暂无摘要。

Insulin-degrading enzyme (IDE) is a highly conserved zinc metallopeptidase and is capable to catalytically cleave several substrates besides insulin, playing a pivotal role in several different biochemical pathways. Although its mechanism of action has been widely investigated, many conundrums still remain, hindering the possibility to rationally design specific modulators which could have important therapeutical applications in several diseases such as diabetes and Alzheimer\'s disease. In this scenario, we have developed a novel surface plasmon resonance (SPR) method which allows for directly measuring the enzyme cooperativity for the binding of insulin in the presence of different IDE activity modulators: carnosine, ATP, and EDTA. Results indicate that both positive and negative modulations of the IDE activity can be correlated to an increase and a decrease of the measured Hill coefficient, respectively, giving a new insight into the IDE activity mechanism. The use of the IDE R767A mutant for which oligomerization is hindered confirmed that the positive allosteric modulation of IDE by carnosine is due to a change in the enzyme oligomeric state occurring also for the enzyme immobilized on the gold SPR chip.

In the present study, an in silico methodology able to define the binding modes adopted by carnosine enantiomers in the setting of the chiral recognition process is described. The inter- and intramolecular forces involved in the enantioseparation process with the Teicoplanin A2-2 chiral selector and carnosine as model compound are successfully identified. This approach fully rationalizes, at a molecular level, the (S) < (R) enantiomeric elution order obtained under reversed-phase conditions. Consistent explanations were achieved by managing molecular dynamics results with advanced techniques of data analysis. As a result, the time-dependent identification of all the interactions simultaneously occurring in the chiral selector-enantiomeric analyte binding process was obtained. Accordingly, it was found that only (R)-carnosine is able to engage a stabilizing charge-charge interaction through its ionized imidazole ring with the carboxylate counter-part on the chiral selector. Instead, (S)-carnosine establishes intramolecular contacts between its ionized functional groups, that limit its conformational freedom and impair the association with the chiral selector unit.

Organic lithium salts containing anionic components (succinate, fumarate, pyruvate and antioxidant ascorbate) were tested for protection of blood plasma proteins and lipids against ethanol-induced oxidation in vitro. We used normothymic lithium carbonate and well-known antioxidant dipeptide carnosine (b-alanyl-L-histidine) as the reference drugs. The oxidized proteins and lipids were determined by the level of carbonylated proteins (CP) and TBA-reactive products (TBA-RP), respectively. In alcoholic patients the level of oxidized proteins and lipids was higher than in healthy persons. Incubation of blood with ethanol resulted in an increase in oxidized proteins and lipids in blood plasma of healthy persons but had no influence on the level of CP and TBA-RP in blood plasma of alcoholic patients. Lithium carbonate, lithium ascorbate, and lithium succinate exhibited protective action against ethanol-induced oxidation of biomolecules of blood plasma of healthy people. These effects were comparable with carnosine action. The studied compounds had no effect on the level of CP and TBA-RP of blood plasma of alcoholic patients.
Issledovali zashchitu belkov i lipidov plazmy krovi ot okisleniia étanolom pri ispol\'zovanii organicheskikh soleĭ litiia, soderzhashchikh v svoem sostave anionnye komponenty (suktsinat, fumarat, piruvat), a takzhe antioksidant askorbat. V kachestve preparatov sravneniia ispol\'zovali normotimik karbonat litiia i izvestnyĭ antioksidant dipeptid karnozin (b-alanil-L-gistidin). Okislennye belki opredeliali po urovniu karbonilirovannykh belkov (KB), okislitel\'nuiu modifikatsiiu lipidov – po TBK-reaktivnym produktam (TBK-RP). U bol\'nykh alkogolizmom uroven\' okislennykh belkov i lipidov povyshen po sravneniiu so zdorovymi litsami. Inkubatsiia krovi s étanolom privodit k uvelicheniiu okislennykh belkov i lipidov v plazme krovi zdorovykh lits, no ne vliiaet na uroven\' okislennykh biomolekul v plazme krovi bol\'nykh alkogolizmom. Zashchitnoe deĭstvie ot étanol-indutsirovannogo okisleniia biomolekul plazmy krovi zdorovykh liudeĭ, sopostavimoe po éffektivnosti s karnozinom, okazyvali karbonat litiia, askorbat litiia i suktsinat litiia. Vliianiia issleduemykh soedineniĭ na uroven\' KB i TBK-RP plazmy krovi bol\'nykh alkogolizmom ne obnaruzheno.

暂无摘要。

暂无摘要。

The ability of carnosine to prevent advanced glycoxidation end products (AGEs) and advanced lipoxidation end products (ALEs) formation, on the one hand, and the convincing evidence that these compounds act as pathogenetic factors, on the other hand, strongly support carnosine as a promising therapeutic agent for oxidative-based diseases. The mechanism/s by which carnosine inhibits AGEs and ALEs is still under investigation but an emerging hypothesis is that carnosine acts by deactivating the AGEs and ALEs precursors and in particular the reactive carbonyl species (RCS) generated by both lipid and sugar oxidation. The ability of carnosine to inhibit AGEs and ALEs formation and the corresponding biological effects has been demonstrated in several in vitro studies and in some animal models. However, such effects are in line of principle, limited in humans, due to the effect of serum carnosinase (absent in rodents), which catalyzes the carnosine hydrolysis to its constitutive amino acids. Such a limitation has prompted a great interest in the design of carnosine derivatives, which maintaining (or improving) the reactivity with RCS, are more resistant to carnosinase. The present paper intends to critically review the most recent studies oriented to obtaining carnosine derivatives, optimized in terms of reactivity with RCS, selectivity (no reaction with physiological aldehydes) and the pharmacokinetic profile (mainly through an enhanced resistance to carnosinase hydrolysis). The review also includes a brief description of AGEs and ALEs as drug targets and the evidence so far reported regarding the ability of carnosine as inhibitor of AGEs and ALEs formation and the proposed reaction mechanisms.

暂无摘要。

A 77-year-old man referred to our hospital three months ago presented with dyspnea on effort and chest radiograph abnormalities. Chest computed tomography showed consolidation and irregular thickening of the peribronchovascular interstitium. Bronchoalveolar lavage fluids showed increases in the percentage of lymphocytes and a decrease of the CD4/8 ratio. Transbronchial lung biopsy specimens showed signs of organizing pneumonia. The patient had been given polaprezinc for the treatment of hypogeusia six months before. A lymphocyte-stimulating test for polaprezinc was positive, and so our diagnosis was polaprezinc-induced pneumonitis.

The appearance of new peaks in the 7.7-8.6 and 6.8-7.4 ppm regions of the postexercise (1)H spectrum of frog muscle is reported. These new peaks result from the splitting of single pre-exercise carnosine C-2 and C-4 peaks into two peaks, representing the intracellular pH (pH(I)) of oxidative and glycolytic fibers. The following data support this conclusion: 1) comparison of means and regression analysis indicates equivalence of the pH(I) measurements by (1)H and (31)P NMR; 2) the pre- and poststimulation concentrations of carnosine are equal; 3) in ischemic rat hindlimb muscles, the presence of a single, more acidic peak in the plantaris; a single, less acidic peak in the soleus; and two peaks (more and less acidic) in the gastrocnemius correspond to published values for the fiber-type composition of these muscles; and 4) in muscles treated with iodoacetate prior to and during stimulation, a second peak never appears. These data indicate that it is feasible to measure separately the pH(I) of oxidative and glycolytic fibers using (1)H NMR spectroscopy.