A new class of compounds, namely highly substituted diaminocyclopentane-l-lysine adducts, have been discovered as potent inhibitors of O-GlcNAcase, an enzyme crucial for protein de-O-glycosylation. These inhibitors exhibit exceptional selectivity and reversibility and are the first example of human O-GlcNAcase inhibitors that are structurally related to the transition state of the rate-limiting step with the "aglycon" still in bond-length proximity. The ease of their preparation, remarkable biological activities, stability, and non-toxicity make them promising candidates for the development of anti-tau-phosphorylation agents holding significant potential for the treatment of Alzheimer's disease.

• Klíčová slova
• Alzheimer’s disease, Diaminocyclopentane, Glycosidase, Hexosaminidase, Inhibition, O-GlcNAcase, Tau protein,
• MeSH
• beta-N-acetylhexosaminidasy antagonisté a inhibitory   metabolismus   MeSH
• cyklopentany chemie   farmakologie   chemická syntéza   MeSH
• inhibitory enzymů * chemie   farmakologie   chemická syntéza   MeSH
• lidé MeSH
• lysin * chemie   farmakologie   MeSH
• molekulární struktura 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
• Názvy látek
• beta-N-acetylhexosaminidasy MeSH
• cyklopentany MeSH
• hexosaminidase C MeSH Prohlížeč
• inhibitory enzymů * MeSH
• lysin * MeSH

OBJECTIVE: To summarise of experimental results performed on rabbit eyes focused to influence the physiological intraocular pressure (lOP) after application of some amino acids mixture with some regularly used antiglaucomatics. MATERIAL AND METHODS: The experiments were performed on adult rabbits (female of the New Zealand White species). The applicated substances were: 10% solution of amino acids (L-lysin.2HCl.2H2O, L-arginine.HCL or L-glycine.HCL) in antiglau-comatics 0.5% timolol (Timoptol) or 0.005% latanoprost (Xalatan). This mixture was applicated to the left eye; right eye was used as control. The measurement of IOP and pupil diameter was performed before instillation, in 15th, 30th, 60th, 180th, 240th minute and 24 hours after application. RESULTS: Functional bioactivity of the used antiglaucomatics in case of decreased lOP is rising after interaction with the relevant specific amino acid. Glycine in timolol showed the highest effect on average decrease of the lOP physiological values (lOP decrease reached - 5,5 torr) followed by arginine in timolol (lOP decrease reached - 3,3 torr). The lOP decrease after other combinations of amino acids and antiglaucomatics was in average lower or nonsignificant. CONCLUSIONS: Through interaction between in vitro prepared mixture free amino acids and antiglaucomatics a new, biologically active substance (metabolite) is created. After instillation in experimental condition achieving stronger and longer decrease of the lOP compared with a single antiglaucomatic or amino acid.

• MeSH
• aminokyseliny farmakologie   MeSH
• arginin farmakologie   MeSH
• glycin farmakologie   MeSH
• králíci MeSH
• latanoprost MeSH
• lysin farmakologie   MeSH
• nitrooční tlak účinky léků   MeSH
• prostaglandiny F syntetické farmakologie   MeSH
• timolol farmakologie   MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• aminokyseliny MeSH
• arginin MeSH
• glycin MeSH
• latanoprost MeSH
• lysin MeSH
• prostaglandiny F syntetické MeSH
• timolol MeSH

Dipeptidyl peptidase-IV (DPP-IV, CD26) is a serine protease almost ubiquitously expressed on cell surface and present in body fluids. DPP-IV has been suggested to proteolytically modify a number of biologically active peptides including substance P (SP) and the chemokine stromal cell derived factor-1alpha (SDF-1alpha, CXCL12). SP and SDF-1alpha have been implicated in the regulation of multiple biological processes and also induce responses that may be relevant for glioma progression. Both SP and SDF-1alpha are signaling through cell surface receptors and use intracellular calcium as a second messenger. The effect of DPP-IV on intracellular calcium mobilization mediated by SP and SDF-1alpha was monitored in suspension of wild type U373 and DPP-IV transfected U373DPPIV glioma cells using indicator FURA-2. Nanomolar concentrations of SP triggered a transient dose dependent increase in intracellular calcium rendering the cells refractory to repeated stimulation, while SDF-1 had no measurable effect. SP signaling in DPP-IV overexpressing U373DPPIV cells was not substantially different from that in wild type cells. However, preincubation of SP with the DPP-IV overexpressing cells lead to the loss of its signaling potential, which could be prevented with DPP-IV inhibitors. Taken together, DPP-IV may proteolytically inactivate local mediators involved in gliomagenesis.

• MeSH
• chemokin CXCL12 metabolismus   MeSH
• dipeptidylpeptidasa 4 genetika   metabolismus   MeSH
• gliom enzymologie   MeSH
• inhibitory dipeptidylpeptidasy 4 MeSH
• inhibitory serinových proteinas farmakologie   MeSH
• lidé MeSH
• lysin analogy a deriváty   farmakologie   MeSH
• mifepriston farmakologie   MeSH
• nádory mozku enzymologie   MeSH
• oligopeptidy farmakologie   MeSH
• pyrrolidiny farmakologie   MeSH
• substance P metabolismus   MeSH
• transfekce MeSH
• U937 buňky MeSH
• vápníková signalizace * účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chemokin CXCL12 MeSH
• dipeptidylpeptidasa 4 MeSH
• diprotin A MeSH Prohlížeč
• DPP4 protein, human MeSH Prohlížeč
• inhibitory dipeptidylpeptidasy 4 MeSH
• inhibitory serinových proteinas MeSH
• lysin MeSH
• lysyl-(Z(nitro))pyrrolidide MeSH Prohlížeč
• mifepriston MeSH
• oligopeptidy MeSH
• pyrrolidiny MeSH
• substance P MeSH

Coagulation abnormalities have been implicated in the pathogenesis of sepsis and organ dysfunction. Nitric oxide (NO) is regarded as a critical mediator of many vascular pathologies, including sepsis. However, limited evidence is available to document a relationship between NO generated by inducible NO synthase (iNOS) and hemostatic abnormalities in sepsis. Therefore, we evaluated the effects of selective iNOS inhibition on markers of endothelial and coagulation homeostasis in a clinically relevant model of porcine bacteremia induced and maintained for 24 hours (h) with a continuous infusion of live P. aeruginosa. After 12 h of sepsis, animals received either vehicle (Control, n=7) or continuous infusion of selective iNOS inhibitor L-NIL (n=7). Before as well as 12, 18 and 24 h after starting P. aeruginosa following variables related to i) endothelial dysfunction (von Willebrand factor [vWf]; tissue plasminogen activator activity [t-PA]; ii) coagulation (thrombin-antithrombin complexes [TAT]; platelet count); iii) fibrinolysis (t-PA activity, activity of plasminogen activator inhibitor type 1 (PAI-1 act); and iv) oxidative/nitrosative stress (isoprostanes, nitrate/nitrite levels) were measured. L-NIL inhibited sepsis-induced increase in plasma nitrate/nitrite and isoprostanes concentrations, prevented hypotension and acidosis. L-NIL significantly attenuated sepsis-induced rise in plasma vWF and TAT. P. aeruginosa-induced drop in t-PA activity was blunted by iNOS inhibition, while increased PAI-1 and reduced platelet count were not reversed by the treatment. In conclusion, selective iNOS inhibition was associated with attenuation of sepsis-induced coagulation and endothelial dysfunction suggesting the interplay between mediators of vascular system and hemostatic balance. Reduction of oxidative stress probably contributes to the beneficial effects afforded by iNOS blockade.

• MeSH
• acidobazická rovnováha účinky léků   MeSH
• bakteriemie krev   metabolismus   mikrobiologie   patofyziologie   MeSH
• časové faktory MeSH
• cévní endotel účinky léků   metabolismus   patofyziologie   MeSH
• fibrinogen účinky léků   MeSH
• hemokoagulace účinky léků   MeSH
• inhibitory enzymů farmakologie   MeSH
• kardiovaskulární systém účinky léků   MeSH
• lysin analogy a deriváty   farmakologie   MeSH
• modely nemocí na zvířatech MeSH
• oxid dusnatý metabolismus   MeSH
• oxidační stres účinky léků   MeSH
• prasata MeSH
• pseudomonádové infekce krev   metabolismus   mikrobiologie   patofyziologie   MeSH
• Pseudomonas aeruginosa MeSH
• synthasa oxidu dusnatého, typ II antagonisté a inhibitory   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fibrinogen MeSH
• inhibitory enzymů MeSH
• lysin MeSH
• N(6)-(1-iminoethyl)lysine MeSH Prohlížeč
• Nos2 protein, rat MeSH Prohlížeč
• oxid dusnatý MeSH
• synthasa oxidu dusnatého, typ II MeSH

UNLABELLED: To evaluate influence of mixture of the 2 amino acids (L-arginine-HCL and L-lysi-ne.2HCL.H2O) in the antiglaucomatic--beta-blocker Timoptol--on the physiologic intraocular pressure (IOP) in rabbits (experiment). METHODS: The mixture of 10% L-lysine.2HCL.H2O + 10% L-arginine.HCL in 0.5% Timoptol was instilled into the left conjunctival sac of the 5 adult rabbit's (female of the New Zealand White species) and the right eye was used as control. The IOP and pupilar diameter were measured before and in 5th, 15y th, 30th, 60th, 120th, 180th and 240th min. and 24 hours after the instillation. RESULTS: The experimental results proved that the non-selective beta-blocker Timoptol interacts at the same time with two amino acids. The mixture of 10% L-lysine.2HCL.H2O + 10% L-arginine.HCL in 0.5% Timoptol decreased the physiologic IOP in two phases. The first phase started from application up to 15th min. In this period parallel IOP decrease occurred also in control eye (with no significant difference). The second phase started in 30th min. after the instillation and lasted until the end of experiment. In this phase the control eye IOP remained linear after the initial over the baseline increase. The eye with instilled mixture showed significant IOP decrease (p < 0.01). Maximum difference between the two IOP's was measured in the 180th (7.3 mmHg; 35.4%). From this moment IOP slightly increased up to the 24th hour showing still significantly lower level--5.0 mmHg (24.3%) compared with the control (p < 0.01). CONCLUSIONS: Results proved that in the mixture of 10% L-lysine.2HCL.H2O + 10% L-argi-nine.HCL in 0,5% Timoptol a new substance, the "specific bioantiglaucomatic" is created by interaction. Compared with the substances alone, mixture of the 2 amino acids in the antiglaucomatic decreased the physiologic intraocular pressure (IOP) in rabbits (experiment) with high significance for 24 hours.

• MeSH
• arginin aplikace a dávkování   farmakologie   MeSH
• beta blokátory aplikace a dávkování   farmakologie   MeSH
• fixní kombinace léků MeSH
• králíci MeSH
• lysin aplikace a dávkování   farmakologie   MeSH
• nitrooční tlak účinky léků   MeSH
• oční roztoky MeSH
• synergismus léků MeSH
• timolol aplikace a dávkování   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• Názvy látek
• arginin MeSH
• beta blokátory MeSH
• fixní kombinace léků MeSH
• lysin MeSH
• oční roztoky MeSH
• timolol MeSH

Pathogenesis of hypoxic pulmonary hypertension is initiated by oxidative injury to the pulmonary vascular wall. Because nitric oxide (NO) can contribute to oxidative stress and because the inducible isoform of NO synthase (iNOS) is often upregulated in association with tissue injury, we hypothesized that iNOS-derived NO participates in the pulmonary vascular wall injury at the onset of hypoxic pulmonary hypertension. An effective and selective dose of an iNOS inhibitor, L-N6-(1-iminoethyl)lysine (L-NIL), for chronic peroral treatment was first determined (8 mg/l in drinking water) by measuring exhaled NO concentration and systemic arterial pressure after LPS injection under ketamine+xylazine anesthesia. A separate batch of rats was then exposed to hypoxia (10% O2) and given L-NIL or a nonselective inhibitor of all NO synthases, N(G)-nitro-L-arginine methyl ester (L-NAME, 500 mg/l), in drinking water. Both inhibitors, applied just before and during 1-wk hypoxia, equally reduced pulmonary arterial pressure (PAP) measured under ketamine+xylazine anesthesia. If hypoxia continued for 2 more wk after L-NIL treatment was discontinued, PAP was still lower than in untreated hypoxic controls. Immunostaining of lung vessels showed negligible iNOS presence in control rats, striking iNOS expression after 4 days of hypoxia, and return of iNOS immunostaining toward normally low levels after 20 days of hypoxia. Lung NO production, measured as NO concentration in exhaled air, was markedly elevated as early as on the first day of hypoxia. We conclude that transient iNOS induction in the pulmonary vascular wall at the beginning of chronic hypoxia participates in the pathogenesis of pulmonary hypertension.

• MeSH
• aplikace orální MeSH
• arteria pulmonalis enzymologie   MeSH
• časové faktory MeSH
• chronická nemoc MeSH
• hypoxie komplikace   enzymologie   metabolismus   patofyziologie   MeSH
• inhibitory enzymů aplikace a dávkování   farmakologie   MeSH
• krysa rodu Rattus MeSH
• lysin aplikace a dávkování   analogy a deriváty   farmakologie   MeSH
• NG-nitroargininmethylester farmakologie   MeSH
• oxid dusnatý MeSH
• plíce metabolismus   MeSH
• plicní hypertenze etiologie   patofyziologie   MeSH
• potkani Wistar MeSH
• synthasa oxidu dusnatého, typ II antagonisté a inhibitory   biosyntéza   MeSH
• tyrosin analogy a deriváty   metabolismus   MeSH
• vydechnutí MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 3-nitrotyrosine MeSH Prohlížeč
• inhibitory enzymů MeSH
• lysin MeSH
• N(6)-(1-iminoethyl)lysine MeSH Prohlížeč
• NG-nitroargininmethylester MeSH
• oxid dusnatý MeSH
• synthasa oxidu dusnatého, typ II MeSH
• tyrosin MeSH

PURPOSE: To show and underline specific character of influence of the mixture of 10% L-lysine.2HCl.2H2O in 0.005% latanoprost on physiological levels of IOP. METHODS: The mixture of 10% L-lysine.2HCl.2H2O in 0.005 % latanoprost (Xalatan), or separately 0.005 % latanoprost and 10% L-lysine.2HCl.2H2O respectively were in weekly intervals instilled into the conjunctival sac of the left eye of five rabbits (females of "New Zealand white" bred). The IOP levels and the size of the pupil were measured in minute 5, 15, 30, 60, 120, 180, and 240 after the instillation. The right eye was considered as a control. RESULTS: The amino acid L-lysine.2HCl.2H2O by itself did not influence the IOP or the size of the pupil; latanoprost until minute 30 lowered the IOP, in minute 55 exceeds the IOP the level of the control eye. Since minute 60 until 240, the IOP changed irregularly and insignificantly. The mixture of 10% solution of L-lysine.2HCl.2H2O in latanoprost 0.005% insignificantly lowered the IOP until min. 30, after rapid elevation in min. 50 exceeds the IOP of the control eye, and since min. 60, the IOP remains above the control eye's IOP with the same course of levels. SUMMARY: The amino acid L-lysine.2HCl.2H2O alone did not change the physiological IOP. Latanoprost 0.005% significantly lowered the IOP until min. 30. High level of interactive specificity as well as duration of influence of the mixture of respective amino acid with respective antiglaucomatic drug was established.

• MeSH
• fixní kombinace léků MeSH
• glaukom farmakoterapie   MeSH
• králíci MeSH
• latanoprost MeSH
• lysin aplikace a dávkování   farmakologie   MeSH
• nitrooční tlak účinky léků   MeSH
• prostaglandiny F syntetické aplikace a dávkování   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fixní kombinace léků MeSH
• latanoprost MeSH
• lysin MeSH
• prostaglandiny F syntetické MeSH

We have recently demonstrated that selective inducible nitric oxide (NO) synthase (iNOS) inhibition with 1400W attenuated the hemodynamic and metabolic alterations affiliated with hyperdynamic porcine endotoxemia. In contrast to endotoxemia, limited evidence is available to document a relationship between NO and organ dysfunction in large animal bacteremic models. Therefore, using the same experimental setup, we investigated the role of selective iNOS blockade in porcine bacteremia induced and maintained for 24 h with a continuous infusion of live Pseudomonas aeruginosa. After 12 h of sepsis, animals received either vehicle (Control, n = 8) or continuous infusion of selective iNOS inhibitor, L-N6-(1-iminoethyl)-lysine (L-NIL; n = 8). Measurements were performed before, and 12, 18, and 24 h after P. aeruginosa infusion. L-NIL inhibited sepsis-induced increase in plasma nitrate/nitrite concentrations and prevented hypotension without affecting cardiac output. Despite comparable hepatosplanchnic macrocirculation, L-NIL blunted the progressive deterioration in ileal mucosal microcirculation and prevented mucosal acidosis. L-NIL largely attenuated mesenteric and hepatic venous acidosis, significantly improved P. aeruginosa-induced impairment of hepatosplanchnic redox state, and mitigated the decline in liver lactate clearance. Furthermore, the administration of L-NIL reduced the hepatocellular injury and prevented the development of renal dysfunction. Finally, treatment with L-NIL significantly attenuated the formation of 8-isoprostane concentrations, a direct marker of lipid peroxidation. Thus, selective iNOS inhibition with L-NIL prevented live bacteria from causing key features of metabolic derangements in porcine hyperdynamic sepsis. Underlying mechanisms probably include reduced oxidative stress with improved microcirculatory perfusion and restoration of cellular respiration.

• MeSH
• arterie metabolismus   MeSH
• bakteriemie patologie   MeSH
• časové faktory MeSH
• dinoprost analogy a deriváty   metabolismus   MeSH
• endotoxemie patologie   MeSH
• játra metabolismus   MeSH
• kyslík metabolismus   MeSH
• laktáty metabolismus   MeSH
• ledviny metabolismus   MeSH
• lysin analogy a deriváty   farmakologie   MeSH
• oxid dusnatý metabolismus   MeSH
• oxidační stres MeSH
• prasata MeSH
• Pseudomonas aeruginosa metabolismus   MeSH
• pyruváty metabolismus   MeSH
• sepse metabolismus   MeSH
• střevní sliznice patologie   MeSH
• synthasa oxidu dusnatého, typ II MeSH
• synthasa oxidu dusnatého antagonisté a inhibitory   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 8-epi-prostaglandin F2alpha MeSH Prohlížeč
• dinoprost MeSH
• kyslík MeSH
• laktáty MeSH
• lysin MeSH
• N(6)-(1-iminoethyl)lysine MeSH Prohlížeč
• oxid dusnatý MeSH
• pyruváty MeSH
• synthasa oxidu dusnatého, typ II MeSH
• synthasa oxidu dusnatého MeSH

In the search for peptides that could effectively enhance the monoclonal antibody production of a model hybridoma, the performance of five lysine-containing peptides was compared. The capacity of the peptides to enhance the monoclonal antibody yield correlated with their growth-suppressing activity. No correlation of the production-enhancing activity with the character of the distribution of cell-cycle phases could be found. All of the tested peptides, including the negative control peptide Gly-Phe-Gly, altered the cell-cycle phases distribution in favor of the proportion of the S phase. The peptides added to the hybridoma culture were found to be gradually decomposed into dipeptides and free amino acids. Among the set of tested lysine-containing di- to pentapeptides, the best results were obtained with the tripeptide Gly-Lys-Gly. The growth-suppressing and production-enhancing capacity of this peptide supplement was obviously associated with the temporary presence of the intact peptide molecule in the culture media, because the addition of a mixture of free amino acids constituting this peptide, i.e., glycine and lysine, displayed a different effect-a slight promotion of cell growth.

• MeSH
• buněčné dělení účinky léků   MeSH
• buněčný cyklus účinky léků   MeSH
• hybridomy cytologie   účinky léků   fyziologie   MeSH
• lysin chemie   farmakologie   MeSH
• monoklonální protilátky biosyntéza   MeSH
• myši MeSH
• oligopeptidy chemie   klasifikace   farmakologie   MeSH
• peptidy chemie   klasifikace   farmakologie   MeSH
• počet buněk MeSH
• polylysin farmakologie   MeSH
• řízení kvality MeSH
• tvorba protilátek účinky léků   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• hodnotící studie MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• lysin MeSH
• monoklonální protilátky MeSH
• oligopeptidy MeSH
• peptidy MeSH
• polylysin MeSH

Based on experiments with rabbit eyes (strain New Zealand white) the authors submit evidence that the metabolite which is formed as a result of interaction of 2% pilocarpine and L-lysine 2 HCl.2H2O has a significantly greater and more rapid effect on the development of miosis than 2% pilocarpine alone. The amino acid lysine does not have a miotic effect. The authors explain the bioactivity of the new metabolite, its effect during the development of miosis and reduction of intraocular pressure. They emphasize a greater and more rapid bioactivity of the new metabolite as compared with pilocarpine. These results provide evidence that during treatment of primary glaucoma it is important to consider not only the effect on reduction of intraocular pressure but also physiological processes which develop in tissue structures after administration of different chemotherapeutic agents.

• MeSH
• králíci MeSH
• lysin aplikace a dávkování   farmakologie   MeSH
• miotika farmakologie   MeSH
• nitrooční tlak účinky léků   MeSH
• pilokarpin aplikace a dávkování   farmakologie   MeSH
• pupila účinky léků   MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• Názvy látek
• lysin MeSH
• miotika MeSH
• pilokarpin MeSH