The C-type lectin DC-SIGN expressed on immature dendritic cells is a promising target for antiviral drug development. Previously, we have demonstrated that mono- and divalent C-glycosides based on d-manno and l-fuco configurations are promising DC-SIGN ligands. Here, we described the convergent synthesis of C-glycoside dendrimers decorated with 4, 6, 9, and 12 α-l-fucopyranosyl units and with 9 and 12 α-d-mannopyranosyl units. Their affinity against DC-SIGN was assessed by surface plasmon resonance (SPR) assays. For comparison, parent O-glycosidic dendrimers were synthesized and tested, as well. A clear increase of both affinity and multivalency effect was observed for C-glycomimetics of both types (mannose and fucose). However, when dodecavalent C-glycosidic dendrimers were compared, there was no difference in affinity regarding the sugar unit (l-fuco, IC50 17 μM; d-manno, IC50 12 μM). For the rest of glycodendrimers with l-fucose or d-mannose attached by the O- or C-glycosidic linkage, C-glycosidic dendrimers were significantly more active. These results show that in addition to the expected physiological stability, the biological activity of C-glycoside mimetics is higher in comparison to the corresponding O-glycosides and therefore these glycomimetic multivalent systems represent potentially promising candidates for targeting DC-SIGN.
- MeSH
- biomimetické materiály chemie farmakologie MeSH
- fukosa chemie MeSH
- inhibiční koncentrace 50 MeSH
- lektiny typu C antagonisté a inhibitory MeSH
- mannosa chemie MeSH
- molekuly buněčné adheze antagonisté a inhibitory MeSH
- receptory buněčného povrchu antagonisté a inhibitory MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Interaction of CD200 with its receptor CD200R has an immunoregulatory role and attenuates various types of neuroinflammatory diseases. METHODS: Immunofluorescence staining, western blot analysis, and RT-PCR were used to investigate the modulatory effects of CD200 fusion protein (CD200Fc) on activation of microglia and astrocytes as well as synthesis of pro- (TNF, IL-1β, IL-6) and anti-inflammatory (IL-4, IL-10) cytokines in the L4-L5 spinal cord segments in relation to behavioral signs of neuropathic pain after unilateral sterile chronic constriction injury (sCCI) of the sciatic nerve. Withdrawal thresholds for mechanical hypersensitivity and latencies for thermal hypersensitivity were measured in hind paws 1 day before operation; 1, 3, and 7 days after sCCI operation; and then 5 and 24 h after intrathecal application of artificial cerebrospinal fluid or CD200Fc. RESULTS: Seven days from sCCI operation and 5 h from intrathecal application, CD200Fc reduced mechanical and thermal hypersensitivity when compared with control animals. Simultaneously, CD200Fc attenuated activation of glial cells and decreased proinflammatory and increased anti-inflammatory cytokine messenger RNA (mRNA) levels. Administration of CD200Fc also diminished elevation of CD200 and CD200R proteins as a concomitant reaction of the modulatory system to increased neuroinflammatory reactions after nerve injury. The anti-inflammatory effect of CD200Fc dropped at 24 h after intrathecal application. CONCLUSIONS: Intrathecal administration of the CD200R1 agonist CD200Fc induces very rapid suppression of neuroinflammatory reactions associated with glial activation and neuropathic pain development. This may constitute a promising and novel therapeutic approach for the treatment of neuropathic pain.
- MeSH
- antigeny povrchové farmakologie terapeutické užití MeSH
- časové faktory MeSH
- CD antigeny metabolismus MeSH
- cytokiny genetika metabolismus MeSH
- fyzikální stimulace škodlivé účinky MeSH
- gliový fibrilární kyselý protein metabolismus MeSH
- hyperalgezie farmakoterapie etiologie MeSH
- ischialgie komplikace farmakoterapie MeSH
- krysa rodu rattus MeSH
- mícha účinky léků metabolismus MeSH
- modely nemocí na zvířatech MeSH
- neuroglie účinky léků metabolismus MeSH
- potkani Wistar MeSH
- práh bolesti účinky léků MeSH
- receptory buněčného povrchu antagonisté a inhibitory terapeutické užití MeSH
- regulace genové exprese účinky léků MeSH
- spinální injekce MeSH
- zánět farmakoterapie etiologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Malaria is a devastating infectious disease caused by Plasmodium parasites transmitted through the bites of infected Anopheles mosquitoes. Salivary glands are the only mosquito tissue invaded by Plasmodium sporozoites, being a key stage for the effective parasite transmission, making the study of Anopheles sialome highly relevant. METHODS: RNA-sequencing was used to compare differential gene expression in salivary glands of uninfected and Plasmodium berghei-infected Anopheles coluzzii mosquitoes. RNA-seq results were validated by quantitative RT-PCR. The transmembrane glucose transporter gene AGAP007752 was selected for functional analysis by RNA interference. The effect of gene silencing on infection level was evaluated. The putative function and tertiary structure of the protein was assessed. RESULTS: RNA-seq data showed that 2588 genes were differentially expressed in mosquitoes salivary glands in response to P. berghei infection, being 1578 upregulated and 1010 downregulated. Metabolism, Immunity, Replication/Transcription/Translation, Proteolysis and Transport were the mosquito gene functional classes more affected by parasite infection. Endopeptidase coding genes were the most abundant within the differentially expressed genes in infected salivary glands (P < 0.001). Based on its putative function and expression level, the transmembrane glucose transporter gene, AGAP007752, was selected for functional analysis by RNA interference. The results demonstrated that the number of sporozoites was 44.3% lower in mosquitoes fed on infected mice after AGAPP007752 gene knockdown when compared to control (P < 0.01). CONCLUSIONS: Our hypothesis is that the protein encoded by the gene AGAPP007752 may play a role on An. coluzzii salivary glands infection by Plasmodium parasite, working as a sporozoite receptor and/or promoting a favorable environment for the capacity of sporozoites.
- MeSH
- Anopheles fyziologie MeSH
- interakce hostitele a patogenu MeSH
- kvantitativní polymerázová řetězová reakce MeSH
- myši MeSH
- Plasmodium berghei růst a vývoj MeSH
- proteiny usnadňující transport glukosy antagonisté a inhibitory MeSH
- receptory buněčného povrchu antagonisté a inhibitory MeSH
- sekvenční analýza RNA MeSH
- slinné žlázy parazitologie MeSH
- stanovení celkové genové exprese * MeSH
- umlčování genů MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Recently we reported 6-(2-hydroxy-3-methylbenzylamino)purine (PI-55) as the first molecule to antagonize cytokinin activity at the receptor level. Here we report the synthesis and in vitro biological testing of eleven BAP derivatives substituted in the benzyl ring and in the C2, N7 and N9 positions of the purine moiety. The ability of the compounds to interact with Arabidopsis cytokinin receptors AHK3 and CRE1/AHK4 was tested in bacterial receptor and in live-cell binding assays, and in an Arabidopsis ARR5:GUS (Arabidopsis response regulator 5) reporter gene assay. Cytokinin activity of the compounds was determined in classical cytokinin biotests (tobacco callus, wheat leaf senescence and Amaranthus bioassays). 6-(2,5-Dihydroxybenzylamino)purine (LGR-991) was identified as a cytokinin receptor antagonist. At the molecular level LGR-991 blocks the cytokinin receptor CRE1/AHK4 with the same potency as PI-55. Moreover, LGR-991 acts as a competitive inhibitor of AHK3, and importantly shows reduced agonistic effects in comparison to PI-55 in the ARR5:GUS reporter gene assay and in cytokinin bioassays. LGR-991 causes more rapid germination of Arabidopsis seeds and increases hypocotyl length of dark-grown seedlings, which are characteristics of plants with a reduced cytokinin status. LGR-991 exhibits a structural motive that might lead to preparation of cytokinin antagonists with a broader specificity and reduced agonistic properties.
Inhibition of the renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in preventing and treating diabetic nephropathy. However, despite documented beneficial effects of RAAS inhibitors in diabetic patients with nephropathy, reversal of the progressive course of this disorder or at least long-term stabilization of renal function are often difficult to achieve, and many patients still progress to end-stage renal disease. Incomplete inhibition of the RAAS has been postulated as one of the reasons for unsatisfactory therapeutic responses to RAAS inhibition in some patients. Inhibition of renin, a rate-limiting step in the RAAS activation cascade, is the logical approach to overcome at least some of the above-mentioned problems associated with the treatment with traditional RAAS inhibitors. This article focuses on experimental and clinical studies evaluating the two principal approaches to renin inhibition: direct renin inhibition with competitive inhibitors (eg, aliskiren) and inhibition of the (pro)renin receptor.
- MeSH
- diabetické nefropatie farmakoterapie patofyziologie MeSH
- inhibitory ACE terapeutické užití MeSH
- lidé MeSH
- receptory buněčného povrchu antagonisté a inhibitory MeSH
- renin-angiotensin systém fyziologie účinky léků MeSH
- renin * antagonisté a inhibitory metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
Monoklonální protilátky se široce uplatňují nejen v diagnostice, ale i v terapii celé řady onemocnění. Kromě jejich použití v transplantační medicíně a v onkologii nelze opomenout ani jejich úlohu v léčbě autoimunitních chorob. V našem článku se zmiňujeme o typech a efektorových mechanismech terapeuticky využívaných monoklonálních protilátek a dalších biologických léčiv registrovaných k léčbě autoimunitních chorob v České republice a uvádíme i preparáty, které zde ještě schváleny nebyly.
Monoclonal antibodies play an important role not only in diagnosis but also in disease therapy. They are used in transplantation medicine and oncology as well as in the treatment of autoimmune diseases. The present article reviews types and effector mechanisms of therapeutically used monoclonal antibodies and other biological drugs registered in the Czech Republic and authorized for use in the treatment of autoimmune diseases. Novel drugs that have not been authorized in the Czech Republic yet are also presented.
- MeSH
- antigeny CD20 farmakologie MeSH
- autoimunitní nemoci imunologie MeSH
- B-buněčný lymfom terapie MeSH
- financování organizované MeSH
- imunosupresiva MeSH
- inaktivátory komplementu terapeutické užití MeSH
- monoklonální protilátky imunologie terapeutické užití MeSH
- receptory buněčného povrchu antagonisté a inhibitory MeSH
- receptory interleukinu-1 antagonisté a inhibitory MeSH
- receptory interleukinu-2 antagonisté a inhibitory MeSH
- specificita protilátek MeSH
- TNF-alfa antagonisté a inhibitory MeSH
- MeSH
- aminokyseliny dikarboxylové farmakologie MeSH
- krysa rodu rattus MeSH
- kyselina kynurenová farmakologie MeSH
- modely nemocí na zvířatech MeSH
- pentylentetrazol MeSH
- receptory buněčného povrchu antagonisté a inhibitory účinky léků MeSH
- věkové faktory MeSH
- záchvaty chemicky indukované MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
