIGNIFICANCE: Our results show that losartan treatment attenuates neuroinflammation and neuropathic pain after SNL. These effects of losartan represent an interesting direction for the development of novel treatments of peripheral neuropathy.
- MeSH
- hyperalgezie farmakoterapie prevence a kontrola MeSH
- krysa rodu rattus MeSH
- losartan metabolismus farmakologie MeSH
- měření bolesti metody MeSH
- mícha účinky léků MeSH
- míšní nervy účinky léků MeSH
- modely nemocí na zvířatech MeSH
- neuralgie metabolismus MeSH
- poranění periferního nervu farmakoterapie MeSH
- potkani Wistar MeSH
- práh bolesti účinky léků MeSH
- spinální ganglia účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
AIMS: Haloperidol is an antipsychotic agent and acts as dopamine D2 receptor (D2R) antagonist, as a prototypical ligand of sigma1 receptors (Sig1R) and it increases expression of type 1 IP3 receptors (IP3R1). However, precise mechanism of haloperidol action on cardiomyocytes through dopaminergic signaling was not described yet. This study investigated a role of dopamine receptors in haloperidol-induced increase in IP3R1 and Sig1R, and compared physiological effect of melperone and haloperidol on basic heart parameters in rats. MATERIALS AND METHODS: We used differentiated NG-108 cells and H9c2 cells. Gene expression, Western blot and immunofluorescence were used to evaluate haloperidol-induced differences; proximity ligation assay (PLA) and immunoprecipitation to determine interactions of D1/D2 receptors. To evaluate cardiac parameters, Wistar albino male rats were used. KEY FINDINGS: We have shown that antagonism of D2R with either haloperidol or melperone results in upregulation of both, IP3R1 and Sig1R, which is associated with increased D2R, but reduced D1R expression. Immunofluorescence, immunoprecipitation and PLA support formation of heteromeric D1/D2 complexes in H9c2 cells. Treatment with haloperidol (but not melperone) caused decrease in systolic and diastolic blood pressure and significant increase in heart rate. SIGNIFICANCE: Because D1R/D2R complexes can engage Gq-like signaling in other experimental systems, these results are consistent with the possibility that disruption of D1R/D2R complex in H9c2 cells might cause a decrease in IP3R1 activity, which in turn may account for the increase expression of IP3R and Sig1R. D2R is probably not responsible for changes in cardiac parameters, since melperone did not have any effect.
- MeSH
- antagonisté dopaminu D2 farmakologie MeSH
- antagonisté dopaminu farmakologie MeSH
- buněčné linie MeSH
- haloperidol farmakologie MeSH
- potkani Wistar MeSH
- receptory dopaminu D1 genetika metabolismus MeSH
- receptory dopaminu D2 genetika metabolismus MeSH
- regulace genové exprese účinky léků MeSH
- signální transdukce účinky léků MeSH
- srdce účinky léků MeSH
- srdeční frekvence účinky léků MeSH
- vazba proteinů účinky léků MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
AIMS: Endoglin is a transmembrane glycoprotein, that plays an important role in regulating endothelium. Proteolytic cleavage of membrane endoglin releases soluble endoglin (sEng), whose increased plasma levels have been detected in diseases related to the cardiovascular system. It was proposed that sEng might damage vascular endothelium, but detailed information about the potential mechanisms involved is not available. Thus, we hypothesized that sEng contributes to endothelial dysfunction, leading to a pro-inflammatory phenotype by a possible modulation of the TGF-β and/or inflammatory pathways. MAIN METHODS: Human umbilical vein endothelial cells (HUVECs) and Human embryonic kidney cell line (HEK293T) were treated with different sEng concentration and time in order to reveal possible effect on biomarkers of inflammation and TGF-β signaling. IL6 and NFκB reporter luciferase assays, quantitative real-time PCR analysis, Western blot analysis and immunofluorescence flow cytometry were used. KEY FINDINGS: sEng treatment results in activation of NF-κB/IL-6 expression, increased expression of membrane endoglin and reduced expression of Id-1. On the other hand, no significant effects on other markers of endothelial dysfunction and inflammation, including eNOS, peNOS(S1177), VCAM-1, COX-1, COX-2 and ICAM-1 were detected. SIGNIFICANCE: As a conclusion, sEng treatment resulted in an activation of NF-κB, IL-6, suggesting activation of pro-inflammatory phenotype in endothelial cells. The precise mechanism of this activation and its consequence remains to be elucidated. A combined treatment of sEng with other cardiovascular risk factors will be necessary in order to reveal whether sEng is not only a biomarker of cardiovascular diseases, but also a protagonist of endothelial dysfunction.
- MeSH
- endoglin biosyntéza MeSH
- endoteliální buňky pupečníkové žíly (lidské) metabolismus MeSH
- HEK293 buňky MeSH
- inhibitor diferenciace 1 biosyntéza MeSH
- interleukin-6 biosyntéza MeSH
- lidé MeSH
- NF-kappa B biosyntéza MeSH
- regulace genové exprese * MeSH
- rozpustnost MeSH
- signální transdukce * MeSH
- zánět chemicky indukované metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
AIMS: The goal of our study was to reveal the important mechanism(s) responsible for the enhanced contractility of isolated arteries from animals suffering genetic hypertension. MAIN METHODS: Contractile force of endothelium-denuded arteries, modulated by various interventions, was measured by wire myography. KEY FINDINGS: Spontaneously hypertensive rat (SHR) and Wistar-Kyoto rat (WKY) arteries were stimulated by norepinephrine, increased extracellular K(+) or tyramine. Strain difference was not observed in the contraction elicited by exogenous norepinephrine but SHR arteries responded more to tyramine (causing endogenous norepinephrine release from neuronal varicosities). K(+)-induced contraction was enhanced in SHR arteries, with no involvement of endogenous catecholamines. The α-adrenoceptor blockade lowered tyramine-induced contraction more in SHR arteries; similar effect was achieved by guanethidine-induced sympathectomy. Partial depolarization of WKY arteries by 20mM K(+) enhanced its contraction to SHR level. The blockade of β-adrenoceptors by propranolol or selective β2-antagonist ICI-118,551 induced contraction of SHR endothelium-denuded arteries but was without significant effects on WKY arteries unless they were stimulated with K(+). Both tyramine-induced and propranolol-induced contractions were attenuated by flupirtine and abolished by nifedipine. SIGNIFICANCE: The differences of SHR and WKY arteries were not related to vascular expression of α- and β-adrenoceptors or G-proteins. Enhanced contractility of SHR arteries is related to both increased presence of endogenous norepinephrine in vascular wall and also to altered vascular smooth muscle membrane potential.
- MeSH
- arterie fyziologie MeSH
- draslík metabolismus MeSH
- hypertenze MeSH
- membránové potenciály MeSH
- noradrenalin metabolismus MeSH
- potkani inbrední SHR fyziologie MeSH
- potkani inbrední WKY MeSH
- svalová kontrakce MeSH
- svaly hladké cévní fyziologie MeSH
- tyramin metabolismus MeSH
- vazokonstrikce * MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
