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Rabbit plasma metabolomic analysis of Nitroproston®: a multi target natural prostaglandin based-drug
Ksenia Shestakova Alex Brito Natalia V. Mesonzhnik Natalia E. Moskaleva Ksenia O. Kurynina Natalia M. Grestskaya Igor V. Serkov Igor I. Lyubimov Vladimir V. Bezuglov Svetlana A. Appolonova 《Metabolomics : Official journal of the Metabolomic Society》2018,14(9):112
Introduction
Nitroproston® is a novel multi-target drug bearing natural prostaglandin E2 (PGE2) and nitric oxide (NO)-donating fragments for treatment of inflammatory and obstructive diseases (i.e., asthma and obstructive bronchitis).Objectives
To investigate the effects of Nitroproston® administration on plasma metabolomics in vivo.Methods
Experimental in vivo study randomly assigning the target drug (treatment group) or a saline solution without the drug (vehicle control group) to 12 rabbits (n?=?6 in each group). Untargeted (5880 initial features; 1869 negative–4011 positive ion peaks; UPLC–IT–TOF/MS) and 84 targeted moieties (Nitroproston® related metabolites, prostaglandins, steroids, purines, pyrimidines and amino acids; HPLC–QQQ–MS/MS) were measured from plasma at 0, 2, 4, 6, 8, 12, 18, 24, 32 and 60 min after administration.Results
PGE2, 13,14-dihydro-15-keto-PGE2, PGB2, 1,3-GDN and 15-keto-PGE2 increased in the treatment group. Steroids (i.e., cortisone, progesterone), organic acids, 3-oxododecanoic acid, nicotinate d-ribonucleoside, thymidine, the amino acids serine and aspartate, and derivatives pyridinoline, aminoadipic acid and uric acid increased (p?<?0.05 AUCROC curve?>?0.75) after treatment. Purines (i.e., xanthine, guanine, guanosine), bile acids, acylcarnitines and the amino acids l-tryptophan and l-phenylalanine were decreased. Nitroproston® impacted steroidogenesis, purine metabolism and ammonia recycling pathways, among others.Conclusion
Nitroproston®, a multi action novel drug based on natural prostaglandins, altered metabolites (i.e., guanine, adenine, cortisol, cortisone and aspartate) involved in purine metabolism, urea and ammonia biological cycles, steroidogenesis, among other pathways. Suggested mechanisms of action, metabolic pathway interconnections and useful information to further understand the metabolic effects of prostaglandin administration are presented.32.
Biophysics - Abstract—Mathematical modeling of applanation and impression tonometry (according to Maklakoff and Schiøtz, respectively) was performed for the eye with artificially induced... 相似文献
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Isolda A. Popova Lizelle Lubbe Pavel A. Petukhov Gavriil F. Kalantarov Ilya N. Trakht Elena R. Chernykh Olga Y. Leplina Alex V. Lyubimov Joe G.N. Garcia Steven M. Dudek Edward D. Sturrock Sergei M. Danilov 《Protein science : a publication of the Protein Society》2021,30(8):1577
Angiotensin I‐converting enzyme (ACE, CD143) plays a crucial role in blood pressure regulation, vascular remodeling, and immunity. A wide spectrum of mAbs to different epitopes on the N and C domains of human ACE have been generated and used to study different aspects of ACE biology, including establishing a novel approach–conformational fingerprinting. Here we characterized a novel set of 14 mAbs, developed against human seminal fluid ACE. The epitopes for these novel mAbs were defined using recombinant ACE constructs with truncated N and C domains, species cross‐reactivity, ACE mutagenesis, and competition with the previously mapped anti‐ACE mAbs. Nine mAbs recognized regions on the N domain, and 5 mAbs–on the C domain of ACE. The epitopes for most of these novel mAbs partially overlap with epitopes mapped onto ACE by the previously generated mAbs, whereas mAb 8H1 recognized yet unmapped region on the C domain where three ACE mutations associated with Alzheimer''s disease are localized and is a marker for ACE mutation T877M. mAb 2H4 could be considered as a specific marker for ACE in dendritic cells. This novel set of mAbs can identify even subtle changes in human ACE conformation caused by tissue‐specific glycosylation of ACE or mutations, and can detect human somatic and testicular ACE in biological fluids and tissues. Furthermore, the high reactivity of these novel mAbs provides an opportunity to study changes in the pattern of ACE expression or glycosylation in different tissues, cells, and diseases, such as sarcoidosis and Alzheimer''s disease. 相似文献
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Kapetanovic IM Bauer KS Tessier DM Lindeblad MO Zakharov AD Lubet R Lyubimov A 《Chemico-biological interactions》2009,179(2-3):233-239
Aspirin is one of the oldest drugs and has been purported to have multiple beneficial effects, including prevention of cardiovascular disease and cancer, in addition to its original indication for treatment of inflammation, fever and pain. In cancer chemoprevention studies using animal models, two methods of aspirin administration have been employed: oral gavage and diet. The untested assumption was that exposure and the resultant pharmacological effects are similar for these two administration methods when dosing is normalized on the basis of mg/kg body weight/day. This study examined and compared time-dependent plasma and colon mucosal concentrations of aspirin metabolite salicylate (aspirin concentrations were below level of quantification), plasma thromboxane B(2) concentrations, and colon mucosal prostaglandin E(2) concentration following these two different dosing paradigms in rats. Diet dosing yielded relatively constant plasma and colon salicylate concentration vs. time profiles. On the other hand, oral gavage dosing led to a rapid peak followed by a fast decline in salicylate concentration in both plasma and colon. Nevertheless, the exposure as measured by the area under plasma or colon concentration-time curve of salicylate was linearly related to dose irrespective of the dosing method. Linear relationships were also observed between colon and plasma salicylate areas under the curve and between colon prostaglandin E(2) and plasma thromboxane B(2) areas under the curve. Therefore, more easily accessible plasma salicylate and thromboxane B(2) concentrations were representative of the salicylate exposure and prostaglandin E(2) pharmacodynamic biomarker in the target colon, respectively. 相似文献
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Lyubimov SE Kalinin VN Tyutyunov AA Olshevskaya VA Dutikova YV Cheong CS Petrovskii PV Safronov AS Davankov VA 《Chirality》2009,21(1):2-5
A series of new fine-tunable monodentate phosphite and phosphoramidite ligands based on carboranes have been synthesized and used for asymmetric Rh-catalyzed hydrogenation of prochiral olefins with the result of up to 99.8% ee. Dependence of the enantioselectivity on the electron-withdrawing or electron-donating properties of the carboranyl substituent has been studied. 相似文献
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Ming Wang Marianna Halasi Kasim Kabirov Aryamitra Banerjee Jennifer Landolfi Alexander V. Lyubimov Andrei L. Gartel 《Cell cycle (Georgetown, Tex.)》2012,11(18):3370-3372
Nanoparticle-encapsulated thiazole antibiotic, thiostrepton, has been shown to be an effective agent for inhibiting tumor growth in solid tumor models through the inhibition of proteasomal activity by the induction of apoptosis in cancer cells. Here, we show the efficacy of thiostrepton-micelles in inhibiting tumor growth in a DEN/PB-induced liver cancer model. We also demonstrate an enhanced anticancer effect of the combination treatment of thiostrepton with bortezomib, another proteasome inhibitor in this liver cancer model. 相似文献
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The tracheal sounds during forced expiration were studied using the mathematical model of forced expiration. It has been shown that separated flow in the region of dynamic constriction of the trachea during forced expiration may cause the generation of tracheal sounds. 相似文献
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