PURPOSE: PI3K signaling is a common feature of B-cell neoplasms, including chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL), and PI3K inhibitors have been introduced into the clinic. However, there remains a clear need to develop new strategies to target PI3K signaling. PI3K activity is countered by Src homology domain 2-containing inositol-5'-phosphatase 1 (SHIP1) and, here, we have characterized the activity of a novel SHIP1 activator, AQX-435, in preclinical models of B-cell malignancies. EXPERIMENTAL DESIGN: In vitro activity of AQX-435 was evaluated using primary CLL cells and DLBCL-derived cell lines. In vivo activity of AQX-435, alone or in combination with the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, was assessed using DLBCL cell line and patient-derived xenograft models. RESULTS: Pharmacologic activation of SHIP1 using AQX-435 was sufficient to inhibit anti-IgM-induced PI3K-mediated signaling, including induction of AKT phosphorylation and MYC expression, without effects on upstream SYK phosphorylation. AQX-435 also cooperated with the BTK inhibitor ibrutinib to enhance inhibition of anti-IgM-induced AKT phosphorylation. AQX-435 induced caspase-dependent apoptosis of CLL cells preferentially as compared with normal B cells, and overcame in vitro survival-promoting effects of microenvironmental stimuli. Finally, AQX-435 reduced AKT phosphorylation and growth of DLBCL in vivo and cooperated with ibrutinib for tumor growth inhibition. CONCLUSIONS: Our results using AQX-435 demonstrate that SHIP1 activation may be an effective novel therapeutic strategy for treatment of B-cell neoplasms, alone or in combination with ibrutinib.

• MeSH
• aktivátory enzymů farmakologie   MeSH
• antitumorózní látky farmakologie   MeSH
• apoptóza účinky léků   MeSH
• chronická lymfatická leukemie farmakoterapie   metabolismus   patologie   MeSH
• difúzní velkobuněčný B-lymfom farmakoterapie   metabolismus   patologie   MeSH
• fosfatidylinositol-3-kinasy chemie   metabolismus   MeSH
• fosfatidylinositol-3,4,5-trisfosfát-5-fosfatasy genetika   metabolismus   MeSH
• lidé MeSH
• myši inbrední NOD MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• seskviterpeny farmakologie   MeSH
• signální transdukce MeSH
• xenogenní modely - testy antitumorózní aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The role of the intrarenal renin-angiotensin system (RAS) in the pathophysiology of malignant hypertension is not fully understood. Accumulating evidence indicates that the recently discovered vasodilator axis of the RAS, angiotensin-converting enzyme (ACE) type 2 (ACE2)/angiotensin 1-7 (ANG 1-7), constitutes an endogenous system counterbalancing the hypertensiogenic axis, ACE/angiotensin II (ANG II)/AT1 receptor. This study aimed to evaluate the role of the intrarenal vasodilator RAS axis in the pathophysiology of ANG II-dependent malignant hypertension in Cyp1a1-Ren-2 transgenic rats. ANG II-dependent malignant hypertension was induced by 13 days' dietary administration of indole-3-carbinol (I3C), a natural xenobiotic that activates the mouse renin gene in Cyp1a1-Ren-2 transgenic rats. It was hypothesized that pharmacologically-induced inhibition of the ACE2/ANG 1-7 complex should aggravate, and activation of this axis should attenuate, the course of ANG II-dependent malignant hypertension. Blood pressure (BP) was monitored by radiotelemetry. ACE2 inhibitor (DX 600, 0.2 μg/day) and ACE2 activator (DIZE, 1 mg/day) were administrated via osmotic minipumps. Even though ACE2 inhibitor significantly decreased and ACE2 activator increased intrarenal ANG 1-7 concentrations, the course of BP, as well as of albuminuria, cardiac hypertrophy and renal glomerular damage, were not altered. It was shown that intrarenal alterations in the ACE2/ANG 1-7 complex did not significantly modify the course of malignant hypertension in I3C-induced Cyp1a1-Ren-2 transgenic rats. Thus, in our experimental setting alterations of this intrarenal vasodilator complex of the RAS do not significantly modify the form of malignant hypertension that clearly depends on the inappropriately increased activity of the ACE/ANG II/AT1 receptor axis.

• MeSH
• aktivátory enzymů farmakologie   MeSH
• albuminurie komplikace   MeSH
• angiotensin I metabolismus   MeSH
• angiotensin konvertující enzym metabolismus   MeSH
• cytochrom P-450 CYP1A1 genetika   MeSH
• diminazen analogy a deriváty   farmakologie   MeSH
• hypertenze maligní komplikace   metabolismus   patofyziologie   moč   MeSH
• krevní tlak účinky léků   MeSH
• krysa rodu rattus MeSH
• ledviny účinky léků   metabolismus   MeSH
• myši MeSH
• peptidové fragmenty metabolismus   MeSH
• peptidy farmakologie   MeSH
• potkani transgenní MeSH
• regulace genové exprese účinky léků   MeSH
• renin-angiotensin systém účinky léků   MeSH
• renin genetika   MeSH
• sodík moč   MeSH
• tělesná hmotnost účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• aktivátory enzymů farmakologie   terapeutické užití   MeSH
• antagonisté mineralokortikoidních receptorů farmakologie   škodlivé účinky   terapeutické užití   MeSH
• benzazepiny farmakokinetika   farmakologie   terapeutické užití   MeSH
• beta blokátory farmakologie   škodlivé účinky   terapeutické užití   MeSH
• chronická nemoc farmakoterapie   MeSH
• erythropoetin analogy a deriváty   terapeutické užití   MeSH
• guanylátkinasy metabolismus   terapeutické užití   MeSH
• hypochromní anemie etiologie   farmakoterapie   MeSH
• inhibitory ACE farmakologie   terapeutické užití   MeSH
• inhibitory fosfodiesteras farmakologie   terapeutické užití   MeSH
• kombinovaná farmakoterapie * metody   MeSH
• lékové formy MeSH
• lidé MeSH
• renin antagonisté a inhibitory   MeSH
• srdeční frekvence účinky léků   MeSH
• srdeční selhání * farmakoterapie   MeSH
• železo aplikace a dávkování   metabolismus   MeSH
• Check Tag
• lidé MeSH

• MeSH
• aktivátory enzymů farmakologie   terapeutické užití   MeSH
• antagonisté mineralokortikoidních receptorů farmakologie   terapeutické užití   MeSH
• beta blokátory farmakologie   terapeutické užití   MeSH
• diferenciální diagnóza MeSH
• diuretika farmakologie   terapeutické užití   MeSH
• dysfunkce pravé srdeční komory farmakoterapie   MeSH
• funkce levé komory srdeční účinky léků   MeSH
• guanylátcyklasa farmakologie   terapeutické užití   MeSH
• inhibitory fosfodiesteras farmakologie   terapeutické užití   MeSH
• plicní hypertenze farmakoterapie   MeSH
• rizikové faktory MeSH
• srdeční frekvence účinky léků   MeSH
• srdeční selhání * diagnóza   epidemiologie   patofyziologie   MeSH
• tepový objem fyziologie   MeSH

The present review is intended to focus on naturally occurring cytoprotective agents such as resveratrol (trans-3,4',5-trihydroxystilbene) and other related compounds, probably with similar molecular mechanisms of action and high capacity to find applications in medical fields. Several physiological aspects have been ascribed to resveratrol and similar compounds. Resveratrol, among others, has been recently described as a silent information regulator T1 (SIRT1) activator that increases AMP-activated protein kinase (AMPK) phosphorylation and reduces the oxidative damage biomarkers during aging in laboratory settings. The reports on resveratrol and other SIRT1 activators from various sources are encouraging. The pharmacological strategies for modulation of sirtuins by small molecules through allosteric mechanisms should gain a greater momentum including human research. Resveratrol and resveratrol-like molecules seem to fulfill the requirement of a new horizon in drug research since these molecules cover a growing research means as antioxidants with allosteric mechanism in epigenetic drug targets. However, one should keep in mind the challenges of extrapolation of basic research into clinical results. Overall, the issue of sirtuins in biology and disease provides an insight on therapeutic potentials of sirtuin-based therapeutics and demonstrates the high complexity of drug-targeting these modalities for human applications.

• MeSH
• aktivace enzymů MeSH
• aktivátory enzymů chemie   farmakologie   MeSH
• alosterická regulace MeSH
• antioxidancia chemie   farmakologie   MeSH
• epigeneze genetická účinky léků   MeSH
• fosforylace MeSH
• lidé MeSH
• molekulární struktura MeSH
• oxidační stres účinky léků   MeSH
• proteinkinasy aktivované AMP metabolismus   MeSH
• sirtuin 1 antagonisté a inhibitory   metabolismus   MeSH
• stilbeny chemie   farmakologie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Uric acid is involved in nitrogenous waste in animals, together with ammonia and urea. Uric acid has also antioxidant properties and is a surrogate marker of metabolic syndrome. We observed that the elevated plasma uric acid of high-fat fed mice was normalized by benzylamine treatment. Indeed, benzylamine is the reference substrate of semicarbazide-sensitive amine oxidase (SSAO), an enzyme highly expressed in fat depots and vessels, which generates ammonia when catalysing oxidative deamination. Ammonia interferes with uric acid metabolism/solubility. Our aim was therefore to investigate whether the lowering action of benzylamine on uric acid was related to an improvement of diabetic complications, or was connected with SSAO-dependent ammonia production. First, we observed that benzylamine administration lowered plasma uric acid in diabetic db/db mice while it did not modify uric acid levels in normoglycemic and lean mice. In parallel, benzylamine improved the glycemic control in diabetic but not in normoglycemic mice, while plasma urea remained unaltered. Then, uric acid plasma levels were measured in mice invalidated for AOC3 gene, encoding for SSAO. These mice were unable to oxidize benzylamine but were not diabetic and exhibited unaltered plasma uric levels. Therefore, activated or abolished ammonia production by SSAO was without influence on uric acid in the context of normoglycemia. Our observations confirm that plasma uric acid increases with diabetes and can be normalized when glucose tolerance is improved. They also show that uric acid, a multifunctional metabolite at the crossroads of nitrogen waste and of antioxidant defences, can be influenced by SSAO, in a manner apparently related to changes in glucose homeostasis.

• MeSH
• aktivace enzymů MeSH
• aktivátory enzymů farmakologie   MeSH
• amoniak metabolismus   MeSH
• benzylaminy farmakologie   MeSH
• časové faktory MeSH
• diabetes mellitus enzymologie   farmakoterapie   krev   MeSH
• down regulace MeSH
• histaminasa genetika   metabolismus   nedostatek   MeSH
• hyperurikemie enzymologie   farmakoterapie   krev   MeSH
• hypoglykemika farmakologie   MeSH
• krevní glukóza metabolismus   účinky léků   MeSH
• kyselina močová krev   MeSH
• modely nemocí na zvířatech MeSH
• molekuly buněčné adheze genetika   metabolismus   nedostatek   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

We examined the effects of model activators of mitogen-activated protein kinases (MAPKs) on basal and rifampicin-, phenobarbital- and dioxin-inducible expression of phase I and phase II biotransformation enzymes in primary human hepatocytes. Cells were treated for 24 h with sorbitol (SOR), anisomycin (ANI) and epidermal growth factor (EGF) in the presence or absence of inducers. The levels of CYP1A1, CYP1A2, CYP2B6, CYP3A4, UGT1A1, UGT2B17, SULT1A1, SULT2A1, SULT1B2, GSTA1, GSTA2 mRNAs were determined. SOR and EGF inhibited the expression of the tested genes, while ANI had no effect. We conclude that MAPKs play important role in the transcriptional regulation of drug-metabolizing enzymes.

• MeSH
• aktivace enzymů účinky léků   MeSH
• aktivátory enzymů farmakologie   MeSH
• anisomycin farmakologie   MeSH
• aromatické hydroxylasy metabolismus   MeSH
• dioxiny farmakologie   MeSH
• epidermální růstový faktor metabolismus   MeSH
• extracelulárním signálem regulované MAP kinasy metabolismus   MeSH
• fenobarbital farmakologie   MeSH
• glukuronosyltransferasa metabolismus   MeSH
• glutathiontransferasa metabolismus   MeSH
• hepatocyty enzymologie   metabolismus   účinky léků   MeSH
• lidé MeSH
• messenger RNA metabolismus   MeSH
• rifampin farmakologie   MeSH
• sorbitol farmakologie   MeSH
• sulfotransferasy metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH

We evaluated the effects of exercise on the vascular constrictor responses to ?-adrenergic stimulation in the db/db mice. Twenty male db/db and their age-matched wild-type (WT) mice were exercised (1 hour/day, five days a week). Mice were anesthetized 7 weeks later, thoracic aortae were mounted in wire myograph and constrictor responses to phenylephrine (PE, 1 nM-10 µM) were obtained. Citrate synthase activity measured in the thigh adductor muscle was significantly increased in db/db mice that were exercise trained. Maximal force generated by PE was markedly greater in db/db aortae and exercise did not attenuate this augmented contractile response. Vessels were incubated with inhibitors of nitric oxide synthase (L-NAME, 200 µM), endothelin receptors (bosentan, 10 µM), protein kinase C (PKC) (calphostin C, 5 µM), cyclooxygenase (indomethacin, 10 µM) or Rho-kinase (Y-27632, 0.1 µM). Only calphostin-C normalized the augmented PE-induced constriction in db/db and db/dbexercised mice to that observed in WT (p<0.05). Cumulative additions of indolactam, a PKC activator, induced significantly greater constrictor responses in aortic rings of db/db mice compared to WT and exercise did not affect this response. Our data suggest that the augmented vasoconstriction observed in the aorta of db/db mice is likely due to increased PKC activity and that exercise do not ameliorate this increased PKC-mediated vasoconstriction.

• Klíčová slova
• Exercise, Vasoconstriction, Diabetes,
• MeSH
• aktivace enzymů MeSH
• aktivátory enzymů farmakologie   MeSH
• aorta thoracica enzymologie   patofyziologie   účinky léků   MeSH
• citrátsynthasa metabolismus   MeSH
• diabetes mellitus 2. typu enzymologie   patofyziologie   MeSH
• financování organizované MeSH
• inhibitory cyklooxygenasy farmakologie   MeSH
• inhibitory proteinkinas farmakologie   MeSH
• inzulin krev   MeSH
• kinázy asociované s rho antagonisté a inhibitory   metabolismus   MeSH
• kosterní svaly enzymologie   MeSH
• krevní glukóza metabolismus   MeSH
• lipidy krev   MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• proteinkinasa C antagonisté a inhibitory   metabolismus   MeSH
• receptor endotelinu A antagonisté a inhibitory   metabolismus   MeSH
• synthasa oxidu dusnatého antagonisté a inhibitory   metabolismus   MeSH
• tělesná hmotnost MeSH
• tělesná námaha MeSH
• vazodilatace MeSH
• vazodilatancia farmakologie   MeSH
• vazokonstrikce účinky léků   MeSH
• vazokonstriktory farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH

Acetylcholinesterase reactivators are crucial antidotes for the treatment of organophosphate intoxication. Eighteen monoquaternary reactivators of acetylcholinesterase with modified side chain were developed in an effort to extend the properties of pralidoxime. The known reactivators (pralidoxime, HI-6, obidoxime, trimedoxime, methoxime) and the prepared compounds were tested in vitro on a model of tabun- and paraoxon-inhibited AChE. Monoquaternary reactivators were not able to exceed the best known compounds for tabun poisoning, but some of them did show reactivation better or comparable with pralidoxime for paraoxon poisoning. However, extensive differences were found by a SAR study for various side chains on the non-oxime part of the reactivator molecule.

• MeSH
• acetylcholinesterasa chemie   účinky léků   MeSH
• aktivace enzymů účinky léků   MeSH
• aktivátory enzymů farmakologie   chemická syntéza   chemie   MeSH
• biologické modely MeSH
• cholinesterasové inhibitory farmakologie   MeSH
• financování organizované MeSH
• krysa rodu rattus MeSH
• molekulární struktura MeSH
• mozek enzymologie   MeSH
• organofosfáty antagonisté a inhibitory   farmakologie   MeSH
• paraoxon antagonisté a inhibitory   farmakologie   MeSH
• preklinické hodnocení léčiv MeSH
• pyridinové sloučeniny farmakologie   chemická syntéza   chemie   MeSH
• racionální návrh léčiv MeSH
• stereoizomerie MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH